Harrison’s Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)

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PATIENT MANAGEMENT ALGORITHMS AGING FIG. 464-5 Algorithm depicting assessment and management of falls in older patients..............3428 FIG. 464-7 Algorithm depicting assessment and management of delirium in hospitalized older patients........................................................3432

ALLERGY, IMMUNOLOGY, RHEUMATOLOGY FIG. 345-4 Algorithm for the diagnosis and management of rhinitis.......................................2504 FIG. 349-2 Algorithm for diagnosis and initial therapy of systemic lupus erythematosus .......2519 FIG. 354-1 Treatment algorithm for Sjögren’s syndrome...............................................................2563 FIG. 355-2 Algorithm for the diagnosis or exclusion of axial spondyloarthritis..................2568 FIG. 356-1 Algorithm for the approach to a patient with suspected diagnosis of vasculitis..............2577 FIG. 360-8 Proposed approach to management of patient with possible sarcoidosis.......................2605 FIG. 360-9 The management of acute sarcoidosis is based on level of symptoms and extent of organ involvement...............................................2606 FIG. 360-10 Approach to chronic disease..............................2606 FIG. 363-1 Algorithm for the diagnosis of musculoskeletal complaints................................2615 FIG. 363-2 Algorithm for consideration of the most common musculoskeletal conditions................2616 FIG. 363-6 Algorithmic approach to the use and interpretation of synovial fluid aspiration and analysis...........................................................2622

ALTERATIONS IN CIRCULATORY AND RESPIRATORY FUNCTIONS FIG. 37-1

FIG. 38-5

Clinical conditions in which a decrease in cardiac output and systemic vascular resistance cause arterial underfilling with resulting neurohumoral activation and renal sodium and water retention.................................238 Differential diagnosis of a holosystolic murmur....................................................................245

CARDIOLOGY FIG. 38-9 Strategy for evaluating heart murmurs..............248 FIG. 231-1 Approach to the evaluation of a heart murmur..................................................................1650 FIG. 244-6 Treatment algorithm for patients presenting with hemodynamically stable paroxysmal supraventricular tachycardia..............................1743 FIG. 254-18 Treatment algorithm for hypertrophic cardiomyopathy...................................................1795

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FIG. 256-4 Management strategy for patients with aortic stenosis...............................................1806 FIG. 257-1 Management of patients with aortic regurgitation.........................................................1812 FIG. 258-1 Management of rheumatic mitral stenosis...................................................................1816 FIG. 259-1 Management of mitral regurgitation.................1820 FIG. 261-1 Management of tricuspid regurgitation...........1825 FIG. 267-3 Evaluation of the patient with known or suspected ischemic heart disease..................1855 FIG. 267-4 Algorithm for management of a patient with ischemic heart disease................................1863 FIG. 268-3 Algorithm for evaluation and management of patients with suspected acute coronary syndrome ..............................................................1867 FIG. 269-5 Algorithm for assessment of need for implantation of a cardioverter-defibrillator.......1883 FIG. 467-1 Composite algorithm for cardiac risk assessment and stratification in patients undergoing noncardiac surgery.........................3448

CLINICAL GENETICS FIG. 67-6

Algorithm for genetic testing in a family with cancer predisposition...................................458 FIG. 457-2 Approach to genetic testing................................3372 FIG. 472-9 Clinical and laboratory investigation of a suspected mitochondrial DNA disorder..................................................................3484

CORONARY AND PERIPHERAL VASCULAR DISEASE FIG. 269-4 Reperfusion therapy for patients with ST-segment elevation myocardial infarction ...............................................................1878

DISORDERS OF THE URINARY TRACT FIG. 307-2 A typical algorithm for early posttransplant care of a kidney recipient....................................2130

EMERGENCY AND CRITICAL CARE FIG. 293-2 Approach to the patient in shock......................2025 FIG. 294-5 Algorithm for the initial management of ARDS.................................................................2034 FIG. 295-2 Algorithm to guide the daily approach to management of patients being considered for weaning off mechanical ventilation ...........2038 FIG. 298-2 Emergency management of patients with cardiogenic shock.................................................2055 FIG. 299-3A Algorithm for approach to cardiac arrest due to VT or VF (shockable rhythm)................2064

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FIG. 299-3B Algorithm for approach to cardiac arrest due to bradyarrhythmias/asystole and pulseless electrical activity..................................2064 FIG. S4-1 General guidelines for treatment of radiation casualties................................................................ S4-4 FIG. S4-2 Algorithm for evacuation in a multicasualty radiologic event.................................................... S4-5

ENDOCRINOLOGY AND METABOLISM FIG. 372-1 Management of adult growth hormone deficiency...............................................................2668 FIG. 373-3 Management of prolactinoma............................2677 FIG. 373-5 Management of acromegaly...............................2679 FIG. 373-6 Management of Cushing’s disease....................2681 FIG. 373-7 Management of a nonfunctioning pituitary mass.......................................................2683 FIG. 376-2 Evaluation of hypothyroidism...........................2701 FIG. 377-2 Evaluation of thyrotoxicosis...............................2705 FIG. 378-4 Approach to the patient with a thyroid nodule....................................................................2718 FIG. 379-10 Management of the patient with suspected Cushing’s syndrome............................................2726 FIG. 379-12 Management of patients with suspected mineralocorticoid excess.....................................2730 FIG. 379-13 Management of the patient with an incidentally discovered adrenal mass...............2732 FIG. 379-16 Management of the patient with suspected adrenal insufficiency............................................2737 FIG. 384-5 Evaluation of gynecomastia................................2780 FIG. 384-6 Evaluation of hypogonadism.............................2782 FIG. 387-2 Algorithm for the evaluation and differential diagnosis of hirsutism.....................2802 FIG. 388-4 Algorithm for menopausal symptom management..........................................................2809 FIG. 390-3 Algorithm for the evaluation and management of patients with erectile dysfunction............................................................2819 FIG. 395-1 Treatment algorithm—chronic disease management model for primary care of patients with overweight and obesity...............2846 FIG. 397-2 Essential elements in comprehensive care of type 2 diabetes.........................................2865 FIG. 397-3 Glycemic management of type 2 diabetes........2869 FIG. 398-4 Screening for albuminuria..................................2878 FIG. 399-2 Hypoglycemia-associated autonomic failure in insulin-deficient diabetes...................2885 FIG. 403-6 Algorithm for the evaluation of patients with hypercalcemia..............................................2934 FIG. 407-3 Algorithm for screening for HFE-associated hemochromatosis.................................................2981

GASTROENTEROLOGY AND HEPATOLOGY FIG. 40-2 FIG. 42-2 FIG. 42-3

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Approach to the patient with dysphagia...........252 Algorithm for the management of acute diarrhea....................................................................262 Algorithm for management of chronic diarrhea....................................................................266

FIG. 42-4 FIG.

FIG. FIG. FIG.

FIG. FIG. FIG. FIG. FIG. FIG. FIG. FIG.

Algorithm for the management of constipation.............................................................268 44-1 Suggested algorithm for patients with acute upper gastrointestinal bleeding based on endoscopic findings..............................274 44-2 Suggested algorithm for patients with acute lower gastrointestinal bleeding............................275 45-1 Evaluation of the patient with jaundice.............278 46-3 Algorithm for the diagnosis of ascites according to the serum-ascites albumin gradient ...................................................................284 317-12 Approach to selecting antibiotics for patients with H. pylori infection.........................2233 317-13 Overview of new-onset dyspepsia....................2235 329-1 Algorithm for evaluation of abnormal liver tests................................................................2336 330-1 Algorithm for the evaluation of chronically abnormal liver tests.........................2339 335-2 Treatment algorithm for alcoholic hepatitis..................................................................2401 337-3 Management of recurrent variceal hemorrhage...........................................................2411 337-5 Treatment of refractory ascites...........................2413 340-1 A stepwise diagnostic approach to the patient with suspected chronic pancreatitis ...........................................................2435

HEMATOLOGY AND ONCOLOGY FIG. 59-17 The physiologic classification of anemia............391 FIG. 59-18 An approach to the differential diagnosis of patients with an elevated hemoglobin (possible polycythemia)........................................393 FIG. 70-2 Algorithm for the diagnosis and treatment of fever and neutropenia....................508 FIG. 71-2 Management of cancer patients with back pain........................................................515 FIG. 71-4 Management of patients at high risk for the tumor lysis syndrome...............................520 FIG. 73-1 Evaluation of a patient with cervical adenopathy..............................................................534 FIG. 74-3 Algorithm for management of non-small-cell lung cancer..............................................................543 FIG. 74-5 Algorithm for management of small-cell lung cancer..............................................................545 FIG. 74-6A Algorithm for evaluation of solitary pulmonary nodule.................................................548 FIG. 74-6B Algorithm for evaluation of solid pulmonary nodule.................................................548 FIG. 74-6C Algorithm for evaluation of semisolid solid pulmonary nodule........................................548 FIG. 74-7 Management of recurrent small-cell lung cancer .............................................................553 FIG. 74-8 Approach to first-line therapy in a patient with stage IV non-small-cell lung cancer ..........554 FIG. 78-8 Staging and treatment schedule for Intrahepatic cholangiocarcinoma proposed by the International Liver Cancer Association..............589 FIG. 88-2 Treatment algorithm for adenocarcinoma and poorly differentiated adenocarcinoma of unknown primary.............................................660

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FIG. 88-3 FIG. 94-3 FIG. 100-2 FIG. 107-6 FIG. 108-1 FIG. 111-2 FIG. 114-1

Treatment algorithm for squamous cell carcinoma of unknown primary..........................661 Pathophysiology of sickle cell crisis....................692 Algorithm for the therapy of newly diagnosed acute myeloid leukemia.....................746 Treatment algorithm for multiple myeloma..................................................................800 Algorithm for the diagnosis of amyloidosis and determination of type....................................805 Algorithm for evaluating the thrombocytopenic patient.....................................824 Classification of antithrombotic drugs...............844

INFECTIOUS DISEASES FIG. 31-2 FIG. FIG.

FIG.

FIG. FIG. FIG.

FIG. FIG. FIG.

FIG. FIG. FIG. FIG.

Algorithm for the diagnosis and treatment of acute pharyngitis...............................................216 123-4 The diagnostic use of transesophageal and transtracheal echocardiography...........................927 127-3 Algorithm for the management of patients with intraabdominal abscesses by percutaneous drainage..........................................956 128-1 Clinical algorithm for the approach to patients with community-acquired infectious diarrhea or bacterial food poisoning...................961 130-4 Diagnostic approach to urinary tract infection..........................................................972 147-1 Clinical and pathologic progression of tetanus....................................................................1103 158-1 Schematic of the relationships between colonization with Helicobacter pylori and diseases of the upper gastrointestinal tract.........................................................................1163 158-2 Algorithm for the management of Helicobacter pylori infection..................................1165 180-3 Algorithm for treatment of relapsing fever.....1297 181-2 Algorithm for the treatment of the various early or late manifestations of Lyme borreliosis..............................................................1302 197-33 Algorithm for the acute HIV syndrome...........1429 197-37 Algorithm for the evaluation of diarrhea in a patient with HIV infection..........................1437 203-6 Algorithm for rabies postexposure prophylaxis............................................................1488 S5-1 Syndromic approach to the differential diagnosis of suspected infection in a veteran who has returned from a foreign war............... S5-7

FIG. 307-2 A typical algorithm for early posttransplant care of a kidney recipient.........2130 FIG. 310-1 Algorithm for the treatment of allergic and other immune-mediated acute interstitial nephritis..............................................2158 FIG. 313-1 Diagnostic approach for urinary tract obstruction in unexplained renal failure.....................................................................2175

NEUROLOGY AND PSYCHIATRY FIG. 133-1 The pathophysiology of the neurologic complications of bacterial meningitis.................999 FIG. 418-2 Evaluation of the adult patient with a seizure....................................................................3058 FIG. 418-5 Pharmacologic treatment of generalized tonic-clonic status epilepticus in adults............3067 FIG. 419-1 Medical management of stroke and TIA..........3069 FIG. 427-7 Treatment options for the management of Parkinson’s disease..........................................3132 FIG. 436-4 Therapeutic decision-making for relapsing multiple sclerosis................................3198 FIG. 438-1 Approach to the evaluation of peripheral neuropathies......................................3205 FIG. 440-2 Algorithm for the management of myasthenia gravis................................................3237 FIG. 441-1 Diagnostic evaluation of intermittent weakness................................................................3241 FIG. 441-2 Diagnostic evaluation of persistent weakness................................................................3241 FIG. 444-1 A guideline for the medical management of major depressive disorder..............................3270

PULMONOLOGY FIG. 33-2 Possible algorithm for the evaluation of the patient with dyspnea.............................................229 FIG. 35-1 Approach to the management of hemoptysis..............................................................233 FIG. 273-3 How to decide whether diagnostic imaging is needed................................................1911 FIG. 273-6 Imaging tests to diagnose DVT and PE............1913 FIG. 273-7 Acute management of pulmonary thromboembolism................................................1914 FIG. 288-1 Approach to the diagnosis of pleural effusions.................................................................2007

NEPHROLOGY

SYSTEMIC CONDITIONS

FIG. FIG. FIG. FIG. FIG. FIG. FIG. FIG.

FIG. 17-1

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48-1 48-2 48-3 48-4 49-5 49-6 49-7 49-8

Approach to the patient with azotemia..............290 Approach to the patient with hematuria............292 Approach to the patient with proteinuria..........293 Approach to the patient with polyuria...............294 The diagnostic approach to hyponatremia........298 The diagnostic approach to hypernatremia.......303 The diagnostic approach to hypokalemia..........307 The diagnostic approach to hyperkalemia.........311

FIG. FIG. FIG. FIG.

Structured approach to patients with fever of unknown origin.................................................119 21-3 An algorithm for the initial workup of a patient with weakness...........................................137 30-2 An algorithm for the approach to hearing loss............................................................................201 57-1 Algorithm for the diagnosis of a patient with photosensitivity.............................................378 386-2 Algorithm for evaluation of amenorrhea.........2796

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Editors of Previous Editions

T. R. Harrison

Editor-in-Chief, Editions 1, 2, 3, 4, 5

W. R. Resnick

Editor, Editions 1, 2, 3, 4, 5

M. M. Wintrobe

Editor, Editions 1, 2, 3, 4, 5 Editor-in-Chief, Editions 6, 7

G. W. Thorn

J. D. Wilson

Editor, Editions 9, 10, 11, 13, 14 Editor-in-Chief, Edition 12

J. B. Martin

Editor, Editions 10, 11, 12, 13, 14

A. S. Fauci

Editor, Editions 11, 12, 13, 15, 16, 18, 19, 20 Editor-in-Chief, Editions 14, 17

Editor, Editions 1, 2, 3, 4, 5, 6, 7 Editor-in-Chief, Edition 8

R. Root

R. D. Adams

D. L. Kasper

Editor, Editions 2, 3, 4, 5, 6, 7, 8, 9, 10

P. B. Beeson

Editor, Editions 1, 2

I. L. Bennett, Jr.

Editor, Editions 3, 4, 5, 6

E. Braunwald

Editor, Editions 6, 7, 8, 9, 10, 12, 13, 14, 16, 17 Editor-in-Chief, Editions 11, 15

K. J. Isselbacher

Editor, Editions 6, 7, 8, 10, 11, 12, 14 Editor-in-Chief, Editions 9, 13

R. G. Petersdorf

Editor, Edition 12 Editor, Editions 13, 14, 15, 17, 18, 20 Editor-in-Chief, Editions 16, 19

S. L. Hauser

Editor, Editions 14, 15, 16, 17, 18, 19, 20

D. L. Longo

Editor, Editions 14, 15, 16, 17, 19, 20 Editor-in-Chief, Edition 18

J. L. Jameson

Editor, Editions 15, 16, 17, 18, 19 Editor-in-Chief, Edition 20

J. Loscalzo

Editor, Editions 17, 18, 19, 20

Editor, Editions 6, 7, 8, 9, 11, 12 Editor-in-Chief, Edition 10

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INTERNAL MEDICINE Editors J. Larry Jameson, MD, PhD

Anthony S. Fauci, MD

Robert G. Dunlop Professor of Medicine; Dean, Raymond and Ruth Perelman School of Medicine; Executive Vice President, University of Pennsylvania for the Health System, Philadelphia, Pennsylvania

Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Dennis L. Kasper, MD

Robert A. Fishman Distinguished Professor, Department of Neurology; Director, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California

William Ellery Channing Professor of Medicine and Professor of Microbiology and Immunobiology, Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts

Dan L. Longo, MD Professor of Medicine, Harvard Medical School; Senior Physician, Brigham and Women’s Hospital; Deputy Editor, New England Journal of Medicine, Boston, Massachusetts

Stephen L. Hauser, MD

Joseph Loscalzo, MD, PhD Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital, Boston, Massachusetts

VOLUME I

New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto

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Copyright © 2018 by McGraw-Hill Education. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-1-25-964404-7 MHID: 1-25-964404-9 The material in this eBook also appears in the print version of this title: ISBN: 978-1-25-964403-0, MHID: 1-25-964403-0. eBook conversion by codeMantra Version 1.0 All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill Education eBooks are available at special quantity discounts to use as premiums and sales promotions or for use in corporate training programs. To contact a representative, please visit the Contact Us page at www.mhprofessional.com. Note: Dr. Fauci’s work as editor and author was performed outside the scope of his employment as a U.S. government employee. This work represents his personal and professional views and not necessarily those of the U.S. government. TERMS OF USE This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill Education’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/ or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

Cover Illustration Beginning with the 6th edition, the cover of Harrison’s has included an image of a bright light—a patient’s perception of being examined with an ophthalmoscope. This allegorical symbol of Harrison’s is a reminder of how the light of knowledge empowers physicians to better diagnose and treat diseases that ultimately afflict all of humankind.

Author Disclosure Policy: McGraw-Hill and the Harrison’s Editorial Board requires all contributors to disclose to the Editors and the Publisher any potential financial or professional conflicts that would raise the possibility of distorting the preparation of a Harrison’s chapter.

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Contents Contributors............................................................................... xix Preface .......................................................................................... xl

PART 1 The Profession of Medicine

1 The Practice of Medicine....................................................1



2 Promoting Good Health.....................................................8



3 Decision-Making in Clinical Medicine.............................13



4 Screening and Prevention of Disease.................................22



5 Health Care Systems in Developed Countries....................27 Richard B. Saltman 6 The Safety and Quality of Health Care..............................33 David W. Bates 7 Racial and Ethnic Disparities in Health Care.....................37 Joseph R. Betancourt, Alexander R. Green 8 Ethical Issues in Clinical Medicine....................................44 Bernard Lo, Christine Grady 9 Palliative and End-of-Life Care........................................47 Ezekiel J. Emanuel



The Editors

Donald M. Lloyd-Jones, Kathleen M. McKibbin Daniel B. Mark, John B. Wong

SECTION 1  Pain



10 Pain: Pathophysiology and Management...........................65 James P. Rathmell, Howard L. Fields 11 Chest Discomfort.............................................................73 David A. Morrow 12 Abdominal Pain................................................................81 Danny O. Jacobs 13 Headache..........................................................................85 Peter J. Goadsby 14 Back and Neck Pain..........................................................89 John W. Engstrom

SECTION 2  Alterations in Body Temperature

15 Fever.............................................................................. 102 Charles A. Dinarello, Reuven Porat 16 Fever and Rash............................................................... 105 Elaine T. Kaye, Kenneth M. Kaye 17 Fever of Unknown Origin............................................... 114 Chantal P. Bleeker-Rovers, Jos W. M. van der Meer

SECTION 3  Nervous System Dysfunction



Katrina A. Armstrong, Gary J. Martin

PART 2 Cardinal Manifestations and Presentation of Diseases



18 Syncope.......................................................................... 122 Roy Freeman 19 Dizziness and Vertigo..................................................... 129 Mark F. Walker, Robert B. Daroff 20 Fatigue........................................................................... 132 Jeffrey M. Gelfand, Vanja C. Douglas

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21 Neurologic Causes of Weakness and Paralysis.................. 135 Michael J. Aminoff 22 Numbness, Tingling, and Sensory Loss........................... 139 Michael J. Aminoff 23 Gait Disorders, Imbalance, and Falls............................... 143 Jessica M. Baker, Lewis R. Sudarsky 24 Confusion and Delirium................................................. 147 S. Andrew Josephson, Bruce L. Miller 25 Dementia........................................................................ 152 William W. Seeley, Bruce L. Miller 26 Aphasia, Memory Loss, Hemispatial Neglect, Frontal Syndromes, and Other Cerebral Disorders.......... 157 M.-Marsel Mesulam 27 Sleep Disorders............................................................... 166 Thomas E. Scammell, Clifford B. Saper, Charles A. Czeisler

SECTION 4  Disorders of Eyes, Ears, Nose, and Throat

28 Disorders of the Eye........................................................ 177 Jonathan C. Horton 29 Disorders of Smell and Taste........................................... 194 Richard L. Doty, Steven M. Bromley 30 Disorders of Hearing...................................................... 200 Anil K. Lalwani 31 Sore Throat, Earache, and Upper Respiratory Symptoms....................................................................... 208 Michael A. Rubin, Larry C. Ford, Ralph Gonzales 32 Oral Manifestations of Disease....................................... 219 Samuel C. Durso

SECTION 5  Alterations in Circulatory and Respiratory Functions

33 Dyspnea......................................................................... 226 Rebecca M. Baron 34 Cough............................................................................ 230 Christopher H. Fanta 35 Hemoptysis.................................................................... 232 Anna K. Brady, Patricia A. Kritek 36 Hypoxia and Cyanosis..................................................... 234 Joseph Loscalzo 37 Edema............................................................................ 237 Eugene Braunwald, Joseph Loscalzo 38 Approach to the Patient with a Heart Murmur................ 240 Patrick T. O’Gara, Joseph Loscalzo 39 Palpitations..................................................................... 249 Joseph Loscalzo

SECTION 6  Alterations in Gastrointestinal Function

40 Dysphagia...................................................................... 249 Ikuo Hirano, Peter J. Kahrilas 41 Nausea, Vomiting, and Indigestion.................................. 253 William L. Hasler 42 Diarrhea and Constipation.............................................. 259 Michael Camilleri, Joseph A. Murray

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SECTION 7  Alterations in Renal and Urinary Tract Function

47 Dysuria, Bladder Pain, and the Interstitial Cystitis/ Bladder Pain Syndrome..................................... 285 John W. Warren 48 Azotemia and Urinary Abnormalities.............................. 288 David B. Mount 49 Fluid and Electrolyte Disturbances................................. 295 David B. Mount 50 Hypercalcemia and Hypocalcemia................................... 312 Sundeep Khosla 51 Acidosis and Alkalosis..................................................... 315 Thomas D. DuBose, Jr.

SECTION 8  Alterations in the Skin

52 Approach to the Patient with a Skin Disorder.................. 324 Kim B. Yancey, Thomas J. Lawley 53 Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders................................ 329 Leslie P. Lawley, Calvin O. McCall, Thomas J. Lawley 54 Skin Manifestations of Internal Disease.......................... 339 Jean L. Bolognia, Irwin M. Braverman 55 Immunologically Mediated Skin Diseases....................... 355 Kim B. Yancey, Thomas J. Lawley 56 Cutaneous Drug Reactions............................................. 362 Robert G. Micheletti, Misha Rosenbach, Bruce U. Wintroub, Kanade Shinkai 57 Photosensitivity and Other Reactions to Light................ 372 Alexander G. Marneros, David R. Bickers

SECTION 9  Hematologic Alterations

58 Interpreting Peripheral Blood Smears.............................. 379 Dan L. Longo 59 Anemia and Polycythemia............................................... 385 John W. Adamson, Dan L. Longo 60 Disorders of Granulocytes and Monocytes...................... 394 Steven M. Holland, John I. Gallin 61 Bleeding and Thrombosis................................................ 404 Barbara A. Konkle 62 Enlargement of Lymph Nodes and Spleen....................... 411 Dan L. Longo

PART 3 Pharmacology

63 Principles of Clinical Pharmacology................................ 419 Dan M. Roden 64 Pharmacogenomics......................................................... 429 Dan M. Roden

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PART 4 Oncology and Hematology SECTION 1  Neoplastic Disorders

65 Approach to the Patient with Cancer............................... 435 Dan L. Longo 66 Prevention and Early Detection of Cancer....................... 443 Jennifer M. Croswell, Otis W. Brawley, Barnett S. Kramer 67 Cancer Genetics............................................................. 452 Fred Bunz, Bert Vogelstein 68 Cancer Cell Biology........................................................ 461 Jeffrey W. Clark, Dan L. Longo 69 Principles of Cancer Treatment....................................... 480 Edward A. Sausville, Dan L. Longo 70 Infections in Patients with Cancer................................... 502 Robert W. Finberg 71 Oncologic Emergencies................................................... 511 Rasim Gucalp, Janice P. Dutcher 72 Cancer of the Skin.......................................................... 522 Brendan D. Curti, Sancy Leachman, Walter J. Urba 73 Head and Neck Cancer................................................... 532 Everett E. Vokes 74 Neoplasms of the Lung................................................... 537 Leora Horn, Christine M. Lovly 75 Breast Cancer................................................................. 555 Daniel F. Hayes, Marc E. Lippman 76 Upper Gastrointestinal Tract Cancers.............................. 566 Robert J. Mayer 77 Lower Gastrointestinal Cancers...................................... 572 Robert J. Mayer 78 Tumors of the Liver and Biliary Tree............................... 578 Josep M. Llovet 79 Pancreatic Cancer........................................................... 591 Daniel D. Von Hoff 80 Neuroendocrine Tumors of the Gastrointestinal Tract and Pancreas.......................................................... 596 Robert T. Jensen 81 Renal Cell Carcinoma..................................................... 616 Robert J. Motzer 82 Cancer of the Bladder and Urinary Tract.......................... 619 Noah M. Hahn 83 Benign and Malignant Diseases of the Prostate................ 623 Howard I. Scher, James A. Eastham 84 Testicular Cancer............................................................ 632 David J. Vaughn 85 Gynecologic Malignancies.............................................. 637 David Spriggs 86 Primary and Metastatic Tumors of the Nervous System.............................................................. 643 Lisa M. DeAngelis, Patrick Y. Wen 87 Soft Tissue and Bone Sarcomas and Bone Metastases............................................................. 653 Shreyaskumar R. Patel 88 Carcinoma of Unknown Primary..................................... 657 Gauri R. Varadhachary, James L. Abbruzzese 89 Paraneoplastic Syndromes: Endocrinologic/ Hematologic................................................................... 662 J. Larry Jameson, Dan L. Longo

CONTENTS



43 Unintentional Weight Loss............................................. 270 J. Larry Jameson 44 Gastrointestinal Bleeding................................................ 272 Loren Laine 45 Jaundice.......................................................................... 276 Savio John, Daniel S. Pratt 46 Abdominal Swelling and Ascites..................................... 281 Kathleen E. Corey, Lawrence S. Friedman

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CONTENTS

90 Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis............................................... 668 Josep Dalmau, Myrna R. Rosenfeld 91 Late Consequences of Cancer and Its Treatment.............. 674 Carl E. Freter, Dan L. Longo

PART 5 Infectious Diseases SECTION 1  Basic Considerations in Infectious Diseases

SECTION 2  Hematopoietic Disorders









92 Hematopoietic Stem Cells............................................... 679 David T. Scadden, Dan L. Longo 93 Iron Deficiency and Other Hypoproliferative Anemias.... 683 John W. Adamson 94 Disorders of Hemoglobin................................................ 690 Edward J. Benz, Jr. 95 Megaloblastic Anemias................................................... 698 A. Victor Hoffbrand 96 Hemolytic Anemias........................................................ 708 Lucio Luzzatto 97 Anemia Due to Acute Blood Loss................................... 723 Dan L. Longo 98 Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia............................... 723 Neal S. Young 99 Polycythemia Vera and Other Myeloproliferative Neoplasms...................................................................... 733 Jerry L. Spivak 100 Acute Myeloid Leukemia................................................ 739 William Blum, Clara D. Bloomfield 101 Chronic Myeloid Leukemia............................................. 748 Hagop Kantarjian, Jorge Cortes 102 Acute Lymphoid Leukemia...............................................757 Dieter Hoelzer 103 Chronic Lymphocytic Leukemia..................................... 763 Jennifer A. Woyach, John C. Byrd 104 Non-Hodgkin’s Lymphoma............................................ 769 Caron A. Jacobson, Dan L. Longo 105 Hodgkin’s Lymphoma..................................................... 780 Caron A. Jacobson, Dan L. Longo 106 Less Common Hematologic Malignancies...................... 783 Ayalew Tefferi, Dan L. Longo 107 Plasma Cell Disorders..................................................... 793 Nikhil C. Munshi, Dan L. Longo, Kenneth C. Anderson 108 Amyloidosis.................................................................... 803 John L. Berk, Vaishali Sanchorawala 109 Transfusion Biology and Therapy.................................... 809 Jeffery S. Dzieczkowski, Pierre Tiberghien, Kenneth C. Anderson 110 Hematopoietic Cell Transplantation................................ 816 Frederick R. Appelbaum

SECTION 3  Disorders of Hemostasis

111 Disorders of Platelets and Vessel Wall.............................. 822 Barbara A. Konkle 112 Coagulation Disorders.................................................... 830 Valder R. Arruda, Katherine A. High 113 Arterial and Venous Thrombosis..................................... 839 Jane E. Freedman, Joseph Loscalzo 114 Antiplatelet, Anticoagulant, and Fibrinolytic Drugs........ 843 Jeffrey I. Weitz

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115 Approach to the Patient with an Infectious Disease.......... 859 Neeraj K. Surana, Dennis L. Kasper 116 Molecular Mechanisms of Microbial Pathogenesis........... 866 Gerald B. Pier 117 Approach to the Acutely Ill Infected Febrile Patient......... 877 Tamar F. Barlam, Dennis L. Kasper 118 Immunization Principles and Vaccine Use....................... 884 Nancy Messonnier, Anne Schuchat, Lisa A. Jackson 119 Health Recommendations for International Travel.......... 892 Jay S. Keystone, Phyllis E. Kozarsky 120 Climate Change and Infectious Disease........................... 900 Aaron S. Bernstein

SECTION 2  Clinical Syndromes: Community-Acquired Infections

121 Pneumonia..................................................................... 908 Lionel A. Mandell, Richard Wunderink 122 Lung Abscess.................................................................. 919 Rebecca M. Baron, Miriam Baron Barshak 123 Infective Endocarditis..................................................... 921 Adolf W. Karchmer 124 Infections of the Skin, Muscles, and Soft Tissues............. 933 Dennis L. Stevens 125 Infectious Arthritis......................................................... 939 Lawrence C. Madoff 126 Osteomyelitis.................................................................. 944 Werner Zimmerli 127 Intraabdominal Infections and Abscesses........................ 952 Miriam Baron Barshak, Dennis L. Kasper 128 Acute Infectious Diarrheal Diseases and Bacterial Food Poisoning................................................ 959 Richelle C. Charles, Stephen B. Calderwood, Regina C. LaRocque 129 Clostridium difficile Infection, Including Pseudomembranous Colitis............................................. 964 Dale N. Gerding, Stuart Johnson 130 Urinary Tract Infections, Pyelonephritis, and Prostatitis................................................................. 968 Kalpana Gupta, Barbara W. Trautner 131 Sexually Transmitted Infections: Overview and Clinical Approach.................................................... 976 Jeanne M. Marrazzo, King K. Holmes 132 Encephalitis.................................................................... 991 Karen L. Roos, Kenneth L. Tyler 133 Acute Meningitis............................................................ 998 Karen L. Roos, Kenneth L. Tyler 134 Chronic and Recurrent Meningitis................................ 1007 Walter J. Koroshetz, Michael R. Wilson, Avindra Nath 135 Brain Abscess and Empyema......................................... 1013 Karen L. Roos, Kenneth L. Tyler 136 Infectious Complications of Bites.................................. 1019 Sandeep S. Jubbal, Florencia Pereyra, Lawrence C. Madoff

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SECTION 3  Clinical Syndromes: Health Care–Associated Infections

SECTION 4  Therapy for Bacterial Diseases

139 Treatment and Prophylaxis of Bacterial Infections......... 1042 David C. Hooper, Erica S. Shenoy, Christy A. Varughese 140 Bacterial Resistance to Antimicrobial Agents................ 1057 David C. Hooper

SECTION 5  Diseases Caused by Gram-Positive Bacteria

141 Pneumococcal Infections............................................... 1062 David Goldblatt, Katherine L. O’Brien 142 Staphylococcal Infections.............................................. 1071 Franklin D. Lowy 143 Streptococcal Infections................................................ 1081 Michael R. Wessels 144 Enterococcal Infections................................................. 1089 Cesar A. Arias, Barbara E. Murray 145 Diphtheria and Other Corynebacterial Infections.......... 1095 William R. Bishai, John R. Murphy 146 Listeria monocytogenes Infections............................... 1100 Elizabeth L. Hohmann, Daniel A. Portnoy 147 Tetanus......................................................................... 1102 C. Louise Thwaites, Lam Minh Yen 148 Botulism....................................................................... 1105 Agam K. Rao, Susan Maslanka 149 Gas Gangrene and Other Clostridial Infections............. 1109 Amy E. Bryant, Dennis L. Stevens

160 Salmonellosis................................................................ 1173 David A. Pegues, Samuel I. Miller 161 Shigellosis..................................................................... 1180 Philippe J. Sansonetti, Jean Bergounioux 162 Infections Due to Campylobacter and Related Organisms....................................................... 1184 Beth D. Kirkpatrick, Martin J. Blaser 163 Cholera and Other Vibrioses......................................... 1186 Matthew K. Waldor, Edward T. Ryan 164 Brucellosis.................................................................... 1192 Nicholas J. Beeching 165 Tularemia..................................................................... 1196 Jeannine M. Petersen, Paul S. Mead 166 Plague and Other Yersinia Infections............................ 1200 Michael B. Prentice 167 Bartonella Infections, Including Cat-Scratch Disease......................................................................... 1209 Michael Giladi, Moshe Ephros 168 Donovanosis................................................................. 1214 Nigel O’Farrell

SECTION 7  Miscellaneous Bacterial Infections







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169 Nocardiosis................................................................... 1215 Gregory A. Filice 170 Actinomycosis............................................................... 1220 Thomas A. Russo 171 Whipple’s Disease......................................................... 1223 Thomas A. Russo 172 Infections Due to Mixed Anaerobic Organisms............. 1227 Neeraj K. Surana, Dennis L. Kasper

SECTION 8  Mycobacterial Diseases

SECTION 6  Diseases Caused by Gram-Negative Bacteria 150 Meningococcal Infections............................................. 1114 Andrew J. Pollard 151 Gonococcal Infections.................................................. 1122 Sanjay Ram, Peter A. Rice 152 Haemophilus and Moraxella Infections........................ 1129 Timothy F. Murphy 153 Infections Due to the HACEK Group and Miscellaneous Gram-Negative Bacteria......................... 1134 Tamar F. Barlam, Dennis L. Kasper 154 Legionella Infections.................................................... 1137 Victor L. Yu, M. Luisa Pedro-Botet, Yusen E. Lin 155 Pertussis and Other Bordetella Infections..................... 1142 Karina A. Top, Scott A. Halperin 156 Diseases Caused by Gram-Negative Enteric Bacilli....... 1146 Thomas A. Russo, James R. Johnson 157 Acinetobacter Infections............................................... 1158 Rossana Rosa, L. Silvia Munoz-Price 158 Helicobacter pylori Infections....................................... 1162 John C. Atherton, Martin J. Blaser 159 Infections Due to Pseudomonas, Burkholderia, and Stenotrophomonas Species..................................... 1167 Reuben Ramphal

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CONTENTS



137 Infections Acquired in Health Care Facilities................. 1022 Robert A. Weinstein 138 Infections in Transplant Recipients............................... 1030 Robert W. Finberg, Joyce D. Fingeroth





173 Tuberculosis.................................................................. 1236 Mario C. Raviglione 174 Leprosy......................................................................... 1259 Robert H. Gelber 175 Nontuberculous Mycobacterial Infections..................... 1266 Steven M. Holland 176 Antimycobacterial Agents............................................. 1270 Divya Reddy, Max R. O’Donnell

SECTION 9  Spirochetal Diseases

177 Syphilis......................................................................... 1279 Sheila A. Lukehart 178 Endemic Treponematoses............................................. 1286 Sheila A. Lukehart 179 Leptospirosis................................................................ 1290 Jirˇi F. P. Wagenaar, Marga G. A. Goris 180 Relapsing Fever............................................................ 1295 Alan G. Barbour 181 Lyme Borreliosis........................................................... 1298 Allen C. Steere

SECTION 10  Diseases Caused by Rickettsiae, Mycoplasmas, and Chlamydiae

182 Rickettsial Diseases....................................................... 1303 David H. Walker, J. Stephen Dumler, Lucas S. Blanton, Thomas Marrie

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183 Infections Due to Mycoplasmas.................................... 1313 R. Doug Hardy 184 Chlamydial Infections................................................... 1316 Charlotte A. Gaydos, Thomas C. Quinn



SECTION 11  Viral Diseases: General Considerations



CONTENTS



185 Medical Virology.......................................................... 1325 Fred Wang, Elliott Kieff 186 Antiviral Chemotherapy, Excluding Antiretroviral Drugs........................................................................... 1334 Lindsey R. Baden

SECTION 12  Infections Due to DNA Viruses

187 Herpes Simplex Virus Infections................................... 1345 Lawrence Corey 188 Varicella-Zoster Virus Infections................................... 1354 Richard J. Whitley 189 Epstein-Barr Virus Infections, Including Infectious Mononucleosis............................................................. 1358 Jeffrey I. Cohen 190 Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8............................................................ 1361 Camille Nelson Kotton, Martin S. Hirsch 191 Molluscum Contagiosum, Monkeypox, and Other Poxvirus Infections........................................................ 1366 Fred Wang 192 Parvovirus Infections.................................................... 1367 Kevin E. Brown 193 Human Papillomavirus Infections................................. 1370 Darron R. Brown, Aaron Ermel

SECTION 13  Infections Due to DNA and RNA Respiratory Viruses

194 Common Viral Respiratory Infections........................... 1375 James E. Crowe, Jr. 195 Influenza...................................................................... 1382 Peter F. Wright

SECTION 14  Infections Due to Human Immunodeficiency Virus and Other Human Retroviruses

196 The Human Retroviruses.............................................. 1388 Dan L. Longo, Anthony S. Fauci 197 Human Immunodeficiency Virus Disease: AIDS and Related Disorders......................................... 1393 Anthony S. Fauci, Gregory K. Folkers, H. Clifford Lane

SECTION 15  Infections Due to RNA Viruses

198 Viral Gastroenteritis..................................................... 1463 Umesh D. Parashar, Roger I. Glass 199 Enterovirus, Parechovirus, and Reovirus Infections....... 1468 Jeffrey I. Cohen 200 Measles (Rubeola)........................................................ 1474 Kaitlin Rainwater-Lovett, William J. Moss 201 Rubella (German Measles)............................................ 1478 Laura A. Zimmerman, Susan E. Reef 202 Mumps......................................................................... 1481 Steven A. Rubin

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203 Rabies and Other Rhabdovirus Infections..................... 1484 Alan C. Jackson 204 Arthropod-Borne and Rodent-Borne Virus Infections............................................................ 1489 Jens H. Kuhn, Rémi N. Charrel 205 Ebolavirus and Marburgvirus Infections........................ 1509 Jens H. Kuhn

SECTION 16   Fungal Infections

206 Diagnosis and Treatment of Fungal Infections............... 1515 John E. Edwards, Jr. 207 Histoplasmosis............................................................. 1518 Chadi A. Hage, L. Joseph Wheat 208 Coccidioidomycosis...................................................... 1521 Neil M. Ampel 209 Blastomycosis............................................................... 1524 S. Travis King, Rathel L. Nolan, III 210 Cryptococcosis.............................................................. 1526 Arturo Casadevall 211 Candidiasis................................................................... 1529 John E. Edwards, Jr. 212 Aspergillosis................................................................. 1532 David W. Denning 213 Mucormycosis............................................................... 1537 Brad Spellberg, Ashraf S. Ibrahim 214 Superficial Mycoses and Less Common Systemic Mycoses......................................................... 1541 Carol A. Kauffman 215 Pneumocystis Infections............................................... 1547 Alison Morris, Henry Masur

SECTION 17  Protozoal and Helminthic Infections: General Considerations

216 Introduction to Parasitic Infections............................... 1551 Sharon L. Reed, Charles E. Davis 217 Agents Used to Treat Parasitic Infections....................... 1556 Thomas A. Moore

SECTION 18  Protozoal Infections

218 Amebiasis and Infection with Free-Living Amebae........ 1568 Rosa M. Andrade, Sharon L. Reed 219 Malaria......................................................................... 1575 Nicholas J. White, Elizabeth A. Ashley 220 Babesiosis..................................................................... 1590 Edouard Vannier, Peter J. Krause 221 Leishmaniasis............................................................... 1594 Shyam Sundar 222 Chagas Disease and African Trypanosomiasis................ 1601 François Chappuis, Yves Jackson 223 Toxoplasma Infections.................................................. 1609 Kami Kim 224 Protozoal Intestinal Infections and Trichomoniasis........ 1615 Peter F. Weller

SECTION 19  Helminthic Infections

225 Introduction to Helminthic Infections........................... 1620 Peter F. Weller

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PART 6 Disorders of the Cardiovascular System SECTION 1  Introduction to Cardiovascular Disorders

231 Approach to the Patient with Possible Cardiovascular Disease................................................. 1649 Joseph Loscalzo 232 Basic Biology of the Cardiovascular System................... 1651 Joseph Loscalzo, Peter Libby, Calum A. MacRae 233 Epidemiology of Cardiovascular Disease....................... 1662 Thomas A. Gaziano, J. Michael Gaziano

SECTION 2  Diagnosis of Cardiovascular Disorders



234 Physical Examination of the Cardiovascular System...... 1666 Patrick T. O’Gara, Joseph Loscalzo 235 Electrocardiography...................................................... 1675 Ary L. Goldberger 236 Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and Magnetic Resonance/ Computed Tomography Imaging................................... 1683 Marcelo F. Di Carli, Raymond Y. Kwong, Scott D. Solomon 237 Diagnostic Cardiac Catheterization and Coronary Angiography................................................. 1709 Jane A. Leopold, David P. Faxon











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SECTION 4  Disorders of the Heart

SECTION 3  Disorders of Rhythm 238 Principles of Electrophysiology...................................... 1716 David D. Spragg, Gordon F. Tomaselli 239 The Bradyarrhythmias: Disorders of the Sinoatrial Node............................................................. 1722 David D. Spragg, Gordon F. Tomaselli 240 The Bradyarrhythmias: Disorders of the Atrioventricular Node................................................... 1727 David D. Spragg, Gordon F. Tomaselli 241 Approach to Supraventricular Tachyarrhythmias........... 1733 Gregory F. Michaud, William G. Stevenson 242 Physiologic and Nonphysiologic Sinus Tachycardia........ 1735 Gregory F. Michaud, William G. Stevenson 243 Focal Atrial Tachycardia................................................ 1736 Gregory F. Michaud, William G. Stevenson 244 Paroxysmal Supraventricular Tachycardias..................... 1739 Gregory F. Michaud, William G. Stevenson 245 Common Atrial Flutter, Macroreentrant, and Multifocal Atrial Tachycardias................................ 1743 Gregory F. Michaud, William G. Stevenson

246 Atrial Fibrillation......................................................... 1746 Gregory F. Michaud, William G. Stevenson 247 Approach to Ventricular Arrhythmias............................ 1750 Roy M. John, William G. Stevenson 248 Premature Ventricular Beats, Non-Sustained Ventricular Tachycardia, and Idioventricular Rhythm.... 1755 Roy M. John, William G. Stevenson 249 Sustained Ventricular Tachycardia................................. 1757 Roy M. John, William G. Stevenson 250 Polymorphic Ventricular Tachycardia and Ventricular Fibrillation................................................. 1759 Roy M. John, William G. Stevenson 251 Electrical Storm and Incessant VT................................ 1762 Roy M. John, William G. Stevenson

CONTENTS



226 Trichinellosis and Other Tissue Nematode Infections.... 1621 Peter F. Weller 227 Intestinal Nematode Infections..................................... 1625 Peter F. Weller, Thomas B. Nutman 228 Filarial and Related Infections....................................... 1629 Thomas B. Nutman, Peter F. Weller 229 Schistosomiasis and Other Trematode Infections........... 1635 Birgitte Jyding Vennervald 230 Cestode Infections........................................................ 1641 A. Clinton White, Jr., Peter F.  Weller



252 Heart Failure: Pathophysiology and Diagnosis...................................................................... 1763 Douglas L. Mann, Murali Chakinala 253 Heart Failure: Management.......................................... 1769 Mandeep R. Mehra 254 Cardiomyopathy and Myocarditis.................................. 1779 Neal K. Lakdawala, Lynne Warner Stevenson, Joseph Loscalzo 255 Cardiac Transplantation and Prolonged Assisted Circulation...................................................... 1797 Mandeep R. Mehra 256 Aortic Valve Disease..................................................... 1802 Patrick T. O’Gara, Joseph Loscalzo 257 Aortic Regurgitation..................................................... 1809 Patrick T. O’Gara, Joseph Loscalzo 258 Mitral Stenosis............................................................. 1813 Patrick T. O’Gara, Joseph Loscalzo 259 Mitral Regurgitation..................................................... 1818 Patrick T. O’Gara, Joseph Loscalzo 260 Mitral Valve Prolapse.................................................... 1821 Patrick T. O’Gara, Joseph Loscalzo 261 Tricuspid Valve Disease................................................. 1823 Patrick T. O’Gara, Joseph Loscalzo 262 Pulmonic Valve Disease................................................ 1826 Patrick T. O’Gara, Joseph Loscalzo 263 Multiple and Mixed Valvular Heart Disease.................. 1827 Patrick T. O’Gara, Joseph Loscalzo 264 Congenital Heart Disease in the Adult.......................... 1829 Anne Marie Valente, Michael J. Landzberg 265 Pericardial Disease........................................................ 1841 Eugene Braunwald 266 Atrial Myxoma and Other Cardiac Tumors.................... 1847 Eric H. Awtry

SECTION 5  Coronary and Peripheral Vascular Disease

267 Ischemic Heart Disease................................................. 1850 Elliott M. Antman, Joseph Loscalzo 268 Non-ST-Segment Elevation Acute Coronary Syndrome (Non-ST-Segment Elevation Myocardial Infarction and Unstable Angina)................. 1866 Robert P. Giugliano, Christopher P. Cannon, Eugene Braunwald

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269 ST-Segment Elevation Myocardial Infarction............... 1872 Elliott M. Antman, Joseph Loscalzo 270 Percutaneous Coronary Interventions and Other Interventional Procedures............................................. 1885 David P. Faxon, Deepak L. Bhatt 271 Hypertensive Vascular Disease...................................... 1890 Theodore A. Kotchen 272 Renovascular Disease.................................................... 1906 Stephen C. Textor 273 Deep Venous Thrombosis and Pulmonary Thromboembolism....................................................... 1910 Samuel Z. Goldhaber 274 Diseases of the Aorta.................................................... 1917 Mark A. Creager, Joseph Loscalzo 275 Arterial Diseases of the Extremities............................... 1923 Mark A. Creager, Joseph Loscalzo 276 Chronic Venous Disease and Lymphedema................... 1930 Mark A. Creager, Joseph Loscalzo 277 Pulmonary Hypertension.............................................. 1935 Aaron B. Waxman, Joseph Loscalzo

PART 7 Disorders of the Respiratory System

PART 8 Critical Care Medicine SECTION 1  Respiratory Critical Care

SECTION 2  Shock and Cardiac Arrest













281 Asthma......................................................................... 1957 Peter J. Barnes 282 Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia.......................................... 1970 Praveen Akuthota, Michael E. Wechsler 283 Occupational and Environmental Lung Disease............ 1976 John R. Balmes 284 Bronchiectasis............................................................... 1983 Rebecca M. Baron, Miriam Baron Barshak 285 Cystic Fibrosis.............................................................. 1986 Eric J. Sorscher 286 Chronic Obstructive Pulmonary Disease....................... 1990 Edwin K. Silverman, James D. Crapo, Barry J. Make 287 Interstitial Lung Disease............................................... 1999 Gary M. Hunninghake, Ivan O. Rosas 288 Disorders of the Pleura.................................................. 2006 Richard W. Light 289 Disorders of the Mediastinum....................................... 2009 Richard W. Light 290 Disorders of Ventilation................................................ 2010 John F. McConville, Julian Solway, Babak Mokhlesi 291 Sleep Apnea.................................................................. 2013 Andrew Wellman, Susan Redline 292 Lung Transplantation................................................... 2018 Elbert P. Trulock, III

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300 Coma........................................................................... 2068 S. Andrew Josephson, Allan H. Ropper, Stephen L. Hauser 301 Severe Acute Encephalopathies and Critical Care Weakness................................................. 2074 J. Claude Hemphill, III, Wade S. Smith, S. Andrew Josephson, Daryl R. Gress 302 Subarachnoid Hemorrhage........................................... 2084 J. Claude Hemphill, III, Wade S. Smith, Daryl R. Gress

PART 9 Disorders of the Kidney and Urinary Tract

SECTION 2  Diseases of the Respiratory System

296 Approach to the Patient with Shock.............................. 2039 Anthony F. Massaro 297 Sepsis and Septic Shock................................................ 2044 Christopher W. Seymour, Derek C. Angus 298 Cardiogenic Shock and Pulmonary Edema.................... 2052 David H. Ingbar, Holger Thiele 299 Cardiovascular Collapse, Cardiac Arrest, and Sudden Cardiac Death............................................................... 2059 Christine M. Albert, William G. Stevenson

SECTION 3  Neurologic Critical Care

SECTION 1  Diagnosis of Respiratory Disorders 278 Approach to the Patient with Disease of the Respiratory System....................................................... 1943 Patricia A. Kritek, Bruce D. Levy 279 Disturbances of Respiratory Function........................... 1945 Edward T. Naureckas, Julian Solway 280 Diagnostic Procedures in Respiratory Disease............... 1951 Anne L. Fuhlbrigge, Augustine M. K. Choi

293 Approach to the Patient with Critical Illness.................. 2023 John P. Kress, Jesse B. Hall 294 Acute Respiratory Distress Syndrome........................... 2030 Rebecca M. Baron, Bruce D. Levy 295 Mechanical Ventilatory Support.................................... 2035 Bartolome R. Celli



303 Cellular and Molecular Biology of the Kidney................ 2089 Alfred L. George, Jr., Eric G. Neilson 304 Acute Kidney Injury...................................................... 2099 Sushrut S. Waikar, Joseph V. Bonventre 305 Chronic Kidney Disease................................................ 2111 Joanne M. Bargman, Karl L. Skorecki 306 Dialysis in the Treatment of Renal Failure..................... 2121 Kathleen D. Liu, Glenn M. Chertow 307 Transplantation in the Treatment of Renal Failure......... 2126 Jamil Azzi, Edgar L. Milford, Mohamed H. Sayegh, Anil Chandraker 308 Glomerular Diseases..................................................... 2132 Julia B. Lewis, Eric G. Neilson 309 Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development.............. 2150 Jing Zhou, Martin R. Pollak 310 Tubulointerstitial Diseases of the Kidney....................... 2157 Laurence H. Beck, Jr., David J. Salant 311 Vascular Injury to the Kidney........................................ 2164 Ronald S. Go, Nelson Leung 312 Nephrolithiasis............................................................. 2168 Gary C. Curhan 313 Urinary Tract Obstruction............................................ 2173 Julian L. Seifter

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SECTION 1  Disorders of the Alimentary Tract





314 Approach to the Patient with Gastrointestinal Disease... 2177 William L. Hasler, Chung Owyang 315 Gastrointestinal Endoscopy.......................................... 2182 Louis Michel Wong Kee Song, Mark Topazian 316 Diseases of the Esophagus............................................. 2209 Peter J. Kahrilas, Ikuo Hirano 317 Peptic Ulcer Disease and Related Disorders................... 2220 John Del Valle 318 Disorders of Absorption................................................ 2244 Henry J. Binder 319 Inflammatory Bowel Disease......................................... 2258 Sonia Friedman, Richard S. Blumberg 320 Irritable Bowel Syndrome.............................................. 2276 Chung Owyang 321 Diverticular Disease and Common Anorectal Disorders...................................................................... 2283 Rizwan Ahmed, Susan L. Gearhart 322 Mesenteric Vascular Insufficiency.................................. 2291 Satinderjit Locham, Mahmoud Malas 323 Acute Intestinal Obstruction......................................... 2294 Danny O. Jacobs 324 Acute Appendicitis and Peritonitis................................ 2298 Danny O. Jacobs

SECTION 2  Nutrition

325 Nutrient Requirements and Dietary Assessment............ 2303 Johanna Dwyer 326 Vitamin and Trace Mineral Deficiency and Excess......... 2309 Paolo M. Suter, Robert M. Russell 327 Malnutrition and Nutritional Assessment..................... 2319 Gordon L. Jensen 328 Enteral and Parenteral Nutrition................................... 2324 L. John Hoffer, Bruce R. Bistrian, David F. Driscoll

SECTION 3  Liver and Biliary Tract Disease

329 Approach to the Patient with Liver Disease................... 2332 Marc G. Ghany, Jay H. Hoofnagle 330 Evaluation of Liver Function......................................... 2338 Daniel S. Pratt 331 The Hyperbilirubinemias.............................................. 2342 Allan W. Wolkoff 332 Acute Viral Hepatitis.................................................... 2347 Jules L. Dienstag 333 Toxic and Drug-Induced Hepatitis................................ 2366 William M. Lee, Jules L. Dienstag 334 Chronic Hepatitis......................................................... 2375 Jules L. Dienstag 335 Alcoholic Liver Disease................................................. 2399 Mark E. Mailliard, Michael F. Sorrell 336 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis.............................................................. 2401 Manal F. Abdelmalek, Anna Mae Diehl

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337 Cirrhosis and Its Complications.................................... 2405 Bruce R. Bacon 338 Liver Transplantation.................................................... 2414 Raymond T. Chung, Jules L. Dienstag 339 Diseases of the Gallbladder and Bile Ducts.................... 2422 Norton J. Greenberger, Gustav Paumgartner

SECTION 4  Disorders of the Pancreas

340 Approach to the Patient with Pancreatic Disease............ 2433 Darwin L. Conwell, Norton J. Greenberger, Peter A. Banks 341 Acute and Chronic Pancreatitis..................................... 2437 Darwin L. Conwell, Peter A. Banks, Norton J. Greenberger

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CONTENTS

PART 10 Disorders of the Gastrointestinal System

PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders SECTION 1  The Immune System in Health and Disease

342 Introduction to the Immune System.............................. 2451 Barton F. Haynes, Kelly A. Soderberg, Anthony S. Fauci 343 The Major Histocompatibility Complex........................ 2480 Gerald T. Nepom 344 Primary Immune Deficiency Diseases........................... 2488 Alain Fischer

SECTION 2  Disorders of Immune-Mediated Injury

345 Urticaria, Angioedema, and Allergic Rhinitis................. 2498 Katherine N. Cahill, Joshua A. Boyce 346 Anaphylaxis.................................................................. 2506 David Hong, Joshua A. Boyce 347 Mastocytosis................................................................. 2508 Cem Akin, Joshua A. Boyce 348 Autoimmunity and Autoimmune Diseases.................... 2510 Betty Diamond, Peter E. Lipsky 349 Systemic Lupus Erythematosus..................................... 2515 Bevra Hannahs Hahn 350 Antiphospholipid Syndrome......................................... 2526 Haralampos M. Moutsopoulos 351 Rheumatoid Arthritis.................................................... 2527 Ankoor Shah, E. William St. Clair 352 Acute Rheumatic Fever................................................. 2541 Jonathan R. Carapetis 353 Systemic Sclerosis (Scleroderma) and Related Disorders...................................................................... 2546 John Varga 354 Sjögren’s Syndrome....................................................... 2560 Haralampos M. Moutsopoulos 355 The Spondyloarthritides............................................... 2563 Joel D. Taurog 356 The Vasculitis Syndromes............................................. 2574 Carol A. Langford, Anthony S. Fauci 357 Behçet’s Syndrome........................................................ 2589 Haralampos M. Moutsopoulos 358 Inflammatory Myopathies............................................. 2590 Steven A. Greenberg, Anthony A. Amato 359 Relapsing Polychondritis............................................... 2597 Carol A. Langford

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CONTENTS



360 Sarcoidosis.................................................................... 2600 Robert P. Baughman, Elyse E. Lower 361 IgG4-Related Disease................................................... 2607 John H. Stone 362 Familial Mediterranean Fever and Other Hereditary Autoinflammatory Diseases.......................................... 2610 Daniel L. Kastner

SECTION 3  Disorders of the Joints and Adjacent Tissues

363 Approach to Articular and Musculoskeletal Disorders...................................................................... 2614 John J. Cush 364 Osteoarthritis............................................................... 2624 David T. Felson, Tuhina Neogi 365 Gout and Other Crystal-Associated Arthropathies........ 2631 H. Ralph Schumacher, Lan X. Chen 366 Fibromyalgia................................................................. 2636 Leslie J. Crofford 367 Arthritis Associated with Systemic Disease, and Other Arthritides.......................................................... 2639 Carol A. Langford, Brian F. Mandell 368 Periarticular Disorders of the Extremities...................... 2646 Carol A. Langford

PART 12 Endocrinology and Metabolism

SECTION 2  Sex- and Gender-Based Medicine

383 Disorders of Sex Development...................................... 2760 John C. Achermann, J. Larry Jameson 384 Disorders of the Testes and Male Reproductive System.......................................................................... 2769 Shalender Bhasin, J. Larry Jameson 385 Disorders of the Female Reproductive System............... 2787 Janet E. Hall 386 Menstrual Disorders and Pelvic Pain............................. 2794 Janet E. Hall 387 Hirsutism..................................................................... 2799 David A. Ehrmann 388 Menopause and Postmenopausal Hormone Therapy..... 2803 JoAnn E. Manson, Shari S. Bassuk 389 Infertility and Contraception........................................ 2810 Janet E. Hall 390 Sexual Dysfunction....................................................... 2816 Kevin T. McVary 391 Women’s Health............................................................ 2823 Andrea Dunaif 392 Men’s Health................................................................ 2828 Shalender Bhasin, Shehzad Basaria 393 Lesbian, Gay, Bisexual, and Transgender (LGBT) Health.......................................................................... 2835 Baligh R. Yehia, Harvey J. Makadon

SECTION 1  Endocrinology

SECTION 3  Obesity, Diabetes Mellitus, and Metabolic Syndrome







369 Approach to the Patient with Endocrine Disorders........ 2649 J. Larry Jameson 370 Mechanisms of Hormone Action.................................. 2653 J. Larry Jameson 371 Physiology of Anterior Pituitary Hormones.................. 2659 Shlomo Melmed, J. Larry Jameson 372 Hypopituitarism........................................................... 2664 Shlomo Melmed, J. Larry Jameson 373 Pituitary Tumor Syndromes.......................................... 2670 Shlomo Melmed, J. Larry Jameson 374 Disorders of the Neurohypophysis................................. 2684 Gary L. Robertson 375 Thyroid Gland Physiology and Testing.......................... 2692 J. Larry Jameson, Susan J. Mandel, Anthony P. Weetman 376 Hypothyroidism............................................................ 2698 J. Larry Jameson, Susan J. Mandel, Anthony P. Weetman 377 Hyperthyroidism.......................................................... 2703 J. Larry Jameson, Susan J. Mandel, Anthony P. Weetman 378 Thyroid Nodular Disease and Thyroid Cancer............... 2710 J. Larry Jameson, Susan J. Mandel, Anthony P. Weetman 379 Disorders of the Adrenal Cortex.................................... 2719 Wiebke Arlt 380 Pheochromocytoma...................................................... 2739 Hartmut P. H. Neumann 381 Multiple Endocrine Neoplasia....................................... 2746 R. V. Thakker 382 Autoimmune Polyendocrine Syndromes........................ 2756 Peter A. Gottlieb, Aaron W. Michels

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394 Pathobiology of Obesity................................................ 2837 Jeffrey S. Flier, Eleftheria Maratos-Flier 395 Evaluation and Management of Obesity........................ 2843 Robert F. Kushner 396 Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology........................................................... 2850 Alvin C. Powers, Kevin D. Niswender, Carmella Evans-Molina 397 Diabetes Mellitus: Management and Therapies............. 2859 Alvin C. Powers, Kevin D. Niswender, Michael R. Rickels 398 Diabetes Mellitus: Complications................................. 2875 Alvin C. Powers, John M. Stafford, Michael R. Rickels 399 Hypoglycemia............................................................... 2883 Philip E.Cryer, Stephen N. Davis 400 Disorders of Lipoprotein Metabolism........................... 2889 Daniel J. Rader, Sekar Kathiresan 401 The Metabolic Syndrome.............................................. 2903 Robert H. Eckel

SECTION 4  Disorders of Bone and Mineral Metabolism



402 Bone and Mineral Metabolism in Health and Disease................................................................... 2909 F. Richard Bringhurst, Marie B. Demay, Henry M. Kronenberg 403 Disorders of the Parathyroid Gland and Calcium Homeostasis................................................................. 2921 John T. Potts, Jr., Harald W. Jüppner 404 Osteoporosis................................................................. 2942 Robert Lindsay, Felicia Cosman

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405 Paget’s Disease and Other Dysplasias of Bone............... 2959 Murray J. Favus, Tamara J. Vokes

SECTION 5  Disorders of Intermediary Metabolism



406 Heritable Disorders of Connective Tissue...................... 2967 Darwin J. Prockop, John F. Bateman 407 Hemochromatosis......................................................... 2977 Lawrie W. Powell 408 Wilson’s Disease........................................................... 2982 George J. Brewer 409 The Porphyrias............................................................. 2984 Robert J. Desnick, Manisha Balwani 410 Disorders of Purine and Pyrimidine Metabolism........... 2997 John N. Mecchella, Christopher M. Burns 411 Lysosomal Storage Diseases.......................................... 3003 Robert J. Hopkin, Gregory A. Grabowski 412 Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism......................... 3009 Priya S. Kishnani, Yuan-Tsong Chen 413 Inherited Disorders of Amino Acid Metabolism in Adults........................................................................... 3015 Nicola Longo 414 Inherited Defects of Membrane Transport.................... 3020 Nicola Longo

PART 13 Neurologic Disorders SECTION 1  Diagnosis of Neurologic Disorders

415 Approach to the Patient with Neurologic Disease.......... 3025 Daniel H. Lowenstein, Joseph B. Martin, Stephen L. Hauser 416 Neuroimaging in Neurologic Disorders......................... 3030 William P. Dillon 417 Pathobiology of Neurologic Diseases............................. 3039 Stephen L. Hauser, Arnold R. Kriegstein, Stanley B. Prusiner





418 Seizures and Epilepsy.................................................... 3050 Daniel H. Lowenstein 419 Cerebrovascular Diseases.............................................. 3068 Wade S. Smith, S. Claiborne Johnston, J. Claude Hemphill, III 420 Ischemic Stroke............................................................ 3079 Wade S. Smith, S. Claiborne Johnston, J. Claude Hemphill, III 421 Intracranial Hemorrhage............................................... 3091 Wade S. Smith, J. Claude Hemphill, III, S. Claiborne Johnston 422 Migraine and Other Primary Headache Disorders......... 3096 Peter J. Goadsby 423 Alzheimer’s Disease...................................................... 3108 William W. Seeley, Bruce L. Miller 424 Frontotemporal Dementia............................................ 3115 William W. Seeley, Bruce L. Miller 425 Vascular Dementia........................................................ 3118 Joel Kramer, William W. Seeley, Bruce L. Miller 426 Dementia with Lewy Bodies.......................................... 3119 William W. Seeley, Caroline M. Tanner, Bruce L. Miller 427 Parkinson’s Disease....................................................... 3120 C. Warren Olanow, Christine Klein, Anthony H. V. Schapira 428 Tremor, Chorea, and Other Movement Disorders.......... 3132 C. Warren Olanow, Christine Klein, Jose A. Obeso

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SECTION 3  Nerve and Muscle Disorders

438 Peripheral Neuropathy.................................................. 3204 Anthony A. Amato, Richard J. Barohn 439 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies................................................................ 3225 Stephen L. Hauser, Anthony A. Amato 440 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction............................................... 3232 Anthony A. Amato 441 Muscular Dystrophies and Other Muscle Diseases........ 3239 Anthony A. Amato, Robert H. Brown, Jr.

SECTION 4  Chronic Fatigue Syndrome

SECTION 2  Diseases of the Central Nervous System

429 Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases........................................................... 3141 Robert H. Brown, Jr. 430 Prion Diseases.............................................................. 3148 Stanley B. Prusiner, Bruce L. Miller 431 Ataxic Disorders........................................................... 3154 Roger N. Rosenberg 432 Disorders of the Autonomic Nervous System................. 3158 Christopher H. Gibbons, John W. Engstrom 433 Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders............................................................ 3166 M. Flint Beal, Stephen L. Hauser 434 Diseases of the Spinal Cord........................................... 3172 Stephen L. Hauser 435 Concussion and Other Traumatic Brain Injuries............ 3183 Geoffrey T. Manley, Stephen L. Hauser, Michael McCrea 436 Multiple Sclerosis......................................................... 3188 Bruce A. C. Cree, Stephen L. Hauser 437 Neuromyelitis Optica.................................................... 3202 Bruce A. C. Cree, Stephen L. Hauser

CONTENTS





442 Chronic Fatigue Syndrome........................................... 3254 Gijs Bleijenberg, Jos W. M. van der Meer

SECTION 5  Psychiatric and Addiction Disorders

443 Biology of Psychiatric Disorders.................................... 3256 Robert O. Messing, Eric J. Nestler, Matthew W. State 444 Psychiatric Disorders.................................................... 3262 Victor I. Reus 445 Alcohol and Alcohol Use Disorders............................... 3277 Marc A. Schuckit 446 Opioid-Related Disorders............................................. 3284 Thomas R. Kosten, Colin N. Haile 447 Cocaine and Other Commonly Used Drugs.................. 3287 Karran A. Phillips, Antonello Bonci 448 Nicotine Addiction....................................................... 3292 David M. Burns

PART 14 Poisoning, Drug Overdose, and Envenomation

449 Heavy Metal Poisoning................................................. 3297 Howard Hu 450 Poisoning and Drug Overdose...................................... 3300 Mark B. Mycyk

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CONTENTS



451 Disorders Caused by Venomous Snakebites and Marine Animal Exposures............................................. 3313 Charles Lei, Kirsten B. Hornbeak, Paul S. Auerbach, Robert L. Norris 452 Ectoparasite Infestations and Arthropod Injuries.......... 3324 Richard J. Pollack, Scott A. Norton

PART 15 Disorders Associated with Environmental Exposures

453 Altitude Illness............................................................. 3333 Buddha Basnyat, Geoffrey Tabin 454 Hypothermia and Peripheral Cold Injuries.................... 3338 Daniel F. Danzl 455 Heat-Related Illnesses.................................................. 3343 Daniel F. Danzl

PART 16 Genes, the Environment, and Disease

456 Principles of Human Genetics....................................... 3347 J. Larry Jameson, Peter Kopp 457 The Practice of Genetics in Clinical Medicine............... 3369 Susan M. Domchek, J. Larry Jameson, Susan Miesfeldt 458 Gene and Cell Based Therapy in Clinical Medicine....... 3375 Katherine A. High, Malcolm K. Brenner 459 The Human Microbiome.............................................. 3379 Neeraj K. Surana, Dennis L. Kasper

PART 17 Global Medicine

460 Global Issues in Medicine............................................. 3391 Joseph J. Rhatigan, Paul Farmer 461 Worldwide Changes in Patterns of Infectious Disease......................................................................... 3401 George W. Rutherford, Jaime Sepulveda 462 Primary Care and Global Health................................... 3404 Tim Evans, Kumanan Rasanathan

PART 18 Aging

463 The Biology of Aging.................................................... 3413 Rafael de Cabo, David G. Le Couteur

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464 Clinical Problems Associated with the Aging Process..... 3420 Joseph G. Ouslander, Bernardo Reyes

PART 19 Consultative Medicine

465 Approach to Medical Consultation................................ 3439 Jack Ende, Jeffrey Berns 466 Medical Disorders During Pregnancy............................ 3440 Robert L. Barbieri, John T. Repke 467 Medical Evaluation of the Surgical Patient.................... 3446 Prashant Vaishnava, Kim A. Eagle

PART 20 Frontiers



468 Behavioral Economics and Health................................. 3453 Kevin G. Volpp, George Loewenstein, David A. Asch 469 Complementary, Alternative, and Integrative Health Approaches................................................................... 3462 Josephine P. Briggs 470 Telomere Disease.......................................................... 3466 Rodrigo T. Calado, Neal S. Young 471 The Role of Epigenetics in Disease and Treatment........ 3471 Brian C. Capell, Shelley L. Berger 472 Mitochondrial DNA and Heritable Traits and Diseases................................................................. 3476 Karl L. Skorecki, Bruce H. Cohen 473 Applications of Stem Cell Biology in Clinical Medicine......................................................... 3488 John A. Kessler 474 Microbial Genomics and Infectious Disease.................. 3491 Roby P. Bhattacharyya, Yonatan H. Grad, Deborah T. Hung 475 The Role of Circadian Biology in Health and Disease....................................................... 3504 Jonathan Cedernaes, Kathryn Moynihan Ramsey, Joseph Bass 476 Network Medicine: Systems Biology in Health and Disease....................................................... 3515 Joseph Loscalzo 477 Emerging Neurotherapeutic Technologies..................... 3522 Jyoti Mishra, Karunesh Ganguly

Index ........................................................................................I-1

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Related Harrison’s 20th Edition Content The following chapters are available online. They can be viewed by opening the table of contents of Harrison’s 20th edition at www.accessmedicine.com/harrisons.

Video Collection

V1 Video Library of Gait Disorders



V2 Primary Progressive Aphasia, Memory Loss, and Other Focal Cerebral Disorders

Gail Kang, Nicholas B. Galifianakis, Michael D. Geschwind

Maria Luisa Gorno-Tempini, Jennifer Ogar, Joel Kramer, Bruce L. Miller, Gil D. Rabinovici, Maria Carmela Tartaglia



V3 Video Library of Neuro-Ophthalmology



V4 Examination of the Comatose Patient



V5 Video Atlas of Gastrointestinal Endoscopic Lesions

Jonathan C. Horton

S. Andrew Josephson

Louis Michel Wong Kee Song, Mark Topazian



V6 The Neurologic Screening Exam



V7 Video Atlas of the Detailed Neurologic Examination

Daniel H. Lowenstein Martin A. Samuels

Supplementary Topics

S1 Fluid and Electrolyte Imbalances and Acid-Base Disturbances: Case Examples



S2 Microbial Bioterrorism



S3 Chemical Terrorism



S4 Radiation Terrorism



S5 Infections in War Veterans



S6 Health Care for Military Veterans



S7 Primary Immunodeficiencies Associated with (or Secondary to) Other Diseases

David B. Mount, Thomas D. DuBose, Jr. H. Clifford Lane, Anthony S. Fauci

Jonathan Newmark, James A. Romano, Jr. Christine E. Hill-Kayser, Eli Glatstein, Zelig A. Tochner Andrew W. Artenstein

Stephen C. Hunt, Charles W. Hoge

Alain Fischer



S8 Cardiac Trauma



S9 Technique of Lumbar Puncture



Eric H. Awtry



S11 Hyperbaric and Diving Medicine



S12 The Clinical Laboratory in Modern Health Care



S13 Laboratory Diagnosis of Infectious Diseases



S14 Laboratory Diagnosis of Parasitic Infections

Michael H. Bennett, Simon J. Mitchell Anthony A. Killeen

Alexander J. McAdam, Andrew B. Onderdonk Sharon L. Reed, Charles E. Davis

Atlases

A1 Atlas of Rashes Associated with Fever



A2 Atlas of Oral Manifestations of Disease



A3 Atlas of Urinary Sediments and Renal Biopsies



A4 Atlas of Skin Manifestations of Internal Disease



A5 Atlas of Hematology



A6 Atlas of Blood Smears of Malaria and Babesiosis



A7 Atlas of Electrocardiography



A8 Atlas of Noninvasive Imaging



A9 Atlas of Cardiac Arrhythmias

Kenneth M. Kaye, Elaine T. Kaye

Samuel C. Durso, Janet A. Yellowitz Agnes B. Fogo, Eric G. Neilson

Thomas J. Lawley, Benjamin K. Stoff, Calvin O. McCall Dan L. Longo

Nicholas J. White, Joel G. Breman Ary L. Goldberger

Marcelo F. Di Carli, Raymond Y. Kwong, Scott D. Solomon Ary L. Goldberger

A10 Atlas of Atherosclerosis Peter Libby

A11 Atlas of Percutaneous Revascularization

Jane A. Leopold, Deepak L. Bhatt, David P. Faxon

A12 Atlas of Chest Imaging

Patricia A. Kritek, John J. Reilly, Jr.

A13 Atlas of Liver Biopsies

Jules L. Dienstag, Atul K. Bhan

A14 Atlas of the Vasculitic Syndromes

Carol A. Langford, Anthony S. Fauci

A15 Atlas of Clinical Manifestations of Metabolic Diseases J. Larry Jameson

A16 Atlas of Neuroimaging

Andre D. Furtado, Luciano Villarinho, William P. Dillon

Elizabeth Robbins, Stephen L. Hauser

S10 Classification of the Spinocerebellar Ataxias Roger N. Rosenberg

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Related Harrison’s Resources A complete collection to meet your educational, clinical, and board prep needs

Harrison’s Online  The online edition of Harrison’s is available at www.accessmedicine.com. It requires an institutional or individual subscription separate from the purchase of the print book. The online edition of Harrison’s features all the chapters from the print edition, plus more than two dozen supplementary chapters in print, atlas, and video formats. Harrison’s Online includes numerous monthly updates, from the editors of Harrison’s, on important new developments in medical research and practice. Easily search across the entire Harrison’s content set, download images and tables for presentations and lectures, view step-by-step videos on common clinical procedures, access the text of the Harrison’s Manual of Medicine, set up a personalized test exam for board prep, get access to chapters from new editions of Harrison’s months before book publication, and more.

The Harrison’s Manual of Medicine  The Harrison’s Manual of Medicine provides high-yield, rapid-access clinical summaries of Harrison’s content, suitable for use at the bedside. Chapters in the Manual reflect those likely to be encountered in both the inpatient and outpatient setting. The format is built for ease of use. The Manual is available in print, eBook, and app. In addition, the full text of the Manual is available to subscribers at accessmedicine.com. This format provides flexibility of format to customers, who can move back and forth between the full scope of Harrison’s Principles of Internal Medicine and the high-yield clinical essentials of the Manual.  The Manual includes more than 200 chapters in 17 sections and covers presenting signs and symptoms and major conditions seen in both inpatient and outpatient settings. The full table of contents is available at www.accessmedicine.com. 

The Harrison’s Self-Assessment and Board Review  This practical resource provides more than 1000 self-assessment questions, most in board-style clinical vignette format with multiple choice answers. The explanations for the questions are comprehensive and provide detailed guidance on correct and incorrect answers. Questionand-answer sets include references to related chapters in Harrison’s Principles of Internal Medicine for more comprehensive understanding. Use this very handy resource for primary and recertification exam prep, for rotational shelf exams, and for general assessment of understanding of the principles of clinical medicine. This resource is available as a print book, an eBook, an app, and on accessmedicine.com, where users can create personalized testing experiences and receive instant scores on practice tests.

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Contributors James L. Abbruzzese, MD, FACP, FASCO, DSc (hon)

Duke Cancer Institute Distinguished Professor of Medical Oncology; Chief, Division of Medical Oncology, Department of Medicine; Associate Director for Clinical Research and Training, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina [88]

Manal F. Abdelmalek, MD, MPH

Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Duke University, Durham, North Carolina [336]

John C. Achermann, MD, PhD, MB

Wellcome Trust Senior Research Fellow in Clinical Science, University College London; Professor of Paediatric Endocrinology, UCL GOS Institute of Child Health, University College London, London, United Kingdom [383]

John W. Adamson, MD

Clinical Professor, Division of Hematology/Oncology, Department of Medicine, University of California at San Diego, San Diego, California [59, 93]

Rizwan Ahmed, MD

Resident in Plastic and Reconstructive Surgery, Department of Surgery, Duke University, Durham, North Carolina [321]

Cem Akin, MD, PhD

Professor of Medicine, Department of Internal Medicine, Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, Michigan [347]

Frederick R. Appelbaum, MD

Deputy Director, Fred Hutchinson Cancer Research Center, Seattle, Washington [110]

Cesar A. Arias, MD, PhD, MSc, FIDSA

Professor of Medicine, Microbiology and Molecular Genetics; Director, Center for Antimicrobial Resistance and Microbial Genomics, McGovern Medical School at the University of Texas Health Science Center; Adjunct Professor, MD Anderson Cancer Center, Houston, Texas; Director, Molecular Genetics and Antimicrobial Unit and International Center for Microbial Genomics, Universidad, El Bosque, Bogota, Colombia [144]

Wiebke Arlt, MD, DSc, FRCP, FMedSci

William Withering Chair of Medicine, Institute of Metabolism and Systems Research, University of Birmingham; Consultant Endocrinologist, University Hospital Birmingham, Birmingham, United Kingdom [379]

Katrina A. Armstrong, MD

Physician-in-Chief, Department of Medicine, Massachusetts General Hospital, Charlestown HealthCare Center, Charlestown, Massachusetts [4]

Valder R. Arruda, MD, PhD

Associate Professor, Division of Hematology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [112]

Andrew W. Artenstein, MD

Praveen Akuthota, MD

Chief Physician Executive and Chief Academic Officer, Baystate Health; Regional Executive Dean and Professor of Medicine, University of Massachusetts Medical School—Baystate, Springfield, Massachusetts [S5]

Christine M. Albert, MD, MPH

David A. Asch, MD, MBA

Associate Clinical Professor, Division of Pulmonary, Critical Care & Sleep Medicine, University of California, San Diego, San Diego, California [282] Professor of Medicine, Harvard Medical School; Staff Physician, Brigham and Women’s Hospital, Boston, Massachusetts [299]

Anthony A. Amato, MD

Professor of Neurology, Harvard Medical School; Vice-Chairman, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts [358, 438-441]

Michael J. Aminoff, MD, DSc, FRCP

Professor of Neurology, School of Medicine, University of California, San Francisco, San Francisco, California [21, 22]

Neil M. Ampel, MD

Professor of Medicine, University of Arizona; Staff Physician, Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona [208]

Kenneth C. Anderson, MD

Kraft Family Professor of Medicine, Harvard Medical School; Chief, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts [107, 109]

Rosa M. Andrade, MD

Assistant Professor of Medicine, Department of Medicine, Division of Infectious Diseases, Microbiology and Molecular Genetics, PRIME-LC, University of California, Irvine; Irvine, California [218]

Derek C. Angus, MD, MPH

Distinguished Professor and Mitchell P. Fink Endowed Chair, Department of Critical Care Medicine University of Pittsburgh Schools of the Health Sciences, Pittsburgh, Pennsylvania [297]

Elliott M. Antman, MD

Professor of Medicine, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital; Associate Dean for Clinical/Translational Research, Harvard Medical School, Boston, Massachusetts [267, 269]

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Executive Director, Penn Medicine Center for Health Care Innovation; Physician, Cresencz Philadelphia VA Medical Center; John Morgan Professor of Medicine, Medical Ethics and Health Policy, Health Care Management, and Operations, Information and Decisions, Perelman School of Medicine and Wharton School, University of Pennsylvania, Philadelphia, Pennsylvania [468]

Elizabeth A. Ashley, MB, BS, PhD, MRCP, FRCPath

Center for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom [219]

John C. Atherton, MD, FRCP

Professor of Gastroenterology; Pro-Vice-Chancellor and Dean of the Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom [158]

Paul S. Auerbach, MD, MS, FACEP, MFAWM, FAAEM

Redich Family Professor, Department of Emergency Medicine, Stanford University School of Medicine, Stanford, California [451]

Eric H. Awtry, MD

Associate Professor of Medicine, Boston University School of Medicine, Cardiology Division, Boston Medical Center, Boston, Massachusetts [266, S8]

Jamil Azzi, MD

Assistant Professor of Medicine, Harvard Medical School; Director, Renal Transplant Fellowship, Associate Physician, Schuster Family Transplantation Research Center, Brigham and Women’s Hospital, Boston, Massachusetts [307]

Bruce R. Bacon, MD

James F. King, MD Endowed Chair in Gastroenterology; Professor of Internal Medicine, Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, Missouri [337]

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xx

Lindsey R. Baden, MD

Associate Professor of Medicine, Harvard Medical School; DanaFarber Cancer Institute, Brigham and Women’s Hospital, Boston, Massachusetts [186]

CONTRIBUTORS

Jessica M. Baker, MD

Fellow in Movement Disorders, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts [23]

John R. Balmes, MD

Professor of Medicine, University of California, San Francisco; Professor, School of Public Health, University of California, Berkeley; Attending Physician, Division of Occupational and Environmental Medicine, San Francisco General Hospital, San Francisco, California [283]

Buddha Basnyat, MD, MSc, FACP, FRCP (Edinburgh)

Director, Oxford University Clinical Research Unit, Patan Academy of Health Sciences; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; Medical Director, Nepal International Clinic and Himalaya Rescue Association, Kathmandu, Nepal [453]

Joseph Bass, MD, PhD

Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Department of Neurobiology, Northwestern University, Chicago, Illinois [475]

Shari S. Bassuk, ScD

Epidemiologist, Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [388]

Manisha Balwani, MD, MS

John F. Bateman, PhD

Peter A. Banks, MD

David W. Bates, MD, MSc

Associate Professor, Department of Genetics and Genomic Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York [409] Professor of Medicine, Harvard Medical School; Senior Physician, Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts [340, 341]

Robert L. Barbieri, MD

Theme Director, Cell Biology; Group Leader, Musculoskeletal Research, Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, Victoria, Australia [406] Professor of Medicine, Harvard Medical School; Chief, General Internal Medicine and Primary Care Division, Brigham and Women’s Hospital; Medical Director, Clinical and Quality Analysis, Partners HealthCare System, Inc., Boston, Massachusetts [6]

Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School; Chair, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts [466]

Robert P. Baughman, MD

Alan G. Barbour, MD

Professor of Medicine and Microbiology and Molecular Genetics, University of California Irvine, Irvine, California [180]

University Professor of Neurology and Neuroscience; Chairman Emeritus; Neurologist, New York Presbyterian Hospital; Weill Cornell Medical College, New York, New York [433]

Joanne M. Bargman, MD, FRCPC

Laurence H. Beck, Jr., MD, PhD

Professor of Medicine; Director, Clinical Fellowship in Nephrology, University of Toronto; Staff Nephrologist; Director, Peritoneal Dialysis Program; Co-Director, Renal-Rheumatology Lupus Clinic, University Health Network; Past-President, International Society for Peritoneal Dialysis, Toronto, Ontario, Canada [305]

Tamar F. Barlam, MD, MSc

Associate Professor of Medicine, Infectious Disease Section, Boston University School of Medicine, Boston, Massachusetts [117, 153]

Peter J. Barnes, FRS, F Med Sci

Margaret Turner-Warwick Professor of Medicine; Head, Respiratory Medicine, Imperial College of London; Airway Disease Section, NHL Institute, London, United Kingdom [281]

Richard J. Barohn, MD

Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio [360]

M. Flint Beal, MD

Associate Professor of Medicine, Boston University School of Medicine, Boston, Massachusetts [310]

Nicholas J. Beeching, MA, BM BCh, FRCP, FRACP, FFTM RCPS(Glasg), FCCP (Hon), FESCMID, DCH, DTM&H

Senior Lecturer (Clinical) in Infectious Diseases, Liverpool School of Tropical Medicine; National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool; Honorary Consultant in Infectious Diseases, Tropical and Infectious Disease Unit, Royal Liverpool University Hospital; Honorary Consultant, Public Health England and Honorary Civilian Consultant in Infectious Diseases, Army Medical Directorate, United Kingdom [164]

Michael H. Bennett, MD, MBBS, MM (Clin Epi)

Gertrude and Dewey Ziegler Professor of Neurology; University Distinguished Professor; Vice Chancellor of Research; President Research Institute; Director, Frontiers: Heartland Institute for Clinical and Translational Research, University of Kansas Medical Center, Kansas City, Kansas [438]

Conjoint Professor in Anesthesia and Hyperbaric Medicine; Faculty of Medicine, University of New South Wales; Academic Head of Department, Wales Anaesthesia, Prince of Wales Hospital, Sydney, Australia [S11]

Rebecca M. Baron, MD

Richard and Susan Smith Distinguished Professor of Medicine; Professor of Pediatrics and Genetics, Harvard Medical School; President and CEO Emeritus, Dana-Farber Cancer Institute; Director and Principal Investigator Emeritus, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts [94]

Miriam Baron Barshak, MD

Shelley L. Berger, PhD

Assistant Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston, Massachusetts [33, 122, 284, 294] Assistant Professor, Harvard Medical School; Physician, Massachusetts General Hospital, Boston, Massachusetts [122, 127, 284]

Shehzad Basaria, MD

Associate Professor of Medicine, Harvard Medical School; Associate Director, Section on Men’s Health, Aging and Metabolism, Brigham and Women’s Hospital, Boston, Massachusetts [392]

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Edward J. Benz, Jr., MD

Daniel S. Och University Professor, Departments of Cell and Developmental Biology; Biology; Genetics; Director, Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania [471]

Jean Bergounioux, MD, PhD, PhC

Pediatric Intensive Care Unit, Hôpital Raymond-Poincaré, Université de Versailles-Saint Quentin, Garches, France [161]

6/4/18 1:55 PM

John L. Berk, MD

Associate Professor of Medicine, Boston University School of Medicine; Assistant Director, Amyloidosis Center, Boston Medical Center, Boston, Massachusetts [108] Professor of Medicine and Pediatrics; Associate Chief, Renal Electrolyte and Hypertension Division; Associate Dean for Graduate Medical Education, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania [465]

Aaron S. Bernstein, MD, MPH

Distinguished University Professor; William G. Pace, III Professor of Cancer Research; Cancer Scholar and Senior Advisor, The Ohio State University Comprehensive Cancer Center; Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio [100]

William Blum, MD

Director, Acute Leukemia Program; Professor, Department of Hematology and Oncology, Winship Cancer Institute and Emory University, Atlanta, Georgia [100]

Pediatric Hospitalist, Boston Children’s Hospital; Associate Director, Center for Health and the Global Environment, Harvard T.H. Chan School of Public Health; Instructor, Harvard Medical School, Boston, Massachusetts [120]

Richard S. Blumberg, MD

Joseph R. Betancourt, MD, MPH

Jean L. Bolognia, MD

Associate Professor of Medicine, Harvard Medical School; Director, The Disparities Solutions Center, Massachusetts General Hospital, Boston, Massachusetts [7]

Atul K. Bhan, MBBS, MD

Professor of Pathology, Harvard Medical School, Associate Director, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts [A13]

Shalender Bhasin, MB, BS

Professor of Medicine, Harvard Medical School; Director, Research Program in Men’s Health: Aging and Metabolism; Director, Boston Claude D. Pepper Older Americans Independence Center; Brigham and Women’s Hospital, Boston, Massachusetts [384, 392]

Deepak L. Bhatt, MD, MPH

Professor of Medicine, Harvard Medical School; Executive Director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart and Vascular Center, Boston, Massachusetts [270, A11]

Roby P. Bhattacharyya, MD, PhD

Instructor in Medicine, Harvard Medical School; Assistant in Medicine, Division of Infectious Disease, Massachusetts General Hospital, Boston, Massachusetts [474]

David R. Bickers, MD

Carl Truman Nelson Professor and Chair, Department of Dermatology, Columbia University Medical Center, New York, New York [57]

Henry J. Binder, MD

Professor Emeritus of Medicine, Senior Research Scientist, Yale University, New Haven, Connecticut [318]

William R. Bishai, MD, PhD

Professor and Co-Director, Center for Tuberculosis Research, Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland [145]

Bruce R. Bistrian, MD, PhD, MPH

Professor of Medicine, Harvard Medical School; Chief, Clinical Nutrition, Beth Israel Deaconess Medical Center, Boston, Massachusetts [328]

Lucas S. Blanton, MD

Assistant Professor, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, Texas [182]

Martin J. Blaser, MD

Muriel and George Singer Professor of Medicine; Professor of Microbiology; Director, Human Microbiome Program, New York University Langone Medical Center, New York, New York [158, 162]

Chantal P. Bleeker-Rovers, MD, PhD

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands [17]

Gijs Bleijenberg, PhD

Professor Emeritus, Expert Centre for Chronic Fatigue, Radboud University Medical Centre, Nijmegen, The Netherlands [442]

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CONTRIBUTORS

Jeffrey Berns, MD

Clara D. Bloomfield, MD

Chief, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Professor of Medicine, Harvard Medical School, Boston, Massachusetts [319] Professor, Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut [54]

Antonello Bonci, MD

Scientific Director, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland [447]

Joseph V. Bonventre, MD, PhD

Samuel L. Levine Professor of Medicine; Chief, Renal Division; Chief, Engineering in Medicine Division, Brigham and Women’s Hospital, Boston, Massachusetts [304]

Joshua A. Boyce, MD

Professor of Medicine and Pediatrics; Albert L. Sheffer Professor of Medicine, Harvard Medical School; Director, Inflammation and Allergic Disease Research Section, Brigham and Women’s Hospital, Boston, Massachusetts [345-347]

Anna K. Brady, MD

Fellow, Division of Pulmonary and Critical Care Medicine, University of Washington Medical Center, Seattle, Washington [35]

Eugene Braunwald, MD, MA (Hon), ScD (Hon), FRCP

Distinguished Hersey Professor of Medicine, Harvard Medical School; Founding Chairman, TIMI Study Group, Brigham and Women’s Hospital, Boston, Massachusetts [37, 265, 268]

Irwin M. Braverman, MD

Professor Emeritus; Senior Research Scientist, Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut [54]

Otis W. Brawley, MD, MACP

Professor of Hematology, Medical Oncology, Medicine and Epidemiology, Emory University; Chief Medical and Scientific Officer, American Cancer Society, Atlanta, Georgia [66]

Joel G. Breman, MD, DTPH

Senior Scientist Emeritus, Fogarty International Center, National Institutes of Health, Bethesda, Maryland [A6]

Malcolm K. Brenner, MB, PhD

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas [458]

George J. Brewer, MD

Morton S. and Henrietta K. Sellner Emeritus, Professor of Human Genetics, Emeritus Professor of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan [408]

Josephine P. Briggs, MD

Director, National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health (NIH), Bethesda, Maryland [469]

F. Richard Bringhurst, MD

Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital, Boston, Massachusetts [402]

6/4/18 1:55 PM

xxii

Steven M. Bromley, MD

Director, South Jersey MS Center, Bromley Neurology PC, Audubon, New Jersey [29]

CONTRIBUTORS

Darron R. Brown, MD, MPH

Arturo Casadevall, MD, PhD

Professor and Chair, Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland [210]

Professor of Medicine; Professor of Microbiology and Immunology; Adjunct Professor of Epidemiology; Member, Simon Cancer Center; Department of Medicine, Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, Indiana [193]

Jonathan Cedernaes, MD, PhD

Kevin E. Brown, MD, MRCP, FRCPath

Bartolome R. Celli, MD

Virus Reference Department, National Infection Service, Public Health England, London, United Kingdom [192]

Robert H. Brown, Jr., MD, PhD

Chairman, Department of Neurology, University of Massachusetts Medical School, Worchester, Massachusetts [429, 441]

Amy E. Bryant, PhD

Research Career Scientist, Veterans Affairs Medical Center, Boise, Idaho; Affiliate Associate Professor, University of Washington School of Medicine, Seattle, Washington [149]

Visiting Postdoctoral Fellow, Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [475] Professor of Medicine, Harvard Medical School; Staff Physician, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [295]

Murali Chakinala, MD

Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri [252]

Anil Chandraker, MBChB, FRCP

Fred Bunz, MD, PhD

Associate Professor of Medicine, Harvard Medical School; Medical Director of Kidney and Pancreas Transplantation; Director, Schuster Family Transplantation Research Center, Brigham and Women’s Hospital, Boston, Massachusetts [307]

Christopher M. Burns, MD

François Chappuis, MD, PhD

David M. Burns, MD

Richelle C. Charles, MD

John C. Byrd, MD

Rémi N. Charrel, MD, PhD

Associate Professor, Johns Hopkins University School of Medicine, Baltimore, Maryland [67] Associate Professor of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire [410] Professor Emeritus, Department of Family and Preventive Medicine, University of California, San Diego School of Medicine, San Diego, California [448] D. Warren Brown Chair of Leukemia Research; Distinguished University Professor of Medicine, Medicinal Chemistry, and Veterinary Biosciences; Director, Division of Hematology, Department of Medicine, The Ohio State University, Columbus, Ohio [103]

Professor, Faculty of Medicine, University of Geneva; Head, Division of Tropical and Humanitarian Medicine, Geneva University Hospitals, Geneva, Switzerland [222] Assistant Professor of Medicine, Harvard Medical School; Assistant Physician, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts [128] Professor of Medicine, Department of Virology; Deputy Director, Research Department, Unité des Virus Emergents, Aix-Marseille University, Marseille, France [204]

Lan X. Chen, MD, PhD

Katherine N. Cahill, MD

Penn Presbyterian Medical Center, Philadelphia, Pennsylvania [365]

Rodrigo T. Calado, MD, PhD

Professor of Pediatrics, Duke University, Durham, North Carolina; Distinguished Research Fellow, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [412]

Assistant Professor of Medicine, Harvard Medical School; Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, Massachusetts [345] Associate Professor of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil [470]

Stephen B. Calderwood, MD

Morton N. Swartz, MD Academy Professor of Medicine (Microbiology and Immunobiology), Harvard Medical School; Chief, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts [128]

Michael Camilleri, MD

Atherton and Winifred W. Bean Professor; Professor of Medicine, Pharmacology, and Physiology, Mayo Clinic School of Medicine, Rochester, Minnesota [42]

Christopher P. Cannon, MD

Professor of Medicine, Harvard Medical School; Cardiovascular Division, Brigham and Women’s Hospital; Baim Institute for Clinical Research, Boston, Massachusetts [268]

Brian C. Capell, MD, PhD

Instructor, Penn Epigenetics Institute and Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania [471]

Jonathan R. Carapetis, MBBS, PhD, FRACP, FAFPHM, FAHMS

Director, Telethon Kids Institute; Professor, The University of Western Australia; Consultant, Perth Children’s Hospital, Perth, Western Australia [352]

HPIM 20e_FM_VOL1_pi-pxlii.indd 22

Yuan-Tsong Chen, MD, PhD

Glenn M. Chertow, MD, MPH

Norman S. Coplon/Satellite Healthcare Professor of Medicine; Chief, Division of Nephrology, Stanford University School of Medicine, Palo Alto, California [306]

Augustine M. K. Choi, MD

Sanford I. Weill Chairman and Professor of Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College; Physician-in-Chief, New York-Presbyterian Hospital-Weill Cornell Medical Center, New York, New York [280]

Raymond T. Chung, MD

Director of Hepatology and Liver Center; Vice Chief, Gastroenterology Division, Kevin and Polly Maroni Research Scholar, Massachusetts General Hospital, Boston, Massachusetts [338]

Jeffrey W. Clark, MD

Associate Professor of Medicine, Harvard Medical School; Medical Director, Clinical Trials Core, Dana-Farber Harvard Cancer Center; Massachusetts General Hospital, Boston, Massachusetts [68]

Bruce H. Cohen, MD

Professor of Pediatrics, Northeast Ohio Medical University; Director; NeuroDevelopmental Science Center; Director; Division of Neurology, Children’s Hospital Medical Center of Akron, Akron, Ohio [472]

Jeffrey I. Cohen, MD

Chief, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [189, 199]

6/4/18 1:55 PM

Darwin L. Conwell, MD, MS

Kathleen E. Corey, MD, MPH

Assistant Professor of Medicine, Harvard Medical School; Director of the MGH Fatty Liver Clinic, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts [46]

Lawrence Corey, MD

Past President and Director, Fred Hutchinson Cancer Research Center; Member, Vaccine and Infectious Disease Division, Clinical Research Division, and Public Health Sciences Division, Fred Hutchinson Cancer Research Center; Professor, Departments of Medicine and Laboratory Medicine, University of Washington, Seattle, Washington [187]

Jorge Cortes, MD

Jane and John Justin Distinguished Chair in Leukemia Research; Deputy Chairman; Section Chief of AML and CML, The University of Texas MD Anderson Cancer Center, Houston, Texas [101]

Frank Baldino, Jr., PhD Professor of Sleep Medicine, Professor of Medicine and Director, Division of Sleep Medicine, Harvard Medical School; Chief, Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, Massachusetts [27]

Josep Dalmau, MD, PhD

ICREA Professor, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Spain; Adjunct Professor, University of Pennsylvania, Philadelphia, Pennsylvania [90]

Daniel F. Danzl, MD

Professor and Chair, Department of Emergency Medicine, University of Louisville, Louisville, Kentucky [454, 455]

Robert B. Daroff, MD

Professor and Chair Emeritus, Department of Neurology, Case Western Reserve University School of Medicine; University Hospitals– Cleveland Medical Center, Cleveland, Ohio [19]

Charles E. Davis, MD

Professor of Medicine, Columbia University, New York, New York; Helen Hayes Hospital, West Haverstraw, New York [404]

Professor of Pathology and Medicine, Emeritus, University of California, San Diego School of Medicine; Director Emeritus, Microbiology, University of California, San Diego Medical Center, San Diego, California [216, S14]

James D. Crapo, MD

Stephen N. Davis, MBBS, FRCP

Felicia Cosman, MD

Professor, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado [286]

xxiii

Mark A. Creager, MD

Theodore E. Woodward Professor and Chairman of the Department of Medicine; Vice President of Clinical Translational Science, University of Maryland Baltimore; Physician-in-Chief, University of Maryland Medical Center, Baltimore, Maryland [399]

Bruce A. C. Cree, MD, PhD, MAS

Chair, Department of Neurology, Memorial Sloan Kettering Cancer Center; Professor of Neurology, Weill Cornell Medical College, New York, New York [86]

Professor of Medicine, Geisel School of Medicine at Dartmouth; Director, Heart and Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire [274-276]

Lisa M. DeAngelis, MD

Associate Professor of Clinical Neurology, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California [436, 437]

Rafael de Cabo, PhD

Leslie J. Crofford, MD

John Del Valle, MD

Professor, Departments of Medicine and Pathology, Microbiology and Immunology, Vanderbilt University; Chief, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee [366]

Jennifer M. Croswell, MD, MPH

Senior Program Officer, Office of the Chief Science Officer, PatientCentered Outcomes Research Institute (PCORI), Washington, DC [66]

James E. Crowe, Jr., MD

Chief, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland [463] Professor and Senior Associate Chair of Medicine, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan [317]

Marie B. Demay, MD

Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital, Boston, Massachusetts [402]

David W. Denning, MBBS, FRCP, FRCPath, FMedSci

Director, Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee [194]

Professor of Infectious Diseases in Global Health; Director, National Aspergillosis Centre, The University of Manchester and Wythenshawe Hospital, Manchester, United Kingdom [212]

Philip E. Cryer, MD

Robert J. Desnick, MD, PhD

Professor of Medicine Emeritus, Washington University in St. Louis; Physician, Barnes-Jewish Hospital, St. Louis, Missouri [399]

Gary C. Curhan, MD

Dean for Genetic and Genomic Medicine; Professor and Chair Emeritus, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York [409]

Professor of Medicine, Harvard Medical School; Professor of Epidemiology, Harvard School of Public Health; Editor-in-Chief, Clinical Journal of the American Society of Nephrology; Channing Division of Network Medicine/Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts [312]

Betty Diamond, MD

Brendan D. Curti, MD

Director, Genitourinary Oncology Research and Clinical Biotherapy Programs; Co-Director, Melanoma Program, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon [72]

Professor, Department of Radiology and Medicine, Harvard Medical School; Chief, Division of Nuclear Medicine and Molecular Imaging; Executive Director, Noninvasive Cardiovascular Imaging Program, Brigham and Women’s Hospital, Boston, Massachusetts [236, A8]

John J. Cush, MD

Anna Mae Diehl, MD

Professor of Medicine and Rheumatology; Director of Clinical Rheumatology, Baylor Research Institute, Baylor University Medical Center, Baylor Scott & White Health, Dallas, Texas [363]

HPIM 20e_FM_VOL1_pi-pxlii.indd 23

CONTRIBUTORS

Professor of Medicine, The Ohio State University College of Medicine; Director, Division of Gastroenterology, Hepatology and Nutrition; The Ohio State University Wexner Medical Center, Columbus, Ohio [340, 341]

Charles A. Czeisler, MD, PhD

The Feinstein Institute for Medical Research, Northwell Health System; Center for Autoimmunity and Musculoskeletal Diseases, Manhasset, New York [348]

Marcelo F. Di Carli, MD

Florence McAlister Professor of Medicine; Director, Duke Liver Center, Duke University, Durham, North Carolina [336]

6/4/18 1:55 PM

xxiv

CONTRIBUTORS

Jules L. Dienstag, MD

James A. Eastham, MD

William P. Dillon, MD

Robert H. Eckel, MD

Carl W. Walter Professor of Medicine, Harvard Medical School; Physician, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts [332-334, 338, A13] Professor and Executive Vice-Chair, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California [416, A16]

Charles A. Dinarello, MD

Distinguished Professor of Medicine and Immunology, University of Colorado Denver, Aurora, Colorado; Professor of Experimental Medicine, Radboud University Medical Center, Nijmegen, The Netherlands [15]

Susan M. Domchek, MD

Basser Professor of Oncology, Abramson Cancer Center, Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania [457]

Richard L. Doty, PhD

Professor, Department of Otorhinolaryngology: Head and Neck Surgery; Director, Smell and Taste Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [29]

Vanja C. Douglas, MD

Associate Professor of Clinical Neurology and Sara and Evan Williams Foundation Endowed Neurohospitalist Chair, University of California, San Francisco, San Francisco, California [20]

David F. Driscoll, PhD

Chief, Urology Service; Peter T. Scardino Chair in Oncology, Department of Surgery, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, New York [83] Professor of Medicine; Professor of Physiology and Biophysics, University of Colorado School of Medicine, Aurora, Colorado [401]

John E. Edwards, Jr., MD

Distinguished Professor of Medicine Emeritus, David Geffen School of Medicine at UCLA; Senior Investigator, LA Biomedical Research Institute at Harbor/UCLA, Torrance, California [206, 211]

David A. Ehrmann, MD

Professor of Medicine, Section of Endocrinology; Director, University of Chicago Center for PCOS, University of Chicago, Chicago, Illinois [387]

Ezekiel J. Emanuel, MD, PhD

Chair, Department of Medical Ethics and Health Policy, Levy University Professor, Perelman School of Medicine and Wharton School, University of Pennsylvania, Philadelphia, Pennsylvania [9]

Jack Ende, MD

The Schaeffer Professor of Medicine; Assistant Vice President, University of Pennsylvania Health System; Assistant Dean for Advanced Medical Practice, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania [465]

John W. Engstrom, MD

Associate Professor of Medicine, University of Massachusetts Medical School, Worchester, Massachusetts [328]

Betty Anker Fife Distinguished Professor and Vice-Chairman; Neurology Residency Program Director, University of California, San Francisco, San Francisco, California [14, 432]

Thomas D. DuBose, Jr., MD, MACP

Moshe Ephros, MD

Professor Emeritus, Wake Forest University, Winston Salem, North Carolina [51, S1]

J. Stephen Dumler, MD

Clinical Associate Professor, Faculty of Medicine, Technion-Israel Institute of Technology; Pediatric Infectious Disease Unit, Carmel Medical Center; Haifa, Israel [167]

Andrea Dunaif, MD

Assistant Professor of Clinical Medicine, Department of Internal Medicine, Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, Indiana [193]

Professor and Chair, Department of Pathology, Uniformed Services University of the Health Sciences; Walter Reed National Military Medical Center; Joint Pathology Center, Bethesda, Maryland [182]

Aaron Ermel, MD

Lillian and Henry M. Stratton Professor of Molecular Medicine; Chief, Hilda and J. Lester Gabrilove Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York [391]

Tim Evans, DPhil, MD

Samuel C. Durso, MD, MBA

Janice P. Dutcher, MD

J.O. Ritchey Scholar in Medicine; Associate Professor, Departments of Medicine and Pediatrics; Director of Diabetes Research in the Herman B Wells Center for Pediatric Research; Associate Director in the IU Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine; Staff Physician, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana [396]

Johanna Dwyer, DSc, RD

Professor of Medicine, Harvard Medical School; Director, Partners Asthma Center; Member, Pulmonary and Critical Care Medicine Division, Brigham and Women’s Hospital, Boston, Massachusetts [34]

Jeffery S. Dzieczkowski, MD

Kolokotrones University Professor, Harvard University; Chair, Department of Global Health and Social Medicine, Harvard Medical School; Chief, Division of Global Health Equity, Brigham and Women’s Hospital; Co-Founder, Partners In Health, Boston, Massachusetts [460]

Mason F. Lord Professor of Medicine; Director, Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine; Executive Vice Chair, Department of Medicine, Johns Hopkins Bayview Medical Center; Baltimore, Maryland [32, A2] Associate Director, Cancer Research Foundation of New York, Chappaqua, New York; Former Professor of Medicine, New York Medical College, Valhalla, New York [71] Professor, Tufts University School of Medicine; Senior Scientist, Jean Mayer USDA Human Nutrition Research Center on Aging; Director, Frances Stern Nutrition Center, Tufts Medical Center, Boston, Massachusetts [325] Physician, Boise VA Medical Center, V-IMPACT Telehealth Program, Boise, Idaho [109]

Kim A. Eagle, MD

Albion Walter Hewlett Professor of Internal Medicine; Director, Frankel Cardiovascular Center, University of Michigan Health System, Ann Arbor, Michigan [467]

HPIM 20e_FM_VOL1_pi-pxlii.indd 24

Senior Director, Health, Nutrition and Population, The World Bank Group, Washington, DC [462]

Carmella Evans-Molina, MD, PhD

Christopher H. Fanta, MD

Paul Farmer, MD, PhD

Anthony S. Fauci, MD

Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [1, 196, 197, 342, 356, A14, S2]

Murray J. Favus, MD

Professor of Medicine, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, Director Bone Program, University of Chicago Medicine, Chicago, Illinois [405]

6/4/18 1:55 PM

David P. Faxon, MD

Anne L. Fuhlbrigge, MD, MS

David T. Felson, MD, MPH

Andre D. Furtado, MD

Senior Lecturer, Harvard Medical School; Associate Chief of Cardiology, Brigham and Women’s Hospital; Boston, Massachusetts [237, 270, A11]

Howard L. Fields, MD, PhD

Senior Associate Dean for Clinical Affairs, University of Colorado School of Medicine; Chief Medical Officer, CU Medicine, Aurora, Colorado [280] Assistant Professor, Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania [A16]

Nicholas B. Galifianakis, MD, MPH

Professor, Department of Neurology, University of California, San Francisco, San Francisco, California [10]

Associate Professor of Neurology, Movement Disorders and Neuromodulation Center, Department of Neurology, University of California, San Francisco, San Francisco, California [V1]

Gregory A. Filice, MD

John I. Gallin, MD

Professor of Medicine, Medical School, and Adjunct Professor of Epidemiology and Community Health, School of Public Health, University of Minnesota; Chief, Infectious Disease Section, Veterans Affairs Healthcare System, Minneapolis, Minnesota [169]

Associate Director for Clinical Research; Chief Scientific Officer, Clinical Center, National Institutes of Health, Bethesda, Maryland [60]

Karunesh Ganguly, MD, PhD

Chair, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts [70, 138]

Associate Professor; Director of NeuroRehabilitation Research, Department of Neurology, University of California, San Francisco; Neurology and Rehabilitation Service, San Francisco VA Medical Center, San Francisco, California [477]

Joyce D. Fingeroth, MD

Charlotte A. Gaydos, DrPh, MS, MPH

Alain Fischer, MD, PhD

J. Michael Gaziano, MD, MPH

Robert W. Finberg, MD

Professor of Medicine, Division of Infectious Disease, University of Massachusetts Medical School, Worcester, Massachusetts [138] Director of Imagine Institute; Professor at College de France, Paris, France [344, S7]

Jeffrey S. Flier, MD

Higginson Professor of Physiology and Medicine; Harvard University Distinguished Service Professor, Harvard Medical School, Boston, Massachusetts [394]

Agnes B. Fogo, MD

Jon L. Shapiro Endowed Chair in Pathology; Professor of Pathology, Medicine and Pediatrics; Director, Renal Pathology/Electron Microscopy Laboratory, Vanderbilt University Medical Center, Nashville, Tennessee [A3]

Gregory K. Folkers, MS, MPH

Chief of Staff, Office of the Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [197]

Larry C. Ford, MD

Clinical Infectious Diseases, Intermountain Healthcare, Provo, Utah [31]

Jane E. Freedman, MD

Professor of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts [113]

Roy Freeman, MD

Professor of Neurology, Harvard Medical School; Director, Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Boston, Massachusetts [18]

Professor of Medicine, Johns Hopkins University, Division of Infectious Diseases, Baltimore, Maryland [184] Professor of Medicine, Harvard Medical School; Chief, Division of Aging, Brigham and Women’s Hospital; Director, Massachusetts Veterans Epidemiology Center, Boston VA Healthcare System, Boston, Massachusetts [233]

Thomas A. Gaziano, MD, MSc

Assistant Professor of Medicine, Harvard Medical School; Assistant Professor, Health Policy and Management, Center for Health Decision Sciences, Harvard School of Public Health; Director, Strategic Planning and Global Cardiovascular Health Policy and Prevention Unit, Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [233]

Susan L. Gearhart, MD

Associate Professor, Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland [321]

Robert H. Gelber, MD

Clinical Professor of Medicine and Dermatology, University of California, San Francisco, San Francisco, California [174]

Jeffrey M. Gelfand, MD, MAS, FAAN

Assistant Professor of Clinical Neurology, Department of Neurology, University of California, San Francisco, San Francisco, California [20]

Alfred L. George, Jr., MD

Magerstadt Professor and Chair, Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [303]

Dale N. Gerding, MD

Carl E. Freter, MD, PhD, FACP

Professor of Medicine (retired), Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Research Physician, Edward Hines Jr. Veterans Affairs Hospital, Hines, Illinois [129]

Lawrence S. Friedman, MD

Michael D. Geschwind, MD, PhD

Professor of Medicine; Director, Division of Hematology and Oncology; Associate Director, Cancer Center, Saint Louis University, St. Louis, Missouri [91] Professor of Medicine, Harvard Medical School; Professor of Medicine, Tufts University School of Medicine; Assistant Chief of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Anton R. Fried, MD Chair, Department of Medicine, NewtonWellesley Hospital, Newton, Massachusetts [46]

Sonia Friedman, MD

Associate Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts [319]

HPIM 20e_FM_VOL1_pi-pxlii.indd 25

CONTRIBUTORS

Professor of Medicine and Epidemiology; Chair, Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts [364]

xxv

Professor of Neurology; Michael J. Homer Chair in Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, California [V1]

Marc G. Ghany, MD, MHSc

Investigator, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland [329]

Christopher H. Gibbons, MD, MMSc

Associate Professor of Neurology, Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, Massachusetts [432]

6/4/18 1:55 PM

xxvi

CONTRIBUTORS

Michael Giladi, MD, MSc

Yonatan H. Grad, MD, PhD

Robert P. Giugliano, MD, SM

Christine Grady, RN, PhD

Associate Professor of Medicine, Sackler Faculty of Medicine, Tel Aviv University; The Infectious Disease Unit and the Bernard Pridan Laboratory for Molecular Biology of Infectious Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel [167] Associate Professor of Medicine, Harvard Medical School; Cardiovascular Medicine, TIMI Study Office, Brigham and Women’s Hospital, Boston, Massachusetts [268]

Roger I. Glass, MD, PhD

Assistant Professor of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health; Associate Physician, Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts [474] Chief, Department of Bioethics, National Institutes of Health Clinical Center, Bethesda, Maryland [8]

Alexander R. Green, MD, MPH

Eli Glatstein, MD

Associate Professor of Medicine, Harvard Medical School; Senior Scientist, Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts [7]

Ronald S. Go, MD

Professor of Neurology, Harvard Medical School; Associate Neurologist, Brigham and Women’s Hospital, Boston, Massachusetts [358]

Director, Fogarty International Center, Bethesda, Maryland [198] Professor Emeritus, Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania [S4] Chair, Core/Consultative Hematology, Division of Hematology, Mayo Clinic Rochester, Rochester, Minnesota [311]

Peter J. Goadsby, MD, PhD, DSc, FRACP, FRCP, FMedSci

Professor, NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, United Kingdom; Professor, Department of Neurology, University of California, San Francisco, San Francisco, California [13, 422]

Ary L. Goldberger, MD

Professor of Medicine, Harvard Medical School; Wyss Institute for Biologically Inspired Engineering, Harvard University; Director, Margret and H. A. Rey Institute for Nonlinear Dynamics in Medicine; Director, NIH-sponsored Research Resource for Complex Physiologic Signals; Associate Chief, Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Boston, Massachusetts [235, A7, A9]

David Goldblatt, MB, ChB, PhD

Professor of Vaccinology and Immunology; Consultant in Paediatric Immunology; Director of Clinical Research and Development; Director, NIHR Biomedical Research Centre, Great Ormond Street Institute of Child Health; University College London; Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom [141]

Samuel Z. Goldhaber, MD

Professor of Medicine, Harvard Medical School; Director, Thrombosis Research Group; Head, Vascular Medicine Section, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts [273]

Ralph Gonzales, MD, MSPH

Professor of Medicine; Associate Dean, Clinical Innovation, University of California, San Francisco, San Francisco, California [31]

Marga G. A. Goris, PhD

Head OIE and National Leptospirosis Reference Centre, Department of Medical Microbiology, AMC (Academic Medical Centre), Amsterdam, The Netherlands [179]

Maria Luisa Gorno-Tempini, MD, PhD

Professor, Department of Neurology; Language Neurobiology Lab, Memory and Aging Center; Dyslexia Center, University of California, San Francisco, San Francisco, California [V2]

Peter A. Gottlieb, MD

Professor of Pediatrics and Medicine, Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado [382]

Gregory A. Grabowski, MD

Professor Emeritus, Department of Pediatrics, University of Cincinnati College of Medicine; Division of Human Genetics, Cincinnati Children’s Hospital Medical Center; Chief Scientific Officer, Kiniksa Pharmaceuticals, Ltd., Wellesley, Massachusetts [411]

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Steven A. Greenberg, MD

Norton J. Greenberger, MD

Clinical Professor of Medicine, Harvard Medical School; Senior Physician, Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts [339-341]

Daryl R. Gress, MD, FAAN, FCCM, FNCS

Professor of Neurology, University of Nebraska, Omaha, Nebraska [301, 302]

Rasim Gucalp, MD, FACP

Professor of Medicine, Albert Einstein College of Medicine; Associate Chairman for Educational Programs, Department of Oncology; Director, Hematology/Oncology Fellowship, Montefiore Medical Center, Bronx, New York [71]

Kalpana Gupta, MD, MPH

Professor, Department of Medicine, Boston University School of Medicine; Chief, Section of Infectious Diseases, VA Boston Healthcare System, Boston, Massachusetts [130]

Chadi A. Hage, MD, FCCP

Associate Professor of Clinical Medicine, Thoracic Transplant Program, Indiana University Health, Indianapolis, Indiana [207]

Bevra Hannahs Hahn, MD

Distinguished Professor of Medicine (Emeritus), University of California, Los Angeles, Los Angeles, California [349]

Noah M. Hahn, MD

Associate Professor of Oncology and Urology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland [82]

Colin N. Haile, MD, PhD

Assistant Professor, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine; Michael E. DeBakey VA Medical Center, Houston, Texas [446]

Janet E. Hall, MD

Clinical Director and Senior Investigator, Division of Intramural Research, NIH/NIEHS, Research Triangle Park, North Carolina [385, 386, 389]

Jesse B. Hall, MD, FCCP

Professor of Medicine, Anesthesia and Critical Care; Chief, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois [293]

Scott A. Halperin, MD

Professor of Pediatrics and Microbiology and Immunology; Head, Pediatric Infectious Diseases; Director, Canadian Center for Vaccinology, Dalhousie University, Halifax, Nova Scotia, Canada [155]

R. Doug Hardy, MD

Infectious Diseases Specialists, PA; Medical City Dallas Hospital and Medical City Children’s Hospital, Dallas; Baylor Regional Medical Center, Plano, Texas [183]

6/4/18 1:55 PM

William L. Hasler, MD

Professor, Division of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan [41, 314] Robert A. Fishman Distinguished Professor, Department of Neurology; Director, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California [1, 300, 415, 417, 433-437, 439, S9]

Daniel F. Hayes, MD, FACP, FASCO

Stuart B Padnos Professor of Breast Cancer Research; Clinical Director of Breast Cancer, University of Michigan Health System and Comprehensive Cancer Center, Ann Arbor, Michigan [75]

Barton F. Haynes, MD

Frederic M. Hanes Professor of Medicine and Immunology, Departments of Medicine and Immunology; Director, Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina [342]

J. Claude Hemphill, III, MD, MAS

Professor of Neurology and Neurological Surgery, University of California, San Francisco; Chief of Neurology, Zuckerberg San Francisco General Hospital, San Francisco, California [301, 302, 419-421]

Katherine A. High, MD

Director of Research and Faculty Development, Department of Global Health; Professor of Medicine and Global Health; Adjunct Professor of Microbiology and Epidemiology; Director, UW Center for AIDS and STD; Co-Director, UW/Fred Hutch Center for AIDS Research (CFAR); Co-PI, UW/UCSF International Training and Education Center for Health (I-TECH); University of Washington, Seattle, Washington [131]

David Hong, MD

Instructor of Medicine, Harvard Medical School; Division of Allergy & Immunology, Brigham and Women’s Hospital, Boston, Massachusetts [346]

Jay H. Hoofnagle, MD

Director, Liver Diseases Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland [329]

David C. Hooper, MD

Professor, Harvard Medical School; Chief, Infection Control Unit; Associate Chief, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts [139, 140]

Robert J. Hopkin, MD

Associate Professor, Department of Pediatrics, University of Cincinnati College of Medicine; Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio [411]

Professor Emerita, Perelman School of Medicine at the University of Pennsylvania; President and Chief Scientific Officer, Spark Therapeutics, Philadelphia, Pennsylvania [112, 458]

Leora Horn, MD, MSc

Christine E. Hill-Kayser, MD

Kirsten B. Hornbeak, MD

Ikuo Hirano, MD

Jonathan C. Horton, MD, PhD

Assistant Professor of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [S4] Professor of Medicine, Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, Illinois [40, 316]

Martin S. Hirsch, MD

Associate Professor, Division of Hematology and Medical Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee [74] Resident, Department of Emergency Medicine, Stanford Kaiser Emergency Medicine Residency, Stanford, California [451] William F. Hoyt Professor of Neuro-ophthalmology, Professor of Ophthalmology, Neurology and Physiology, University of California, San Francisco School of Medicine, San Francisco, California [28, V3]

Professor of Medicine, Harvard Medical School; Professor of Immunology and Infectious Diseases, Harvard School of Public Health; Physician, Massachusetts General Hospital, Boston, Massachusetts [190]

Howard Hu, MD, MPH, ScD

Dieter Hoelzer, PhD, MD

Deborah T. Hung, MD, PhD

Emeritus Director of Internal Medicine, University of Frankfurt, Frankfurt, Germany [102]

xxvii

Dean; Professor of Environmental Health, Epidemiology and Global Health, Dalla Lana School of Public Health; Professor of Medicine, University of Toronto, Toronto, Ontario, Canada [449]

A. Victor Hoffbrand, DM

Associate Professor of Genetics and Associate Professor of Medicine, Harvard Medical School; Brigham and Women’s Hospital; Massachusetts General Hospital, Boston, Massachusetts; Co-Director, Infectious Disease & Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts [474]

L. John Hoffer, MD, PhD

Gary M. Hunninghake, MD, MPH

Emeritus Professor of Haematology, University College, London, London, United Kingdom [95] Professor, Faculty of Medicine, McGill University; Senior Physician, Divisions of Internal Medicine and Endocrinology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada [328]

Charles W. Hoge, MD

Senior Scientist, Center for Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland [S6]

Elizabeth L. Hohmann, MD

Associate Professor of Medicine and Infectious Diseases, Harvard Medical School; Massachusetts General Hospital, Boston, Massachusetts [146]

Steven M. Holland, MD

Director, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Chief, Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [60, 175]

HPIM 20e_FM_VOL1_pi-pxlii.indd 27

CONTRIBUTORS

Stephen L. Hauser, MD

King K. Holmes, MD, PhD

Assistant Professor of Medicine, Harvard Medical School; Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [287]

Stephen C. Hunt, MD, MPH

National Director, VA Post-Deployment Integrated Care Initiative; Clinical Associate Professor of Medicine, Department of Medicine, Division of General Internal Medicine, Occupational and Environmental Medicine Program, University of Washington, Seattle, Washington [S6]

Ashraf S. Ibrahim, PhD

Professor, Department of Medicine, Geffen School of Medicine, University of California, Los Angeles (UCLA); Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, California [213]

6/4/18 1:55 PM

xxviii

David H. Ingbar, MD

CONTRIBUTORS

Professor, Medicine, Pediatrics and Integrative Biology and Physiology; Director, Pulmonary, Allergy, Critical Care and Sleep Division; CTSI Associate Director, Education, Career Development and Training; Executive Director, Center for Lung Science and Health, University of Minnesota School of Medicine, Minneapolis, Minnesota [298]

Alan C. Jackson, MD, FRCPC

Professor of Medicine (Neurology) and of Medical Microbiology, University of Manitoba; Section Head of Neurology, Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada [203]

Lisa A. Jackson, MD, MPH

Kaiser Permanente Washington Health Research Institute, Seattle, Washington [118]

Yves Jackson, MD, MPH, PhD

Senior Physician, Geneva University Hospital; Investigator, Institute of Global Health, University of Geneva, Switzerland [222]

Danny O. Jacobs, MD, MPH, FACS

Executive Vice President, Provost, and Dean of the School of Medicine; Thomas N. and Gleaves T. James Distinguished Chair, The University of Texas Medical Branch at Galveston, Galveston, Texas [12, 323, 324]

Caron A. Jacobson, MD

Instructor in Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts [104, 105]

J. Larry Jameson, MD, PhD

Robert G. Dunlop Professor of Medicine; Dean, Raymond and Ruth Perelman School of Medicine; Executive Vice President, University of Pennsylvania for the Health System, Philadelphia, Pennsylvania [1, 43, 89, 369-373, 375-378, 383, 384, 456, 457, A15]

Gordon L. Jensen, MD, PhD

Senior Associate Dean for Research; Professor of Medicine and Nutrition, University of Vermont College of Medicine, Burlington, Vermont [327]

Robert T. Jensen, MD

Chief, Cell Biology Section, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland [80]

Roy M. John, MBBS, PhD, FRCP

Associate Professor of Medicine; Director, Center for Advanced Management of Ventricular Arrhythmias, Vanderbilt Heart and Vascular Institute, Nashville, Tennessee [247-251]

Savio John, MD

Director of Hepatology, State University of New York Upstate Medical University, Syracuse, New York [45]

James R. Johnson, MD

Professor of Medicine, University of Minnesota; Veterans Affairs Medical Center, Minneapolis, Minnesota [156]

Stuart Johnson, MD

Professor of Medicine, Loyola University Chicago Stritch School of Medicine; Staff Physician, Edward Hines Jr. VA Hospital, Hines, Illinois [129]

S. Claiborne Johnston, MD, PhD

Dean, Dell Medical School; Frank Denius Distinguished Dean’s Chair in Medical Leadership; Vice President for Medical Affairs, University of Texas, Austin, Austin, Texas [419-421]

S. Andrew Josephson, MD

Professor and Chairman, Department of Neurology, University of California, San Francisco, San Francisco, California [24, 300, 301, V4]

Sandeep S. Jubbal, MD

Assistant Professor of Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts [136]

HPIM 20e_FM_VOL1_pi-pxlii.indd 28

Harald W. Jüppner, MD

Professor of Pediatrics, Endocrine Unit and Pediatric Nephrology Unit, Harvard Medical School; Massachusetts General Hospital, Boston, Massachusetts [403]

Peter J. Kahrilas, MD

Gilbert H. Marquardt Professor of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [40, 316]

Gail Kang, MD

Private Practice, Berkeley, California [V1]

Hagop Kantarjian, MD

Chairman, Leukemia Department; Professor of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas [101]

Adolf W. Karchmer, MD

Professor of Medicine, Harvard Medical School; Former Chief, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts [123]

Dennis L. Kasper, MD

William Ellery Channing Professor of Medicine and Professor of Microbiology and Immunobiology, Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts [1, 115, 117, 127, 153, 172, 459]

Daniel L. Kastner, MD, PhD

Scientific Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland [362]

Sekar Kathiresan, MD

Associate Professor of Medicine, Harvard Medical School; Director, Center for Genomic Medicine, Massachusetts General Hospital; Director, Cardiovascular Disease Initiative, Broad Institute, Boston, Massachusetts [400]

Carol A. Kauffman, MD

Professor of Internal Medicine, University of Michigan Medical School; Chief, Infectious Diseases Section, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan [214]

Elaine T. Kaye, MD

Assistant Professor of Dermatology, Harvard Medical School; Boston Children’s Hospital, Boston, Massachusetts [16, A1]

Kenneth M. Kaye, MD

Associate Professor of Medicine, Harvard Medical School; Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts [16, A1]

John A. Kessler, MD

Davee Professor of Stem Cell Biology, Davee Department of Neurology; Director, Northwestern University Stem Cell Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [473]

Jay S. Keystone, CM, MD, FRCPC, MSc(CTM)

Professor of Medicine, University of Toronto, Toronto, Ontario, Canada [119]

Sundeep Khosla, MD

Dr. Francis Chucker and Nathan Landow Research Professor; Mayo Foundation Distinguished Investigator; Director, Mayo Clinic Center for Clinical and Translational Science; Dean for Clinical and Translational Science, Mayo Clinic College of Medicine, Rochester, Minnesota [50]

Elliott Kieff, MD, PhD

Harriet Ryan Albee Professor of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [185]

Anthony A. Killeen, MD, PhD

Professor, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota [S12]

6/4/18 1:55 PM

Kami Kim, MD

Professor, Division of Infectious Diseases and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida [223]

Associate Professor, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington [35, 278, A12]

Henry M. Kronenberg, MD

Clinical Pharmacy Specialist—Infectious Diseases, Ochsner Medical Center, New Orleans, Louisiana [209]

Professor of Medicine, Harvard Medical School; Chief, Endocrine Division, Massachusetts General Hospital, Boston, Massachusetts [402]

Beth D. Kirkpatrick, MD

Jens H. Kuhn, MD, PhD, MS

Priya S. Kishnani, MD

Robert F. Kushner, MD

Professor of Medicine, Division of Infectious Diseases, Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont [162] C. L. and Su Chen Professor of Pediatrics; Medical Director, YT and Alice Chen Pediatrics Genetics and Genomics Center; Division Chief, Medical Genetics, Duke University Medical Center, Durham, North Carolina [412]

Christine Klein, MD

Professor of Neurology and Neurogenetics, Institute of Neurogenetics and Department of Neurology, University of Lübeck and University Hospital Schleswig-Holstein, Lübeck, Germany [427, 428]

Barbara A. Konkle, MD

Professor of Medicine, Hematology, University of Washington; Associate Chief Scientific Officer, Bloodworks Northwest, Seattle, Washington [61, 111]

Peter Kopp, MD

Professor of Medicine, Division of Endocrinology, Metabolism and Molecular Science and Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois [456]

Walter J. Koroshetz, MD

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland [134]

Thomas R. Kosten, MD

J. H. Waggoner Professor of Psychiatry, Pharmacology, Immunology, Neuroscience, Baylor College of Medicine, Houston, Texas [446]

Theodore A. Kotchen, MD

Professor Emeritus and Associate Dean for Clinical Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin [271]

Camille Nelson Kotton, MD, FIDSA, FAST

Clinical Director, Transplant and Immunocompromised Host Infectious Diseases, Infectious Diseases Division, Massachusetts General Hospital; Harvard Medical School, Boston, Massachusetts [190]

xxix

CONTRIBUTORS

S. Travis King, PharmD, BCPS (AQ ID)

Patricia A. Kritek, MD, EdM

Research Leader, Battelle Memorial Institute and Lead Virologist, NIH/NIAID/DCR/Integrated Research Facility at Fort Detrick (IRF-Frederick), Fort Detrick, Frederick, Maryland [204, 205] Professor of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [395]

Raymond Y. Kwong, MD, MPH

Associate Professor of Medicine, Harvard Medical School; Director of Cardiac Magnetic Resonance Imaging, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [236, A8]

Loren Laine, MD

Professor of Medicine, Yale School of Medicine, New Haven, Connecticut; VA Connecticut Healthcare System, West Haven, Connecticut [44]

Neal K. Lakdawala, MD

Instructor in Medicine, Harvard Medical School; Associate Physician, Cardiovascular Medicine, Brigham and Women’s Hospital; Boston VA Healthcare; Boston, Massachusetts [254]

Anil K. Lalwani, MD

Professor and Vice Chair for Research; Director, Division of Otology, Neurotology and Skull Base Surgery; Director, Columbia Cochlear Implant Center, Columbia University College of Physicians and Surgeons; Medical Director of Perioperative Services, New York Presbyterian–Columbia University Irving Medical Center, New York, New York [30]

Michael J. Landzberg, MD

Associate Professor of Medicine, Harvard Medical School; Director, Boston Adult Congenital Heart Disease and Pulmonary Hypertension Program, Boston Children’s Hospital, Brigham and Women’s Hospital, Boston, Massachusetts [264]

H. Clifford Lane, MD

Clinical Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [197, S2]

Carol A. Langford, MD, MHS

Phyllis E. Kozarsky, MD

Harold C. Schott Endowed Chair; Director, Center for Vasculitis Care and Research, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, Ohio [356, 359, 367, 368, A14]

Barnett S. Kramer, MD, MPH, FACP

Regina C. LaRocque, MD, MPH

Professor of Medicine and Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia [119] Director, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland [66]

Joel Kramer, PsyD

Professor of Neuropsychology in Neurology; Director of Neuropsychology, Memory and Aging Center, University of California, San Francisco, San Francisco, California [425, V2]

Assistant Professor of Medicine, Harvard Medical School; Assistant Physician, Massachusetts General Hospital, Boston, Massachusetts [128]

Leslie P. Lawley, MD

Assistant Professor, Department of Dermatology, School of Medicine, Emory University, Atlanta, Georgia [53]

Peter J. Krause, MD

Thomas J. Lawley, MD

John P. Kress, MD

Sancy Leachman, MD, PhD

Senior Research Scientist, Yale School of Public Health; Yale School of Medicine, New Haven, Connecticut [220] Professor of Medicine, Director, Medical Intensive Care Unit, University of Chicago, Chicago, Illinois [293]

Arnold R. Kriegstein, MD, PhD

Professor of Neurology; Director, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California [417]

HPIM 20e_FM_VOL1_pi-pxlii.indd 29

William Patterson Timmie Professor of Dermatology, Former Dean, Emory University School of Medicine, Atlanta, Georgia [52, 53, 55, A4] Professor and Chair, Department of Dermatology; Director, Melanoma Research Program, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon [72]

David G. Le Couteur, MD, PhD

Professor of Geriatric Medicine and Director of the Ageing and Alzheimer’s Institute, University of Sydney and Concord Hospital, Sydney, Australia [463]

6/4/18 1:55 PM

xxx

William M. Lee, MD

Professor of Internal Medicine; Meredith Mosle Chair in Liver Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas [333]

Bernard Lo, MD

CONTRIBUTORS

Charles Lei, MD

President, The Greenwall Foundation, New York; Professor of Medicine Emeritus and Director Emeritus of the Program in Medical Ethics, University of California, San Francisco, San Francisco, California [8]

Jane A. Leopold, MD

Postdoctoral Research Fellow, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland [322]

Assistant Professor, Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee [451]

Satinderjit Locham, MD

Associate Professor of Medicine, Harvard Medical School; Director, Women’s Interventional Cardiology Health Initiative, Brigham and Women’s Hospital, Boston, Massachusetts [237, A11]

George Loewenstein, PhD

Nelson Leung, MD

Dan L. Longo, MD, MACP

Professor of Medicine, Division of Nephrology and Hypertension, Division of Hematology, Mayo Clinic Rochester, Rochester, Minnesota [311]

Bruce D. Levy, MD

Professor of Medicine, Harvard Medical School; Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [278, 294]

Julia B. Lewis, MD

Professor, Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee [308]

Peter Libby, MD

Mallinckrodt Professor of Medicine, Harvard Medical School; Cardiovascular Specialist, Brigham and Women’s Hospital, Boston, Massachusetts [232, A10]

Richard W. Light, MD

Professor of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee [288, 289]

Yusen E. Lin, PhD, MBA

Professor and Director, Center for Environmental Laboratory Services; National Kaohsiung Normal University, Kaohsiung, Taiwan [154]

Robert Lindsay, MD, PhD

Professor of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York; Chief, Internal Medicine; Helen Hayes Hospital, West Haverstraw, New York [404]

Marc E. Lippman, MD, MACP, FRCP

Leonard M. Miller Professor of Internal Medicine, Psychiatry and Behavioral Sciences; Deputy Director, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida [75]

Peter E. Lipsky, MD

Charlottesville, Virginia [348]

Kathleen D. Liu, MD, PhD, MAS

Professor, Division of Nephrology, Department of Medicine, Division of Critical Care Medicine, Department of Anesthesiology, University of California, San Francisco, San Francisco, California [306]

Josep M. Llovet, MD, PhD

Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Translational Research Laboratory, Barcelona Clínic Liver Cancer Group (BCLC), Liver Unit, IDIBAPS-Hospital Clínic, CIBERehd, University of Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain [78]

Donald M. Lloyd-Jones, MD, ScM

Senior Associate Dean for Clinical and Translational Research; Chair, Department of Preventive Medicine; Director, Northwestern University Clinical and Translational Sciences Institute (NUCATS), Northwestern University, Feinberg School of Medicine, Chicago, Illinois [2]

HPIM 20e_FM_VOL1_pi-pxlii.indd 30

Herb Simon Professor of Economics and Psychology, Carnegie Mellon University, Pittsburgh Pennsylvania [468] Professor of Medicine, Harvard Medical School; Senior Physician, Brigham and Women’s Hospital; Deputy Editor, New England Journal of Medicine, Boston, Massachusetts [1, 58, 59, 62, 65, 68, 69, 89, 91, 92, 97, 104-107, 196, A5]

Nicola Longo, MD, PhD

Professor and Chief, Division of Medical Genetics, Departments of Pediatrics and Pathology; Medical Co-Director, Biochemical Genetics Laboratory, ARUP Laboratories, University of Utah, Salt Lake City, Utah [413, 414]

Joseph Loscalzo, MD, PhD

Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital, Boston, Massachusetts [1, 36-39, 113, 231, 232, 234, 254, 256-263, 267, 269, 274-277, 476]

Christine M. Lovly, MD, PhD

Assistant Professor of Medicine, Division of Hematology-Oncology; Assistant Professor of Cancer Biology, Vanderbilt Ingram Cancer Center; Vanderbilt University Medical Center, Nashville, Tennessee [74]

Daniel H. Lowenstein, MD

Dr. Robert B. and Mrs. Ellinor Aird Professor of Neurology; Director, Epilepsy Center; Executive Vice Chancellor and Provost, University of California, San Francisco, San Francisco, California [415, 418, V6]

Elyse E. Lower, MD

Department of Internal Medicine, Division of Hematology-Oncology, University of Cincinnati, Cincinnati, Ohio [360]

Franklin D. Lowy, MD

Clyde ’56 and Helen Wu Professor of Medicine and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York [142]

Sheila A. Lukehart, PhD

Professor, Departments of Medicine and Global Health, University of Washington, Seattle, Washington [177, 178]

Lucio Luzzatto, MD, FRCP, FRCPath

Professor of Haematology, Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania; Honorary Professor of Hematology, University of Florence, Firenze, Italy [96]

Calum A. MacRae, MD, PhD

Associate Professor of Medicine, Harvard Medical School, Chief, Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [232]

Lawrence C. Madoff, MD

Professor of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; Director, Division of Epidemiology and Immunization, Massachusetts Department of Public Health, Jamaica Plain, Massachusetts [125, 136]

Mark E. Mailliard, MD

Frederick F. Paustian Professor; Chief, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska College of Medicine, Omaha, Nebraska [335]

6/4/18 1:55 PM

Harvey J. Makadon, MD, FACP

Gary J. Martin, MD

Barry J. Make, MD

Joseph B. Martin, MD, PhD

Professor of Medicine, Harvard Medical School; Director of Education and Training Programs, The Fenway Institute, Boston, Massachusetts [393]

Mahmoud Malas, MD, MHS, FACS

Associate Professor of Surgery and Epidemiology, Johns Hopkins University; Director of Endovascular Surgery; Director of The Vascular and Endovascular Clinical Research Center, Johns Hopkins Bayview Medical Center, Director of the Center of Research Excellence and Surgical Trial, Johns Hopkins Hospital, Baltimore, Maryland [322]

Susan J. Mandel, MD, MPH

Professor of Medicine; Associate Chief, Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [375-378]

Brian F. Mandell, MD, PhD

Professor and Chairman of Medicine, Cleveland Clinic Lerner College of Medicine, Department of Rheumatic and Immunologic Disease, Cleveland Clinic, Cleveland, Ohio [367]

Lionel A. Mandell, MD, FRCPC

Professor Emeritus of Medicine, McMaster University, Hamilton, Ontario, Canada [121]

Geoffrey T. Manley, MD, PhD

Professor and Vice Chairman of Neurological Surgery, University of California, San Francisco; Chief of Neurosurgery, Zuckerberg San Francisco General Hospital and Trauma Center; Co-Director, Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, California [435]

Douglas L. Mann, MD

Lewin Chair and Chief, Cardiovascular Division; Professor of Medicine, Cell Biology and Physiology, Washington University School of Medicine, Cardiologist-in-Chief, Barnes Jewish Hospital, St. Louis, Missouri [252]

JoAnn E. Manson, MD, DrPH

Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School; Chief, Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [388]

Eleftheria Maratos-Flier, MD

Professor of Medicine, Harvard Medical School; Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts [394]

Raymond J. Langenbach, MD Professor of Medicine; Vice Chairman for Faculty Affairs, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois [4] Lefler R. and Anne G. Lefler Professor of Neurobiology, Emeritus, Harvard Medical School, Boston, Massachusetts [415]

Susan Maslanka, PhD

Enteric Diseases Laboratory Branch, Centers for Disease Control and Prevention, Atlanta, Georgia [148]

Anthony F. Massaro, MD

Instructor, Harvard Medical School; Director, Medical Intensive Care Unit, Division of Pulmonary and Critical Care, Brigham and Women’s Hospital, Boston, Massachusetts [296]

Henry Masur, MD

Clinical Professor of Medicine, George Washington University School of Medicine, Washington, DC; Chief, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland [215]

Robert J. Mayer, MD

Faculty Vice President for Academic Affairs, Dana-Farber Cancer Institute; Stephen B. Kay Family Professor of Medicine, Harvard Medical School, Boston, Massachusetts [76, 77]

Alexander J. McAdam, MD, PhD

Associate Professor of Pathology, Harvard Medical School; Medical Director, Infectious Diseases Diagnostic Laboratory, Children’s Hospital of Boston, Boston, Massachusetts [S13]

Calvin O. McCall, MD

Clinical Professor, Department of Dermatology, Virginia Commonwealth University Medical Center, Richmond, Virginia; Chief, Dermatology Section, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia [53, A4]

John F. McConville, MD

Associate Professor of Medicine; Director, Internal Medicine Residency Program; Vice Chair for Education, University of Chicago, Department of Medicine, Chicago, Illinois [290]

Michael McCrea, PhD, ABPP

Professor and Eminent Scholar; Vice Chair of Research; Director of Brain Injury Research, Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin [435]

Kathleen M. McKibbin, MD

Staff Physician, Northwestern University Health Services, Evanston, Illinois [2]

Kevin T. McVary, MD, FACS

Professor and Chairman, Division of Urology, Southern Illinois University School of Medicine, Springfield, Illinois [390]

Daniel B. Mark, MD, MPH

Paul S. Mead, MD, MPH

Alexander G. Marneros, MD, PhD

John N. Mecchella, DO, MPH

Jeanne M. Marrazzo, MD, MPH, FACP, FIDSA

Mandeep R. Mehra, MD, FACC, FESC, FHFSA, FRCP

Professor of Medicine, Duke University Medical Center; Director, Outcomes Research, Duke Clinical Research Institute, Durham, North Carolina [3] Associate Professor, Department of Dermatology, Harvard Medical School; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts [57] C. Glenn Cobbs, MD, Endowed Professor in Infectious Diseases; Director, Division of Infectious Diseases, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama [131]

Thomas Marrie, MD

Dean Emeritus, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada [182]

HPIM 20e_FM_VOL1_pi-pxlii.indd 31

CONTRIBUTORS

Co-Director, COPD Program; Professor, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, University of Colorado Denver School of Medicine, Denver, Colorado [286]

xxxi

Chief, Bacterial Diseases Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado [165] Assistant Professor of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire [410] Professor of Medicine, Harvard Medical School; Medical Director, Brigham and Women’s Hospital Heart and Vascular Center; Executive Director, Center for Advanced Heart Disease, Brigham and Women’s Hospital; Editor-in-Chief, The Journal of Heart and Lung Transplantation, Boston, Massachusetts [253, 255]

Shlomo Melmed, MB ChB, MACP, FRCP

Executive Vice President and Dean of the Medical Faculty; Professor of Medicine, Cedars-Sinai Medical Center, Los Angeles, California [371-373]

6/4/18 1:55 PM

xxxii

Robert O. Messing, MD

William J. Moss, MD, MPH

Nancy Messonnier, MD (CAPT, USPHS)

Robert J. Motzer, MD

M.-Marsel Mesulam, MD

David B. Mount, MD

Gregory F. Michaud, MD

Haralampos M. Moutsopoulos, MD, FACP, FRCP(hc), Master ACR

Professor of Neurology and Neuroscience; Director, Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, Texas [443]

CONTRIBUTORS

Director, National Center for Immunization and Respiratory Diseases, Office of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia [118] Professor of Neuroscience and Neurology, Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois [26] Chief, Arrhythmia Section; Professor of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee [241-246]

Professor, Departments of Epidemiology, International Health, and Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland [200] Attending Physician, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York [81] Assistant Professor of Medicine, Harvard Medical School; Renal Division, Brigham and Women’s Hospital, Renal Division, Boston VA Healthcare System, Boston, Massachusetts [48, 49, S1]

Robert G. Micheletti, MD

Professor Emeritus, Medical School, National University of Athens, Athens, Greece [350, 354, 357]

Aaron W. Michels, MD

Professor of Medicine, Department of Medicine, Division of Infectious Diseases, Enterprise Epidemiologist, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin [157]

Assistant Professor of Dermatology and Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania [56] Associate Professor of Pediatrics and Medicine, Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado [382]

Susan Miesfeldt, MD

Medical Oncology, Medical Director, Cancer Risk and Prevention Clinic, Maine Medical Center, Scarborough, Maine [457]

Edgar L. Milford, MD

Associate Professor of Medicine, Harvard Medical School; Director, Tissue Typing Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts [307]

L. Silvia Munoz-Price, MD, PhD

Nikhil C. Munshi, MD

Professor of Medicine, Harvard Medical School; Boston VA Healthcare System; Director of Basic and Correlative Sciences; Associate Director, Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts [107]

John R. Murphy, PhD

Professor of Medicine and Microbiology, Boston University School of Medicine, Boston Massachusetts, and Adjunct Professor of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland [145]

Timothy F. Murphy, MD

Bruce L. Miller, MD

SUNY Distinguished Professor; Director, UB Clinical and Translational Research Center; Senior Associate Dean for Clinical and Translational Research; Jacobs School of Medicine and Biomedical Sciences; University at Buffalo, State University of New York, Buffalo, New York [152]

Samuel I. Miller, MD

Barbara E. Murray, MD

A. W. and Mary Margaret Clausen Distinguished Professor of Neurology, Memory and Aging Center, Global Brain Health Institute, University of California, San Francisco School of Medicine, San Francisco, California [24, 25, 423-426, 430, V2] Professor, Departments of Microbiology, Medicine and Genome Sciences, University of Washington, Seattle, Washington [160]

Jyoti Mishra, PhD

Department of Psychiatry, University of California, San Diego, La Jolla, California [477]

Simon J. Mitchell, MB ChB, PhD, FUHM, FANZCA

Professor, Department of Anaesthesiology, University of Auckland and Auckland City Hospital, Auckland, New Zealand [S11]

Babak Mokhlesi, MD, MSc

Professor of Medicine, Section of Pulmonary and Critical Care; Director, Sleep Disorders Center, Director, Sleep Medicine Fellowship, University of Chicago, Chicago, Illinois [290]

Thomas A. Moore, MD, FACP, FIDSA

Clinical Professor of Medicine, University of Kansas School of Medicine, Wichita, Kansas [217]

Alison Morris, MD, MS

Professor, Vice Chair for Clinical Research, Department of Medicine and Immunology; Director, University of Pittsburgh HIV Lung Research Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania [215]

David A. Morrow, MD, MPH

Professor of Medicine, Harvard Medical School; Director, Samuel A. Levine Cardiac Intensive Care Unit, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts [11]

HPIM 20e_FM_VOL1_pi-pxlii.indd 32

J. Ralph Meadows Professor and Director, Division of Infectious Diseases; Professor of Microbiology and Molecular Genetics, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas [144]

Joseph A. Murray, MD

Professor of Medicine, Departments of Internal Medicine and Immunology, Mayo Clinic School of Medicine, Rochester, Minnesota; Adjunct Professor of Pediatrics, University of Southern Denmark, Odense, Denmark [42]

Mark B. Mycyk, MD

Associate Professor, Department of Emergency Medicine, Northwestern University Feinberg School of Medicine; Research Director, Toxikon Consortium, Cook County Health and Hospitals System, Chicago, Illinois [450]

Avindra Nath, MD

Chief, Section of Infections of the Nervous System; Clinical Director, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, Maryland [134]

Edward T. Naureckas, MD

Professor of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois [279]

Eric G. Neilson, MD

Lewis Landsberg Dean and Vice President of Medical Affairs, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [303, 308, A3]

6/4/18 1:55 PM

Tuhina Neogi, MD, PhD

Gerald T. Nepom, MD, PhD

Professor (Affiliate), University of Washington School of Medicine; Director, Immune Tolerance Network, Benaroya Research Institute, Seattle, Washington [343]

Eric J. Nestler, MD, PhD

Nash Family Professor, Department of Neuroscience; Director, Friedman Brain Institute; Dean for Academic and Scientific Affairs, Ichan School of Medicine at Mount Sinai, New York, New York [443]

Hartmut P. H. Neumann, MD

Professor and Chairman Emeritus, Department of Neurology; Professor Emeritus, Department of Neuroscience, Mount Sinai School of Medicine, New York, New York; CEO, Clintrex, LLC [427, 428]

Andrew B. Onderdonk, PhD

Professor of Pathology, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [S13]

Joseph G. Ouslander, MD

Professor and Senior Associate Dean for Geriatric Programs; Chair, Department of Integrated Medical Sciences; Interim Director, FAU Internal Medicine Residency Program, Charles E. Schmidt College of Medicine; Professor (Courtesy), Christine E. Lynn College of Nursing, Florida Atlantic University, Boca Raton, Florida [464]

Chung Owyang, MD

Unit for Preventive Medicine, Department of Nephrology and General Medicine, Albert-Ludwigs University of Freiburg, Freiburg, Germany [380]

H. Marvin Pollard Professor of Internal Medicine; Professor of Molecular and Integrative Physiology; Chief, Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, Michigan [314, 320]

Jonathan Newmark, MD, MM

Umesh D. Parashar, MBBS, MPH

Colonel (retired), Medical Corps, U.S. Army; Adjunct Professor of Neurology, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Department of Neurology, Washington DC Veterans’ Affairs Medical Center, Washington, DC [S3]

Kevin D. Niswender, MD, PhD

Associate Professor of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee [396, 397]

Rathel L. Nolan, III, MD

Professor, Department of Medicine, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, Mississippi [209]

Robert L. Norris, MD

Professor Emeritus, Department of Emergency Medicine; Stanford University School of Medicine, Stanford, California [451]

Scott A. Norton, MD, MPH, MSc

Chief of Dermatology, Children’s National Health Systems, Washington, DC [452]

Thomas B. Nutman, MD

Head, Helminth Immunology Section, Head, Clinical Parasitology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [227, 228]

xxxiii

Lead, Viral Gastroenteritis Epidemiology Team, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia [198]

Shreyaskumar R. Patel, MD

Robert R. Herring Distinguished Professor of Medicine; Center Medical Director, Sarcoma Center, The University of Texas M.D. Anderson Cancer Center, Houston, Texas [87]

Gustav Paumgartner, MD

Professor Emeritus of Medicine, University of Munich, Munich, Germany [339]

M. Luisa Pedro-Botet, MD, PhD

Professor of Medicine, Autonomous University of Barcelona; Head of the Infectious Diseases Unit; Investigator of CIBEres, Instituto de Investigación Carlos III; Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain [154]

David A. Pegues, MD

Professor of Medicine, Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [160]

Florencia Pereyra, MD

Jose A. Obeso, MD

Instructor in Medicine, Harvard Medical School; Associate Physician, Infectious Disease Division, Brigham and Women’s Hospital, Boston, Massachusetts [136]

Katherine L. O’Brien, MD, MPH

Research Microbiologist, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado [165]

Max R. O’Donnell, MD, MPH

Clinical Director, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland [447]

Nigel O’Farrell, MD, FRCP

Professor of Medicine (Microbiology and Immunobiology), Harvard Medical School; Brigham and Women’s Hospital, Division of Infectious Diseases, Boston, Massachusetts [116]

Professor of Neurology and Director, CIINAC, Hospital de Madrid; Medical School, CEU-San Pablo, Madrid, Spain [428] Professor, Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland [141] Assistant Professor of Medicine and Epidemiology, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Medical Center, New York, New York [176] Consultant Physician, London North West Healthcare NHS Trust, London, United Kingdom [168]

Jennifer Ogar, MS CCC-SLP

Speech-Language Pathologist, Memory and Aging Center, University of California, San Francisco, San Francisco, California [V2]

Patrick T. O’Gara, MD

Professor of Medicine, Harvard Medical School; Watkins Family Distinguished Chair in Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts [38, 234, 256-263]

HPIM 20e_FM_VOL1_pi-pxlii.indd 33

CONTRIBUTORS

Professor of Medicine, Sections of Clinical Epidemiology and Rheumatology, Department of Medicine, Boston University School of Medicine; Professor of Epidemiology, Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts [364]

C. Warren Olanow, MD, FRCPC, FRCP(hon)

Jeannine M. Petersen, PhD

Karran A. Phillips, MD, MSc Gerald B. Pier, PhD

Richard J. Pollack, PhD

Instructor, Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, Massachusetts; Senior Environmental Public Health Officer, Department of Environmental Health and Safety, Harvard University, Cambridge, Massachusetts; President and Chief Scientific Officer, IdentifyUS LLC, Needham, Massachusetts [452]

Martin R. Pollak, MD

Professor of Medicine, Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, Massachusetts [309]

6/4/18 1:55 PM

xxxiv

Andrew J. Pollard, PhD, FRCPCH, FMedSci

Professor of Paediatric Infection and Immunity, Department of Paediatrics, University of Oxford, Oxford, United Kingdom [150]

Reuben Ramphal, MD

CONTRIBUTORS

Reuven Porat, MD

Adjunct Professor of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida College of Medicine, Gainesville, Florida [159]

Daniel A. Portnoy, PhD

Research Assistant Professor, Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [475]

John T. Potts, Jr., MD

Medical Officer, Division of Foodborne, Waterborne, and Environmental Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia [148]

Professor of Medicine, Department of Internal Medicine, Tel Aviv Souarsky Medical Center; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel [15] Professor, Department of Molecular and Cell Biology and the School of Public Health, University of California, Berkeley, Berkeley, California [146]

Kathryn Moynihan Ramsey, PhD

Agam K. Rao, MD

Jackson Distinguished Professor of Clinical Medicine, Harvard Medical School; Director of Research and Physician-in-Chief Emeritus, Massachusetts General Hospital, Boston, Massachusetts [403]

Kumanan Rasanathan, MBChB, MPH, FAFPHM

Lawrie W. Powell, AC, MD, PhD

James P. Rathmell, MD

Professor Emeritus, The University of Queensland and the Royal Brisbane and Women’s Hospital Queensland, Australia [407]

Alvin C. Powers, MD

Coordinator, Health Systems (HSD), World Health Organization, Phnom Penh, Cambodia [462] Leroy D. Vandam Professor of Anaesthesia, Harvard Medical School; Chair, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [10]

Joe C. Davis Chair in Biomedical Science; Professor of Medicine, Molecular Physiology and Biophysics; Director, Vanderbilt Diabetes Center; Chief, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee [396-398]

Mario C. Raviglione, FRCP (UK), FERS, Hon RSP (RF)

Daniel S. Pratt, MD

Pulmonary Division, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York [176]

Assistant Professor of Medicine, Harvard Medical School; Clinical Director, Liver Transplantation; Director, Autoimmune and Cholestatic Liver Center, Massachusetts General Hospital, Boston, Massachusetts [45, 330]

Michael B. Prentice, MB ChB, PhD, MRCP(UK), FRCPath, FFPRCPI

Professor of Medical Microbiology, Departments of Microbiology and Pathology, University College Cork, Cork, Ireland [166]

Darwin J. Prockop, MD, PhD

Professor and Director, Institute for Regenerative Medicine, Texas A&M Health Science Center, Temple, Texas [406]

Stanley B. Prusiner, MD

Director, Global Health Centre, Milan Institute for Innovative Health Research—MIC, University of Milan, Milan, Italy [173]

Divya Reddy, MD, MPH

Susan Redline, MD, MPH

Peter C. Farrell Professor of Sleep Medicine, Harvard Medical School; Brigham and Women’s Hospital; Beth Israel Deaconess Medical Center, Boston, Massachusetts [291]

Sharon L. Reed, MD, MSCTM, D(ABMM)

Professor of Pathology and Medicine; Director, Microbiology Laboratory, University of California, San Diego School of Medicine, La Jolla, California [216, 218, S14]

Susan E. Reef, MD

Team Leader, Rubella Team, Global Immunization Division, Centers for Disease Control and Prevention, Atlanta, Georgia [201]

Director, Institute for Neurodegenerative Diseases; Professor, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California; Professor, Department of Biochemistry and Biophysics, University of California, San Francisco, California [417, 430]

John J. Reilly, Jr., MD

Thomas C. Quinn, MD

University Professor and Chairman, Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine; Obstetrician-Gynecologist In-Chief, The Milton S. Hershey Medical Center, Hershey, Pennsylvania [466]

Professor of Medicine, Johns Hopkins University, Baltimore, Maryland; Senior Investigator, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [184]

Gil D. Rabinovici, MD

Ed Fein and Pearl Landrith Distinguished Professor, Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California [V2]

Daniel J. Rader, MD

Seymour Gray Professor of Molecular Medicine; Chair, Department of Genetics; Chief, Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania [400]

Kaitlin Rainwater-Lovett, PhD, MPH

Senior Staff Scientist, Applied Biological Sciences, Asymmetric Operations, Johns Hopkins University Applied Physics Laboratory, Laurel, Maryland [200]

Sanjay Ram, MBBS

Professor of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts [151]

HPIM 20e_FM_VOL1_pi-pxlii.indd 34

Richard Krugman Endowed Chair; Vice Chancellor for Health Affairs; Dean, University of Colorado School of Medicine, Aurora, Colorado [A12]

John T. Repke, MD, FACOG

Victor I. Reus, MD

Distinguished Professor of Psychiatry, University of California, San Francisco School of Medicine; UCSF Weill Institute for Neurosciences, San Francisco, California [444]

Bernardo Reyes, MD

Assistant Professor, Department of Integrated Medical Sciences; Assistant Director, Internal Medicine Residency Program, Charles E Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida [464]

Joseph J. Rhatigan, MD

Associate Professor, Harvard Medical School, Harvard School of Public Health; Associate Chief, Division of Global Health Equity, Brigham and Women’s Hospital, Boston, Massachusetts [460]

Peter A. Rice, MD

Professor of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts [151]

6/4/18 1:55 PM

Michael R. Rickels, MD, MS

Associate Professor of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania [397, 398] Clinical Professor of Pediatrics, University of California, San Francisco, San Francisco, California [S9]

Gary L. Robertson, MD

Emeritus Professor of Medicine, Northwestern University School of Medicine, Chicago, Illinois [374]

Dan M. Roden, MD

Professor of Medicine, Pharmacology, and Biomedical Informatics; Director, Oates Institute for Experimental Therapeutics; Senior Vice-President for Personalized Medicine, Vanderbilt University Medical Center, Nashville, Tennessee [63, 64]

James A. Romano, Jr., PhD, DABT, ATS

Principal Senior Life Scientist Advisor, Tunnell Government Services, Inc., Rockville, Maryland [S3]

Karen L. Roos, MD

John and Nancy Nelson Professor of Neurology; Professor of Neurological Surgery, Indiana University School of Medicine, Indianapolis, Indiana [132, 133, 135]

Allan H. Ropper, MD, FRCP, FACP

Professor of Neurology, Harvard Medical School; Raymond D. Adams Master Clinician; Executive Vice Chair, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts [300]

Rossana Rosa, MD

Adjunct Clinical Assistant Professor in Medicine, University of Iowa Carver College of Medicine; Infectious Diseases Physician, UnityPoint Health, Des Moines, Iowa [157]

Ivan O. Rosas, MD

Associate Professor of Medicine, Harvard Medical School; Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [287]

Misha Rosenbach, MD

Assistant Professor, Perelman School of Medicine at the University of Pennsylvania, Departments of Dermatology and Internal Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania [56]

Roger N. Rosenberg, MD

Zale Distinguished Chair and Professor of Neurology, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas [431, S10]

Myrna R. Rosenfeld, MD, PhD

Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; Adjunct Professor, University of Pennsylvania, Philadelphia, Pennsylvania [90]

Michael A. Rubin, MD, PhD

Professor of Medicine, University of Utah School of Medicine, Salt Lake City, Utah [31]

Steven A. Rubin, PhD

Chief, Laboratory of Method Development, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland [202]

Robert M. Russell, MD

Professor Emeritus of Medicine and Nutrition, Tufts University Friedman School of Nutrition Science and Policy; Jaharis Family Center for Biomedical and Nutrition Sciences, Boston, Massachusetts [326]

Thomas A. Russo, MD, CM

xxxv

Salvatore Pablo Lucia Professor of Epidemiology, Preventive Medicine, Pediatrics and History; Vice Chair, Department of Epidemiology and Biostatistics; Head, Division of Infectious Disease Epidemiology, University of California, San Francisco, San Francisco, California [461]

Edward T. Ryan, MD, FACP, FIDSA, FASTMH, FAAM

Professor of Medicine, Harvard Medical School; Professor of Immunology and Infectious Diseases, Harvard School of Public Health; Director, Global Infectious Diseases, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts [163]

CONTRIBUTORS

Elizabeth Robbins, MD

George W. Rutherford, MD, MA

David J. Salant, MD

Professor of Medicine, Boston University School of Medicine; Chief, Section of Nephrology, Boston Medical Center, Boston, Massachusetts [310]

Richard B. Saltman, PhD

Professor of Health Policy and Management, Rollins School of Public Health, Emory University, Atlanta, Georgia [5]

Martin A. Samuels, MD, DSc(hon), FAAN, MACP, FRCP, FANA Miriam Sydney Joseph Professor of Neurology, Harvard Medical School; Chair, Department of Neurology, Brigham and Women’s Hospital; Director, Brigham and Women’s Institute for the Neurosciences, Boston, Massachusetts [V7]

Vaishali Sanchorawala, MD

Professor of Medicine; Director, Autologous Stem Cell Transplant Program; Associate Director, Amyloidosis Center, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts [108]

Philippe J. Sansonetti, MD

Professor, Collège de France; Institut Pasteur, Paris, France [161]

Clifford B. Saper, MD, PhD

James Jackson Putnam Professor of Neurology and Neuroscience, Harvard Medical School; Chairman, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts [27]

Edward A. Sausville, MD, PhD

Professor of Medicine, University of Maryland School of Medicine; Associate Director for Clinical Research, Marlene and Stewart Greenbaum Cancer Center, Baltimore, Maryland [69]

Mohamed H. Sayegh, MD, FAHA, FASN, ASCI, AAP, FRCP Raja N. Khuri Dean, Faculty of Medicine; Vice President of Medical Affairs; Professor of Medicine and Immunology, American University of Beirut; Lecturer in Medicine, Schuster Family Transplantation Research Center, Brigham and Women’s Hospital, Boston, Massachusetts [307]

David T. Scadden, MD

Gerald and Darlene Jordan Professor of Medicine; Chair and Professor, Department of Stem Cell and Regenerative Biology, Harvard University; Director, Center for Regenerative Medicine; Massachusetts General Hospital, Co-director, Harvard Stem Cell Institute; Cambridge, Massachusetts [92]

Thomas E. Scammell, MD

Professor, Harvard Medical School; Beth Israel Deaconess Medical Center; Boston Children’s Hospital, Boston, Massachusetts [27]

Anthony H. V. Schapira, MD, DSc, FRCP, FMedSci

Head and Professor, Department of Clinical Neurosciences, UCL Institute of Neurology; Director of UCL Royal Free Campus; Vice-Dean UCL, London, United Kingdom [427]

Staff Physician, Western New York VA Healthcare System; Professor of Medicine and Microbiology and Immunology; Vice Chair of Medicine; Head, Division of Infectious Disease, University at Buffalo, State University of New York, Buffalo, New York [156, 170, 171]

HPIM 20e_FM_VOL1_pi-pxlii.indd 35

6/4/18 1:55 PM

xxxvi

CONTRIBUTORS

Howard I. Scher, MD

Julian Solway, MD

Anne Schuchat, MD

Michael F. Sorrell, MD

Marc A. Schuckit, MD

Eric J. Sorscher, MD

H. Ralph Schumacher,† Jr., MD

Brad Spellberg, MD, FIDSA, FACP

Professor of Medicine, Joan and Sanford Weill College of Medicine of Cornell University; D. Wayne Calloway Chair in Urologic Oncology; Attending Physician and Chief, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York [83] RADM, U.S. Public Health Service; Assistant Surgeon General, Centers for Disease Control and Prevention, Atlanta, Georgia [118] Distinguished Professor of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California [445] Professor of Medicine, Division of Rheumatology, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania [365]

William W. Seeley, MD

Professor of Neurology and Pathology, Memory and Aging Center, University of California, San Francisco, San Francisco, California [25, 423-426]

Walter L. Palmer Distinguished Service Professor of Medicine and Pediatrics, Dean for Translational Medicine, Biological Sciences Division; Vice Chair for Research, Department of Medicine; Chair, Committee on Molecular Medicine, University of Chicago, Chicago, Illinois [279, 290] UNMC Distinguished Chair in Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska [335] Hertz Professor of Cystic Fibrosis Research, Emory University, Georgia Research Alliance Eminent Scholar, Atlanta, Georgia [285] Chief Medical Officer, LAC+USC Medical Center; Associate Dean for Clinical Affairs; Professor of Clinical Medicine, Division of Infectious Diseases, Keck School of Medicine at USC, Los Angeles, California [213]

Jerry L. Spivak, MD

Julian L. Seifter, MD

Professor of Medicine and Oncology, Hematology Division, Johns Hopkins University School of Medicine, Baltimore, Maryland [99]

Jaime Sepulveda, MD, MPH, DSc

Associate Professor, Department of Medicine, Johns Hopkins University, Baltimore, Maryland [238-240]

Christopher W. Seymour, MD, MSc

Faculty Member, Harvard Medical School; Program Director of Gynecologic Oncology at the Massachusetts General Hospital Cancer Center, Boston, Massachusetts [85]

Associate Professor of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [313] Haile T. Debas Distinguished Professor of Global Health; Director, Institute for Global Health Sciences, University of California, San Francisco, San Francisco, California [461]

David D. Spragg, MD

David Spriggs, MD, FACP, FASCO

Assistant Professor, Department of Critical Care and Emergency Medicine; The CRISMA Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania [297]

E. William St. Clair, MD

Ankoor Shah, MD

John M. Stafford, MD, PhD

Assistant Professor, Department of Medicine, Division of Rheumatology and Immunology, Duke University Medical Center, Durham, North Carolina [351]

Erica S. Shenoy, MD, PhD

Professor of Medicine and Immunology, Department of Medicine, Duke University Medical Center, Durham, North Carolina [351] Associate Professor of Medicine, Diabetes and Endocrinology, Vanderbilt University School of Medicine, Nashville, Tennessee [398]

Matthew W. State, MD, PhD

Assistant Professor of Medicine, Harvard Medical School; Associate Chief, Infection Control Unit, Massachusetts General Hospital, Boston, Massachusetts [139]

Oberndorf Family Distinguished Professor in Psychiatry; Chair, Department of Psychiatry; Director, Langley Porter Psychiatric Institute and Hospital, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California [443]

Kanade Shinkai, MD, PhD

Allen C. Steere, MD

Edwin K. Silverman, MD, PhD

Dennis L. Stevens, MD, PhD

Karl L. Skorecki, MD, FRCP(C), FASN

Lynne Warner Stevenson, MD

Associate Professor, Department of Dermatology, University of California, San Francisco, San Francisco, California [56] Professor of Medicine, Harvard Medical School; Chief, Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [286] Annie Chutick Professor in Medicine (Nephrology); Director, Rappaport Research Institute, Technion-Israel Institute of Technology; Director, Medical and Research Development, Rambam Health Care Campus, Haifa, Israel [305, 472]

Wade S. Smith, MD, PhD

Professor of Neurology, Daryl R. Gress Endowed Chair of Neurocritical Care and Stroke; Director, University of California, San Francisco Neurovascular Service, San Francisco, California [301, 302, 419-421]

Kelly A. Soderberg, PhD, MPH

Associate Director, Duke Center for HIV/AIDS Vaccine ImmunologyImmunogen Discovery, Duke Human Vaccine Institute, Duke University, Durham, North Carolina [342]

Scott D. Solomon, MD

Professor, Harvard Medical School; Director, Noninvasive Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts [236, A8] Deceased

†

HPIM 20e_FM_VOL1_pi-pxlii.indd 36

Professor of Medicine, Harvard Medical School; Massachusetts General Hospital, Boston, Massachusetts [181] Professor of Medicine, University of Washington School of Medicine, Seattle, Washington; ACOS for Research and Development, Veterans Affairs Medical Center, Boise, Idaho [124, 149] Lisa M. Jacobson Professor of Medicine; Director of Cardiomyopathy, Vanderbilt University Medical Center, Nashville, Tennessee [254]

William G. Stevenson, MD

Professor of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee [241-251, 299]

Benjamin K. Stoff, MD, MAB

Assistant Professor of Dermatology, Emory University School of Medicine, Senior Faculty Fellow, Emory Center for Ethics, Atlanta, Georgia [A4]

John H. Stone, MD, MPH

Professor of Medicine, Harvard Medical School; The Edward A. Fox Chair in Medicine; Director, Clinical Rheumatology, Massachusetts General Hospital, Boston, Massachusetts [361]

Lewis R. Sudarsky, MD

Associate Professor of Neurology, Harvard Medical School; Director, Division of Movement Disorders, Brigham and Women’s Hospital, Boston, Massachusetts [23]

6/4/18 1:55 PM

Shyam Sundar, MD, FRCP, FNA

Professor of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India [221] Instructor in Pediatrics, Harvard Medical School; Assistant in Medicine, Boston Children’s Hospital, Boston, Massachusetts [115, 172, 459]

Paolo M. Suter, MD, MS

Professor of Medicine, Clinic and Policlinic of Internal Medicine, University Hospital, Zurich, Switzerland [326]

Geoffrey Tabin, MD

Fairweather Foundation Endowed Chair; Professor of Ophthalmology and Global Health, Stanford University; Director, Himalayan Cataract Project, Palo Alto, California [453]

Caroline M. Tanner, MD, PhD

Professor, Department of Neurology, University of California, San Francisco; Director, Parkinson’s Disease Research Education and Clinical Center, San Francisco Veteran’s Affairs Health Care System, San Francisco, California [426]

Maria Carmela Tartaglia, MD

Associate Professor, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada [V2]

Joel D. Taurog, MD

Professor of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, Texas [355]

Ayalew Tefferi, MD

Professor of Medicine and Hematology, Mayo Clinic, Rochester, Minnesota [106]

Stephen C. Textor, MD

Professor of Medicine, Division of Nephrology and Hypertension, Mayo Clinic School of Medicine, Rochester, Minnesota [272]

R. V. Thakker, FRS, FMedSci

May Professor of Medicine, Academic Endocrine Unit, University of Oxford; O.C.D.E.M., Churchill Hospital, Headington, Oxford, United Kingdom [381]

Holger Thiele, MD

Professor of Medicine, University of Luebeck, Germany, Director, University Heart Center Luebeck, Cardiology/Angiology and Intensive Care Medicine, Luebeck, Germany [298]

C. Louise Thwaites, MD, MBBS

Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam [147]

Pierre Tiberghien, MD, PhD

Professor of Medicine, Bourgogne Franche-Comté University; Director, Medicine and Research, Etablissement Français du Sang, Paris, France [109]

Zelig A. Tochner, MD

Professor Emeritus of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania [S4]

Gordon F. Tomaselli, MD

Michel Mirowski, MD Professor of Cardiology; Professor of Medicine and Cellular and Molecular Medicine; Chief, Division of Cardiology, Johns Hopkins University, Baltimore, Maryland [238-240]

Karina A. Top, MD, MS

Assistant Professor of Pediatrics and Community Health & Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada [155]

Mark Topazian, MD

Professor of Medicine, Mayo Clinic, Rochester, Minnesota [315, V5]

xxxvii

Associate Professor, Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine; Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas [130]

Elbert P. Trulock, III, MD

Rosemary and I. Jerome Flance Professor in Pulmonary Medicine, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine; The Lung Transplantation Program, Barnes-Jewish Hospital, St. Louis, Missouri [292]

CONTRIBUTORS

Neeraj K. Surana, MD, PhD

Barbara W. Trautner, MD, PhD

Kenneth L. Tyler, MD

Reuler-Lewin Family Professor and Chair of Neurology; Professor of Medicine, Immunology, and Microbiology, University of Colorado School of Medicine, Aurora, Colorado; Neurologist, Denver Veterans Affairs Medical Center, Denver, Colorado [132, 133, 135]

Walter J. Urba, MD, PhD

Physician Director of Research; Co-Director, Melanoma Program, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon [72]

Prashant Vaishnava, MD

Assistant Professor of Medicine, Icahn School of Medicine at Mount Sinai Director of Quality, Mount Sinai Heart, Mount Sinai Hospital New York, New York [467]

Anne Marie Valente, MD

Associate Professor of Medicine and Pediatrics, Harvard Medical School; Director of Outpatient Services, Boston Adult Congenital Heart Disease and Pulmonary Hypertension Program, Boston Children’s Hospital, Brigham and Women’s Hospital, Boston, Massachusetts [264]

Jos W. M. van der Meer, MD, PhD

Professor of Medicine, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands [17, 442]

Edouard Vannier, PharmD, PhD

Assistant Professor, Division of Geographic Medicine and Infectious Diseases, Department of Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts [220]

Gauri R. Varadhachary, MD

Professor, Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas [88]

John Varga, MD

John Hughes Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois [353]

Christy A. Varughese, PharmD, BCPS

Clinical Pharmacy Specialist; Co-Director, Antimicrobial Stewardship Program, Department of Pharmacy, Rush University Medical Center, Chicago, Illinois [139]

David J. Vaughn, MD

Genitourinary Medical Oncology Professor, Perelman School of Medicine at the University of Pennsylvania, Perelman Center for Advanced Medicine, Philadelphia, Pennsylvania [84]

Birgitte Jyding Vennervald, MD, MSA

Professor, Section for Parasitology and Aquatic Pathobiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark [229]

Luciano Villarinho, MD

Chief of Radiology, Department of Tacchini Hospital—Bento Goncalves, Rio Grande do Sul, Brazil [A16]

Bert Vogelstein, MD

Professor and Director, Ludwig Center at Johns Hopkins University School of Medicine, Baltimore, Maryland; Investigator, Howard Hughes Medical Institute, Chevy Chase, Maryland; Scholar, Lustgarten Foundation For Cancer Research, Bethpage, New York [67]

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xxxviii

Everett E. Vokes, MD

Robert A. Weinstein, MD

Tamara J. Vokes, MD

Jeffrey I. Weitz, MD, FRCP(C), FRSC, FACP

John E. Ultmann Professor; Chairman, Department of Medicine; Physician-in-Chief, University of Chicago Medicine and Biological Sciences, Chicago, Illinois [73]

CONTRIBUTORS

Professor, Department of Medicine, Section of Endocrinology, University of Chicago, Chicago, Illinois [405]

Kevin G. Volpp, MD, PhD

The C. Anderson Hedberg, MD Professor of Internal Medicine, Rush Medical College; Chief Academic Officer, Cook County Health and Hospitals System, Chicago, Illinois [137] Professor of Medicine and Biochemistry and Biomedical Sciences, McMaster University; Executive Director, Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada [114]

Director of the Center for Health Incentives and Behavioral Economics; Vice Chairman for Health Policy in Medical Ethics and Health Policy; Physician, Cresencz Philadelphia VA Medical Center; Professor of Medicine and Health Care Management, Perelman School of Medicine and Wharton School, University of Pennsylvania, Philadelphia, Pennsylvania [468]

Peter F. Weller, MD

Daniel D. Von Hoff, MD, FACP, FASCO, FAACR

Assistant Professor of Medicine, Division of Sleep Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [291]

Physician-in-Chief, Distinguished Professor, Translational Genomics Research Institute (TGEN), Phoenix, Arizona; Virginia G. Piper Distinguished Chair for Innovative Cancer Research and Chief Scientific Officer, Honor Health Research Institute; Chief Scientific Officer, US Oncology; Senior Consultant-Clinical Investigations, City of Hope; Professor of Medicine, Mayo Clinic, Scottsdale, Arizona [79]

Jiˇri F. P. Wagenaar, MD, PhD

Leptospirosis Reference Center, Academic Medical Center, Medical Microbiology, Amsterdam, The Netherlands [179]

Sushrut S. Waikar, MD

Associate Professor of Medicine, Harvard Medical School; Constantine L. Hampers, MD Distinguished Chair in Renal Medicine; Director of Translational Research and Ambulatory Services, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts [304]

Matthew K. Waldor, MD, PhD

Edward H. Kass Professor of Medicine, Division of Infectious Diseases, Brigham and Women’s Hospital; Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts [163]

David H. Walker, MD

The Carmage and Martha Walls Distinguished University Chair in Tropical Diseases; Professor, Department of Pathology; Executive Director, Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas [182]

Mark F. Walker, MD

Associate Professor, Neurology, Case Western Reserve University; Cleveland VA Medical Center, Cleveland, Ohio [19]

Fred Wang, MD

Professor of Medicine and Professor of Microbiology and Immunobiology, Harvard Medical School; Medical Director, Clinical Virology Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts [185, 191]

John W. Warren, MD

Professor of Medicine, University of Maryland School of Medicine, Baltimore, Maryland [47]

Aaron B. Waxman, MD, PhD

Associate Professor of Medicine, Harvard Medical School; Executive Director, Center for Pulmonary Heart Disease; Director, Pulmonary Vascular Disease Program, Pulmonary Critical Care Medicine, Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [277]

Michael E. Wechsler, MD, MMSc

Professor of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado [282]

Anthony P. Weetman, MD, DSc

University of Sheffield, School of Medicine Sheffield, United Kingdom [375-378]

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William B. Castle Professor of Medicine, Harvard Medical School; Chief, Infectious Disease Division; Chief, Allergy and Inflammation Division; Beth Israel Deaconess Medical Center, Boston, Massachusetts [224-228, 230]

Andrew Wellman, MD, PhD

Patrick Y. Wen, MD

Professor of Neurology, Harvard Medical School; Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute; Director, Division of Neuro-Oncology, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts [86]

Michael R. Wessels, MD

John F. Enders Professor of Pediatrics; Professor of Medicine, Harvard Medical School; Chief, Division of Infectious Diseases, Boston Children’s Hospital, Boston, Massachusetts [143]

L. Joseph Wheat, MD

President and Medical Director, MiraVista Diagnostics, LLC, Indianapolis, Indiana [207]

A. Clinton White, Jr., MD

Professor, Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas [230]

Nicholas J. White, DSc, MD, FRCP, F Med Sci, FRS

Professor of Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Mahidol-Oxford Research Unit, Bangkok, Thailand [219, A6]

Richard J. Whitley, MD

Distinguished Professor; Loeb Eminent Scholar Chair in Pediatrics; Professor of Pediatrics, Microbiology, Medicine and Neurosurgery, The University of Alabama at Birmingham, Birmingham, Alabama [188]

Michael R. Wilson, MD, MAS

Assistant Professor in Neurology, University of California San Francisco; Staff Physician, University of California San Francisco Medical Center and Zuckerberg San Francisco General Hospital, San Francisco, California [134]

Bruce U. Wintroub, MD

Professor and Chair, Department of Dermatology, University of California, San Francisco, San Francisco, California [56]

Allan W. Wolkoff, MD

The Herman Lopata Chair in Liver Disease Research; Professor of Medicine and Anatomy and Structural Biology; Associate Chair of Medicine for Research; Chief, Division of Gastroenterology and Liver Diseases; Director, Marion Bessin Liver Research Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York [331]

John B. Wong, MD

Professor of Medicine, Tufts University School of Medicine; Chief, Division of Clinical Decision Making, Department of Medicine; Tufts New England Medical Center, Boston, Massachusetts [3]

Louis Michel Wong Kee Song, MD

Professor of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota [315, V5]

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Jennifer A. Woyach, MD

Associate Professor, Division of Hematology, The Ohio State University, Columbus, Ohio [103] Professor of Pediatrics, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire [195]

Richard Wunderink, MD

Professor, Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine, Chicago, Illinois [121]

Kim B. Yancey, MD

Professor and Chair, Department of Dermatology, University of Texas Southwestern Medical Center in Dallas, Dallas, Texas [52, 55]

Baligh R. Yehia, MD, MPP, MSc

Johns Hopkins University School of Medicine, Baltimore, Maryland [393]

Janet A. Yellowitz, DMD, MPH

Associate Professor; Director, Special Care and Geriatric Dentistry, University of Maryland School of Dentistry, Baltimore, Maryland [A2]

Lam Minh Yen, MD

Director, Tetanus Intensive Care Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam [147]

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Chief, Hematology Branch, National Heart, Lung and Blood Institute; Director, NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland [98, 470]

Victor L. Yu, MD

Professor of Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania [154]

Jing Zhou, MD, PhD, FASN

Professor of Medicine, Harvard Medical School; Director, Laboratory of Molecular Genetics and Developmental Biology of Disease, Renal Division; Director, Center for Polycystic Kidney Disease Research, Brigham and Women’s Hospital; Boston, Massachusetts [309]

CONTRIBUTORS

Peter F. Wright, MD

Neal S. Young, MD

Werner Zimmerli, MD

Professor of Medicine, Basel University; Interdisciplinary Unit of Orthopaedic Infection, Kantonspital Baselland, Liestal, Switzerland [126]

Laura A. Zimmerman, MPH

Epidemiologist, Centers for Disease Control and Prevention, Atlanta, Georgia [201]

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Preface The Editors are pleased to present the 20th edition of Harrison’s Principles of Internal Medicine. This 20th edition is a true landmark in medicine, spanning 68 years and multiple generations of trainees and practicing clinicians. While medicine and medical education have evolved, readers will appreciate how this classic textbook has retained enduring features that have distinguished it among medical texts—a sharp focus on the clinical presentation of disease, expert in-depth summaries of pathophysiology and treatment, and highlights of emerging frontiers of science and medicine. Indeed, Harrison’s retains its conviction that, in the profession of medicine, we are all perpetual students and lifelong learning is our common goal. Harrison’s is intended for learners throughout their careers. For students, Part 1, Chapter 1 begins with an overview of “The Practice of Medicine.” In this introductory chapter, the editors continue the tradition of orienting clinicians to the science and the art of medicine, emphasizing the values of our profession while incorporating new advances in technology, science, and clinical care. Part 2, “Cardinal Manifestations and Presentation of Diseases” is a signature feature of Harrison’s. These chapters eloquently describe how patients present with common clinical conditions, such as headache, fever, cough, palpitations, or anemia, and provide an overview of typical symptoms, physical findings, and differential diagnosis. Mastery of these topics prepares students for subsequent chapters on specific diseases they will encounter in courses on pathophysiology and in clinical clerkships. For residents and fellows caring for patients and preparing for board exams, Harrison’s remains a definitive source of trusted content written by internationally renowned experts. Trainees will be reassured by the depth of content, comprehensive tables, and illuminating figures and clinical algorithms. Many exam questions are based on key testing points derived from Harrison’s chapters. A useful companion book, Harrison’s Self-Assessment and Board Review, includes over 1000 questions, offers comprehensive explanations of the correct answer, and provides links to the relevant chapter in the textbook. Practicing clinicians must keep up with an ever-changing knowledge base and clinical guidelines as part of lifelong learning. Clinicians can trust that chapters are updated extensively with each edition of Harrison’s. The text is an excellent point-ofcare reference for clinical questions, differential diagnosis, and patient management. In addition to the expanded and detailed Treatment sections, Harrison’s continues its tradition of including “Approach to the Patient” sections, which provide an expert’s overview of the practical management of common but often complex clinical conditions. This edition has been modified extensively in its format as well as its content. We have reincorporated chapters that in previous editions were available only online. The 20th edition marks the return of Harrison’s “Further Reading” citations at the end of each chapter, providing references carefully selected by our contributors. The authors and editors have rigorously curated and synthesized the vast amount of information that comprises general internal medicine—and each of the major specialties—into a highly readable and informative twovolume book. Readers will appreciate the concise writing style and consistency of format that have always characterized Harrison’s. This book has a sharp focus on essential information with a goal of providing clear and definitive answers to clinical questions. In addition to the printed book, Harrison’s is available on multiple digital platforms, including eBook and app versions, and via an online subscription available through McGraw-Hill’s popular Access Medicine (www.accessmedicine.com) collection. The digital editions feature an array of supplementary videos, databases, and photographic atlases as well as new literature updates, tutorials, animations, and audio discussions covering key topics in medicine. Harrison’s Manual of Medicine is a condensed pocket version of clinical essentials derived from the more comprehensive Harrison’s Principles of Internal Medicine. The Manual is also available as an eBook and an app and via Access Medicine. Together, these platforms form a potent Harrison’s collection of reference, test prep, and point-of-care online content.

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In the 20th edition, examples of new chapters include “Promoting Good Health,” focusing on prevention and practical lifestyle changes to enhance longevity and well-being; “Health Care Systems in Developed Countries,” providing a comparison of health delivery models from around the world; “Pharmacogenomics,” applying new approaches for selecting precision medicines and appropriate doses; “Bacterial Resistance to Antimicrobial Agents,” highlighting the widespread and often inappropriate use of antibiotics in clinical care and agriculture; “LGBT Health,” outlining strategies to enhance access and care models for populations with distinctive health care needs; “Neuromyelitis Optica,” summarizing disorders with similarities to multiple sclerosis but requiring different treatments; “Worldwide Changes in Patterns of Infectious Disease,” reviewing the dynamic evolution of new infectious diseases and the containment of older disorders, some of which have plagued humankind for centuries; and “Approach to the Medical Consultation,” providing practical advice to ensure that the consultant addresses the needs of the referring clinician. In addition to these and other new topics, the 20th edition presents a fascinating new series of chapters entitled “Frontiers,” which foreshadows cutting-edge science that will change medical practice in the near term. Examples of new Frontier chapters include “Telomere Disease,” “The Role of Epigenetics in Disease and Treatment,” “The Role of Circadian Biology in Health and Disease,” and “Behavioral Economics and Health.” In addition to these new topics, major advances in each subspecialty of internal medicine have been incorporated into this edition. Of particular note in this 20th edition are critical updates in the classic chapter on HIV/AIDS, which offers a clinically pragmatic focus as well as a comprehensive and analytical approach to pathogenesis. The updates cover the latest treatment protocols and address the issue of combination prevention modalities, making the chapter the most up-to-date treatise on HIV disease available. Readers will find expanded coverage of neurodegenerative diseases, highlighting important advances in their classification and management and delineating new mechanisms responsible for the deposition and spread of pathogenic protein aggregates in these disorders. Practical guidance for the use of highly effective therapies for multiple sclerosis is another highlight of the new edition. The chapter on chronic hepatitis discusses in detail the dramatic new discoveries in the use of direct-acting antiviral agents for the treatment and cure of chronic hepatitis C virus disease; these agents are responsible for some of the most exciting therapeutic advances in medicine today. The promise of the Human Genome Project continues to be realized in clinical medicine. This is reflected throughout the book but particularly highlighted by advances in our understanding of genetic heterogeneity of cancers, including molecular nosology that distinguishes distinct entities that share histologic similarities. The tools of genetics also inform the use of therapies targeting specific genetic lesions and immune system activation. Genetic counseling for patients with genetic predisposition to cancer (e.g., BRCA 1/2) is informing prevention strategies and reducing cancer risk. Our understanding of the microbiome, its relevance to normal physiology and disease pathogenesis, and its implications for treatment of a variety of diseases is expanding rapidly, and these advances are captured in a completely rewritten chapter “The Human Microbiome” and a thoroughly updated chapter “Microbial Genomics and Infectious Disease.” The classification and management of diabetes has been thoroughly updated on the basis of new studies, clinical guidelines, and treatments. Updated guidelines for testosterone management and replacement are based on the results of new clinical trials. We have many people to thank for their efforts in producing this book. First, the authors have done a superb job of producing authoritative chapters that synthesize vast amounts of scientific and clinical data to create informative and practical approaches to managing patients. In today’s information-rich, rapidly evolving environment, they have ensured that this information is current. We are most

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production of this multi-authored textbook proceeded smoothly and efficiently. Priscilla Beer and Armen Ovsepyen oversaw the production of our videos and animations. Jeffrey Herzich, along with other members of the McGraw-Hill Education staff, shepherded the production of this new edition. We are privileged to have compiled this 20th edition and are enthusiastic about all that it offers our readers. We learned much in the process of editing Harrison’s and hope that you will find this edition uniquely valuable as a clinical and educational resource. The Editors

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PREFACE

grateful to our colleagues who work closely with each editor to facilitate communication with the authors and help us keep Harrison’s content current. In particular, we wish to acknowledge the expert support of Patricia Conrad, Patricia L. Duffey, Gregory K. Folkers, Julie B. McCoy, Elizabeth Robbins, Anita Rodriguez, and Stephanie Tribuna. Scott Grillo and James Shanahan, our long-standing partners at McGraw-Hill Education’s Professional Publishing group, have inspired the creative and dynamic evolution of Harrison’s, guiding the development of the book and its related products in new formats. Kim Davis, as Managing Editor, has adeptly ensured that the complex

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The Profession of Medicine

1

The Practice of Medicine The Editors

ENDURING VALUES OF THE MEDICAL PROFESSION

No greater opportunity, responsibility, or obligation can fall to the lot of a human being than to become a physician. In the care of the suffering, [the physician] needs technical skill, scientific knowledge, and human understanding.… Tact, sympathy, and understanding are expected of the physician, for the patient is no mere collection of symptoms, signs, disordered functions, damaged organs, and disturbed emotions. [The patient] is human, fearful, and hopeful, seeking relief, help, and reassurance. —Harrison’s Principles of Internal Medicine, 1950

The practice of medicine has changed in significant ways since the first edition of this book appeared in 1950. The advent of molecular genetics, sophisticated new imaging techniques, robotics, and advances in bioinformatics and information technology have contributed to an explosion of scientific information that has changed fundamentally the way physicians define, diagnose, treat, and attempt to prevent disease. This growth of scientific knowledge is ongoing and accelerating. The widespread use of electronic medical records and the Internet have altered the way physicians access and exchange information as a routine part of medical practice (Fig. 1-1). As today’s physicians strive to integrate copious amounts of scientific knowledge into everyday practice, it is critically important to remember two things: first, the ultimate goal of medicine is to prevent disease and, when it occurs, to diagnose it early and provide effective treatment; and second, despite nearly 70 years of scientific advances since the first edition of this text, a trusting relationship between physician and patient still lies at the heart of successful patient care.

■■THE SCIENCE AND ART OF MEDICINE

Deductive reasoning and applied technology form the foundation for the solution to many clinical problems. Spectacular advances in biochemistry, cell biology, and genomics, coupled with newly developed imaging techniques, allow access to the innermost parts of the cell and provide a window into the most remote recesses of the body. Revelations about the nature of genes and single cells have opened a portal for formulating a new molecular basis for the physiology of systems. Increasingly, physicians are learning how subtle changes in many different genes can affect the function of cells and organisms. Researchers are deciphering the complex mechanisms by which genes are regulated. Clinicians have developed a new appreciation of the role of stem cells in normal tissue function, in the development of cancer and other disorders, and in the treatment of certain diseases. Entirely new areas of research, including studies of chronobiology, the human microbiome, and epigenetics, have become important for understanding both health and disease. Information technology enables the interrogation of medical records from millions of individuals, yielding new insights into the etiology, characteristics, and stratification of many diseases. The knowledge gleaned from the science of medicine continues to enhance the understanding by physicians of complex pathologic processes and to provide new approaches to disease prevention, diagnosis, and treatment. Yet skill in the most sophisticated applications of laboratory technology and in the use of the latest therapeutic modality alone does not make a good physician. When a patient poses challenging clinical problems, an effective physician must be able to identify the crucial elements in a complex history and physical examination; order the appropriate laboratory, imaging, and diagnostic tests; and extract the key results from densely

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PART 1

populated computer screens to determine whether to treat or to “watch.” As the number of tests increases, so does the likelihood that some incidental finding, completely unrelated to the clinical problem at hand, will be uncovered. Deciding whether a clinical clue is worth pursuing or should be dismissed as a “red herring” and weighing whether a proposed test, preventive measure, or treatment entails a greater risk than the disease itself are essential judgments that a skilled clinician must make many times each day. This combination of medical knowledge, intuition, experience, and judgment defines the art of medicine, which is as necessary to the practice of medicine as is a sound scientific base.

■■CLINICAL SKILLS History-Taking  The recorded history of an illness should include all the facts of medical significance in the life of the patient. Recent events should be given the most attention. Patients should, at some early point, have the opportunity to tell their own story of the illness without frequent interruption and, when appropriate, should receive expressions of interest, encouragement, and empathy from the physician. Any event related by a patient, however trivial or seemingly irrelevant, may provide the key to solving the medical problem. A methodical review of systems is important to elicit features of an underlying disease that might not be mentioned in the patient’s narrative. In general, patients who feel comfortable with the physician will offer more complete information; thus, putting the patient at ease contributes substantially to obtaining an adequate history. An informative history is more than an orderly listing of symptoms. By listening to patients and noting the way in which they describe their symptoms, physicians can gain valuable insight. Inflections of voice, facial expression, gestures, and attitude (i.e., “body language”) may offer important clues to patients’ perception of their symptoms. Because patients vary considerably in their medical sophistication and ability to recall facts, the reported medical history should be corroborated whenever possible. The social history also can provide important insights into the types of diseases that should be considered and can identify practical considerations for subsequent management. The family history not only identifies rare Mendelian disorders but often reveals risk factors for common disorders, such as coronary heart disease, hypertension, autoimmunity, and asthma. A thorough family history may require input from multiple relatives to ensure completeness and accuracy. An experienced clinician can usually formulate a relevant differential diagnosis from the history alone, using the physical examination and diagnostic tests to narrow the list or reveal unexpected findings that lead to more focused inquiry. The very act of eliciting the history provides the physician with an opportunity to establish or enhance a unique bond that forms the basis for a good patient–physician relationship. This process helps the physician develop an appreciation of the patient’s view of the illness, the patient’s expectations of the physician and the health care system, and the financial and social implications of the illness for the patient. Although current health care settings may impose time constraints on patient visits, it is important not to rush the encounter. A hurried approach may lead patients to believe that what they are relating is not of importance to the physician, and thus they may withhold relevant information. The confidentiality of the patient–physician relationship cannot be overemphasized. Physical Examination  The purpose of the physical examination is to identify physical signs of disease. The significance of these objective indications of disease is enhanced when they confirm a functional or structural change already suggested by the patient’s history. At times, however, physical signs may be the only evidence of disease and may not have been suggested by the history. The physical examination should be methodical and thorough, with consideration given to the patient’s comfort and modesty. Although

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2

PART 1 The Profession of Medicine FIGURE 1-1  Woodcuts from Johannes de Ketham’s Fasciculus Medicinae, the first illustrated medical text ever printed, show methods of information access and exchange in medical practice during the early Renaissance. Initially published in 1491 for use by medical students and practitioners, Fasciculus Medicinae appeared in six editions over the next 25 years. Left: Petrus de Montagnana, a well-known physician and teacher at the University of Padua and author of an anthology of instructive case studies, consults medical texts dating from antiquity up to the early Renaissance. Right: A patient with plague is attended by a physician and his attendants. (Courtesy, U.S. National Library of Medicine.)

attention is often directed by the history to the diseased organ or part of the body, the examination of a new patient must extend from head to toe in an objective search for abnormalities. The results of the examination, like the details of the history, should be recorded at the time they are elicited—not hours later, when they are subject to the distortions of memory. Physical examination skills should be learned under direct observation of experienced clinicians. Even highly experienced clinicians can benefit from ongoing coaching and feedback. Simulation laboratories and standardized patients play an increasingly important role in the development of clinical skills. Although the skills of physical diagnosis are acquired with experience, it is not merely technique that determines success in identifying signs of disease. The detection of a few scattered petechiae, a faint diastolic murmur, or a small mass in the abdomen is not a question of keener eyes and ears or more sensitive fingers, but of a mind alert to those findings. Because physical findings can change with time, the physical examination should be repeated as frequently as the clinical situation warrants. Given the many highly sensitive diagnostic tests now available (particularly imaging techniques), it may be tempting to place less emphasis on the physical examination. Indeed, many patients are seen by consultants after a series of diagnostic tests have been performed and the results are known. This fact should not deter the physician from performing a thorough physical examination since important clinical findings may have escaped detection. The act of examining (touching) the patient also offers an opportunity for communication and may have reassuring effects that foster the patient–physician relationship.

Diagnostic Studies  Physicians rely increasingly on a wide array of laboratory and imaging tests to make diagnoses and ultimately to

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solve clinical problems. However, accumulated results do not relieve the physician from the responsibility of carefully observing and examining the patient. It is also essential to appreciate the limitations of diagnostic tests. By virtue of their apparent precision, these tests often gain an aura of certainty regardless of the fallibility of the tests themselves, the instruments used in the tests, and the individuals performing or interpreting the tests. Physicians must weigh the expense involved in laboratory procedures against the value of the information these procedures are likely to provide. Single laboratory tests are rarely ordered. Instead, physicians generally request “batteries” of multiple tests, which often prove useful and can be performed with a single specimen at relatively low cost. For example, abnormalities of hepatic function may provide the clue to nonspecific symptoms such as generalized weakness and increased fatigability, suggesting a diagnosis of chronic liver disease. Sometimes a single abnormality, such as an elevated serum calcium level, points to a particular disease, such as hyperparathyroidism or an underlying malignancy. The thoughtful use of screening tests (e.g., measurement of lowdensity lipoprotein cholesterol) may allow early intervention to prevent disease (Chap. 4). Screening tests are most informative when they are directed toward common diseases and when their results indicate whether other useful—but often costly—tests or interventions are needed. On the one hand, biochemical measurements, together with simple laboratory determinations such as routine serum chemistries, blood counts, and urinalysis, often provide a major clue to the presence of a pathologic process. On the other hand, the physician must learn to evaluate occasional screening-test abnormalities that do not necessarily connote significant disease. An in-depth workup after the report

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Team-Based Care  Medical practice has long involved teams, par-

ticularly physicians working with nurses. Advances in medicine have increased our ability to manage very complex clinical situations (e.g., intensive care units [ICUs], bone marrow transplantation) and have shifted the burden of disease toward chronic illnesses. Because an individual patient may have multiple chronic diseases, he or she may be cared for by different specialists as well as a primary care physician. In the inpatient setting, care may involve multiple consultants along with the primary admitting physician. Communication through the medical record is necessary but not sufficient, particularly when patients have complex medical problems or when difficult decisions need to be made about the optimal management plan. Physicians should willingly meet face-to-face or by phone to ensure clear communication and thoughtful planning. It is important to note that patients often receive or perceive different messages from various care providers; attempts should be made to provide consistency among these messages to the patient. Management plans and treatment options should be outlined succinctly and clearly for the patient. Another dimension of team-based care involves allied health professions. It is not unusual for a hospitalized patient to encounter physical therapists, pharmacists, respiratory therapists, radiology technicians, social workers, dieticians, and transport personnel (among others) in addition to physicians and nurses. Each of these individuals contributes to clinical care as well as to the patient’s experience with the health care system. In the outpatient setting, disease screening and chronic disease management are often carried out by nurses, physician assistants, or other allied health professionals. The growth of team-based care has important implications for medical culture, student and resident training, and the organization of health care systems. Despite diversity in training, skills, and responsibilities among health care professionals, common values need to be espoused and reinforced. Many medical schools have incorporated interprofessional teamwork into their curricula. Effective communication is inevitably the most challenging aspect of implementing team-based care. While communication can be aided by electronic devices, including medical records, apps, or text messages, it is vitally important to balance efficiency with taking the necessary time to speak directly with colleagues.

The Dichotomy of Inpatient and Outpatient Internal Medicine  The hospital environment has experienced sweeping changes over the last few decades. Emergency departments and critical

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3

The Practice of Medicine

■■MANAGEMENT OF PATIENT CARE

care units have evolved to manage critically ill patients, allowing them to survive formerly fatal conditions. In parallel, there is increasing pressure to reduce the length of stay in the hospital and to manage complex disorders in the outpatient setting. This transition has been driven not only by efforts to reduce costs but also by the availability of new outpatient technologies, such as imaging and percutaneous infusion catheters for long-term antibiotics or nutrition, minimally invasive surgical procedures, and evidence that outcomes often are improved by reducing inpatient hospitalization. In addition to traditional medical beds, hospitals now encompass multiple distinct levels of care, such as the emergency department, procedure rooms, overnight observation units, critical care units, and palliative care units. A consequence of this differentiation has been the emergence of new specialties (e.g., emergency medicine and endof-life care) and the provision of in-hospital care by hospitalists and intensivists. Most hospitalists are board-certified internists who bear primary responsibility for the care of hospitalized patients and whose work is limited entirely to the hospital setting. The shortened length of hospital stay means that most patients receive only acute care while hospitalized; the increased complexities of inpatient medicine make the presence of an internist with specific training, skills, and experience in the hospital environment extremely beneficial. Intensivists are board-certified physicians who are further certified in critical care medicine and who direct and provide care for very ill patients in critical care units. Clearly, an important challenge in internal medicine today is to ensure the continuity of communication and information flow between a patient’s primary care physician and those who are in charge of the patient’s hospital care. Maintaining these channels of communication is frequently complicated by patient “handoffs”—i.e., transitions from the outpatient to the inpatient environment, from the critical care unit to a general medicine floor, from a medical to a surgical service and vice versa, and from the hospital to the outpatient environment. The involvement of many care providers in conjunction with these transitions can threaten the traditional one-to-one relationship between patient and primary care physician. Of course, patients can benefit greatly from effective collaboration among a number of health care professionals; however, it is the duty of the patient’s principal or primary physician to provide cohesive guidance through an illness. To meet this challenge, primary care physicians must be familiar with the techniques, skills, and objectives of specialist physicians and allied health professionals who care for their patients in the hospital. In addition, primary care physicians must ensure that their patients benefit from scientific advances and the expertise of specialists, both in and out of the hospital. Primary care physicians should explain the role of these specialists to reassure patients that they are in the hands of physicians best trained to manage an acute illness. However, the primary care physician should assure patients and their families that decisions are being made in consultation with these specialists. The evolving concept of the “medical home” incorporates team-based primary care with subspecialty care in a cohesive environment that ensures smooth transitions of care.

CHAPTER 1

of an isolated laboratory abnormality in a person who is otherwise well is often wasteful and unproductive. Because so many tests are performed routinely for screening purposes, it is not unusual for one or two values to be slightly abnormal. Nevertheless, even if there is no reason to suspect an underlying illness, tests yielding abnormal results ordinarily are repeated to rule out laboratory error. If an abnormality is confirmed, it is important to consider its potential significance in the context of the patient’s condition and other test results. There is almost continual development of technically improved imaging studies with greater sensitivity and specificity. These tests provide remarkably detailed anatomic information that can be pivotal in informing medical decision-making. Ultrasonography, CT, MRI, a variety of isotopic scans, and positron emission tomography (PET) have supplanted older, more invasive approaches and opened new diagnostic vistas. In light of their capabilities and the rapidity with which they can lead to a diagnosis, it is tempting to order a battery of imaging studies. All physicians have had experiences in which imaging studies revealed findings that led to an unexpected diagnosis. Nonetheless, patients must endure each of these tests, and the added cost of unnecessary testing is substantial. Furthermore, investigation of an unexpected abnormal finding may be associated with risk and/ or expense and may lead to the diagnosis of an irrelevant or incidental problem. A skilled physician must learn to use these powerful diagnostic tools judiciously, always considering whether the results will alter management and benefit the patient.

Mitigating the Stress of Acute Illness  Few people are pre-

pared for a new diagnosis of cancer or anticipate the occurrence of a myocardial infarction, stroke, or major accident. The care of a frightened or distraught patient is confounded by these understandable responses to life-threatening events. The physician and other health providers can reduce the shock of life-changing events by providing information in a clear, calm, consistent, and reassuring manner. Often, information and reassurance need to be repeated. Caregivers should also recognize that, for outsiders, hospital emergency rooms, operating rooms, ICUs, and general medical floors represent an intimidating environment. Hospitalized patients find themselves surrounded by air jets, buttons, and glaring lights; invaded by tubes and wires; and beset by the numerous members of the health care team—hospitalists, specialists, nurses, nurses’ aides, physicians’ assistants, social workers, technologists, physical therapists, medical students, house officers, attending and consulting physicians, and many others. They may be

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transported to special laboratories and imaging facilities replete with blinking lights, strange sounds, and unfamiliar personnel; they may be left unattended at times; and they may be obligated to share a room with other patients who have their own health problems. It is little wonder that patients may be stressed by this environment. Physicians who appreciate the hospital experience from the patient’s perspective and who make an effort to guide the patient through this experience may make a stressful situation more tolerable and enhance the patient’s chances for an optimal recovery.

The Profession of Medicine

Medical Decision-Making  Medical decision-making is a fundamental responsibility of the physician and occurs at each stage of the diagnostic and therapeutic process. The decision-making process involves the ordering of additional tests, requests for consultations, decisions about treatment, and predictions concerning prognosis. This process requires an in-depth understanding of the pathophysiology and natural history of disease. Formulating a differential diagnosis requires not only a broad knowledge base but also the ability to assess the relative probabilities of various diseases for a given patient. Application of the scientific method, including hypothesis formulation and data collection, is essential to the process of accepting or rejecting a particular diagnosis. Analysis of the differential diagnosis is an iterative process. As new information or test results are acquired, the group of disease processes being considered can be contracted or expanded appropriately. Whenever possible, decisions should be evidence-based, taking advantage of rigorously designed clinical trials or objective comparisons of different diagnostic tests. Evidence-based medicine is in sharp contrast to anecdotal experience, which is often biased. Unless attuned to the importance of using larger, objective studies for making decisions, even the most experienced physicians can be influenced to an undue extent by recent encounters with selected patients. Evidence-based medicine has become an increasingly important part of routine medical practice and has led to the publication of many useful practice guidelines. Despite the importance of evidence-based medicine, much medical decision-making still relies on good clinical judgment, an attribute that is difficult to quantify or even to assess qualitatively. Physicians must use their knowledge and experience as a basis for weighing known factors, along with the inevitable uncertainties, and then making a sound judgment; this synthesis of information is particularly important when a relevant evidence base is not available. Several quantitative tools may be invaluable in synthesizing the available information, including diagnostic tests, Bayes’ theorem, and multivariate statistical models. Diagnostic tests serve to reduce uncertainty about an individual’s diagnosis or prognosis and help the physician decide how best to manage that individual’s condition. The battery of diagnostic tests complements the history and the physical examination. The accuracy of a particular test is ascertained by determining its sensitivity (true-positive rate) and specificity (true-negative rate) as well as the predictive value of a positive and a negative result. See Chap. 3 for a more thorough discussion of decision-making in clinical medicine. Practice Guidelines  Many professional organizations and gov-

ernment agencies have developed formal clinical-practice guidelines to aid physicians and other caregivers in making diagnostic and therapeutic decisions that are evidence-based, cost-effective, and most appropriate to a particular patient and clinical situation. As the evidence base of medicine increases, guidelines can provide a useful framework for managing patients with particular diagnoses or symptoms. Clinical guidelines can protect patients—particularly those with inadequate health care benefits—from receiving substandard care. These guidelines also can protect conscientious caregivers from inappropriate charges of malpractice and society from the excessive costs associated with the overuse of medical resources. There are, however, caveats associated with clinical-practice guidelines since they tend to oversimplify the complexities of medicine. Furthermore, groups with different perspectives may develop divergent recommendations regarding issues as basic as the need for screening of women

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by mammography or of men by serum prostate-specific antigen (PSA). Finally, guidelines, as the term implies, do not—and cannot be expected to—account for the uniqueness of each individual and his or her illness. The physician’s challenge is to integrate into clinical practice the useful recommendations offered by experts without accepting them blindly or being inappropriately constrained by them.

Precision Medicine  The concept of precision or personalized medi-

cine reflects the growing recognition that diseases once lumped together can be further stratified on the basis of genetic, biomarker, phenotypic, and/or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations. Inherent in this concept is the goal of targeting therapies in a more specific way to improve clinical outcomes for the individual patient and minimize unnecessary side effects for those less likely to respond to a particular treatment. In some respects, precision medicine represents the evolution of clinical practice guidelines, which are usually developed for populations of patients or a particular diagnosis (e.g., hypertension, thyroid nodule). As the pathophysiology, prognosis, and treatment responses of subgroups within these diagnoses become better understood, the relevant clinical guidelines incorporate progressively more refined recommendations for individuals within these subgroups. The role of precision medicine is particularly important for cancers in which genetic testing is able to predict responses (or the lack thereof) to targeted therapies (Chap. 69). One can anticipate similar applications of precision medicine in pharmacogenomics, immunologic disorders, and diseases in which biomarkers better predict treatment responses.

Evaluation of Outcomes  Clinicians generally use objective and readily measurable parameters to judge the outcome of a therapeutic intervention. These measures may oversimplify the complexity of a clinical condition as patients often present with a major clinical problem in the context of multiple complicating background illnesses. For example, a patient may present with chest pain and cardiac ischemia, but with a background of chronic obstructive pulmonary disease and renal insufficiency. For this reason, outcome measures such as mortality, length of hospital stay, or readmission rates are typically riskadjusted. An important point to remember is that patients usually seek medical attention for subjective reasons; they wish to obtain relief from pain, to preserve or regain function, and to enjoy life. The components of a patient’s health status or quality of life can include bodily comfort, capacity for physical activity, personal and professional function, sexual function, cognitive function, and overall perception of health. Each of these important domains can be assessed through structured interviews or specially designed questionnaires. Such assessments provide useful parameters by which a physician can judge patients’ subjective views of their disabilities and responses to treatment, particularly in chronic illness. The practice of medicine requires consideration and integration of both objective and subjective outcomes. Many health systems use survey and patient feedback data to assess qualitative features such as patient satisfaction, access to care, and communication with nurses and physicians. In the United States, HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems) surveys are used by many systems and are publically reported. Social media is also being used to assess feedback in real time as well as to share patient experiences with health care systems. Errors in the Delivery of Health Care  A series of reports

from the Institute of Medicine (now the National Academy of Medicine [NAM]) called for an ambitious agenda to reduce medical error rates and improve patient safety by designing and implementing fundamental changes in health care systems. It is the responsibility of hospitals and health care organizations to develop systems to reduce risk and ensure patient safety. Medication errors can be reduced through the use of ordering systems that rely on electronic processes or, when electronic options are not available, that eliminate misreading of handwriting. Whatever the clinical situation, it is the physician’s responsibility to use powerful therapeutic measures wisely, with due regard for their beneficial actions, potential dangers, and cost. Implementation of infection

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computers and the strength of information technology now play central roles in medicine, including efforts to reduce medical errors. Laboratory data are accessed almost universally through computers. Many medical centers now have electronic medical records (EMRs), computerized order entry, and bar-coded tracking of medications. Some of these systems are interactive, sending reminders or warning of potential medical errors. EMRs offer rapid access to information that is invaluable in enhancing health care quality and patient safety, including relevant data, historical and clinical information, imaging studies, laboratory results, and medication records. These data can be used to monitor and reduce unnecessary variations in care and to provide real-time information about processes of care and clinical outcomes. Ideally, patient records are easily transferred across the health care system. However, technological limitations and concerns about privacy and cost continue to limit broad-based use of EMRs in many clinical settings. For all of the advantages of EMRs, they can create distance between the physician and patient if care is not taken to preserve face-to-face contact. EMRs also require training and time for data entry. Many providers spend significant time entering information to generate structured data and to meet billing requirements. They may feel pressured to take short cuts, such as “cutting and pasting” parts of earlier notes into the daily record, thereby increasing the risk of errors. EMRs also structure information in a manner that disrupts the traditional narrative flow across time and among providers. These features, which may be frustrating for some providers, must be weighed against the advantages of ready access to past medical history, imaging, laboratory data, and consultant notes. It is important to emphasize that information technology is merely a tool and can never replace the clinical decisions that are best made by the physician. Clinical knowledge and an understanding of a patient’s needs, supplemented by quantitative tools, still represent the best approach to decision-making in the practice of medicine.

THE PATIENT–PHYSICIAN RELATIONSHIP

The significance of the intimate personal relationship between physician and patient cannot be too strongly emphasized, for in an extraordinarily large number of cases both the diagnosis and treatment are directly dependent on it. One of the essential qualities of the clinician is interest in humanity, for the secret of the care of the patient is in caring for the patient. —Francis W. Peabody, October 21, 1925, Lecture at Harvard Medical School

Physicians must never forget that patients are individuals with problems that all too often transcend their physical complaints. They are not “cases” or “admissions” or “diseases.” Patients do not fail treatments; treatments fail to benefit patients. This point is particularly important in this era of high technology in clinical medicine. Most patients are anxious and fearful. Physicians should instill confidence and offer reassurance, but they must never come across as arrogant or patronizing. A professional attitude, coupled with warmth and openness, can do much to alleviate anxiety and to encourage patients to share all aspects of their medical history. Empathy and compassion are the essential features of a caring physician. The physician needs to consider the setting in which an illness occurs—in terms not only of patients themselves

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Informed Consent  The fundamental principles of medical ethics

require physicians to act in the patient’s best interest and to respect the patient’s autonomy. These requirements are particularly relevant to the issue of informed consent. Patients are required to sign consent forms for most diagnostic or therapeutic procedures. Many patients possess limited medical knowledge and must rely on their physicians for advice. Communicating in a clear and understandable manner, physicians must fully discuss the alternatives for care and explain the risks, benefits, and likely consequences of each alternative. The physician is responsible for ensuring that the patient thoroughly understands these risks and benefits; encouraging questions is an important part of this process. It may be necessary to go over certain issues with the patient more than once. This is the very definition of informed consent. Complete, clear explanation and discussion of the proposed procedures and treatment can greatly mitigate the fear of the unknown that commonly accompanies hospitalization. Often the patient’s understanding is enhanced by repeatedly discussing the issues in an unthreatening and supportive way, answering new questions that occur to the patient as they arise. Clear communication can also help alleviate misunderstandings in situations where complications of intervention occur. Special care should be taken to ensure that a physician seeking a patient’s informed consent has no real or apparent conflict of interest.

5

The Practice of Medicine

Electronic Medical Records  Both the growing reliance on

but also of their familial, social, and cultural backgrounds. The ideal patient–physician relationship is based on thorough knowledge of the patient, mutual trust, and the ability to communicate.

CHAPTER 1

control systems, enforcement of hand-washing protocols, and careful oversight of antibiotic use can minimize the complications of nosocomial infections. Central-line infection rates have been dramatically reduced at many centers by careful adherence of trained personnel to standardized protocols for introducing and maintaining central lines. Rates of surgical infection and wrong-site surgery can likewise be reduced by the use of standardized protocols and checklists. Falls by patients can be minimized by judicious use of sedatives and appropriate assistance with bed-to-chair and bed-to-bathroom transitions. Taken together, these and other measures are saving thousands of lives each year.

Approach to Grave Prognoses and Death  No circumstance

is more distressing than the diagnosis of an incurable disease, particularly when premature death is inevitable. What should the patient and family be told? What measures should be taken to maintain life? What can be done to optimize quality of life? Transparency of information, delivered in an appropriate manner, is essential in the face of a terminal illness. Even patients who seem unaware of their medical circumstances, or whose family members have protected them from diagnoses or prognoses, often have keen insights into their condition. They may also have misunderstandings that can lead to additional anxiety. The patient must be given an opportunity to talk with the physician and ask questions. A wise and insightful physician uses such open communication as the basis for assessing what the patient wants to know and when he or she wants to know it. On the basis of the patient’s responses, the physician can assess the right tempo for sharing information. Ultimately, the patient must understand the expected course of the disease so that appropriate plans and preparations can be made. The patient should participate in decision-making with an understanding of the goal of treatment (palliation) and its likely effects. The patient’s religious beliefs should be taken into consideration. Some patients may find it easier to share their feelings about death with their physician, nurses, or members of the clergy than with family members or friends. The physician should provide or arrange for emotional, physical, and spiritual support and must be compassionate, unhurried, and open. In many instances, there is much to be gained by the laying on of hands. Pain should be controlled adequately, human dignity maintained, and isolation from family and close friends avoided. These aspects of care tend to be overlooked in hospitals, where the intrusion of life-sustaining equipment can detract from attention to the whole person and encourage concentration instead on the life-threatening disease, against which the battle ultimately will be lost in any case. In the face of terminal illness, the goal of medicine must shift from cure to care in the broadest sense of the term. Primum succurrere, first hasten to help, is a guiding principle. In offering care to a dying patient, a physician should be prepared to provide information to family members and deal with their grief and sometimes their feelings of guilt or even anger. It is important for the physician to assure the family that everything reasonable is being done. A substantial challenge in these discussions is that the physician often does not know how to gauge the prognosis. In addition, various members of the health care team may offer different opinions. Good communication among providers is

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essential so that consistent information is provided to patients. This is especially important when the best path forward is uncertain. Advice from experts in palliative and terminal care should be sought whenever appropriate to ensure that clinicians are not providing patients with unrealistic expectations. For a more complete discussion of end-of-life care, see Chap. 9.

Maintaining Humanism and Professionalism  Many trends

The Profession of Medicine

in the delivery of health care tend to make medical care impersonal. These trends, some of which have been mentioned already, include (1) vigorous efforts to reduce the escalating costs of health care; (2) the growing number of managed-care programs, which are intended to reduce costs but in which the patient may have little choice in selecting a physician; (3) increasing reliance on technological advances and computerization; and (4) the need for numerous physicians and other health professionals to be involved in the care of most patients who are seriously ill. In light of these changes in the medical care system, it is a major challenge for physicians to maintain the humane aspects of medical care. The American Board of Internal Medicine, working together with the American College of Physicians–American Society of Internal Medicine and the European Federation of Internal Medicine, has published a Charter on Medical Professionalism that underscores three main principles in physicians’ contract with society: (1) the primacy of patient welfare, (2) patient autonomy, and (3) social justice. While medical schools appropriately place substantial emphasis on professionalism, a physician’s personal attributes, including integrity, respect, and compassion, also are extremely important. In the United States, the Gold Humanism Society recognizes individuals who are exemplars of humanistic patient care and serve as role models for medical education and training. Availability to the patient, expression of sincere concern, willingness to take the time to explain all aspects of the illness, and a nonjudgmental attitude when dealing with patients whose cultures, lifestyles, attitudes, and values differ from those of the physician are just a few of the characteristics of a humane physician. Every physician will, at times, be challenged by patients who evoke strongly negative or positive emotional responses. Physicians should be alert to their own reactions to such situations and should consciously monitor and control their behavior so that the patient’s best interest remains the principal motivation for their actions at all times. Another important aspect of patient care involves an appreciation of the patient’s “quality of life,” a subjective assessment of what each patient values most. This assessment requires detailed, sometimes intimate knowledge of the patient, which usually can be obtained only through deliberate, unhurried, and often repeated conversations. Time pressures will always threaten these interactions, but they should not diminish the importance of understanding and seeking to fulfill the priorities of the patient.

■■EXPANDING FRONTIERS IN MEDICAL PRACTICE The Era of “Omics”  In the spring of 2003, announcement of the

complete sequencing of the human genome officially ushered in the genomic era. However, even before that landmark accomplishment, the practice of medicine had been evolving as a result of insights into both the human genome and the genomes of a wide variety of microbes. The clinical implications of these insights are illustrated by the complete genome sequencing of H1N1 influenza virus in 2009 and the rapid identification of H1N1 influenza as a potentially fatal pandemic illness, leading to the swift development and dissemination of an effective protective vaccine. Today, gene expression profiles are being used to guide therapy and inform prognosis for a number of diseases, and genotyping is providing a new means to assess the risk of certain diseases as well as variations in response to a number of drugs. Despite these advances, the use of complex genomics in the diagnosis, prevention, and treatment of disease is still in its early stages. The task of physicians is complicated by the fact that phenotypes generally are determined not by genes alone but by the interplay of genetic and environmental factors.

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Rapid progress is also being made in other areas of molecular medicine. Epigenetics is the study of alterations in chromatin and histone proteins and methylation of DNA sequences that influence gene expression (Chap. 471). Every cell of the body has identical DNA sequences; the diverse phenotypes a person’s cells manifest are the result of epigenetic regulation of gene expression. Epigenetic alterations are associated with a number of cancers and other diseases. Proteomics, the study of the entire library of proteins made in a cell or organ and the complex relationship of these proteins to disease, is enhancing the repertoire of the 23,000 genes in the human genome through alternate splicing, posttranslational processing, and posttranslational modifications that often have unique functional consequences. The presence or absence of particular proteins in the circulation or in cells is being explored for diagnostic and disease-screening applications. Microbiomics is the study of the resident microbes in humans and other mammals, which together compose the microbiome. The human haploid genome has ~23,000 genes, whereas the microbes residing on and in the human body encompass more than 3–4 million genes; these resident microbes are likely to be of great significance with regard to health status. Ongoing research is demonstrating that the microbes inhabiting human mucosal and skin surfaces play a critical role in maturation of the immune system, in metabolic balance, and in disease susceptibility. A variety of environmental factors, including the use and overuse of antibiotics, have been tied experimentally to substantial increases in disorders such as obesity, metabolic syndrome, atherosclerosis, and immune-mediated diseases in both adults and children. Metagenomics, of which microbiomics is a part, is the genomic study of environmental species that have the potential to influence human biology directly or indirectly. An example is the study of exposures to microorganisms in farm environments that may be responsible for the lower incidence of asthma among children raised on farms. Metabolomics is the study of the range of metabolites in cells or organs and the ways they are altered in disease states. The aging process itself may leave telltale metabolic footprints that allow the prediction (and possibly the prevention) of organ dysfunction and disease. It seems likely that disease-associated patterns will be found in lipids, carbohydrates, membranes, mitochondria, and other vital components of cells and tissues. Exposomics is the study of the exposome—i.e., the environmental exposures such as smoking, sunlight, diet, exercise, education, and violence that together have an enormous impact on health. All of this new information represents a challenge to the traditional reductionist approach to medical thinking. The variability of results in different patients, together with the large number of variables that can be assessed, creates challenges in identifying preclinical disease and defining disease states unequivocally. Accordingly, the tools of systems biology and network medicine are being applied to the enormous body of information now obtainable for every patient and may eventually provide new approaches to classifying disease. For a more complete discussion of a complex systems approach to human disease, see Chap. 476. The rapidity of these advances may seem overwhelming to practicing physicians. However, physicians have an important role to play in ensuring that these powerful technologies and sources of new information are applied judiciously to patient care. Since “omics” are evolving so rapidly, physicians and other health care professionals must engage in continuous learning so that they can apply this new knowledge to the benefit of their patients’ health and well-being. Genetic testing requires wise counsel based on an understanding of the value and limitations of the tests as well as the implications of their results for specific individuals. For a more complete discussion of genetic testing, see Chap. 457.

The Globalization of Medicine  Physicians should be cog-

nizant of diseases and health care services beyond local boundaries. Global travel has implications for disease spread, and it is not uncommon for diseases endemic to certain regions to be seen in other regions after a patient has traveled to and returned from those regions. The outbreak of Zika virus infections in the Americas is a cogent example of this phenomenon. In addition, factors such as wars, the migration of refugees, and climate change are contributing to changing disease

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positive effect on the practice of medicine; through personal computers, a wide range of information is available to physicians and patients almost instantaneously at any time and from anywhere in the world. This medium holds enormous potential for the delivery of current information, practice guidelines, state-of-the-art conferences, journal content, textbooks (including this text), and direct communications with other physicians and specialists, expanding the depth and breadth of information available to the physician regarding the diagnosis and care of patients. Medical journals are now accessible online, providing rapid sources of new information. By bringing them into direct and timely contact with the latest developments in medical care, this medium also serves to lessen the information gap that has hampered physicians and health care providers in remote areas. Patients, too, are turning to the Internet in increasing numbers to acquire information about their illnesses and therapies and to join Internet-based support groups. Patients often arrive at a clinic visit with sophisticated information about their illnesses. In this regard, physicians are challenged in a positive way to keep abreast of the latest relevant information while serving as an “editor” as patients navigate this seemingly endless source of information, the accuracy and validity of which are not uniform. A critically important caveat is that virtually anything can be published on the Internet, with easy circumvention of the peer-review process that is an essential feature of academic publications. Both physicians and patients who search the Internet for medical information must be aware of this danger. Notwithstanding this limitation, appropriate use of the Internet is revolutionizing information access for physicians and patients and in this regard represents a remarkable resource that was not available to practitioners a generation ago.

Public Expectations and Accountability  The general pub-

lic’s level of knowledge and sophistication regarding health issues has grown rapidly over the last few decades. As a result, expectations of the health care system in general and of physicians in particular have risen. Physicians are expected to master rapidly advancing fields (the science of medicine) while considering their patients’ unique needs (the art of medicine). Thus, physicians are held accountable not only for the technical aspects of the care they provide but also for their patients’ satisfaction with the delivery and costs of care. In many parts of the world, physicians increasingly are expected to account for the way in which they practice medicine by meeting certain standards prescribed by federal and local governments. The hospitalization of patients whose health care costs are reimbursed by the government and other third parties is subjected to utilization review. Thus, a physician must defend the cause for and duration of a patient’s hospitalization if it falls outside certain “average” standards. Authorization for reimbursement increasingly is based on documentation of the nature and complexity of an illness, as reflected by recorded elements of the history and physical examination. A growing “payfor-performance” movement seeks to link reimbursement to quality of care. The goal of this movement is to improve standards of health care and contain spiraling health care costs. In many parts of the United States, managed (capitated) care contracts with insurers have replaced traditional fee-for-service care, placing the onus of managing the cost of all care directly on the providers and increasing the emphasis on preventive strategies. In addition, physicians are expected to give evidence of their current competence through mandatory continuing education, patient record audits, maintenance of certification, and relicensing.

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Learning Medicine  More than a century has passed since the

publication of the Flexner Report, a seminal study that transformed medical education and emphasized the scientific foundations of medicine as well as the acquisition of clinical skills. In an era of burgeoning information and access to medical simulation and informatics, many schools are implementing new curricula that emphasize lifelong learning and the acquisition of competencies in teamwork, communication skills, system-based practice, and professionalism. The tools of medicine also change continuously, necessitating formal training in the use of EMRs, large datasets, ultrasound, robotics, and new imaging techniques. These and other features of the medical school curriculum provide the foundation for many of the themes highlighted in this chapter and are expected to allow physicians to progress, with experience and learning over time, from competency to proficiency to mastery. At a time when the amount of information that must be mastered to practice medicine continues to expand, increasing pressures both within and outside of medicine have led to the implementation of restrictions on the amount of time a physician-in-training can spend in the hospital and in clinics. Because the benefits associated with continuity of medical care and observation of a patient’s progress over time were thought to be outstripped by the stresses imposed on trainees by long hours and by fatigue-related errors, strict limits were set on the number of patients that trainees could be responsible for at one time, the number of new patients they could evaluate in a day on call, and the number of hours they could spend in the hospital. In 1980, residents in medicine worked in the hospital more than 90 hours per week on average. In 1989, their hours were restricted to no more than 80 per week. Resident physicians’ hours further decreased by ~10% between 1996 and 2008, and in 2010 the Accreditation Council for Graduate Medical Education further restricted (i.e., to 16 hours per shift) consecutive in-hospital duty hours for first-year residents. The impact of these changes is still being assessed, but the evidence that medical errors have decreased as a consequence is sparse. An unavoidable by-product of fewer hours at the bedside is an increase in the number of “handoffs” of patient responsibility from one physician to another. These transfers often involve a transition from a physician who knows the patient well, having evaluated that individual on admission, to a physician who knows the patient less well. It is imperative that these transitions of responsibility be handled with care and thoroughness, with all relevant information exchanged and acknowledged.

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The Practice of Medicine

Medicine on the Internet  On the whole, the Internet has had a

Medical Ethics and New Technologies  The rapid pace of technological advances has profound implications for medical applications that go far beyond the traditional goals of disease prevention, treatment, and cure. Cloning, genetic engineering, gene therapy, human–computer interfaces, nanotechnology, and use of targeted therapies have the potential to modify inherited predispositions to disease, select desired characteristics in embryos, augment “normal” human performance, replace failing tissues, and substantially prolong life span. Given their unique training, physicians have a responsibility to help shape the debate on the appropriate uses of and limits placed on these new techniques and to consider carefully the ethical issues associated with the implementation of such interventions. As medicine becomes more complex, shared decision-making is increasingly important, particularly in areas such as genetic counseling and end-of-life care, but also in most instances of considering diagnostic and treatment options.

CHAPTER 1

profiles worldwide. Patients have broader access to unique expertise or clinical trials at distant medical centers, and the cost of travel may be offset by the quality of care at those distant locations. As much as any other factor influencing global aspects of medicine, the Internet has transformed the transfer of medical information throughout the world. This change has been accompanied by the transfer of technological skills through telemedicine and international consultation—for example, interpretation of radiologic images and pathologic specimens. For a complete discussion of global issues, see Chap. 460.

The Physician as Perpetual Student  From the time physi-

cians graduate from medical school, it becomes all too apparent that this milestone is symbolic and that they must embrace the role of a “perpetual student.” This realization is at the same time exhilarating and anxiety-provoking. It is exhilarating because physicians can apply constantly expanding knowledge to the treatment of their patients; it is anxiety-provoking because physicians realize that they will never know as much as they want or need to know. Ideally, physicians will translate the latter feeling into energy through which they can continue to improve and reach their potential. It is the physician’s responsibility to pursue new knowledge continually by reading, attending

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conferences and courses, and consulting colleagues and the Internet. This is often a difficult task for a busy practitioner; however, a commitment to continued learning is an integral part of being a physician and must be given the highest priority.

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The Physician as Citizen  Being a physician is a privilege. The

The Profession of Medicine

capacity to apply one’s skills for the benefit of fellow human beings is a noble calling. The physician–patient relationship is inherently unbalanced in the distribution of power. In light of their influence, physicians must always be aware of the potential impact of what they do and say and must always strive to strip away individual biases and preferences to find what is best for their patients. To the extent possible, physicians should also act within their communities to promote health and alleviate suffering. Meeting these goals begins by setting a healthy example and continues in taking action to deliver needed care even when personal financial compensation may not be available.

Research, Teaching, and the Practice of Medicine  The

word doctor is derived from the Latin docere, “to teach.” As teachers, physicians should share information and medical knowledge with colleagues, students of medicine and related professions, and their patients. The practice of medicine is dependent on the sum total of medical knowledge, which in turn is based on an unending chain of scientific discovery, clinical observation, analysis, and interpretation. Advances in medicine depend on the acquisition of new information through research, and improved medical care requires the transmission of that information. As part of their broader societal responsibilities, physicians should encourage patients to participate in ethical and properly approved clinical investigations if these studies do not impose undue hazard, discomfort, or inconvenience. Physicians engaged in clinical research must be alert to potential conflicts of interest between their research goals and their obligations to individual patients. The best interests of the patient must always take priority. To wrest from nature the secrets which have perplexed philosophers in all ages, to track to their sources the causes of disease, to correlate the vast stores of knowledge, that they may be quickly available for the prevention and cure of disease—these are our ambitions. —William Osler, 1849–1919

■■FURTHER READING

Cheston CC et al: Social media use in medical education: A systematic review. Acad Med 88:893, 2013. Cooke M et al: American medical education 100 years after the Flexner report. N Engl J Med 355:1339, 2006. Institute of Medicine: Dying in America: Improving quality and honoring individual preferences near the end of life. Washington, DC, National Academies Press, 2015. Institute of Medicine: Improving diagnosis in health care. Washington, DC, National Academies of Sciences, Engineering, and Medicine, 2015. Jameson JL, Longo DL: Precision medicine—personalized, problematic, and promising. N Engl J Med 372:2229, 2015. Reeves S et al: Interprofessional education: Effects on professional practice and healthcare outcomes (update). Cochrane Database Syst Rev 28:CD02213, 2013. Stern DT, Papadakis M: The developing physician—becoming a professional. N Engl J Med 355:1794, 2006. Vickrey BG et al: How neurologists think: A cognitive psychology perspective on missed diagnoses. Ann Neurol 67:425, 2010. West P et al: Intervention to promote physician well-being, job satisfaction, and professionalism. A randomized clinical trial. JAMA Intern Med 174:527, 2014.

Promoting Good Health Donald M. Lloyd-Jones, Kathleen M. McKibbin

■■GOALS AND APPROACHES TO PREVENTION

Prevention of acute and chronic diseases before their onset has been recognized as one of the hallmarks of excellent medical practice for centuries, and is now used as a metric for highly functioning healthcare systems. The ultimate goal of preventive strategies is to avoid premature death. However, as longevity has increased dramatically worldwide over the last century (largely as a result of public health practices), increasing emphasis is placed on prevention for the purpose of preserving quality of life and extending the healthspan, not just the lifespan. Given that all patients will eventually die, the goal of prevention ultimately becomes compression of morbidity toward the end of the lifespan; that is, reduction of the amount of burden and time spent with disease prior to dying. As shown in Fig. 2-1, normative aging tends to involve a steady decline in the stock of health, with accelerating decline over time. Successful prevention offers the opportunity both to extend life and to extend healthy life, thus “squaring the curve” of health loss during aging. Prevention strategies have been characterized as tertiary, secondary, primary, and primordial. Tertiary prevention requires rapid action to prevent imminent death in the setting of acute illness, such as through percutaneous coronary intervention in the setting of ST-segment elevation myocardial infarction. Secondary prevention strategies focus on avoiding the recurrence of disease and death in an individual who is already affected. For example, tamoxifen is recommended for women with surgically treated early-stage, estrogen-receptor-positive breast cancer, because it reduces the risk of recurrent breast cancer (including in the contralateral breast) and death. Primary prevention attempts to reduce the risk of incident disease among individuals with a risk factor. Treatment of elevated blood pressure in individuals who have not yet experienced cardiovascular disease represents one example of primary prevention that has proven effective in reducing the incidence of stroke, heart failure, and coronary heart disease. Primordial prevention is a more recent concept (first introduced in 1979) which focuses on prevention of the development of risk factors for disease, not just prevention of disease. Primordial prevention strategies emphasize upstream determinants of risk for chronic diseases, such as eating patterns, physical activity, and environmental and social determinants of health. It therefore encompasses medical treatment strategies for individuals as well as a strong reliance on public health and social policy. It is increasingly clear that primordial prevention represents the ultimate means for reducing the burden of chronic diseases of aging. Once risk factors develop, it is difficult 1 Squaring the curve with compression of morbidity

0.8 Stock of health

8

0.6 Normative aging with gradual loss of stock of health

0.4 0.2 0

0

20

40

60

80

100

Age FIGURE 2-1  Loss of health with aging. Representation of normative aging with loss of the full stock of health with which individuals are born (indicating gain of morbidity), contrasted with a squared curve with greater longevity and fuller stock of health (less morbidity) until shortly before death. The “squared curve” represents the likely ideal situation for most patients.

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In recent decades, medical practice has increasingly focused on public health approaches to promote health, and not just prevent disease. Prevention of disease is a worthy individual and societal goal in and of itself, but it does not necessarily guarantee health. Health is a broader construct encompassing more than just absence of disease. It includes biological, physiological, and psychological domains (among others) in a continuum, rather than occurring as a dichotomous trait. Health is therefore somewhat subjective, but attempts have been made to use more objective criteria to define health in order to raise awareness, prevent disease, and promote healthy longevity. For example, in 2010 the American Heart Association (AHA) defined a new construct of “cardiovascular health” based on evidence of associations with longevity, disease avoidance, healthy longevity, and quality of life. The definition of cardiovascular health is based on seven health behaviors and health factors (eating pattern, physical activity, body mass, smoking status, and levels of blood pressure, blood cholesterol, and blood glucose) and includes a spectrum from poor to ideal. Individuals with optimal levels of all seven metrics simultaneously are considered to have ideal cardiovascular health. The state of cardiovascular health for an individual or a population can be assessed with simple scoring by counting the number of ideal metrics (out of 7) or applying 0 points for each poor metric, 1 point for each intermediate metric, and 2 points for each ideal metric, thus creating a composite cardiovascular health score ranging from 0 to 14 points. Higher cardiovascular health scores in younger and middle ages have been associated with greater longevity, lower incidence of cardiovascular disease, lower incidence of other chronic diseases of aging (including dementia, cancer, and more), compression of morbidity, greater quality of life, and lower healthcare costs, achieving both individual and societal goals for healthy aging, and further establishing the critical importance of primordial prevention and cardiovascular health promotion. Focusing on health promotion, rather than just disease prevention, may also provide greater motivation for patients to pursue lifestyle changes or adhere to clinician recommendations. Extensive literature suggests that providing patients solely with information regarding disease risk, or risk reduction with treatment, is unlikely to motivate desired behavior change. Empowering patients with strategies to achieve positive health goals after discussing risks can provide more effective adherence and better long-term outcomes. In the case of smoking cessation, enumerating only the risks of smoking can lead to patient inertia and therapeutic nihilism, and has proven an ineffective approach, whereas strategies that incorporate positive

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9

■■PRIORITIZING PREVENTION STRATEGIES

In secondary prevention, the patient already has manifest clinical disease, and is therefore at high risk for progression. The approach should be to work with the patient to implement all evidence-based strategies that will help to prevent recurrence or progression. This will typically include drug therapy as well as therapeutic lifestyle changes to control ongoing risk factors which may have caused disease in the first place. Juggling priorities can be difficult, and barriers to implementation are many, including costs, time, patient health literacy, and patient and caregiver capacity to organize the regimen. Addressing these potential barriers with the patient can help to forge a therapeutic bond and may improve adherence; ignoring them will likely lead to therapeutic failure. Numerous studies demonstrate that, even in high-functioning health systems, only ~50% of patients are taking recommended, evidence-based secondary prevention medications, such as statins, by 1 year after a myocardial infarction. In patients who are eligible for primary prevention strategies, it is important to frame the discussion around the overall evidence base as well as an individual patient’s likelihood of benefit from a given preventive intervention. A first step is to understand the patient’s estimated absolute risk for disease in the foreseeable future, or during their remaining lifespan. However, absolute risk estimation and presentation of those risks is generally insufficient to motivate behavior change. It is critical to assess the patient’s understanding and tolerance of the risk, their readiness to implement lifestyle changes or adhere to drug therapy, and their overall preferences regarding use of drug therapy to prevent an event (e.g., cancer, myocardial infarction, stroke). The clinician can help the patient by informing them of the risks for disease and potential for absolute benefits (and harms) from the available evidence-based choices. This may take more than one conversation, but given that diseases, such as cancer and cardiovascular disease, are the leading causes of premature death and disability, the time is well spent. Partnering with the patient through motivational interviewing may assist in the process of selecting initial approaches to prevention. Selecting an area that the patient feels they are ready to change can lead to better adherence and greater achievement of success in the short and longer term. If the patient is uncertain what course to choose, prudence would dictate focusing on control of risk factors that may lead to the most rapid reduction in risk for acute events. For example, blood pressure is both a chronic risk factor and an acute trigger for cardiovascular events. Thus, if a patient has both significant elevations in blood pressure and dyslipidemia, it would be appropriate to focus initial efforts on blood pressure control. Likewise, focus on smoking cessation can lead to more rapid reductions in risk for acute events than some other lifestyle interventions.

Promoting Good Health

■■HEALTH PROMOTION

health messaging, support and feedback, with appropriate use of evidence-based therapies, have proven far more effective.

CHAPTER 2

to restore risk to the low level of someone who never developed the risk factor. The time spent with adverse levels of the risk factor often causes irreversible damage that precludes complete restoration of low risk. For example, individuals with hypertension who are treated back to optimal levels (64 >18 Up to age 27 >60   Aged 50 to 59 years with a ≥10% 10-year CVD risk Women planning or capable of pregnancy Women at high risk for breast cancer >64 at increased risk for falls

FREQUENCY   Every 10 years Two doses One dose 13 followed by 23 valent Yearly If not done prior Once    

CHAPTER 118, 119                  

 

 

   

   

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TABLE 4-6  Preventive Counseling Recommended by the U.S. Preventive Services Task Force (USPSTF)

PART 1 The Profession of Medicine

TOPIC Alcohol and drug use Genetic counseling for BRCA1/2 testing among women at increased risk for deleterious mutations Nutrition and diet Sexually transmitted infections Sun exposure Tobacco use

CHAPTER REFERENCE 445–447 75, 457 

325, 326 131, 197 57 448

■■IMPLEMENTING DISEASE PREVENTION AND SCREENING

models suggest that appropriate frequencies of each technique may be associated with similar numbers of lives saved and cost to society per life saved ($10,000–25,000). Thus, although one patient may prefer the ease of preparation, less time disruption, and the lower risk of flexible sigmoidoscopy, others may prefer the sedation, thoroughness and time interval of colonoscopy.

■■COUNSELING ON HEALTHY BEHAVIORS

these are challenging problems, evidence strongly supports the role of counseling by health care providers (Table 4-6) in effecting health behavior change. Educational campaigns, public policy changes, and community-based interventions have also proven to be important parts of a strategy for addressing these factors in some settings. Although the USPSTF found that the evidence was conclusive to recommend a relatively small set of counseling activities, counseling in areas such as physical activity and injury prevention (including seat belts and bicycle and motorcycle helmets) has become a routine part of primary care practice.

In considering the impact of preventive services, it is important to recognize that tobacco and alcohol use, diet, and exercise constitute the vast majority of factors that influence preventable deaths in developed countries. Perhaps the single greatest preventive health care measure is to help patients quit smoking (Chap. 448). However, efforts in these areas frequently require behavior changes (e.g., weight loss, exercise) or the management of addictive conditions (e.g., tobacco and alcohol use) that are often recalcitrant to intervention. Although

The implementation of disease prevention and screening strategies in practice is challenging. A number of techniques can assist physicians with the delivery of these services. An appropriately configured electronic health record can provide reminder systems that make it easier for physicians to track and meet guidelines. Some systems give patients secure access to their medical records, providing an additional means to enhance adherence to routine screening. Systems that provide nurses and other staff with standing orders are effective for immunizations. The USPSTF has developed flow sheets and electronic tools to assist clinicians (https://www.uspreventiveservicestaskforce.org/ Page/Name/tools-and-resources-for-better-preventive-care). Many of these tools use age categories to help guide implementation. Age-specific recommendations for screening and counseling are summarized in Table 4-7. Many patients see a physician for ongoing care of chronic illnesses, and this visit provides an opportunity to include a “measure of prevention”

TABLE 4-7  Age-Specific Causes of Mortality and Corresponding Preventive Options AGE GROUP 15–24                        

LEADING CAUSES OF AGE-SPECIFIC MORTALITY  1. Accident   2.  Homicide   3.  Suicide  4. Malignancy   5.  Heart disease                

 

 

 

 

    25–44    

     1. Accident  2. Malignancy   3.  Heart disease   4.  Suicide   5.  Homicide   6.  HIV

     

SCREENING PREVENTION INTERVENTIONS TO CONSIDER FOR EACH SPECIFIC POPULATION •  Counseling on routine seat belt use, bicycle/motorcycle/ATV helmets (1) •  Counseling on diet and exercise (5) •  Discuss dangers of alcohol use while driving, swimming, boating (1) •  Assess and update vaccination status (tetanus, diphtheria, hepatitis B, MMR, rubella, varicella, meningitis, HPV) •  Ask about gun use and/or gun possession (2,3) •  Assess for substance abuse history including alcohol (2,3) •  Screen for domestic violence (2,3) •  Screen for depression and/or suicidal/homicidal ideation (2,3) •  Pap smear for cervical cancer screening after age 21 (4) •  Discuss skin, breast awareness, and testicular self-examinations (4) •  Recommend UV light avoidance and regular sunscreen use (4) •  Measurement of blood pressure, height, weight, and body mass index (5) •  Discuss health risks of tobacco use, consider emphasis on cosmetic and economic issues to improve quit rates for younger smokers (4,5) •  Chlamydia and gonorrhea screening and contraceptive counseling for sexually active females, discuss STD prevention •  Hepatitis B, and syphilis testing if there is high-risk sexual behavior(s) or any prior history of sexually transmitted disease •  HIV testing •  Continue annual influenza vaccination As above plus consider the following: •  Readdress smoking status, encourage cessation at every visit (2,3) •  Obtain detailed family history of malignancies and begin early screening/prevention program if patient is at significant increased risk (2) •  Assess all cardiac risk factors (including screening for diabetes and hyperlipidemia) and consider primary prevention with aspirin for patients at >3% 5-year risk of a vascular event (3) •  Assess for chronic alcohol abuse, risk factors for viral hepatitis, or other risks for development of chronic liver disease •  Consider individualized breast cancer screening with mammography at age 40 (2) (Continued)

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TABLE 4-7  Age-Specific Causes of Mortality and Corresponding Preventive Options (Continued) AGE GROUP

           

SCREENING PREVENTION INTERVENTIONS TO CONSIDER FOR EACH SPECIFIC POPULATION •  Consider prostate cancer screen with annual PSA and digital rectal examination at age 50 (or possibly earlier in African Americans or patients with family history) (1) •  Begin colorectal cancer screening at age 50 with fecal occult blood testing, flexible sigmoidoscopy, or colonoscopy (1) •  Reassess and update vaccination status at age 50 and vaccinate all smokers against S. pneumoniae at age 50 (6) •  Consider screening for coronary disease in higher-risk patients (2,5) •  Consider screening for hepatitis C in adults born between 1945 and 1965 (7) •  Zoster vaccination at age 60 •  Begin mammography screening by age 50 

Health Care Systems in Developed Countries

≥65      

 1. Malignancy   2.  Heart disease   3.  Accident  4. Diabetes mellitus  5. Cerebrovascular disease   6. Chronic lower respiratory disease   7.  Chronic liver disease and cirrhosis   8.  Suicide   1.  Heart disease  2. Malignancy   3.  Cerebrovascular disease   4. Chronic lower respiratory disease  5. Alzheimer’s disease   6.  Influenza and pneumonia   7.  Diabetes mellitus   8.  Kidney disease  9. Accidents 10.  Septicemia

CHAPTER 5

45–64              

LEADING CAUSES OF AGE-SPECIFIC MORTALITY

As above plus consider the following: •  Readdress smoking status, encourage cessation at every visit (1,2,3,4) •  One-time ultrasound for AAA in men 65–75 who have ever smoked •  Consider pulmonary function testing for all long-term smokers to assess for development of chronic obstructive pulmonary disease (4,6) •  Screen all postmenopausal women (and all men with risk factors) for osteoporosis •  Continue annual influenza vaccination and vaccinate against S. pneumoniae at age 65 (4,6) •  Screen for visual and hearing problems, home safety issues, and elder abuse (9)

 

Note: The numbers in parentheses refer to areas of risk in the mortality column affected by the specified intervention. Abbreviations: AAA, abdominal aortic aneurysm; ATV, all-terrain vehicle; HPV, human papillomavirus; MMR, measles-mumps-rubella; PSA, prostate-specific antigen; STD, sexually transmitted disease; UV, ultraviolet.

for other health problems. For example, a patient seen for management of hypertension or diabetes can have breast cancer screening incorporated into one visit and a discussion about colon cancer screening at the next visit. Other patients may respond more favorably to a clearly defined visit that addresses all relevant screening and prevention interventions. Because of age or comorbidities, it may be appropriate with some patients to abandon certain screening and prevention activities, although there are fewer data about when to “sunset” these services. For many screening tests, the benefit of screening does not accrue until 5–10 years of follow-up, and there are generally few data to support continuing screening for most diseases past age 75. In addition, for patients with advanced diseases and limited life expectancy, there is considerable benefit from shifting the focus from screening procedures to the conditions and interventions more likely to affect quality and length of life.

■■FURTHER READING

Bretthauer M et al: America, We Are Confused: The Updated U.S. Preventive Services Task Force Recommendation on Colorectal Cancer Screening. Ann Intern Med 166:139, 2017. Hayes JH et al: Observation versus initial treatment for men with localized, low-risk prostate cancer: A cost-effectiveness analysis. Ann Intern Med 158:853, 2013. Hugosson J et al: Mortality results from the Goteborg randomized population-based prostate-cancer screening trial. Lancet Oncol 11:725, 2010. Oeffinger KC et al: Breast Cancer Screening for Women at Average Risk 2015. Guideline Update from the American Cancer Society. JAMA 314:1599, 2015. US Preventive Services Task Force: Screening for Colorectal Cancer. US Preventive Services Task Force Recommendation Statement. JAMA 315:2564, 2016.

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5

Health Care Systems in Developed Countries Richard B. Saltman

Health care systems are highly complex organizations, with many interdependent components. Traditionally, health systems in the developed world have been classified by their type of financing—i.e., either predominantly tax-funded (such as the National Health Service in England and publicly operated regional care systems in the four European Nordic countries) or predominantly statutory social health insurance (SHI)-funded (such as in Germany, the Netherlands, and France). Over the last decade, however, there has been structural convergence in the technical characteristics of both funding arrangements, and also in the associated delivery systems, making analytic observations about the differences across national systems more difficult. A second confounding factor has been that former Soviet Bloc countries have, since 1991, replaced their former Soviet-style Semashko models (a top-down, national government–controlled structure with a parallel Communist Party apparatus) with various hybrid arrangements built on government-run SHI financing. Distinctions across health systems, especially in Europe, have been further compressed by the continuing negative impact of the 2008 global financial crisis on public revenues in many countries. This chapter focuses on the individual patient care system: on the financing and delivery of individual clinical and preventive services. The individual patient care system is composed of the financing and delivery of necessary services to prevent death or serious harm (“rule of rescue”); to maintain quality of life; and to manage, reduce, and/ or prevent the burden of illness on individual patients. While the

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PART 1 The Profession of Medicine

technical dimensions of most clinical services are similar across countries, their organizational, social, and economic characteristics differ markedly. Health systems in different countries exhibit substantial differences, for example, in access to care; in the design and reliance on quality assurance and provider payment mechanisms; in the relationship of primary care to hospital services; in the coordination of health care with home care and nursing home services; in the design and use of provider management strategies; in the way physicians work and are paid; in the decision-making roles of politically elected officials and of national, regional and municipal governments; and in participation of both citizens and patients. These differences reflect differing country contexts (geographical, social, economic and political), differences in national culture (consisting of prioritized norms and values), and substantial variation in how health sector institutions are structured.

■■FINANCING INDIVIDUAL PATIENT CARE SERVICES

Funding for individual care services in developed countries comes from the particular national mix among four possible sources of revenue: national, regional and/or municipal taxes; mandatory social health insurance; private health insurance; and out-of-pocket payments. Most countries have one preponderant payer, which then defines its funding arrangements and serves to frame the structure of its delivery system as well. The Organization for Economic Co-operation and Development (OECD) data from 2015 (adjusted for purchasing power parities) show that total health care expenditures in developed countries vary across a considerable range, tied to health system structure as well as national history and culture. Total health expenditures in tax-funded health systems in Western Europe ranged from a low of 9.0% of GDP in Spain and 9.6% in Finland to a high of 10.6% in Denmark and 11.1% in Sweden. In SHI-funded systems in Western Europe, the range was about 1% higher, running from 10.4% in Belgium and 10.8% in the Netherlands to a high of 11.1% in Germany and 11.5% in Switzerland. Central European health care systems, reflecting the economic and health system consequences of their pre-1991 Soviet Bloc history, spend considerably lower percentages of their GDP on health care: from a low of 5.6% in Latvia and 6.1% in Estonia to 7.7% in the Czech Republic and 8.4% in Slovenia. In Asia, total health expenditures ranged widely from 4.9% in 2014 in Singapore to 7.1% in 2015 in South Korea to 11.4% in 2015 in Japan. Total health expenditures in the United States in 2015 were 16.9% of GDP.

Tax-Funded Systems  In the United Kingdom, 79% of all health care funding was furnished through general tax revenues allocated by the national government in its annual budget process (all figures from OECD 2016). In Sweden, all public taxes combined raised 83.7% of total health care spending in 2015. Sweden’s 21 regional level elected governments provide approximately 70% of that 83.7%, with the remaining 13.7% of total health spending raised by national and municipal taxes. In Canada, 71% of total health spending was raised by tax revenues, with 66% of that 71% coming from provincial or territorial taxes, while 5% came from national and local government taxes. Social Insurance–Funded Systems  In Western Europe, SHI funds have traditionally been organized on a private not-for-profit basis, but with statutory responsibilities under national law. When former Soviet Bloc countries in Eastern Europe regained their independence in 1991, they returned to pre-WWII SHI models, but since there was no remaining organizational infrastructure, these post-1991 arrangements typically became a single SHI fund, run as an arm of the national government. In the United States, the Medicare social insurance system for citizens over age 65, enacted in 1965, is organized as a single fund tied to the national Social Security (public pension) Administration, an independent agency within the national government, with reimbursement arrangements supervised by the Centers for Medicare & Medicaid Services inside the Department of Health and Human Services. Medicare covers inpatient hospital care plus limited post-hospital nursing home services (Medicare Part A). Supplemental private insurance policies are bought by covered individuals to help pay for outpatient physician

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visits (Medicare Part B) and for outpatient pharmaceuticals (Medicare Part D). In Germany, 85% of the population is enrolled in 132 not-for-profit private social health insurance funds (in addition, 11% of the population are enrolled in private health insurance, and 4% in sector-specific public programs such as the military). Since 2009, all SHI members pay a flat tax on gross monthly income as a contribution (8.2% in 2013), which is sent by their SHI fund to a national pool. In addition, employers send 7.3% of each employee’s salary to the same national pool. Special arrangements exist for payments from self-employed, retired, and unemployed workers. Since 1995 there has been a separate mandatory social insurance fund for long-term care (LTC), with an annual premium of 1.95% of each adult’s gross monthly income, split 50%–50% with their employer. Pensioners since 2004 are required to pay the full amount from their pensions. Childless SHI enrollees pay a surcharge of 0.25% of monthly gross income. Overall, 85% of all health care expenditures in Germany were paid from public and/or mandatory private SHI sources. In the Netherlands since 2006, all adult citizens pay a fixed premium (about 1290 euros in 2015) to their choice among 35 private health insurers (not-for-profit and for-profit). In addition, employers pay 6.95% of salary below 51,400 euro for each employee into a national health insurance fund. Self-employed individuals pay 4.85% into the national fund for taxable income up to the same limit. Retired and unemployed individuals also make payments. In addition to the individual premiums paid to their choice of private insurance fund, payments from the national health insurance fund, adjusted by individual age, sex, and health characteristics, also are made to the individual’s chosen insurer. The Netherlands also has a separate mandatory social insurance fund for LTC (the ABWZ, since 2015 the WLZ, and now only for residential nursing home care) to which each employee pays 9.5% of taxable income beneath 33,600 euros every year. Self-employed, unemployed, and retired individuals also are required to pay premiums to the WLZ. Overall, including SHI revenues, public spending provided 87% of total health expenditures in 2014. In Estonia, a former Soviet Republic that re-established a social health insurance system in 1991 upon regaining its independence, there is one national social health insurance fund that is an arm of the national government. This fund collects mandatory payments of 13% from salaried workers and 20% from self-employed individuals, covering both health care and retirement pensions. Overall, including SHI revenues, public spending accounted for 78.8% of total health expenditures. Singapore, Japan, South Korea, and Taiwan have predominantly SHI systems of funding for individual care services. In these Asian countries (except Japan) there is one SHI fund that typically is operated as an arm of the national government. In Singapore, starting in 1983, all employees up to age 50 have been required to place 20% of their income (employers add 16% more) into a health savings account to pay for direct health care costs, managed in their name by the Singapore government, called a Medisave account. Medisave accounts have a maximum amount, are tax-exempt, and receive interest payments (currently set at 4%). Consistent with a Confucian emphasis on family, the funds that accumulate in the Medisave account can be spent on health care for family members as well. If the accumulated funds are not spent on health care during the insured’s life, they become part of the individual’s personal estate and are distributed as an inheritance to his/her designated heirs. In addition, Singaporean citizens are also automatically enrolled into a second government-run health insurance plan called MediShield that pays for supplemental catastrophic, chronic, and long-term care. While citizens can opt out, 90% of citizens remain in the program. The Singapore government also operates a third, wholly tax-funded payer called Medifund that, with approval of a local neighborhood committee, will pay hospital costs for 3–4% of the population who are recognized as indigent. In part reflecting the high level of mandatory individual saving, tax funds provided only 41.7% of total health expenditures in 2014. In South Korea, a state-run social health insurance system was established in 1977, which in 1990 covered 30.9% of total health care costs.

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Hospital Services  In Europe, hospitals in both tax-funded and

SHI-funded health systems are mostly publicly owned and operated by regional or municipal governments. In tax-funded health systems, most hospital-based physicians are civil servants, employed on a negotiated salary basis (often by a physician labor union), and subject to most of the usual advantages and disadvantages of being a public sector employee. There are somewhat more private hospitals in SHIfunded health systems. However, most larger hospitals are public institutions operated by local governments, and most hospital physicians (with the notable exception of the Netherlands, where they are private contractors organized in private group practices) are, like those in tax-funded systems, public sector employees. In most tax-funded European countries (but not continental SHI-funded countries), few specialist physicians have office-based practices, and in both tax- and SHI-funded systems, office-based specialists do not have admitting privileges to publicly operated hospitals. Most public hospitals in both tax-funded and SHI-funded health systems are single free-standing institutions that can be classified into three broad categories by complexity of patients admitted and number of specialties available: (1) district hospitals (four specialties: internal medicine, general surgery, obstetrics, and psychiatry); (2) regional hospitals (20 specialties); and (3) university hospitals (>40 specialties). In addition, many countries have a number of small, 15- to 20-bed, freestanding, private (typically for-profit) clinics. Recently, some countries have begun to merge district and regional hospitals in an effort to improve the quality of care and create financial efficiencies (for example, Norway; planned for Finland starting in 2019). Institutional

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Health Care Systems in Developed Countries

■■DELIVERING INDIVIDUAL PATIENT CARE SERVICES

mergers can be difficult to negotiate among publicly operated hospitals, due to the role that these large institutions play as important care providers and as large employers in smaller cities and towns, especially given political and union concerns about maintaining current employment levels. In the United States, financial and reimbursement pressures triggered by the implementation of the 2010 ACA have generated a number of private sector hospital mergers into larger hospital groups. In tax-funded health systems, publicly funded patients who are admitted for an elective procedure cannot choose their specialist physician (except private-pay patients in “pay beds” in NHS hospitals in England). Specialists are assigned by the clinic to a patient based on availability, with both junior and senior doctors placed in rotation. Capital costs (buildings, large medical equipment) are publicly funded in all tax-funded systems and in most traditional SHI systems. For example, in Germany capital costs for all public hospitals are paid for by the regional governments. As a result, new capital investment is often allocated politically, according to location and political priorities. In Finland, local politicians in the 1980s would say that it “takes 10 years to build a hospital,” meaning that it took that long to become a political priority for the regional government that controlled capital expenditures. As a result, local politicians would regularly overbuild when they got their one opportunity to obtain new capital. Because capital was not depreciated on the operating budget, such investment was perceived to be “free.” As a result, new equipment often was not properly serviced or kept in use, as maintenance costs came from the operating budget, which was held by a different level political organization (municipalities in Finland). Recently, efforts have been made to make public hospitals more responsible for their use of capital. In the Netherlands, public hospitals were shifted into private not-for-profit entities that are expected either to fund new capital from operating surplus or to borrow the funds from a bank with a viable business plan. In England, more than 100 hospitals have been built using the Public Finance Initiative (PFI) program, in which private developers build turn-key facilities (thus taking capital costs off the public borrowing limit), and then rent these facilities back to the NHS and/or the relevant NHS Foundation Trust. In Singapore or South Korea, both of which are SHI funded, larger hospitals are publicly operated. However, there are a substantial number of smaller private clinics typically owned by specialist physicians. In the United States, the passage of the 2010 ACA has triggered the selling of many private specialist group practices to hospital groups, transforming previously independent practicing physicians into hospital employees.

CHAPTER 5

This percentage paid by the SHI system rose to 43.6% of total costs in 2011, leaving out-of-pocket costs at 35.2% of total costs. In 2000, three types of public SHI funds were merged into a single national state-run fund. As of 2011, 5.64% of an employee’s salary must be paid as a social insurance contribution into this fund, with employees and employers each paying 50% of that amount. In 2008, an additional SHI fund was introduced to pay for LTC, operated by the main state-run SHI fund to reduce administrative costs. Contributions to the LTC fund are set at 6.55% of the individual’s regular SHI contribution, coupled with 20% copayments for institutional care and 15% copayments for home care services. There is no single preponderant source of health care spending in the United States. The source of health care revenues is fairly evenly divided among (1) national, state, county, and municipal taxes at 20% of all health spending in 2011 (for Medicaid, Children’s Health Insurance Program [CHIP], the Veteran’s Administration Hospitals, the Public Health Service, and the Indian Health Service); (2) mandatory social health insurance (for Medicare for all citizens over 65) at 23% of all spending; and (3) private health insurance (company and individual) at 35% of all spending. Out-of-pocket payments make up the remaining 14%. The World Bank, combining tax and social insurance funding, sets public funding in the United States at 48.3% of total health expenditures in 2014. In 2010, the passage of the Affordable Care Act (ACA) extended privately provided but heavily regulated and federally subsidized health insurance to a number of low- and middle-income uninsured individuals and families. Since the same act reduced the availability of existing individually purchased private health insurance, the total increase in the number of newly covered individuals was less than expected. Insurance premium increases for 2017 have risen from 20% to over 100%, depending on the particular state, with additional increases in up-front deductible requirements, raising serious questions about the long-term sustainability of the ACA initiative. The current Republican administration has sought to repeal major financial and tax elements of the ACA (using congressional budget reconciliation rules) and to replace existing subsidy arrangements with a system of refundable tax credits toward the establishment of individual health savings accounts and/or purchase of private health insurance on open cross-state markets.

Primary Care Services  Most primary health care in SHI-funded

health systems, and also in an increasing number of tax-funded health systems (except in low-income areas of some large cities), is delivered by independent private general practitioners (GPs), working either individually or in small privately owned group practices. Recent changes in tax-funded health systems include Norway, where most primary care moved from municipally employed physicians to private-practice GPs in 2003, and Sweden, where, following a 2010 change in national reimbursement requirements, new privately owned not-for-profit and for-profit GP practices were established and now deliver 50% of all primary care visits. In Finland, where public primary health care centers used to provide most primary care visits, delays in getting public health center appointments have pushed up to 40% of all visits to a parallel occupational health system, as well as to publicly employed primary care physicians working privately in the afternoons, seeing patients who are partly reimbursed by Finland’s separate Social Insurance Institution (known as KELA). In England, most primary care physicians are private GPs who are contractors to the NHS, working either independently or in small group practices. These private GPs own their own practices, which they can sell when they retire. However, as part of the original agreement establishing the NHS in 1948 (which most physicians strongly opposed), private GPs also receive a national government pension upon retirement. In the inner cities in England, there are some larger primary health clinics.

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In 2001, England’s private primary care doctors were organized into geographically based Primary Care Trusts (PCTs). These PCTs were allocated 80% of the total NHS budget to contract for elective hospital services required by their patients with both NHS hospital trusts as well as private hospitals. In 2013, PCTs were restructured into Clinical Commissioning Groups with similar contracting responsibilities. In 2004, the Quality Outcomes Framework (QOF) was introduced as a quality of care–tied approach to providing additional income for NHS GPs. This regulatory mechanism in 2010 set 134 different standards for best practice primary care in four main domains: 86 clinical, 36 organizational, 4 preventive service, and 3 patient experience. GPs income grew on average by 25% through the introduction of the QOF, with general practices averaging 96% of possible QOF points. Total spending on QOF in 2014 in England consumed 15% of all primary care expenditures. In Central European countries like Poland and Estonia that were formerly within the Soviet Bloc, primary care provision had to be newly established after independence was regained in 1991, since first-line care in the former Semashko model was provided in specialist polyclinics. Primary care doctors rapidly emerged as almost entirely private for-profit GPs working on contract from the national SHI fund. Private GPs in most Central European countries now are paid on a per-visit basis, in an amount set by the national SHI fund. This arrangement was heavily influenced by the structure of primary care in Germany’s SHI-based health system. In Asian countries such as Singapore, South Korea, and Japan, most primary care is provided by private for-profit GPs working independently or in small group practices. Private GPs are reimbursed at a set per-service fee by the national SHI fund(s). Developed countries have varying policies regarding access to individual preventive services. Health systems in most countries provide vaccinations and mammography as part of funded health care services. In the United States, most insured individuals—and in Canada, most covered residents—automatically receive an annual physical exam including full blood profiles. In Norway and Denmark, adult physical exams are provided only upon special request by the individual, and in Sweden adult physical exams are provided only to pregnant women. In Sweden, adults who wish to know their cholesterol or PSA levels have begun to purchase blood tests out-of-pocket from private laboratories. Lack of physical exams and accompanying blood profiles may contribute to lower health care expenditures in the Nordic region.

Access to Elective Specialist Care  Approximately half of all

European health care systems have a gatekeeping system that requires referrals from primary care physicians to book specialist visits (for publicly paid visits). In most tax-funded health systems (although not in most SHI systems), there are substantial waiting times, typically several months or more, for elective specialist appointments and hightech diagnostic procedures, especially for cancer and other elective surgical or high-demand services. In England, a patient who requires a further consultation with a second specialist typically has to return to their primary care physician for a second referral, and then has to wait in the regular patient queue for that second appointment. In Finland, middle class families purchase separate private health insurance for their children to enable them to skip the long waiting times for primary and secondary pediatric health care services. More than 400,000 Finnish children have privately purchased policies. There is also substantial waiting time for radiologic imaging services in most tax-funded systems. In Malta, the tax-funded health system’s recent efforts to prioritize elective MRI investigations have succeeded in reducing waiting times from 18 months to 4 months. In both Alberta and British Columbia Provinces in Canada, waiting time in 2016 for a publicly funded elective MRI is approximately 6 months, whereas privately paid MRIs are available in both provinces within 1 week. This issue of waiting times in tax-funded health systems reflects a combination of growing demand (including increasing clinical indications), financial constraints, and insufficient capacity, including inadequate physician working hours. In the 1980s, when several surgical procedures for the elderly became more routine practice (e.g., hip

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replacement, coronary artery bypass graft, corneal lens implantation), the waiting list problem worsened. It had been mitigated somewhat by the early 2000s, only to return as a growing policy challenge once public sector financial resources became constrained after 2008. Timely cancer diagnosis and care have been a particularly sensitive issue, with tax-funded systems often taking several months for a patient to see an oncologist and then months more to begin treatment. In Sweden, a newspaper journalist set off a political storm in 2013 when he wrote extensively about women patients in one large county council (Malmo) who had to wait 47 days to receive the results from their breast cancer biopsy. In response to patient anger in the early 2000s, a number of taxfunded health care systems introduced maximum waiting times for elective hospital procedures. (Most Western European SHI systems do not have long waiting times or treatment guarantees.) These maximum waiting times typically include initial primary care visits as well as specialist evaluations and treatment. In Denmark, a patient has the right to go to a different Danish public hospital for care after waiting 30 days without treatment. In Sweden, under the 2005 “waiting time guarantee,” an untreated patient’s local county council is required to pay for care in another county’s hospital after 180 days. Beginning in 1997, the European Union Court of Justice has slowly expanded the right of all EU citizens to travel to another EU country to receive “timely” care, with their home country health system required to pay for that care.

Long-Term Care Services  LTC (consisting of residential and

home-based services) consumes a relatively small but increasing proportion of gross domestic product (GDP) in developed countries. In Sweden, LTC consumes 3.6% of GDP, mostly from public funds, whereas in Switzerland LTC services consume 2.1% of GDP, with only 0.8% of GDP coming from public funding. In the United States, total LTC expenditures represent 1.0% of total GDP, with 0.6% of GDP representing public funds, mostly from state-based Medicaid programs, which typically spend about 40% of their total funding on nursing home services. (Note that these figures do not include emergency, inpatient, or outpatient hospital costs generated by elderly patients.) Since nursing home care is far more expensive than home care (nursing home care requiring the provision of housing, food, and around-the-clock care providers), government policymakers seek to keep the elderly and the chronically ill out of nursing homes for as long as feasible. Moreover, in developed countries like Sweden and Norway, some 70% of all home care services come from informal caregivers: spouses, children (typically daughters), neighbors, and friends. While some SHI systems (e.g., Germany) make available cash payments for LTC that can be used to compensate informal caregivers, most policymakers work hard to not monetize what is a large amount of essentially free care. Indeed, they actively seek to encourage those providing these services to continue to do so as long as possible, trying to postpone caregiver burnout by providing support services such as free respite care, special call-in lines for caregiving advice, pension points toward retirement for the informal caregiver (Nordic countries), and free daycare center services. In most tax-funded and SHI-funded European countries, home care services are organized at the municipal government level. In taxfunded systems, these services are also delivered mostly by municipal employees, working according to union-negotiated protocols. In some European SHI systems, and recently in tax-funded Sweden and Finland, private companies also provide home care services on contract to municipal governments. In combination with national legislation, these municipal systems also provide important support for informal caregivers, since the financial costs of caring for adults in their own home are substantially less than providing housing, food, and caregiver support in publicly funded homes for the aged or in nursing homes. A high proportion of nursing homes in European tax-funded and SHI-funded health systems are publicly owned facilities operated by municipal governments; in some instances in SHI-funded systems (Israel, Netherlands), they are operated by private not-for-profit organizations. Recently, in some tax-funded systems (e.g., Sweden), private for-profit chains have begun to open nursing homes that are funded on

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Health Care Systems in Developed Countries

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nursing home care. Some private insurers have also raised premiums after individuals have paid in for many years and canceled policies if the new higher rate is not affordable. The 2010 ACA contained a new public LTC insurance program. However, the program was designed to be voluntary, and U.S. Department of Health and Human Services administrators decided not to implement that portion of the law. In addition to the tax-funded Medicaid program, and privately purchased LTC insurance, many middle-class families pay for care from savings, by selling the elderly person’s home, or by direct contribution from children and other family members. Expenses can reach more than $60,000 per year depending on the location of a facility and who operates it. Nursing home care in the United States is provided by a wide mix of private not-for-profit and for-profit providers, ranging from churchowned single-site homes to large stock market–listed companies. Many of these homes are purpose-built as assisted-living residences. There also are special units and facilities designed to care for the memory impaired. Home care services are delivered by a mix of private and not-for-profit and for-profit providers. In Japan, a national LTC insurance fund was introduced in 2000. Although the new fund applies uniformly across the country, the program is administered by municipal governments and the premium level differs across municipalities, with an average monthly premium of 3000 yen (about $30 USD). In South Korea, an SHI fund for LTC is funded by mandatory contributions of 4.78% of a person’s regular national health insurance contribution, with an additional 20% of total LTC expenditures provided by national government funds. The client copayment for home care is set at 15% of expenses and at 20% for residential care.

CHAPTER 5

a contract basis with local municipal governments. Costs for nursing home care can be expensive: in Norway, the cost per patient is often over $100,000 per year in a publicly funded home, with the patient responsible for paying up to 80% depending on the family’s economic status. In Sweden, patients living in publicly funded nursing homes in Stockholm County pay a relatively small official fee, but they also pay room rent and up to 2706 Swedish Krona (SEK) per month (about $350 USD) for food out of their pensions. In 2012, in an effort to reduce demand for expensive hospital and nursing home services, Norway and Denmark both began a number of elderly care reforms that shifted service delivery as well as funding responsibilities to municipal governments. Among innovations in Norway, municipalities are required to establish a municipal acute bed unit (MAU) to treat stable elderly patients and provide observation beds for evaluation. Partial funding for these units is provided by the four regional health care administrations. Some municipalities have also embedded primary care units inside their regional hospital to arrange discharge and to coordinate care for the chronically ill elderly. Norwegian municipalities are also responsible through their contracted (mostly private) primary care physicians to implement the National Pathways Program, which established treatment protocols for crosssector conditions such as diabetes and cardiovascular conditions. A differently configured structural innovation to better integrate LTC for the chronically ill elderly with clinical individual health services has been to consolidate both social and health care services within the same public administrative organization. In proposed 2019 health reforms in Finland, as well as a pilot decentralization program in England for 2.8 million people in Greater Manchester, social and health care programs are to be administered by a single responsible agency. In the SHI-funded system in the Netherlands, almost 7% of the population live in a residential home. National government legislation revised the structure of nursing home funding and care in 2015. Three acts restructured the separate public LTC SHI fund, which requires mandatory payments by 100% of Dutch adults, and introduced delivery-related reforms that reduced the number and overall cost of nursing home patients paid for by the fund. Determination of eligibility for public payment for nursing home care is now made by an independent national assessment body (the Centre for Needs Assessment). Moreover, municipal governments now play a stronger role in funding and delivering home care services. The reforms created social care teams that hold “kitchen table talks” to steer the elderly first toward seeking care from family, neighbors, churches, and other local community organizations before they qualify for publicly paid in-home care. In 2012, some 1.5 million people (12% of total population) provided informal care to ill or disabled persons, averaging 22 hours per week of care per person. Home care recipients in the Netherlands can choose to set up a “personal budget,” using their public funding allocation to select their preferred individual care personnel (either publicly employed or publicly approved private providers). This arrangement also enables these home care recipients to determine the particular mix of services they want, as well as to augment the allocated public funds with personal funds. A number of innovative not-for-profit nursing homes have been created to provide additional services to elderly living in their neighborhood (primary care home visits), as well as terminal hospice care (e.g., the Saffier De Residentie Groep residences in The Haag). In the United States, nursing home and home care are funded and delivered in a variety of different ways. For individuals who have minimal financial assets, nursing home costs are paid by a joint federalregional (state) welfare program called Medicaid. Most state government Medicaid programs pay out more than 40% of their total budget for nursing home care. In the past, Medicaid did not pay for home care services. However, some states have programs with private for-profit and not-for-profit providers that provide home care as a way to forestall the need for the more expensive nursing home care. Many private individuals take out private LTC insurance, typically from commercial insurance companies. These policies require individuals to make premium payments for years in advance (often 20 or more) before the individual learns whether they will, in fact, require home or

■■PHARMACEUTICALS

Pharmaceutical expenditures in developed countries (inpatient and outpatient combined) vary widely across different health system types, as well as between different countries within those different institutional types. OECD figures for 2014 show drug expenditures in tax-funded countries in Western Europe ranging from 6.7% of total health expenditures (THE) in Denmark to 12.2% of THE in the United Kingdom and 17.9% of THE in Spain. In SHI-funded Western European systems, pharmaceuticals absorbed 7.6% of THE in the Netherlands, while in Germany that figure was 14.5%. In the hybrid tax-funded SHI systems of Central Europe, pharmaceuticals were much higher: 18% of THE in Estonia to 30.2% of THE in Hungary. In Asian SHI systems, pharmaceuticals consumed 20.6% of THE in South Korea and 21% of THE (in 2012) in Japan. The OECD’s 2014 figures for pharmaceutical spending in North America are 12.3% of THE in the United States and 17.2% in Canada. Contributing factors to this wide-ranging variation are (1) the ratio problem (relatively fixed level of pharmaceutical costs due to international prices—the numerator—divided by a greatly varying per-capita health expenditure cost in different developed country health systems); (2) the range and type of pharmaceutical price controls in each country; and (3) the degree of limitation placed on pharmaceutical supply, tied to formularies and/or explicit forms of drug rationing. Most European health systems have tight national controls on the cost and, in some tax-based countries, on the availability of pharmaceuticals. Most European countries also use a number of different regulatory measures to limit prices and/or availability of both inpatient and outpatient drugs, including mandatory generic prescribing, reference pricing, patient copays (sometimes with an annual ceiling, after which copayments are no longer required), and (particularly in tax-funded systems) national formularies tied to clinical effectiveness. (Norway, for example, allows only about 2300 different preparations—including dosage, delivery method, and box size—to be stocked by pharmacies.) Prices for drugs can vary considerably across different European countries, tied to economic development and domestic pricing patterns. One consequence of these differential national pricing controls has been the development of a parallel import market, in which drug wholesalers and pharmacists in the more expensive countries purchase supplies from a cheaper market elsewhere in Europe.

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Access to expensive drugs has also been intentionally limited in some tax-funded health systems in Europe. One basis for rationing, as noted above, has been rationing tied to QALYs (quality-adjusted life-years). Rationing also reflects a clash between strained public drug budgets and public pressure. For example, in the case of cancer drugs in England, the recommendation of NICE against funding the breast cancer drug trastuzumab (Herceptin) was subsequently overturned by the Minister of Health. Expensive cancer drugs continue to be rationed in England where the NHS Cancer Drug Fund, established to provide access on a case-by-case basis, ran out of funds and was forced to close down for 3 months to restructure its operations. As part of the medical tradition in Asian countries, office-based physicians fill prescriptions as well as prescribing drugs to patients. These sales serve to supplement their income in the setting of relatively low per-visit payments from state-run SHI funds. Korea has now implemented restrictions on these office-based sales. Japan has attempted to reduce physician sale of pharmaceuticals by various changes in reimbursement rates, reducing the total percentage of physician-sold pharmaceuticals to 42.8% of all outpatient prescriptions.

■■GOVERNANCE AND REGULATION

Health care services in developed countries are steered, constrained, monitored, and (to varying degrees) assessed by governments and governmentally established and/or empowered bodies. Although these measures apply particularly to the financial efficiency of governmentfunded services, they also seek to promote patient and community safety, equity of access, and high-quality clinical outcomes. This oversight is often strongly focused on privately operated and contracted providers and insurers, although in principle it applies to publicly operated organizations as well. Governance consists of macro national-level policy, meso institutional-level management, and micro clinic-level care decisions. This complex mix of governance decisions is often shared among different national, regional, and local governments, depending on the degree of centralization, decentralization, or, recently, recentralization (e.g., Norway). While most systems officially prioritize “good governance,” governance activities frequently comingle with political objectives as core policy concepts are developed and transformed into concrete organizational targets. In Sweden, health system governance is shared among national, regional (county), and local municipal governments. The national government has responsibility to pass “frame” legislation, which establishes the basic structure of the system. To cite one example, until recently, the national government had limited an adult patient’s total copayments for outpatient physician (specialist and primary care) and pharmaceuticals to 2800 SEK (about $350 USD) for a 12-month period. The 20 regional governments, in turn, made policy decisions within that legislation, deciding how to apportion the specific copayments for each primary care and specialist outpatient visit. Since Swedes can self-refer to specialists, some counties double the copayment to hospital-based doctors to discourage unnecessary appointments. Similarly, fiscal policy normally is shared between the regional government, which raises about 70% of total health expenditures through its own county-set flat income tax, and the national government, which provides additional purpose-tied funds for national objectives such as consolidating openheart surgery across county lines and balancing lower tax receipts in rural counties with smaller working populations. However, this normal funding relationship across governments can change. In the early 1990s, the national government placed a “stop” on raising county taxes prior to Sweden’s admission in 1995 to the European Union. In 2016, each of the 20 counties could set their own ceilings, which were almost all at 3300 SEK (about $370 USD). In Spain’s tax-funded health system (70.9% publicly funded), 17 regional “autonomous communities” were given full managerial responsibility for the provision of health services in a decentralization process, along with ownership of all publicly owned hospitals. The national government generates a substantial proportion of health care resources, which are included in the broad block grants it allocates to the regional governments, which then add regional tax revenue to

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make up the full public-sector budget. In a mechanism to further influence operating policy, the national Spanish government established a joint federal-regional council to review quality and performance data (through the 2003 Health System Cohesion and Quality Act). Italy’s tax-funded health system (75.6% publicly funded) is similarly operated by 20 regional governments, which pay for the publicly operated system through a complicated mix of national, and nationally stipulated but regionally collected, taxes. Again like Spain, the national government established a federal-regional government council, which seeks to coordinate care standards and information among the regions and with national government agencies. In Germany, where funding for the health system is formally the responsibility of 132 private not-for-profit sickness funds, governance decisions are shared among these private sector sickness funds and public-sector national, regional, and municipal governments. The sickness funds receive a risk-adjusted premium payment for each enrolled individual, determined by a national government–determined formula, and from a national government–run health insurance pool. Most hospitals are owned and operated by municipal governments, while investment capital for structural renovations and new building comes from the 16 regional Länder taken from their tax revenues. Payment frameworks and amounts for public hospitals are negotiated between associations of these municipally owned hospitals and associations of the private sickness funds, without formal government participation. Regulation is an essential element of an effective health care system and a key component of overall health system governance. Regulation incorporates both broad standard requirements that affect all organizations that operate in a country (e.g., hiring, firing, and wage decisions) as well as specific health sector–related regulations (e.g., proper handling, use, and disposal of low-grade nuclear waste from radiation treatments). Recent examples of health sector regulation in England, for example, include the following: 1. Requiring all cancer drugs adopted for use in the NHS to cost no more than £30,000/QALY; 2. Requiring in their employment contract that junior doctors in hospitals work a specific number of Sundays; and 3. Requiring that all emergency department patients receive care within 4 h of their arrival. A powerful tool that has the force of law, regulation can have substantial negative as well as positive effects. A well-known political science corollary of regulatory power is that “the right to regulate is also the right to destroy.” For example, in the United States, the federal Environmental Protection Agency, as part of its pursuit of cleaner air, issued wide-ranging regulatory orders setting performance standards that resulted in the closing of many West Virginia coal mines, resulting in the loss of tens of millions of dollars of productive capacity and thousands of high-paying jobs. Similarly, in some tax-funded European systems, such as those in Sweden and England, there is growing pressure from public health advocates to prohibit the making of a profit from publicly paid funds. In Sweden, the national government’s Reepalu report honored a pledge made by the Social Democratic government to its Left (socialist) Party ally by calling for a legislated ban on profit-making in the provision of publicly funded health care services. The Report’s publication resulted in substantial divestment of existing investor-owned primary care, nursing home, and home care companies.

■■FUTURE CHALLENGES

Health systems in developed countries face serious challenges in the coming years. These include financial, organizational, and policy dilemmas for which institutionally viable, financially sustainable, and politically supportable solutions will be complicated to develop and difficult to implement. On the delivery side, a key question is whether privately structured GP-based primary care is more efficient and effective than various clinic-based forms of primary care services. Recent movement in Northern and Central Europe toward more private GPs, along with continued private office–based primary care in much of

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While the structure and complexity of resolving these specific organizational challenges will vary depending on a country’s cultural and institutional context, the commonality of these problems suggests that health systems in the developed world will require a new, broader range of targeted policy strategies and solutions.

■■FURTHER READING

Figueras J, McKee M (eds): Health Systems, Health, Wealth, and Societal Well-Being: Assessing the Case for Investing in Health Systems. Maidenhead, Open University Press/McGraw-Hill Education, 2011. www.euro.who.int/__data/assets/pdf_file/0007/164383/e96159.pdf. Haseltine W: Affordable Excellence: The Singapore Health Story. Washington, Brookings Institution Press, 2013. www.brookings.edu/ wp-www.brookings.edu/wp-content/uploads/2016/07/AffordableExcellencePDF.pdf. Kuhlmann E et al (eds): The Palgrave International Handbook on Healthcare Policy and Governance. London, Palgrave MacMillan, 2015. Oliver E, Mossialos E: European health systems reforms: Looking backward to see forward? J Health Polit Policy Law 30:7, 2005. Rice T et al: United States of America: Health System Review. Health in Transition (HiT) Series 15 (3). Brussels, European Observatory on Health Systems and Policies, 2013. www.euro.who.int/__data/assets/ pdf_file/0019/215155/HiT-United-States-of-America.pdf.

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The Safety and Quality of Health Care

1. Finding a more sustainable balance between ethics and funding. Policymakers in publicly funded health systems face a growing gap between patient expectations of high-quality clinical care, staff expectations of better compensation, and the economic imperative of no new taxes. While the present solidaristic foundation for raising collective revenues is insufficient, available non-solidaristic tools (copayments, supplemental insurance, private pay) inevitably contribute to overall inequality. But what then are the realistic policy alternatives? The minimalist new policy goal necessarily will have to become one of raising new revenues while doing the least economic and social harm. 2. Developing better strategies to steer provider diversity. Health systems in developed countries are becoming more diverse with more and different types of public owners: hospital trusts, state enterprises, and mixed public-private hospital owners/managers. There also are more and different types of private providers: not-forprofit community groups, foundations, and cooperatives, as well as for-profit small local entrepreneurs, large international companies, and risk capital funds (venture capital). Furthermore, new innovative delivery models are reorganizing traditional service boundaries: not-for-profit private nursing homes in the Netherlands also provide outpatient primary care to neighborhood elderly patients, as well as hospice care; Israeli technology companies combine high-tech homebased patient monitoring with standard medical and custodial home care services. Public pressure from citizens for more choice and better outcomes will pressure policymakers toward new, more accommodative health system arrangements. 3. Ensuring better coordination between social and health services. Tax-funded and SHI-funded systems alike are under intense policy pressure to develop better strategies to integrate services for the chronically ill elderly, as a way to improve the quality of services that these patients receive and to keep them at home healthier and longer, reducing expensive acute visits to hospitals and emergency departments. The clear delivery system goal will increasingly be to keep the elderly out of nursing homes and acute care facilities for as long as possible. 4. Building labor unions into provider innovation. In many developed countries, health sector staff, including hospital physicians, are members of labor unions. Effective policymaking will require finding mechanisms to build these personnel unions into accelerated health system restructuring processes. This process

will necessarily involve integrating unions into more innovative, flexible, fiscally sustainable organizational arrangements with contracts that reward active participation in organizational change, contracts that pay incentives to more productive employees, quicker reassignment and redundancy procedures (firing health sector workers can take a year or longer in some European health systems), and establishing profit-sharing payments to teams/unions, also in public sector organizations.

CHAPTER 6

Canada, the United States, and economically developed countries in Asia, raises complex policy issues for international organizations like the World Health Organization (WHO), as well as national policymakers. In the hospital sector, existing levels of clinical quality and patient responsiveness in publicly operated command-and-control institutions will increasingly have to compete with those of semi-autonomous public hospitals, as well as various types of private, sometimes very innovative providers. In the financing arena, continued pressure on publicly raised health system revenues is likely to erode longtime commitments in some tax-funded health systems to minimal patient copayments and low out-of-pocket funding. An additional set of challenges will arise from recent commitments by international organizations like WHO to restructure health systems in developed countries to better address the social determinants of health. This new, incomplete strategy calls for a dramatic expansion of health sector responsibility to include a wide range of existing institutional arrangements in housing, education, work-life, and social and political decision-making. The influential 2010 Strategic Review of Health Inequalities in England entitled “Fair Society, Healthy Lives,” led by Sir Michael Marmot, a British epidemiologist, called for the elimination of all “inequities in power, money, and resources.” Separate from the political dimensions of this proposed new paradigm, how such fundamental societal change will be funded has yet to be addressed. Looking forward, among the most essential challenges to national decision-makers in the coming period will be four specific health system imperatives:

The Safety and Quality of Health Care David W. Bates

Safety and quality are two of the central dimensions of health care. In recent years it has become easier to measure safety and quality, and it is increasingly clear that performance in both dimensions could be much better. The public is—with good justification—demanding measurement and accountability, and payment for services will increasingly be based on performance in these areas. Thus, physicians must learn about these two domains, how they can be improved, and the relative strengths and limitations of the current ability to measure them. Safety and quality are closely related but do not completely overlap. The Institute of Medicine has suggested in a seminal series of reports that safety is the first part of quality and that the health care system must first and foremost guarantee that it will deliver safe care, although quality is also pivotal. In the end, it is likely that more net clinical benefit will be derived from improving quality than from improving safety, though both are important and safety is in many ways more tangible to the public. The first section of this chapter will address issues relating to the safety of care and the second will cover quality of care.

■■SAFETY IN HEALTH CARE Safety Theory and Systems Theory  Safety theory clearly points out that individuals make errors all the time. Think of driving home from the hospital: you intend to stop and pick up a quart of milk on the way home but find yourself entering your driveway without realizing how you got there. Everybody uses low-level, semiautomatic behavior for many activities in daily life; this kind of error is called a slip. Slips

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PART 1 The Profession of Medicine

Other holes due to latent conditions (resident “pathogens”) Losses Successive layers of defenses, barriers and safeguards FIGURE 6-1  “Swiss cheese” diagram. Reason argues that most accidents occur when a series of “latent failures” are present in a system and happen to line up in a given instance, resulting in an accident. Examples of latent failures in the case of a fall might be that the unit is unusually busy and the floor happens to be wet. (Adapted from J Reason: BMJ 320:768, 2000; with permission.)

occur often during care delivery—e.g., when people intend to write an order but forget because they have to complete another action first. Mistakes, by contrast, are errors of a higher level; they occur in new or nonstereotypic situations in which conscious decisions are being made. An example would be dosing of a medication with which a physician is not familiar. The strategies used to prevent slips and mistakes are often different. Systems theory suggests that most accidents occur as the result of a series of small failures that happen to line up in an individual instance so that an accident can occur (Fig. 6-1). It also suggests that most individuals in an industry such as health care are trying to do the right thing (e.g., deliver safe care) and that most accidents thus can be seen as resulting from defects in systems. Systems should be designed both to make errors less likely and to identify those that do inevitably occur.

Factors that Increase the Likelihood of Errors  Many factors

ubiquitous in health care systems can increase the likelihood of errors, including fatigue, stress, interruptions, complexity, and transitions. The effects of fatigue in other industries are clear, but its effects in health care have been more controversial until recently. For example, the accident rate among truck drivers increases dramatically if they work over a certain number of hours in a week, especially with prolonged shifts. A recent study of house officers in the intensive care unit demonstrated that they were about one-third more likely to make errors when they were on a 24-h shift than when they were on a schedule that allowed them to sleep 8 h the previous night. The American College of Graduate Medical Education has moved to address this issue by putting in place the 80-h workweek. Although this stipulation is a step forward, it does not address the most important cause of fatigue-related errors: extended-duty shifts. High levels of stress and heavy workloads also can increase error rates. Thus, in extremely high-pressure situations, such as cardiac arrests, errors are more likely to occur. Strategies such as using protocols in these settings can be helpful, as can simple recognition that the situation is stressful. Interruptions also increase the likelihood of error and occur frequently in health care delivery. It is common to forget to complete an action when one is interrupted partway through it by a page, for example. Approaches that may be helpful in this area include minimizing interruptions and setting up tools that help define the urgency of an interruption. Complexity represents a key issue that contributes to errors. Providers are confronted by streams of data (e.g., laboratory tests and vital signs), many of which provide little useful information but some of which are important and require action or suggest a specific diagnosis. Tools that emphasize specific abnormalities or combinations of abnormalities may be helpful in this area. Transitions between providers and settings are also common in health care, especially with the advent of the 80-h workweek, and

Harrisons_20e_Part1_p0001-p0064.indd 34

generally represent points of vulnerability. Tools that provide structure in exchanging information—for example, when transferring care between providers—may be helpful.

The Frequency of Adverse Events in Health Care  Most large studies focusing on the frequency and consequences of adverse events have been performed in the inpatient setting; some data are available for nursing homes, but much less information is available about the outpatient setting. The Harvard Medical Practice Study, one of the largest studies to address this issue, was performed with hospitalized patients in New York. The primary outcome was the adverse event: an injury caused by medical management rather than by the patient’s underlying disease. In this study, an event either resulted in death or disability at discharge or prolonged the length of hospital stay by at least 2 days. Key findings were that the adverse event rate was 3.7% and that 58% of the adverse events were considered preventable. Although New York is not representative of the United States as a whole, the study was replicated later in Colorado and Utah, where the rates were essentially similar. Since then, other studies using analogous methodologies have been performed in various developed nations, and the rates of adverse events in these countries appear to be ~10%. Rates of safety issues appear to be even higher in developing and transitional countries; thus, this is clearly an issue of global proportions. The World Health Organization has focused on this area, forming the World Alliance for Patient Safety. In the Harvard Medical Practice Study, adverse drug events (ADEs) were most common, accounting for 19% of all adverse events, and were followed in frequency by wound infections (14%) and technical complications (13%). Almost half of adverse events were associated with a surgical procedure. Among nonoperative events, 37% were ADEs, 15% were diagnostic mishaps, 14% were therapeutic mishaps, 13% were procedure-related mishaps, and 5% were falls. ADEs have been studied more than any other error category. Studies focusing specifically on ADEs have found that they appear to be much more common than was suggested by the Harvard Medical Practice Study, although most other studies use more inclusive criteria. Detection approaches in the research setting include chart review and the use of a computerized ADE monitor, a tool that explores the database and identifies signals that suggest an ADE may have occurred. Studies that use multiple approaches find more ADEs than does any individual approach, and this discrepancy suggests that the true underlying rate in the population is higher than would be identified by a single approach. About 6–10% of patients admitted to U.S. hospitals experience an ADE. Injuries caused by drugs are also common in the outpatient setting. One study found a rate of 21 ADEs per every 100 patients per year when patients were called to assess whether they had had a problem with one of their medications. The severity level was lower than in the inpatient setting, but approximately one-third of these ADEs were preventable. The period immediately after a patient is discharged from the hospital appears to be very risky. A recent study of patients hospitalized on a medical service found an adverse event rate of 19%; about one-third of those events were preventable, and another one-third were ameliorable (i.e., they could have been made less severe). ADEs were the single leading error category. Prevention Strategies  Most work on strategies to prevent adverse events has targeted specific types of events in the inpatient setting, with nosocomial infections and ADEs having received the most attention. Nosocomial infection rates have been reduced greatly in intensive care settings, especially through the use of checklists. For ADEs, several strategies have been found to reduce the medication error rate, although it has been harder to demonstrate that they reduce the ADE rate overall, and no studies with adequate power to show a clinically meaningful reduction have been published. Implementation of checklists to ensure that specific actions are carried out has had a major impact on rates of catheter-associated bloodstream infection and ventilator-associated pneumonia, two of the most serious complications occurring in intensive care units. The checklist

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Measurement of Safety  Measuring the safety of care is difficult and expensive, since adverse events are, fortunately, rare. Most hospitals rely on spontaneous reporting to identify errors and adverse events, but the sensitivity of this approach is very low, with only ~1 in 20 ADEs reported. Promising research techniques involve searching the electronic record for signals suggesting that an adverse event has occurred. These methods are not yet in wide use but will probably be used routinely in the future. Claims data have been used to identify the frequency of adverse events; this approach works much better for surgical care than for medical care and requires additional validation. The net result is that, except for a few specific types of events (e.g., falls and nosocomial infections), hospitals have little idea about the true frequency of safety issues. Nonetheless, all providers have the responsibility to report problems with safety as they are identified. All hospitals have spontaneous reporting systems, and, if providers report events as they occur, those events can serve as lessons for subsequent improvement. Conclusions about Safety  It is abundantly clear that the safety

of health care can be improved substantially. As more areas are studied closely, more problems are identified. Much more is known about the epidemiology of safety in the inpatient setting than in outpatient settings. A number of effective strategies for improving inpatient safety have been identified and are increasingly being applied. Some effective

Harrisons_20e_Part1_p0001-p0064.indd 35

Assessment of quality of care has remained somewhat elusive, although the tools for this purpose have increasingly improved. Selection of health care and measurement of its quality are components of a complex process.

Quality Theory  Donabedian has suggested that quality of care

can be categorized by type of measurement into structure, process, and outcome. Structure refers to whether a particular characteristic is applicable in a particular setting—e.g., whether a hospital has a catheterization laboratory or whether a clinic uses an electronic health record. Process refers to the way care is delivered; examples of process measures are whether a Pap smear was performed at the recommended interval or whether an aspirin was given to a patient with a suspected myocardial infarction. Outcome refers to what actually happens—e.g., the mortality rate in myocardial infarction. It is important to note that good structure and process do not always result in a good outcome. For instance, a patient may present with a suspected myocardial infarction to an institution with a catheterization laboratory and receive recommended care, including aspirin, but still die because of the infarction. Quality theory also suggests that overall quality will be improved more in the aggregate if the performance level of all providers is raised rather than if a few poor performers are identified and punished. This view suggests that systems changes are especially likely to be helpful in improving quality, since large numbers of providers may be affected simultaneously. The theory of continuous quality improvement suggests that organizations should be evaluating the care they deliver on an ongoing basis and continually making small changes to improve their individual processes. This approach can be very powerful if embraced over time. A number of specific tools have been developed to help improve process performance. One of the most important is the Plan-DoCheck-Act cycle (Fig. 6-2). This approach can be used for “rapid cycle” improvement of a process—e.g., the time that elapses between a diagnosis of pneumonia and administration of antibiotics to the patient. Specific statistical tools, such as control charts, are often used in conjunction to determine whether progress is being made. Because most medical care includes one or many processes, this tool is especially important for improvement.

Adopt or abandon strategies based on results

t Ac

Pl

an

Identify potential improvement strategies

Ch Measure effectiveness of strategies

ec k

Do

the National Quality Forum and the Joint Commission, have made recommendations for improving safety. In particular, the National Quality Forum has released recommendations to U.S. hospitals about what practices will most improve the safety of care, and all hospitals are expected to implement these recommendations. Many of these practices arise frequently in routine care. One example is “readback,” the practice of recording all verbal orders and immediately reading them back to the physician to verify the accuracy of what was heard. Another is the consistent use of standard abbreviations and dose designations; some abbreviations and dose designations are particularly prone to error (e.g., 7U may be read as 70).

■■QUALITY IN HEALTH CARE

35

The Safety and Quality of Health Care

The National Safety Picture  Several organizations, including

strategies are also available for the outpatient setting. Transitions appear to be especially risky. The solutions to improving care often entails the consistent use of systematic techniques such as checklists and often involves leveraging of information technology. Nevertheless, solutions will also include many other domains, such human factors techniques, team training, and a culture of safety.

CHAPTER 6

concept is based on the premise that several specific actions can reduce the frequency of these issues; when these actions are all taken for every patient, the result has been an extreme reduction in the frequency of the associated complication. These practices have been disseminated across wide areas, in particular in the state of Michigan. Computerized physician order entry (CPOE) linked with clinical decision support reduces the rate of serious medication errors, defined as those that harm someone or have the potential to do so. In one study, CPOE, even with limited decision support, decreased the serious medication error rate by 55%. CPOE can prevent medication errors by suggesting a default dose, ensuring that all orders are complete (e.g., that they include dose, route, and frequency), and checking orders for allergies, drug–drug interactions, and drug–laboratory issues. In addition, clinical decision support can suggest the right dose for a patient, tailoring it to level of renal function and age. In one study, patients with renal insufficiency received the appropriate dose only one-third of the time without decision support, whereas that fraction increased to approximately two-thirds with decision support; moreover, with such support, patients with renal insufficiency were discharged from the hospital half a day earlier. As of 2017, over 90% of U.S. hospitals have implemented CPOE, though the decision support often is still limited. Another technology that can improve medication safety is bar coding linked with an electronic medication administration record. Bar coding can help ensure that the right patient gets the right medication at the right time. Electronic medication administration records can make it much easier to determine what medications a patient has received. Studies to assess the impact of bar coding on medication safety are under way, and the early results are promising. Another technology to improve medication safety is “smart pumps.” These pumps can be set according to which medication is being given and at what dose; the health care professional will receive a warning if too high a dose is about to be administered.

Try out strategies

FIGURE 6-2  Plan-Do-Check-Act cycle. This approach can be used to improve a specific process rapidly. First, planning is undertaken, and several potential improvement strategies are identified. Next, these strategies are evaluated in small “tests of change.” “Checking” entails measuring whether the strategies have appeared to make a difference, and “acting” refers to acting on the results.

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36

PART 1 The Profession of Medicine

Factors Relating to Quality  Many factors can decrease the level of quality, including stress to providers, high or low levels of production pressure, and poor systems. Stress can have an adverse effect on quality because it can lead providers to omit important steps, as can a high level of production pressure. Low levels of production pressure sometimes can result in worse quality, as providers may be bored or have little experience with a specific problem. Poor systems can have a tremendous impact on quality, and even extremely dedicated providers typically cannot achieve high levels of performance if they are operating within a poor system.

Community

Resources and policies Selfmanagement Support

Health System

Organization of health care Delivery system design

Decision support

Clinical information systems

Data about the Current State of Quality  A study published

by the RAND Corporation in 2006 provided the most complete picture of quality of care delivered in the United States to date. The results were sobering. The authors found that, across a wide range of quality parameters, patients in the United States received only 55% of recommended care overall; there was little variation by subtype, with scores of 54% for preventive care, 54% for acute care, and 56% for care of chronic conditions. The authors concluded that, in broad terms, the chances of getting high-quality care in the United States were little better than those of winning a coin flip. Work from the Dartmouth Atlas of Health Care evaluating geographic variation in use and quality of care demonstrates that, despite large variations in utilization, there is no positive correlation between the two variables at the regional level. An array of data demonstrate, however, that providers with larger volumes for specific conditions, especially for surgical conditions, do have better outcomes.

Strategies for Improving Quality and Performance  A number of specific strategies can be used to improve quality at the individual level, including rationing, education, feedback, incentives, and penalties. Rationing has been effective in some specific areas, such as persuading physicians to prescribe within a formulary, but it generally has been resisted. Education is effective in the short run and is necessary for changing opinions, but its effect decays fairly rapidly with time. Feedback on performance can be given at either the group or the individual level. Feedback is most effective if it is individualized and is given in close temporal proximity to the original events. Incentives can be effective, and many believe that they will prove to be a key to improving quality, especially if pay-for-performance with sufficient incentives is broadly implemented (see below). Penalties produce provider resentment and are rarely used in health care. Another set of strategies for improving quality involves changing the systems of care. An example would be introducing reminders about which specific actions needed to be taken at a visit for a specific patient—a strategy that has been demonstrated to improve performance in certain situations, such as the delivery of preventive services. Another approach that has been effective is the development of “bundles” or groups of quality measures that can be implemented together with a high degree of fidelity. A number of hospitals have implemented a bundle for ventilator-associated pneumonia in the intensive care unit that includes five measures (e.g., ensuring that the head of the bed is elevated). These hospitals have been able to improve performance substantially. Perhaps the most pressing need is to improve the quality of care for chronic diseases. The Chronic Care Model has been developed by Wagner and colleagues (Fig. 6-3); it suggests that a combination of strategies is necessary (including self-management support, changes in delivery system design, decision support, and information systems) and that these strategies must be delivered by a practice team composed of several providers, not just a physician. Available evidence about the relative efficacy of strategies in reducing hemoglobin A1c (HbA1c) in outpatient diabetes care supports this general premise. It is especially notable that the outcome was the HbA1c level, as it has generally been much more difficult to improve outcome measures than process measures (such as whether HbA1c was measured). In this meta-analysis, a variety of strategies were effective, but the most effective ones were the use of team changes and the use of a case manager. When cost-effectiveness is considered in addition, it appears likely that an amalgam of strategies will be needed. However,

Harrisons_20e_Part1_p0001-p0064.indd 36

Informed, activated patient

Productive interactions

Prepared, proactive practice team

Improved Outcomes FIGURE 6-3  The Chronic Care Model, which focuses on improving care for chronic diseases, suggests that (1) delivery of high-quality care requires a range of strategies that must closely involve and engage the patient and (2) team care is essential. (From EH Wagner et al: Eff Clin Pract 1:2, 1998.)

the more expensive strategies, such as the use of case managers, probably will be implemented widely only if pay-for-performance takes hold.

National State of Quality Measurement  In the inpatient

setting, quality measurement is now being performed by a very large proportion of hospitals for several conditions, including myocardial infarction, congestive heart failure, pneumonia, and surgical infection prevention; 20 measures are included in all. This is the result of the Hospital Quality Initiative, which represents a collaboration among many entities, including the Hospital Quality Alliance, the Joint Commission, the National Quality Forum, and the Agency for Healthcare Research and Quality. The data are housed at the Center for Medicare and Medicaid Services, which publicly releases performance data on the measures on a website called Hospital Compare (www.cms .gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/ HospitalQualityInits/HospitalCompare.html). These data are reported voluntarily and are available for a very high proportion of the nation’s hospitals. Analyses demonstrate substantial regional variation in quality and important differences among hospitals. Analyses by the Joint Commission for similar indicators reveal that performance on measures by hospitals has improved over time and that, as might be hoped, lower performers have improved more than higher performers.

Public Reporting  Overall, public reporting of quality data is

becoming increasingly common. There are now commercial websites that have quality-related data for most regions of the United States, and these data can be accessed for a fee. Similarly, national data for hospitals are available. The evidence to date indicates that patients have not made much use of such data, but that the data have had an important effect on provider and organization behavior. Instead, patients have relied on provider reputation to make choices, partly because little information was available until very recently and the information that was available was not necessarily presented in ways that were easy for patients to access. Many authorities think that, as more information about quality becomes available, it will become increasingly central to patients’ choices about where to access care.

Pay-for-Performance  Currently, providers in the United States get paid exactly the same amount for a specific service, regardless of the quality of care delivered. The pay-for-performance theory suggests that, if providers are paid more for higher-quality care, they will invest in strategies that enable them to deliver that care. The current key issues in the pay-for-performance debate relate to (1) how effective it is, (2) what levels of incentives are needed, and (3) what perverse

6/1/18 9:11 AM

The safety and quality of care in the United States could be improved substantially. A number of available interventions have been shown to improve the safety of care and should be used more widely; others are undergoing evaluation or soon will be. Quality also could be dramatically better, and the science of quality improvement continues to mature. Implementation of value-based approaches such as accountable care which include pay-for-performance related to safety and quality should make it much easier for organizations to justify investments in improving safety and quality parameters, including health information technology. However, many improvements will also require changing the structure of care—e.g., moving to a more team-oriented approach and ensuring that patients are more involved in their own care. Payment reform focusing on value seems very likely to progress and will likely include both positive incentives and penalties related to safety and quality performance. Measures of safety are still relatively immature and could be made much more robust; it would be particularly useful if organizations had measures they could use in routine operations to assess safety at a reasonable cost, and substantial research is addressing this. Although the quality measures available are more robust than those for safety, they still cover a relatively small proportion of the entire domain of quality, and more measures need to be developed. The public and payers are demanding better information about safety and quality as well as better performance in these areas. The clear implication is that these domains will have to be addressed directly by providers.

■■FURTHER READING

Bates DW et al: Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. JAMA 280:1311, 1998. Berwick DM: Era 3 for medicine and health care. JAMA 315:1329, 2016. Brennan TA et al: Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I. N Engl J Med 324:370, 1991. Chertow GM et al: Guided medication dosing for inpatients with renal insufficiency. JAMA 286:2839, 2001. Institute of Medicine. Crossing the quality chasm: A new health system for the 21st century. 2001. https://www.nationalacademies.org/ hmd/~/media/Files/Report%20Files/2001/Crossing-the-Quality-Chasm/ Quality%20Chasm%202001%20%20report%20brief.pdf. Institute of Medicine. Report: To err is human: Building a safer health system. 1999. http://www.nationalacademies.org/hmd/~/media/ Files/Report%20Files/1999/To-Err-is-Human/To%20Err%20is%20 Human%201999%20%20report%20brief.pdf. Landrigan C et al: Effect of reducing interns’ work hours on serious medical errors in intensive care units. N Engl J Med 351:1838, 2004. McGlynn et al: The quality of health care delivered to adults in the United States. N Engl J Med 348:2635, 2003.

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7

Racial and Ethnic Disparities in Health Care Joseph R. Betancourt, Alexander R. Green

Over the course of its history, the United States has experienced dramatic improvements in overall health and life expectancy, largely as a result of initiatives in public health, health promotion, disease prevention, and chronic care management. Our ability to prevent, detect, and treat diseases in their early stages has allowed us to target and reduce rates of morbidity and mortality. Despite interventions that have improved the overall health of the majority of Americans, racial and ethnic minorities (blacks, Hispanics/Latinos, Native Americans/ Alaskan Natives, Asian/Pacific Islanders) have benefited less from these advances than whites and have suffered poorer health outcomes from many major diseases, including cardiovascular disease, cancer, and diabetes. These disparities highlight the importance of recognizing and addressing the social determinants of health, which contribute enormously to health outcomes. Research has revealed that minorities may receive less care and lower-quality care than whites, even when confounders such as stage of presentation, comorbidities, and health insurance are controlled. These differences in quality are called racial and ethnic disparities in health care. These health care disparities have taken on greater importance with the significant transformation of the U.S. health care system and value-based purchasing. The shift toward creating financial incentives and disincentives to achieve quality goals makes focusing on those who receive lower-quality care more important than ever before. This chapter will provide an overview of racial and ethnic disparities in health and health care, identify root causes, and provide key recommendations to address these disparities at both the clinical and health system levels.

37

Racial and Ethnic Disparities in Health Care

■■CONCLUSIONS

Pronovost P et al: An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med 355:2725, 2006. Erratum in: N Engl J Med 356:2660, 2007. Starmer AJ et al: Rates of medical errors and preventable adverse events among hospitalized children following implementation of a resident handoff bundle. JAMA 310:2262, 2013.

CHAPTER 7

consequences are produced. The evidence on effectiveness is fairly limited, although a number of studies are ongoing. With respect to incentive levels, most quality-based performance incentives have accounted for merely 1–2% of total payment in the United States to date. In the United Kingdom, however, 40% of general practitioners’ salaries have been placed at risk according to performance across a wide array of parameters; this approach has been associated with substantial improvements in reported quality performance, although it is still unclear to what extent this change represents better performance versus better reporting. The potential for perverse consequences exists with any incentive scheme. One problem is that, if incentives are tied to outcomes, there may be a tendency to transfer the sickest patients to other providers and systems. Another concern is that providers will pay too much attention to quality measures with incentives and ignore the rest of the quality picture. The validity of these concerns remains to be determined. Nonetheless, it appears likely that, under health care reform, the use of various pay-for-performance schemes is likely to increase.

■■NATURE AND EXTENT OF DISPARITIES

Minority Americans have poorer health outcomes than whites from preventable and treatable conditions such as cardiovascular disease, diabetes, asthma, cancer, and HIV/AIDS (Fig. 7-1). Multiple factors contribute to these racial and ethnic disparities in health. First and foremost, social determinants—such as lower socioeconomic status (SES; e.g., lower income, less wealth, and lower educational attainment), inadequate and unsafe housing, and racism—are strongly linked to poor health outcomes. These factors disproportionately impact minority populations. In fact, SES has consistently been found to be one of the strongest predictors of health outcomes. While the mechanisms are complex (i.e., does poverty cause poor health, or does poor health cause poverty?), it is clear that low-SES populations experience disparities in health and that low SES is a major factor in racial/ethnic disparities. Racial/ethnic disparities are documented globally, although their assessment has centered more on the comparison of individuals by SES in other countries than in the United States. Similar to the U.S. pattern, low-SES residents of other nations tend to have poorer health outcomes. It is noteworthy that results are mixed when the health status of nations is compared by SES. High-SES nations such as the United States do not necessarily have health outcomes that correlate with their high expenditures for health care. For example, as of 2016, the United States ranks 27th in the world—just behind Serbia—on basic public health measures such as infant mortality. This ranking may be due in

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38

White

Black

Asian/Pacific Islander

Native American, Alaskan Native

350

Hispanic

329.8

PART 1

300

293.7 258.0

250

228.3

222.3

The Profession of Medicine

200

192.4

179.6

173.2 152.7

147.6

150

168.2

155.2 141.1

133.0

105.9

100

102.0

94.5

50

129.1

115.9 91.9

28.2 4.0

3.6

0 Malignant neoplasms

1.0

7.5

0.8

HIV

12.0

Malignant neoplasms

Heart disease

1.5

0

1.9

HIV

Male

Heart disease

Female

FIGURE 7-1  Age-adjusted death rates for selected causes by race and ethnic origin, 2005. (From the U.S. Census Bureau, 2009.)

part to the correlation between wealth distribution and SES rather than just absolute SES. This area of active research is outside the scope of this chapter. Racism has more recently been shown to predict poorer health outcomes. The physiologic impact of the stress imposed by racism (and poverty), including increased cortisol levels, can lead to chronic adverse effects on health. Lack of access to care also takes a significant toll. Uninsured individuals are less likely to have a regular source of care and are more likely to delay seeking care and to go without needed care; this limited access results in avoidable hospitalizations, emergency hospital care, and adverse health outcomes. In addition to racial and ethnic disparities in health, there are racial and ethnic disparities in the quality of care for persons with access to the health care system. For instance, disparities have been found in the treatment of pneumonia (Fig. 7-2) and congestive heart failure, with blacks receiving less optimal care than whites when hospitalized for these conditions. Moreover, blacks with end-stage renal disease are referred less often to the transplant list than are their white Race

100

2005 2006 81.5 74.6

76.9 69.5

74.2

73.3

76.8

75.8

66.2

60

40

20

0

60

Black

Hispanic

Native American

Asian

FIGURE 7-2  Recommended hospital care received by Medicare patients with pneumonia, by race/ethnicity, 2006. The reference population consisted of Medicare beneficiaries with pneumonia who were hospitalized. The composite was calculated by averaging the percentage of the population that received each of the five incorporated components of care. (Adapted from Agency for Healthcare Research and Quality: The 2008 National Health Care Disparities Report.)

Harrisons_20e_Part1_p0001-p0064.indd 38

82.2

80.3

80

68.9 59.6

67.9

57.9 40.3

40

40.6

20 0

White

Black women White women Black men White men

100

68.7

Percentage of patients

80

counterparts (Fig. 7-3). Disparities have been found, for example, in the use of cardiac diagnostic and therapeutic procedures (with blacks being referred less often than whites for cardiac catheterization and bypass grafting), prescription of analgesia for pain control (with blacks and Latinos receiving less pain medication than whites for long-bone fractures and cancer), and surgical treatment of lung cancer (with blacks receiving less curative surgery than whites for non-small-cell lung cancer). Again, many of these disparities have occurred even when variations in factors such as insurance status, income, age, comorbid conditions, and symptom expression are taken into account. However, one additional factor—disparities in the quality of care provided at the sites where minorities tend to receive care—has been shown to be an important contributor to overall disparities. Little progress has been made in addressing racial/ethnic disparities in cardiovascular procedures and other advanced surgical procedures, whereas some progress has been made in eliminating disparities in primary-care process measures. Data from the National Registry of Myocardial Infarction found evidence of continued disparities in guideline-based admission, procedural, and discharge therapy use from 1994 to 2006. Black patients were less likely than white patients

Referred for evaluation

Placed on waiting list or received transplant

FIGURE 7-3  Referral for evaluation at a transplantation center or placement on a waiting list/receipt of a renal transplant within 18 months after the start of dialysis among patients who wanted a transplant, according to race and sex. The reference population consisted of 239 black women, 280 white women, 271 black men, and 271 white men. Racial differences were statistically significant among both the women and the men (p350,000 patients with unspecified presumed non-cardiopulmonary chest discomfort, the mortality rate 1 year after discharge was 30 min Variable; hours to days; may be episodic

Pressure, tightness, squeezing, heaviness, burning

Retrosternal; often radiation to neck, jaw, shoulders, or arms; sometimes epigastric

S4 gallop or mitral regurgitation murmur (rare) during pain; S3 or rales if severe ischemia or complication of myocardial infarction

Pleuritic, sharp

Retrosternal or toward cardiac apex; may radiate to left shoulder Anterior chest, often radiating to back, between shoulder blades

May be relieved by sitting up and leaning forward; pericardial friction rub Associated with hypertension and/or underlying connective tissue disorder; murmur of aortic insufficiency; loss of peripheral pulses Dyspnea, tachypnea, tachycardia, and hypotension

Acute aortic syndrome

Sudden onset of unrelenting pain

Tearing or ripping; knifelike

Pulmonary embolism

Sudden onset

Pulmonary hypertension Pneumonia or pleuritis Spontaneous pneumothorax

Variable; often exertional

Pleuritic; may manifest as heaviness with massive pulmonary embolism Pressure

Variable

Pleuritic

Sudden onset

Pleuritic

10–60 min

Burning

Substernal, epigastric

2–30 min

Pressure, tightness, burning Burning

Retrosternal

Worsened by postprandial recumbency; relieved by antacids Can closely mimic angina

Epigastric, substernal

Relieved with food or antacids

Aching or colicky

Epigastric, right upper quadrant; sometimes to the back Sternal

May follow meal

Non-cardiopulmonary Gastrointenstinal Esophageal reflux Esophageal spasm Peptic ulcer

Prolonged; 60–90 min after meals Gallbladder disease Prolonged Neuromuscular

Psychological

Often lateral, on the side of the embolism Substernal

Dyspnea, signs of increased venous pressure Unilateral, often localized Dyspnea, cough, fever, rales, occasional rub Lateral to side of Dyspnea, decreased breath pneumothorax sounds on side of pneumothorax

Costochondritis

Variable

Aching

Cervical disk disease Trauma or strain

Variable; may be sudden Usually constant

Aching; may include numbness Aching

Herpes zoster

Usually prolonged

Sharp or burning

Emotional and psychiatric conditions

Variable; may be fleeting or prolonged

Variable; often manifests Variable; may be as tightness and retrosternal dyspnea with feeling of panic or doom

Harrisons_20e_Part2_p0065-p0418.indd 74

Arms and shoulders Localized to area of strain Dermatomal distribution

Sometimes swollen, tender, warm over joint; may be reproduced by localized pressure on examination May be exacerbated by movement of neck Reproduced by movement or palpation Vesicular rash in area of discomfort Situational factors may precipitate symptoms; history of panic attacks, depression

6/1/18 3:14 PM

■■MYOCARDIAL ISCHEMIA/INJURY

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Mechanisms of Cardiac Pain  The neural pathways involved in ischemic cardiac pain are poorly understood. Ischemic episodes are thought to excite local chemosensitive and mechanoreceptive receptors that, in turn, stimulate release of adenosine, bradykinin, and other substances that activate the sensory ends of sympathetic and vagal afferent fibers. The afferent fibers traverse the nerves that connect to the upper five thoracic sympathetic ganglia and upper five distal thoracic roots of the spinal cord. From there, impulses are transmitted to the thalamus. Within the spinal cord, cardiac sympathetic afferent impulses may converge with impulses from somatic thoracic structures, and this convergence may be the basis for referred cardiac pain. In addition, cardiac vagal afferent fibers synapse in the nucleus tractus solitarius of the medulla and then descend to the upper cervical spinothalamic tract, and this route may contribute to anginal pain experienced in the neck and jaw.

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Chest Discomfort

Characteristics of Ischemic Chest Discomfort  The clinical characteristics of angina pectoris, often referred to simply as “angina,” are highly similar whether the ischemic discomfort is a manifestation of stable ischemic heart disease, unstable angina, or MI; the exceptions are differences in the pattern and duration of symptoms associated with these syndromes (Table 11-1). Heberden initially described angina as a sense of “strangling and anxiety.” Chest discomfort characteristic of myocardial ischemia is typically described as aching, heavy, squeezing, crushing, or constricting. However, in a substantial minority of patients, the quality of discomfort is extremely vague and may be

described as a mild tightness, or merely an uncomfortable feeling, that sometimes is experienced as numbness or a burning sensation. The site of the discomfort is usually retrosternal, but radiation is common and generally occurs down the ulnar surface of the left arm; the right arm, both arms, neck, jaw, or shoulders may also be involved. These and other characteristics of ischemic chest discomfort pertinent to discrimination from other causes of chest pain are discussed later in this chapter (see “Approach to the Patient”). Stable angina usually begins gradually and reaches its maximal intensity over a period of minutes before dissipating within several minutes with rest or with nitroglycerin. The discomfort typically occurs predictably at a characteristic level of exertion or psychological stress. By definition, unstable angina is manifest by anginal chest discomfort that occurs with progressively lower intensity of physical activity or even at rest. Chest discomfort associated with MI is typically more severe, is prolonged (usually lasting ≥30 min), and is not relieved by rest.

CHAPTER 11

Myocardial ischemia causing chest discomfort, termed angina pectoris, is a primary clinical concern in patients presenting with chest symptoms. Myocardial ischemia is precipitated by an imbalance between myocardial oxygen requirements and myocardial oxygen supply, resulting in insufficient delivery of oxygen to meet the heart’s metabolic demands. Myocardial oxygen consumption may be elevated by increases in heart rate, ventricular wall stress, and myocardial contractility, whereas myocardial oxygen supply is determined by coronary blood flow and coronary arterial oxygen content. When myocardial ischemia is sufficiently severe and prolonged in duration (as little as 20 min), irreversible cellular injury occurs, resulting in MI. Ischemic heart disease is most commonly caused by atheromatous plaque that obstructs one or more of the epicardial coronary arteries. Stable ischemic heart disease (Chap. 267) usually results from the gradual atherosclerotic narrowing of the coronary arteries. Stable angina is characterized by ischemic episodes that are typically precipitated by a superimposed increase in oxygen demand during physical exertion and relieved upon resting. Ischemic heart disease becomes unstable most commonly when rupture or erosion of one or more atherosclerotic lesions triggers coronary thrombosis. Unstable ischemic heart disease is classified clinically by the presence or absence of detectable myocardial injury and the presence or absence of ST-segment elevation on the patient’s electrocardiogram (ECG). When acute coronary atherothrombosis occurs, the intracoronary thrombus may be partially obstructive, generally leading to myocardial ischemia in the absence of ST-segment elevation. Marked by ischemic symptoms at rest, with minimal activity, or in an accelerating pattern, unstable ischemic heart disease is classified as unstable angina when there is no detectable myocardial injury and as non–ST elevation MI (NSTEMI) when there is evidence of myocardial necrosis (Chap. 268). When the coronary thrombus is acutely and completely occlusive, transmural myocardial ischemia usually ensues, with ST-segment elevation on the ECG and myocardial necrosis leading to a diagnosis of ST elevation MI (STEMI, see Chap. 269). Clinicians should be aware that unstable ischemic symptoms may also occur predominantly because of increased myocardial oxygen demand (e.g., during intense psychological stress or fever) or because of decreased oxygen delivery due to anemia, hypoxia, or hypotension. However, the term acute coronary syndrome, which encompasses unstable angina, NSTEMI, and STEMI, is in general reserved for ischemia precipitated by acute coronary atherothrombosis. In order to guide therapeutic strategies, a standardized system for classification of MI has been expanded to discriminate MI resulting from acute coronary thrombosis (type 1) from MI occurring secondary to other imbalances of myocardial oxygen supply and demand (type 2; see Chap. 268). Other contributors to stable and unstable ischemic heart disease, such as endothelial dysfunction, microvascular disease, and vasospasm, may exist alone or in combination with coronary atherosclerosis and may be the dominant cause of myocardial ischemia in some patients. Moreover, non-atherosclerotic processes, including congenital abnormalities of the coronary vessels, myocardial bridging, coronary arteritis, and radiation-induced coronary disease, can lead to coronary obstruction. In addition, conditions associated with extreme myocardial oxygen demand and impaired endocardial blood flow, such as aortic valve disease (Chap. 274), hypertrophic cardiomyopathy, or idiopathic dilated cardiomyopathy (Chap. 254), can precipitate myocardial ischemia in patients with or without underlying obstructive atherosclerosis.

■■OTHER CARDIOPULMONARY CAUSES Pericardial and Other Myocardial Diseases (See also Chap. 265)  Inflammation of the pericardium due to infectious

or noninfectious causes can be responsible for acute or chronic chest discomfort. The visceral surface and most of the parietal surface of the pericardium are insensitive to pain. Therefore, the pain of pericarditis is thought to arise principally from associated pleural inflammation. Because of this pleural association, the discomfort of pericarditis is usually pleuritic pain that is exacerbated by breathing, coughing, or changes in position. Moreover, owing to the overlapping sensory supply of the central diaphragm via the phrenic nerve with somatic sensory fibers originating in the third to fifth cervical segments, the pain of pleural pericarditis is often referred to the shoulder and neck. Involvement of the pleural surface of the lateral diaphragm can lead to pain in the upper abdomen. Acute inflammatory and other non-ischemic myocardial diseases can also produce chest discomfort. The symptoms of Takotsubo (stressrelated) cardiomyopathy often start abruptly with chest pain and shortness of breath. This form of cardiomyopathy, in its most recognizable form, is triggered by an emotionally or physically stressful event and may mimic acute MI because of its commonly associated ECG abnormalities, including ST-segment elevation, and elevated biomarkers of myocardial injury. Observational studies support a predilection for women >50 years of age. The symptoms of acute myocarditis are highly varied. Chest discomfort may either originate with inflammatory injury of the myocardium or be due to severe increases in wall stress related to poor ventricular performance.

Diseases of the Aorta (See also Chap. 274)  Acute aortic dissection (Fig. 11-1) is a less common cause of chest discomfort but is important because of the catastrophic natural history of certain subsets of cases when recognized late or left untreated. Acute aortic syndromes encompass a spectrum of acute aortic diseases related to disruption of the media of the aortic wall. Aortic dissection involves a tear in the aortic intima, resulting in separation of the media and creation of a separate “false” lumen. A penetrating ulcer has been described as ulceration of an aortic atheromatous plaque that extends through the intima and

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into the aortic media, with the potential to initiate an intramedial dissection or rupture into the adventitia. Intramural hematoma is an aortic wall hematoma with no demonstrable intimal flap, no radiologically apparent intimal tear, and no false lumen. Intramural hematoma can occur due to either rupture of the vasa vasorum or, less commonly, a penetrating ulcer. Each of these subtypes of acute aortic syndrome typically presents with chest discomfort that is often severe, sudden in onset, and sometimes described as “tearing” in quality. Acute aortic syndromes involving the ascending aorta tend to cause pain in the midline of the anterior chest, whereas descending aortic syndromes most often present with pain in the back. Therefore, dissections that begin in the ascending aorta and extend to the descending aorta tend to cause pain in the front of the chest that extends toward the back, between the shoulder blades. Proximal aortic dissections that involve the ascending aorta (type A in the Stanford nomenclature) are at high risk for major complications that may influence the clinical presentation, including (1) compromise of the aortic ostia of the coronary arteries, resulting in MI; (2) disruption of the aortic valve, causing acute aortic insufficiency; and (3) rupture of the hematoma into the pericardial space, leading to pericardial tamponade. Knowledge of the epidemiology of acute aortic syndromes can be helpful in maintaining awareness of this relatively uncommon group of disorders (estimated annual incidence, 3 cases per 100,000 population). Nontraumatic aortic dissections are very rare in the absence of hypertension or conditions associated with deterioration of the elastic or muscular components of the aortic media, including pregnancy, bicuspid aortic disease, or inherited connective tissue diseases, such as Marfan and Ehlers-Danlos syndromes. Although aortic aneurysms are most often asymptomatic, thoracic aortic aneurysms can cause chest pain and other symptoms by compressing adjacent structures. This pain tends to be steady, deep, and occasionally severe. Aortitis, whether of noninfectious or infectious etiology, in the absence of aortic dissection is a rare cause of chest or back discomfort.

Pulmonary Conditions  Pulmonary and pulmonary-vascular conditions that cause chest discomfort usually do so in conjunction with dyspnea and often produce symptoms that have a pleuritic nature.

Pulmonary emboli (annual incidence, ~1 per 1000) can produce dyspnea and chest discomfort that is sudden in onset. Typically pleuritic in pattern, the chest discomfort associated with pulmonary embolism may result from (1) involvement of the pleural surface of the lung adjacent to a resultant pulmonary infarction; (2) distention of the pulmonary artery; or (3) possibly, right ventricular wall stress and/or subendocardial ischemia related to acute pulmonary hypertension. The pain associated with small pulmonary emboli is often lateral and pleuritic and is believed to be related to the first of these three possible mechanisms. In contrast, massive pulmonary emboli may cause severe substernal pain that may mimic an MI and that is plausibly attributed to the second and third of these potential mechanisms. Massive or submassive pulmonary embolism may also be associated with syncope, hypotension, and signs of right heart failure. Other typical characteristics that aid in the recognition of pulmonary embolism are discussed later in this chapter (see “Approach to the Patient”). PULMONARY EMBOLISM (SEE ALSO CHAP. 273) 

Primary spontaneous pneumothorax is a rare cause of chest discomfort, with an estimated annual incidence in the United States of 7 per 100,000 among men and 10 min before relief is obtained after nitroglycerin suggests that the symptoms either are not caused by ischemia or are caused by severe ischemia, such as during acute MI. Associated Symptoms  Symptoms that accompany myocardial ischemia may include diaphoresis, dyspnea, nausea, fatigue, faintness, and eructations. In addition, these symptoms may exist in isolation as anginal equivalents (i.e., symptoms of myocardial ischemia

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INCREASED LIKELIHOOD OF AMI Radiation to right arm or shoulder Radiation to both arms or shoulders Associated with exertion Radiation to left arm Associated with diaphoresis Associated with nausea or vomiting

PART 2

Worse than previous angina or similar to previous MI Described as pressure DECREASED LIKELIHOOD OF AMI

Cardinal Manifestations and Presentation of Diseases

Inframammary location Reproducible with palpation Described as sharp Described as positional Described as pleuritic 0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Likelihood ratio for AMI FIGURE 11-2  Association of chest pain characteristics with the probability of acute myocardial infarction (AMI). Note that a subsequent larger study showed a non-significant association with radiation to the right arm. (Figure prepared from data in CJ Swap, JT Nagurney: JAMA 294:2623, 2005.)

other than typical angina), particularly in women and the elderly. Dyspnea may occur with multiple conditions considered in the differential diagnosis of chest pain and thus is not discriminative, but the presence of dyspnea is important because it suggests a cardiopulmonary etiology. Sudden onset of significant respiratory distress should lead to consideration of pulmonary embolism and spontaneous pneumothorax. Hemoptysis may occur with pulmonary embolism, or as blood-tinged frothy sputum in severe heart failure but usually points toward a pulmonary parenchymal etiology of chest symptoms. Presentation with syncope or pre-syncope should prompt consideration of hemodynamically significant pulmonary embolism or aortic dissection as well as ischemic arrhythmias. Although nausea and vomiting suggest a gastrointestinal disorder, these symptoms may occur in the setting of MI (more commonly inferior MI), presumably because of activation of the vagal reflex or stimulation of left ventricular receptors as part of the Bezold-Jarisch reflex. Past Medical History  The past medical history is useful in assessing the patient for risk factors for coronary atherosclerosis and venous thromboembolism (Chap. 273) as well as for conditions that may predispose the patient to specific disorders. For example, a history of connective tissue diseases such as Marfan syndrome should heighten the clinician’s suspicion of an acute aortic syndrome or spontaneous pneumothorax. A careful history may elicit clues about depression or prior panic attacks. PHYSICAL EXAMINATION In addition to providing an initial assessment of the patient’s clinical stability, the physical examination of patients with chest discomfort can provide direct evidence of specific etiologies of chest pain (e.g., unilateral absence of lung sounds) and can identify potential precipitants of acute cardiopulmonary causes of chest pain (e.g., uncontrolled hypertension), relevant comorbid conditions (e.g., obstructive pulmonary disease), and complications of the presenting syndrome (e.g., heart failure). However, because the findings on physical examination may be normal in patients with unstable ischemic heart disease, an unremarkable physical examination is not definitively reassuring.

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General  The patient’s general appearance is helpful in establishing an initial impression of the severity of illness. Patients with acute MI or other acute cardiopulmonary disorders often appear anxious, uncomfortable, pale, cyanotic, or diaphoretic. Patients who are massaging or clutching their chests may describe their pain with a clenched fist held against the sternum (Levine’s sign). Occasionally, body habitus is helpful—for example, in patients with Marfan syndrome or the prototypical young, tall, thin man with spontaneous pneumothorax. Vital Signs  Significant tachycardia and hypotension are indicative of important hemodynamic consequences of the underlying cause of chest discomfort and should prompt a rapid survey for the most severe conditions, such as acute MI with cardiogenic shock, massive pulmonary embolism, pericarditis with tamponade, or tension pneumothorax. Acute aortic emergencies usually present with severe hypertension but may be associated with profound hypotension when there is coronary arterial compromise or dissection into the pericardium. Sinus tachycardia is an important manifestation of submassive pulmonary embolism. Tachypnea and hypoxemia point toward a pulmonary cause. The presence of low-grade fever is nonspecific because it may occur with MI and with thromboembolism in addition to infection. Pulmonary  Examination of the lungs may localize a primary pulmonary cause of chest discomfort, as in cases of pneumonia, asthma, or pneumothorax. Left ventricular dysfunction from severe ischemia/infarction as well as acute valvular complications of MI or aortic dissection can lead to pulmonary edema, which is an indicator of high risk. Cardiac  The jugular venous pulse is often normal in patients with acute myocardial ischemia but may reveal characteristic patterns with pericardial tamponade or acute right ventricular dysfunction (Chaps. 234 and 265). Cardiac auscultation may reveal a third or, more commonly, a fourth heart sound, reflecting myocardial systolic or diastolic dysfunction. Murmurs of mitral regurgitation or a ventricular-septal defect may indicate mechanical complications of STEMI. A murmur of aortic insufficiency may be a complication of proximal aortic dissection. Other murmurs may reveal underlying

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cardiac disorders contributory to ischemia (e.g., aortic stenosis or hypertrophic cardiomyopathy). Pericardial friction rubs reflect pericardial inflammation.

ELECTROCARDIOGRAPHY Electrocardiography is crucial in the evaluation of nontraumatic chest discomfort. The ECG is pivotal for identifying patients with ongoing ischemia as the principal reason for their presentation as well as secondary cardiac complications of other disorders. Professional society guidelines recommend that an ECG be obtained within 10 min of presentation, with the primary goal of identifying patients with ST-segment elevation diagnostic of MI who are candidates for immediate interventions to restore flow in the occluded coronary artery. ST-segment depression and symmetric T-wave inversions at least 0.2 mV in depth are useful for detecting myocardial ischemia in the absence of STEMI and are also indicative of higher risk of death or recurrent ischemia. Serial performance of ECGs (every 30–60 min) is recommended in the ED evaluation of suspected ACS. In addition, an ECG with right-sided lead placement should be considered in patients with clinically suspected ischemia and a nondiagnostic standard 12-lead ECG. Despite the value of the resting ECG, its sensitivity for ischemia is poor—as low as 20% in some studies. Abnormalities of the ST segment and T wave may occur in a variety of conditions, including pulmonary embolism, ventricular hypertrophy, acute and chronic pericarditis, myocarditis, electrolyte imbalance, and metabolic disorders. Notably, hyperventilation associated with panic disorder can also lead to nonspecific ST and T-wave abnormalities. Pulmonary embolism is most often associated with sinus tachycardia but can also lead to rightward shift of the ECG axis, manifesting as an S-wave in lead I, with a Q-wave and T-wave in lead III (Chaps. 235 and 273). In patients with ST-segment elevation, the presence of diffuse lead involvement not corresponding to a specific coronary anatomic distribution and PR-segment depression can aid in distinguishing pericarditis from acute MI. CHEST RADIOGRAPHY (See Chap. A12) Plain radiography of the chest is performed routinely when patients present with acute chest discomfort and selectively when individuals who are being evaluated as outpatients have subacute or chronic pain. The chest radiograph is most useful for identifying pulmonary processes, such as pneumonia or pneumothorax. Findings are often unremarkable in patients with ACS, but pulmonary edema may be evident. Other specific findings include widening of the mediastinum in some patients with aortic dissection, Hampton’s hump or Westermark’s sign in patients with

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Musculoskeletal  Pain arising from the costochondral and chondrosternal articulations may be associated with localized swelling, redness, or marked localized tenderness. Pain on palpation of these joints is usually well localized and is a useful clinical sign, though deep palpation may elicit pain in the absence of costochondritis. Although palpation of the chest wall often elicits pain in patients with various musculoskeletal conditions, it should be appreciated that chest wall tenderness does not exclude myocardial ischemia. Sensory deficits in the upper extremities may be indicative of cervical disk disease.

CARDIAC BIOMARKERS Laboratory testing in patients with acute chest pain is focused on the detection of myocardial injury. Such injury can be detected by the presence of circulating proteins released from damaged myocardial cells. Owing to the time necessary for this release, initial biomarkers of injury may be in the normal range, even in patients with STEMI. Because of superior cardiac tissue-specificity compared with creatine kinase MB, cardiac troponin is the preferred biomarker for the diagnosis of MI and should be measured in all patients with suspected ACS at presentation and repeated in 3–6 h. Testing after 6 h is required only when there is uncertainty regarding the onset of pain or when stuttering symptoms have occurred. It is not necessary or advisable to measure troponin in patients without suspicion of ACS unless this test is being used specifically for risk stratification (e.g., in pulmonary embolism or heart failure). The development of cardiac troponin assays with progressively greater analytical sensitivity has facilitated detection of substantially lower blood concentrations of troponin than was previously possible. This evolution permits earlier detection of myocardial injury, enhances the overall accuracy of a diagnosis of MI, and improves risk stratification in suspected ACS. The greater negative predictive value of a negative troponin result with current-generation assays is an advantage in the evaluation of chest pain in the ED. Rapid rule-out protocols that use serial testing and changes in troponin concentration over as short a period as 1–2 h appear promising and have been adopted in some centers where high-sensitivity assays for troponin are used routinely. In patients presenting >2 h after symptom onset, a concentration of cardiac troponin below the limit of detection using a high-sensitivity assay may be sufficient to exclude MI with a negative predictive value >99% at the time of hospital presentation. However, with these advantages has come a trade-off: myocardial injury is detected in a larger proportion of patients who have non-ACS cardiopulmonary conditions than with previous, less sensitive assays. This evolution in testing for myocardial necrosis has rendered other aspects of the clinical evaluation critical to the practitioner’s determination of the probability that the symptoms represent ACS. In addition, observation of a change in cardiac troponin concentration between serial samples is useful in discriminating acute causes of myocardial injury from chronic elevation due to underlying structural heart disease, end-stage renal disease, or interfering antibodies. The diagnosis of MI is reserved for acute myocardial injury that is marked by a rising and/or falling pattern—with at least one value exceeding the 99th percentile reference limit—and that is caused by ischemia. Other non-ischemic insults, such as myocarditis, may result in myocardial injury but should not be labeled MI. Other laboratory assessments may include the D-dimer test to aid in exclusion of pulmonary embolism (Chap. 273). Measurement of a B-type natriuretic peptide is useful when considered in conjunction with the clinical history and examination for the diagnosis of heart failure. B-type natriuretic peptides also provide prognostic information among patients with ACS and those with pulmonary embolism.

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Abdominal  Localizing tenderness on the abdominal examination is useful in identifying a gastrointestinal cause of the presenting syndrome. Abdominal findings are infrequent with purely acute cardiopulmonary problems, except in the case of underlying chronic cardiopulmonary disease or severe right ventricular dysfunction leading to hepatic congestion. Vascular pulse deficits may reflect underlying chronic atherosclerosis, which increases the likelihood of coronary artery disease. However, evidence of acute limb ischemia with loss of the pulse and pallor, particularly in the upper extremities, can indicate catastrophic consequences of aortic dissection. Unilateral lower-extremity swelling should raise suspicion about venous thromboembolism.

pulmonary embolism (Chaps. 273 and A12), or pericardial calcification in chronic pericarditis.

INTEGRATIVE DECISION-AIDS Multiple clinical algorithms have been developed to aid in decisionmaking during the evaluation and disposition of patients with acute nontraumatic chest pain. Such decision-aids estimate either of two closely related but not identical probabilities: (1) the probability of a final diagnosis of ACS and (2) the probability of major cardiac events during short-term follow-up. Such decision-aids are used most commonly to identify patients with a low clinical probability of ACS who are candidates either for early provocative testing for ischemia or for discharge from the ED. Goldman and Lee developed one of the first such decision-aids, using only the ECG and risk indicators—hypotension, pulmonary rales, and known ischemic heart disease—to categorize patients into four risk categories

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HEART Score

PART 2 Cardinal Manifestations and Presentation of Diseases

History

Highly suspicious Moderately suspicious Slightly suspicious

2 1 0

ECG

Significant ST-depression Non-specific abnormality Normal

2 1 0

Age

≥65 y 45–90% of patients who present

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89

Acknowledgment The editors acknowledge the contributions of Neil H. Raskin to earlier editions of this chapter.

■■FURTHER READING

Headache Classification Committee of the International Headache Society: The International Classification of Headache Disorders, 3rd ed. Cephalalgia 33:629, 2018. Kernick D, Goadsby PJ: Headache: A Practical Manual. Oxford: Oxford University Press, 2008. Lance JW, Goadsby PJ: Mechanism and Management of Headache, 7th ed. New York, Elsevier, 2005. Olesen J et al: The Headaches. Philadelphia, Lippincott, Williams & Wilkins, 2005. Silberstein SD, Lipton RB, Dodick D: Wolff’s Headache and Other Head Pain, 8th ed. New York, Oxford, 2008.

14

Back and Neck Pain

Posttraumatic Headache  A traumatic event can trigger a headache process that lasts for many months or years after the event. The term trauma is used here in a very broad sense: headache can develop following an injury to the head, but it can also develop after an infectious episode, typically viral meningitis, a flulike illness, or a parasitic infection. Complaints of dizziness, vertigo, and impaired memory can accompany the headache. Symptoms may remit after several weeks or persist for months and even years after the injury. Typically the neurologic examination is normal and CT or MRI studies are unrevealing. Chronic subdural hematoma may on occasion mimic this disorder. Posttraumatic headache may also be seen after carotid dissection and subarachnoid hemorrhage and after intracranial surgery. The underlying theme appears to be that a traumatic event involving the pain-producing meninges can trigger a headache process that lasts for many years.

to primary care with a complaint of headache will have migraine (Chap. 422). In general, patients who do not have a clear diagnosis, have a primary headache disorder other than migraine or tension-type headache, or are unresponsive to two or more standard therapies for the considered headache type should be considered for referral to a specialist. In a practical sense, the threshold for referral is also determined by the experience of the primary care physician in headache medicine and the availability of secondary care options.

CHAPTER 14

be performed even in the absence of overt ophthalmic involvement. Headache on rising in the morning or nocturnal headache is also characteristic of obstructive sleep apnea or poorly controlled hypertension. Evaluation of patients suspected to have raised CSF pressure requires brain imaging. It is most efficient to obtain an MRI, including an MR venogram, as the initial study. If there are no contraindications, the CSF pressure should be measured by LP; this should be done when the patient is symptomatic so that both the pressure and the response to removal of 20–30 mL of CSF can be determined. An elevated opening pressure and improvement in headache following removal of CSF are diagnostic in the absence of fundal changes. Initial treatment is with acetazolamide (250–500 mg bid); the headache may improve within weeks. If ineffective, topiramate is the next treatment of choice; it has many actions that may be useful in this setting, including carbonic anhydrase inhibition, weight loss, and neuronal membrane stabilization, likely mediated via effects on phosphorylation pathways. Severely disabled patients who do not respond to medical treatment require intracranial pressure monitoring and may require shunting.

Back and Neck Pain John W. Engstrom

The importance of back and neck pain in our society is underscored by the following: (1) the cost of chronic back pain in the United States is estimated at $177 billion annually; approximately one-third of this cost is due to direct health care expenses and two-thirds are indirect costs resulting from loss of wages and productivity; (2) back symptoms are the most common cause of disability in individuals 70 years Intravenous drug use Glucocorticoid use History of a rapidly progressive neurologic deficit Examination Unexplained fever Unexplained weight loss Palpation/percussion tenderness over the midline spine Abdominal, rectal, or pelvic mass Internal/external rotation of the leg at the hip; heel percussion sign Straight leg- or reverse straight leg-raising signs Progressive focal neurologic deficit

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between referred pain and radiculopathy, although a burning or electric quality favors radiculopathy. Pain associated with muscle spasm is commonly associated with many spine disorders. The spasms may be accompanied by an abnormal posture, tense paraspinal muscles, and dull or achy pain in the paraspinal region. Knowledge of the circumstances associated with the onset of back pain is important when weighing possible serious underlying causes for the pain. Some patients involved in accidents or workrelated injuries may exaggerate their pain for the purpose of compensation or for psychological reasons. EXAMINATION A physical examination that includes the abdomen and rectum is advisable. Back pain referred from visceral organs may be reproduced during palpation of the abdomen (pancreatitis, abdominal aortic aneurysm [AAA]) or percussion over the costovertebral angles (pyelonephritis). The normal spine has a cervical and lumbar lordosis and a thoracic kyphosis. Exaggeration of these normal alignments may result in hyperkyphosis of the thoracic spine or hyperlordosis of the lumbar spine. Inspection may reveal a lateral curvature of the spine (scoliosis). An asymmetry in the prominence of the paraspinal muscles suggests muscle spasm. Spine pain reproduced by palpation over the spinous process reflects injury of the affected vertebrae or adjacent pain-sensitive structures. Forward bending is often limited by paraspinal muscle spasm; the latter may flatten the usual lumbar lordosis. Flexion at the hips is normal in patients with lumbar spine disease, but flexion of the lumbar spine is limited and sometimes painful. Lateral bending to the side opposite the injured spinal element may stretch the damaged tissues, worsen pain, and limit motion. Hyperextension of the spine (with the patient prone or standing) is limited when nerve

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root compression, facet joint pathology, or other bony spine disease is present. Pain from hip disease may mimic the pain of lumbar spine disease. Hip pain can be reproduced by passive internal and external rotation at the hip with the knee and hip in flexion or by percussing the heel with the examiner’s palm with the leg extended (heel percussion sign). The straight leg-raising (SLR) maneuver is a simple bedside test for nerve root disease. With the patient supine, passive straight leg flexion at the hip stretches the L5 and S1 nerve roots and the sciatic nerve; dorsiflexion of the foot during the maneuver adds to the stretch. In healthy individuals, flexion to at least 80° is normally possible without causing pain, although a tight, stretching sensation in the hamstring muscles is common. The SLR test is positive if the maneuver reproduces the patient’s usual back or limb pain. Eliciting the SLR sign in both the supine and sitting positions can help determine if the finding is reproducible. The patient may describe pain in the low back, buttocks, posterior thigh, or lower leg, but the key feature is reproduction of the patient’s usual pain. The crossed SLR sign is present when flexion of one leg reproduces the usual pain in the opposite leg or buttocks. In disk herniation, the crossed SLR sign is less sensitive but more specific than the SLR sign. The reverse SLR sign is elicited by standing the patient next to the examination table and passively extending each leg with the knee fully extended. This maneuver, which stretches the L2-L4 nerve roots, lumbosacral plexus, and femoral nerve, is considered positive if the patient’s usual back or limb pain is reproduced. For all of these tests, the nerve or nerve root lesion is always on the side of the pain. The neurologic examination includes a search for focal weakness or muscle atrophy, focal reflex changes, diminished sensation in the legs, or signs of spinal cord injury. The examiner should be alert to the possibility of breakaway weakness, defined as fluctuations in the maximum power generated during muscle testing. Breakaway weakness may be due to pain, inattention, or a combination of pain and underlying true weakness. Breakaway weakness without pain is usually due to a lack of effort. In uncertain cases, electromyography (EMG) can determine if true weakness due to nerve tissue injury is present. Findings with specific lumbosacral nerve root lesions are shown in Table 14-2 and are discussed below.

Cardinal Manifestations and Presentation of Diseases

LABORATORY, IMAGING, AND EMG STUDIES Laboratory studies are rarely needed for the initial evaluation of nonspecific acute (60 years or a sign of bilateral S1 radiculopathy. An absent deep tendon reflex or focal sensory loss may indicate injury to a nerve root, but other sites of injury along the nerve must also be considered. For example, an absent knee reflex may be due to a femoral neuropathy or an L4 nerve root injury, and a loss of sensation over the foot and lateral lower calf may result from a peroneal or lateral sciatic neuropathy or an L5 nerve root injury. Focal muscle atrophy may reflect injury to the anterior horn cells of the spinal cord, a nerve root, peripheral nerve, or disuse. A lumbar spine MRI scan or CT myelogram can often confirm the location and type of pathology. Spine MRIs yield exquisite views of intraspinal and adjacent soft tissue anatomy, whereas bony lesions of the lateral recess or intervertebral foramen are optimally visualized by CT myelography. The correlation of neuroradiologic findings to clinical symptoms, particularly pain, is not simple. Contrast-enhancing tears in the annulus fibrosus or disk protrusions are widely accepted as common sources of back pain; however, studies have found that many asymptomatic adults have similar findings. Entirely asymptomatic disk protrusions are also common, occurring in up to one-third of adults, and these may also enhance with contrast. Furthermore, in patients with known disk herniation treated either medically or surgically, persistence of the herniation 10 years later had no relationship to the clinical outcome. In summary, MRI findings of disk protrusion, tears in the annulus fibrosus, or hypertrophic facet joints are common incidental findings that, by themselves, should not dictate management decisions for patients with back pain. The diagnosis of nerve root injury is most secure when the history, examination, results of imaging studies, and the EMG are concordant. There is often good correlation between CT and EMG for localization of nerve root injury. Management of lumbar disk disease is discussed below. Cauda equina syndrome (CES) signifies an injury of multiple lumbosacral nerve roots within the spinal canal distal to the termination

CHAPTER 14

spine fusion surgery. (4) Do not use EMG and nerve conduction studies (NCSs) to determine the cause of axial lumbar, thoracic or cervical spine pain. (5) Do not recommend bed rest for >48 h when treating LBP. In an observational study, application of this strategy was associated with lower rates of repeat imaging, opioid use, and referrals for physical therapy. Electrodiagnostic studies can be used to assess the functional integrity of the peripheral nervous system (Chap. 438). Sensory NCSs are normal when focal sensory loss confirmed by examination is due to nerve root damage because the nerve roots are proximal to the nerve cell bodies in the dorsal root ganglia. Injury to nerve tissue distal to the dorsal root ganglion (e.g., plexus or peripheral nerve) results in reduced sensory nerve signals. Needle EMG complements NCSs by detecting denervation or reinnervation changes in a myotomal (segmental) distribution. Multiple muscles supplied by different nerve roots and nerves are sampled; the pattern of muscle involvement indicates the nerve root(s) responsible for the injury. Needle EMG provides objective information about motor nerve fiber injury when clinical evaluation of weakness is limited by pain or poor effort. EMG and NCSs will be normal when sensory nerve root injury or irritation is the pain source.

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LSS accompanied by neurogenic claudication responds to surgical decompression of the stenotic segments. The same processes leading to LSS may cause lumbar foraminal or lateral recess narrowing resulting in coincident Herniated L4 disc lumbar radiculopathy that may require treatment as well. A recent trial for LSS accompanied by leg pain did not show an overall benefit for epidural glucocorticoids plus Herniated L4 disc lidocaine, but subgroup analysis showed a small improvement in disability scores at 6 weeks of uncertain clinical significance. Compressed Conservative treatment of symptomatic LSS can Compressed L5 root include nonsteroidal anti-inflammatory drugs (NSAIDs), Thecal Sac acetaminophen, exercise programs, and symptomatic treatment of acute pain episodes. There is insufficient evidence to support the routine use of epidural glucocorticoid injections. Surgical therapy is considered when medical therapy does not relieve symptoms sufficiently A B to allow for resumption of activities of daily living or FIGURE 14-4  Left L5 radiculopathy. A. Sagittal T2-weighted image on the left reveals disk when focal neurologic signs are present. Most patients herniation at the L4-L5 level. B. Axial T1-weighted image shows paracentral disk herniation with with neurogenic claudication who are treated medically displacement of the thecal sac medially and the left L5 nerve root posteriorly in the left lateral do not improve over time. Surgical management with recess. laminectomy can produce significant relief of exertional back and leg pain, leading to less disability and improved of the spinal cord at L1-L2. LBP, weakness and areflexia in the legs, functional outcome at 4 years. Laminectomy and fusion is usually saddle anesthesia, or loss of bladder function may occur. The problem reserved for patients with LSS and spondylolisthesis. Predictors of must be distinguished from disorders of the lower spinal cord (conus a poor surgical outcome include impaired walking preoperatively, medullaris syndrome), acute transverse myelitis (Chap. 434), and Guil- depression, cardiovascular disease, and scoliosis. Up to one-quarter of lain-Barré syndrome (Chap. 439). Combined involvement of the conus surgically treated patients develop recurrent stenosis at the same spinal medullaris and cauda equina can occur. CES is most commonly due level or at an adjacent level within 7–10 years; recurrent symptoms to a large ruptured lumbosacral intervertebral disk, but other causes usually respond to a second surgical decompression. include lumbosacral spine fracture, hematoma within the spinal canal Neural foraminal narrowing with radiculopathy is a common con(sometimes following lumbar puncture in patients with coagulopathy), sequence of osteoarthritic processes that cause LSS (Figs. 14-1 and and tumor or other compressive mass lesions. Treatment is surgical 14-6), including osteophytes, lateral disk protrusion, calcified diskdecompression, sometimes on an urgent basis in an attempt to restore osteophytes, facet joint hypertrophy, uncovertebral joint hypertrophy or preserve motor or sphincter function, or radiotherapy for metastatic (in the cervical spine), congenitally shortened pedicles, or, frequently, tumors (Chap. 86). a combination of these processes. Neoplasms (primary or metastatic), fractures, infections (epidural abscess), or hematomas are other less ■■DEGENERATIVE CONDITIONS common causes. Most common is bony foraminal narrowing leading to Lumbar spinal stenosis (LSS) describes a narrowed lumbar spinal canal. nerve root ischemia and persistent symptoms, in contrast to the inflamNeurogenic claudication consists of pain, typically in the back and but- mation associated with a herniated disk and radiculopathy. These tock or leg, that is brought on by walking or standing and relieved by conditions can produce unilateral nerve root symptoms or signs due sitting. Symptoms in the legs are usually bilateral. Unlike vascular clau- to compression at the intervertebral foramen or in the lateral recess; dication, symptoms are often provoked by standing without walking. symptoms are indistinguishable from disk-related radiculopathy, but Unlike lumbar disk disease, symptoms are usually relieved by sitting. treatment may differ depending on the specific etiology. The history Patients with neurogenic claudication can often walk much farther and neurologic examination alone cannot distinguish between these when leaning over a shopping cart and can pedal a stationary bike with possibilities. Neuroimaging (CT or MRI) is required to identify the ease while sitting. These flexed positions increase the anteroposterior anatomic cause. Neurologic findings from the examination and EMG spinal canal diameter and reduce intraspinal venous hypertension, producing pain relief. Focal weakness, sensory loss, or reflex changes may occur when spinal stenosis is associated with neural foraminal narrowing and radiculopathy. Severe neurologic deficits, including paralysis and urinary incontinence, occur only rarely. LSS by itself is common (6–7% of adults) and is freCompressed Thecal sac quently asymptomatic. The correlation between the severity of symptoms and the degree of spinal canal stenosis is variable. LSS is most often acquired (75%), but can also be congenital or due to a mixture of both. Congenital forms (achondroplasia and idiopathic) are Normal characterized by short, thick pedicles that produce Thecal sac Normal both spinal canal and lateral recess stenosis. Acquired Nerve roots factors that contribute to spinal stenosis include Facet joints degenerative diseases (spondylosis, spondylolisthesis, and scoliosis), trauma, spine surgery, metabolic or A B endocrine disorders (epidural lipomatosis, osteoporoFIGURE 14-5  Axial T2-weighted images of the lumbar spine. A. The image shows a normal thecal sis, acromegaly, renal osteodystrophy, and hypopara- sac within the lumbar spinal canal. The thecal sac is bright. The lumbar roots are dark punctate dots thyroidism), and Paget’s disease. MRI provides the in the posterior thecal sac with the patient supine. B. The thecal sac is not well visualized due to best definition of the abnormal anatomy (Fig. 14-5). severe lumbar spinal canal stenosis, partially the result of hypertrophic facet joints.

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*

Sag T2

Back and Neck Pain

*

Normal right L4-5 intervertebral foramen, L4 root, and high signal A

Left L5-S1 foramen open

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Stenotic right L5-S1 intervertebral foramen

Stenotic right L5-S1 intervertebral foramen; loss of high signal around exiting root

Open right and left Axial T2 lateral B recesses FIGURE 14-6  Right L5 radiculopathy. A. Sagittal T2-weighted image. There is normal high signal around the exiting right L4 nerve root in the right neural foramen at L4-L5; effacement of the high signal in the right L5-S1 foramen is present one level caudal on the right at L5-S1. B. Axial T2-weighted image. The lateral recesses are normal bilaterally; the intervertebral foramen is normal on the left, but severely stenotic on the right. *Severe right L5-S1 foraminal stenosis.

can help direct the attention of the radiologist to specific nerve roots, especially on axial images. For facet joint hypertrophy, surgical foraminotomy produces long-term relief of leg and back pain in 80–90% of patients. Facet joint blocks for back or neck pain are sometimes used to help determine the anatomic origin of back pain or for treatment, but there is a lack of clinical data to support their utility. Medical causes of lumbar or cervical radiculopathy unrelated to anatomic spine disease include infections (e.g., herpes zoster and Lyme disease), carcinomatous meningitis, and root avulsion or traction (trauma).

■■SPONDYLOSIS AND SPONDYLOLISTHESIS

Spondylosis, or osteoarthritic spine disease, typically occurs in later life and primarily involves the cervical and lumbosacral spine. Patients often complain of back pain that increases with movement, is associated with stiffness, and is better with inactivity. The relationship between clinical symptoms and radiologic findings is usually not straightforward. Pain may be prominent when x-ray, CT, or MRI findings are minimal, and prominent degenerative spine disease can be seen in asymptomatic patients. Osteophytes, combined diskosteophytes, or thickened ligamentum flavum may cause or contribute to central spinal canal stenosis, lateral recess stenosis, or neural foraminal narrowing. Spondylolisthesis is the anterior slippage of the vertebral body, pedicles, and superior articular facets, leaving the posterior elements behind. Spondylolisthesis can be associated with spondylolysis, congenital anomalies, degenerative spine disease, or other causes of mechanical weakness of the pars interarticularis (e.g., infection, osteoporosis, tumor, trauma, prior surgery). The slippage may be asymptomatic or may cause LBP and hamstring tightness, nerve root injury (the L5 root most frequently), symptomatic spinal stenosis, or CES in severe cases. A “step-off” on palpation or tenderness may be elicited near the segment that has “slipped” forward (most often L4 on L5 or occasionally L5 on S1). Focal anterolisthesis or retrolisthesis can occur at any cervical or lumbar level and be the source of neck or LBP. Plain x-rays of the neck or low back in flexion and extension will reveal movement at the abnormal spinal segment. Surgery is performed for spinal instability (slippage 5–8 mm) and considered for pain symptoms

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that do not respond to conservative measures (e.g., rest, physical therapy), cases with progressive neurologic deficit, or scoliosis.

■■NEOPLASMS

Back pain is the most common neurologic symptom in patients with systemic cancer and is the presenting symptom in 20%. The cause is usually vertebral body metastasis (85–90%) but can also result from spread of cancer through the intervertebral foramen (especially with lymphoma), carcinomatous meningitis, or metastasis to the spinal cord. The thoracic spine is most often affected. Cancer-related back pain tends to be constant, dull, unrelieved by rest, and worse at night. By contrast, mechanical causes of LBP usually improve with rest. MRI, CT, and CT myelography are the studies of choice when spinal metastasis is suspected. Once a metastasis is found, imaging of the entire spine is essential, as it reveals additional tumor deposits in one-third of patients. MRI is preferred for soft tissue definition, but the most rapidly available imaging modality is best because the patient’s condition may worsen quickly without intervention. Early diagnosis is crucial. A strong predictor of outcome is the baseline neurologic function prior to diagnosis. Half to three quarters of patients are nonambulatory at the time of diagnosis and few regain the ability to walk. The management of spinal metastasis is discussed in detail in Chap. 86.

■■INFECTIONS/INFLAMMATION

Vertebral osteomyelitis is most often caused by hematogenous seeding of staphylococci, but other bacteria or tuberculosis (Pott’s disease) may be responsible. The primary source of infection is usually the skin or urinary tract; IV drug use, poor dentition, endocarditis, pulmonary disease, IV catheters, or post-operative wound sites may also be responsible. Back pain at rest, tenderness over the involved vertebra, and an elevated ESR or CRP are the most common findings in vertebral osteomyelitis. Fever or an elevated white blood cell count is found in a minority of patients. MRI and CT are sensitive and specific for early detection of osteomyelitis. The intervertebral disk can also be affected by infection (diskitis) and almost never by tumor. Extension of the infection posteriorly from the vertebra can produce a spinal epidural abscess. Spinal epidural abscess (Chap. 434) presents with back pain (aggravated by movement or spinous process palpation), fever, radiculopathy,

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or signs of spinal cord compression. The subacute development of two or more of these findings should increase the index of suspicion for spinal epidural abscess. The abscess is best delineated by spine MRI and may track over multiple spinal levels. Lumbar adhesive arachnoiditis with radiculopathy is due to fibrosis following inflammation within the subarachnoid space. The fibrosis results in nerve root adhesions and presents as back and leg pain associated with multifocal motor, sensory, or reflex changes. Causes of arachnoiditis include multiple lumbar operations (most common in the United States), chronic spinal infections (especially tuberculosis in the developing world), spinal cord injury, intrathecal hemorrhage, myelography (rare), intrathecal injections (glucocorticoids, anesthetics, or other agents), and foreign bodies. The MRI shows clumped nerve roots on axial views or loculations of cerebrospinal fluid within the thecal sac. Clumped nerve roots alone are not diagnostic and may also occur with demyelinating polyneuropathy or neoplastic infiltration. Treatment is usually unsatisfactory. Microsurgical lysis of adhesions, dorsal rhizotomy, dorsal root ganglionectomy, and epidural glucocorticoids have been tried, but outcomes have been poor. Dorsal column stimulation for pain relief has produced varying results.

■■TRAUMA

A patient complaining of back pain and an inability to move the legs may have a spine fracture or dislocation; with fractures above L1 the spinal cord is at risk for compression. Care must be taken to avoid further damage to the spinal cord or nerve roots by immobilizing the back or neck pending the results of radiologic studies. Vertebral fractures frequently occur in the absence of trauma in association with osteoporosis, glucocorticoid use, osteomyelitis, or neoplastic infiltration.

Sprains and Strains  The terms low back sprain, strain, and mechani-

cally induced muscle spasm refer to minor, self-limited injuries associated with lifting a heavy object, a fall, or a sudden deceleration such as in an automobile accident. These terms are used loosely and do not clearly describe a specific anatomic lesion. The pain is usually confined to the lower back. Patients with paraspinal muscle spasm often assume unusual postures.

Traumatic Vertebral Fractures  Most traumatic fractures of the

lumbar vertebral bodies result from injuries producing anterior wedging or compression. With severe trauma, the patient may sustain a fracture-dislocation or a “burst” fracture involving the vertebral body and posterior elements. Traumatic vertebral fractures are caused by falls from a height, sudden deceleration in an automobile accident, or direct injury. Neurologic impairment is common, and early surgical treatment is indicated. In victims of blunt trauma, CT scans of the chest, abdomen, or pelvis can be reformatted to detect associated vertebral fractures. Rules have been developed to avoid unnecessary spine imaging associated with low risk trauma, but these studies excluded patients aged >65—a group that can sustain fractures with minor trauma.

■■METABOLIC CAUSES Osteoporosis and Osteosclerosis  Immobilization, osteom-

alacia, the postmenopausal state, renal disease, multiple myeloma, hyperparathyroidism, hyperthyroidism, metastatic carcinoma, or glucocorticoid use may accelerate osteoporosis and weaken the vertebral body, leading to compression fractures and pain. Up to two-thirds of compression fractures seen on radiologic imaging are asymptomatic. The most common nontraumatic vertebral body fractures are due to postmenopausal or senile osteoporosis (Chap. 404). The risk of an additional vertebral fracture 1 year following a first vertebral fracture is 20%. The presence of fever, weight loss, fracture at a level above T4, any fracture in a young adult, or the predisposing conditions described above should increase suspicion for a cause other than senile osteoporosis. The sole manifestations of a compression fracture may be localized back or radicular pain exacerbated by movement and often reproduced by palpation over the spinous process of the affected vertebra. Relief of acute pain can often be achieved with acetaminophen, NSAIDs, opioids, or a combination of these medications. Both pain and disability are improved with bracing. Antiresorptive drugs are not recommended in the setting of acute pain, but are the preferred

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treatment to prevent additional fractures. Less than one-third of patients with prior compression fractures are adequately treated for osteoporosis despite the increased risk for future fractures; even fewer at-risk patients without a history of fracture are adequately treated. The literature for percutaneous vertebroplasty (PVP) or kyphoplasty for osteoporotic compression fractures associated with debilitating pain is mixed, but meta-analyses do not support their utility. Osteosclerosis, an abnormally increased bone density often due to Paget’s disease, is readily identifiable on routine x-ray studies and can sometimes be a source of back pain. It may be associated with an isolated increase in alkaline phosphatase in an otherwise healthy older person. Spinal cord or nerve root compression can result from bony encroachment. The diagnosis of Paget’s disease as the cause of a patient’s back pain is a diagnosis of exclusion. For further discussion of these bone disorders, see Chaps. 403, 404, and 405.

■■AUTOIMMUNE INFLAMMATORY ARTHRITIS

Autoimmune inflammatory disease of the spine can present with the insidious onset of low back, buttock, or neck pain. Examples include rheumatoid arthritis (RA) (Chap. 351), ankylosing spondylitis, reactive arthritis, psoriatic arthritis, or inflammatory bowel disease (Chaps. 319 and 355).

■■CONGENITAL ANOMALIES OF THE LUMBAR SPINE

Spondylolysis is a bony defect in the vertebral pars interarticularis (a segment near the junction of the pedicle with the lamina); the cause is usually a stress microfracture in a congenitally abnormal segment. It occurs in up to 6% of adolescents. The defect (usually bilateral) is best visualized on plain x-rays or CT scan and is frequently asymptomatic. Symptoms may occur in the setting of a single injury, repeated minor injuries, or during a growth spurt. Spondylolysis is the most common cause of persistent LBP in adolescents and is often associated with sports-related activities. Scoliosis refers to an abnormal curvature in the coronal (lateral) plane of the spine. With kyphoscoliosis, there is, in addition, a forward curvature of the spine. The abnormal curvature may be congenital, due to abnormal spine development, acquired in adulthood due to degenerative spine disease, or occasionally progressive due to neuromuscular disease. The deformity can progress until ambulation or pulmonary function is compromised. Spina bifida occulta (closed spinal dysraphism) is a failure of closure of one or several vertebral arches posteriorly; the meninges and spinal cord are normal. A dimple or small lipoma may overlie the defect, but the skin is intact. Most cases are asymptomatic and discovered incidentally during an evaluation for back pain. Tethered cord syndrome usually presents as a progressive cauda equina disorder (see below), although myelopathy may also be the initial manifestation. The patient is often a child or young adult who complains of perineal or perianal pain, sometimes following minor trauma. MRI studies typically reveal a low-lying conus (below L1 and L2) and a short and thickened filum terminale.

■■REFERRED PAIN FROM VISCERAL DISEASE

Diseases of the thorax, abdomen, or pelvis may refer pain to the spinal segment that innervates the diseased organ. Occasionally, back pain may be the first and only manifestation. Upper abdominal diseases generally refer pain to the lower thoracic or upper lumbar region (eighth thoracic to the first and second lumbar vertebrae), lower abdominal diseases to the midlumbar region (second to fourth lumbar vertebrae), and pelvic diseases to the sacral region. Local signs (pain with spine palpation, paraspinal muscle spasm) are absent, and little or no pain accompanies routine movements.

Low Thoracic or Lumbar Pain with Abdominal Disease  Tumors of the posterior wall of the stomach or duodenum typically produce epigastric pain (Chaps. 76 and 317), but back pain may occur if retroperitoneal extension is present. Fatty foods occasionally induce back pain associated with biliary or pancreatic disease. Pathology in retroperitoneal structures (hemorrhage, tumors, and pyelonephritis) can produce paraspinal pain that radiates to the lower abdomen, groin,

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Sacral Pain with Gynecologic and Urologic Disease  Pel-

■■OTHER CAUSES OF BACK PAIN Postural Back Pain  There is a group of patients with nonspecific

chronic low back pain (CLBP) in whom no specific anatomic lesion can be found despite exhaustive investigation. Exercises to strengthen the paraspinal and abdominal muscles are sometimes helpful.

Psychiatric Disease  CLBP may be encountered in patients who seek financial compensation; in malingerers; or in those with concurrent substance abuse. Many patients with CLBP have a history of psychiatric illness (depression, anxiety states) or childhood trauma (physical or sexual abuse) that antedates the onset of back pain. Preoperative psychological assessment has been used to exclude patients with marked psychological impairments that predict a poor surgical outcome from spine surgery. ■■IDIOPATHIC

The cause of low back pain occasionally remains unclear. Some patients have had multiple operations for disk disease. The original indications for surgery may have been questionable, with back pain only, no definite neurologic signs, or a minor disk bulge noted on CT or MRI. Scoring systems based on neurologic signs, psychological factors, physiologic studies, and imaging studies have been devised to minimize the likelihood of unsuccessful surgery.

■■GLOBAL CONSIDERATIONS

While many of the history and examination features described in this chapter apply to all patients, information regarding the global epidemiology and prevalence of LBP is limited. The Global Burden of Diseases Study 2010 reported that LBP ranked #6 overall as a cause of disability-related life years (DALYs), and was the #1 cause overall for total years lived with disability (YLD). These numbers increased substantially from 1990 estimates, and with the aging of the population worldwide, the numbers of individuals suffering from low back pain are expected to increase further in the future. Although rankings for low back pain generally were higher in developed regions of the world, this was not uniformly the case; for example, in North Africa and the Middle East low back pain ranked #2 for DALYs. Another area of uncertainty is the extent to which regional differences exist in terms of

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TREATMENT

Back Pain Mounting evidence of morbidity from long-term opioid therapy (including overdose, dependency, addiction, falls, fractures, accident risk, and sexual dysfunction) has prompted efforts to reduce its use for chronic pain, including back pain (Chap. 10). Safety may be improved with automated notices for high doses, early refills, prescriptions from multiple pharmacies, and overlapping opioid and benzodiazepine prescriptions. Greater access to alternative treatments for chronic pain, such as tailored exercise programs and cognitive-behavioral therapy (CBT), may also reduce opioid prescribing. Public concern in the United States resulted in passage of the Comprehensive Addiction and Recovery Act of 2016. The high cost, wide geographic variations, and rapidly increasing rates of spinal fusion surgery have prompted scrutiny regarding the lack of standardization of appropriate indications. Some insurance carriers have begun to limit coverage for the most controversial indications, such as low back pain without radiculopathy. Finally, educating patients and the public about the risks of overtreatment may be necessary.

Back and Neck Pain

vic organs rarely cause LBP. Uterine malposition (retroversion, descensus, and prolapse) may cause traction on the uterosacral ligament. The pain is referred to the sacral region, sometimes appearing after prolonged standing. Endometriosis or uterine cancers can invade the uterosacral ligaments. Pain associated with endometriosis is typically premenstrual and often continues until it merges with menstrual pain. Menstrual pain with poorly localized, cramping pain can radiate down the legs. LBP that radiates into one or both thighs is common in the last weeks of pregnancy. Continuous and worsening pain unrelieved by rest or at night may be due to neoplastic infiltration of nerves or nerve roots. Urologic sources of lumbosacral back pain include chronic prostatitis, prostate cancer with spinal metastasis (Chap. 83), and diseases of the kidney or ureter. Infectious, inflammatory, or neoplastic renal diseases may produce ipsilateral lumbosacral pain, as can renal artery or vein thrombosis. Paraspinal lumbar pain may be a symptom of ureteral obstruction due to nephrolithiasis.

the specific etiologies of LBP and how these are managed. For example, the most common cause of arachnoiditis in developing countries is prior spine infection, but in developed countries is multiple lumbar spine surgeries. The longstanding history and acceptance of acupuncture in China may also explain the large number of studies from China regarding the efficacy of acupuncture in many pain settings.

CHAPTER 14

or anterior thighs. A mass in the iliopsoas region can produce unilateral lumbar pain with radiation toward the groin, labia, or testicle. The sudden appearance of lumbar pain in a patient receiving anticoagulants suggests retroperitoneal hemorrhage. Isolated LBP occurs in some patients with a contained rupture of an AAA. The classic clinical triad of abdominal pain, shock, and back pain occurs in 12 weeks; it accounts for 50% of total back pain costs. Risk factors include obesity, female gender, older age, prior history of back pain, restricted spinal mobility, pain radiating into a leg, high levels of psychological distress, poor selfrated health, minimal physical activity, smoking, job dissatisfaction, and widespread pain. In general, the same treatments that are recommended for ALBP can be useful for patients with CLBP. In this setting, however, the benefit of opioid therapy or muscle relaxants is less clear. In general, activity tolerance is the primary goal, while pain relief is secondary. Evidence supports the use of exercise therapy to alleviate pain symptoms and improve function. Exercise can be one of the mainstays of treatment for CLBP. Effective regimens have generally included a combination of core strengthening exercises, stretching, and gradually increasing aerobic exercise. A program of supervised exercise can improve compliance. Supervised intensive physical exercise or “work hardening” regimens have been effective in returning some patients to work, improving walking distance, and reducing pain. In addition, some forms of yoga have been evaluated in randomized trials and may be helpful for patients who are interested. A long-term benefit of spinal manipulation or massage for CLBP is unproven. Medications for CLBP may include short courses of NSAIDs or acetaminophen. Tricyclic antidepressants can provide modest pain relief for some patients without evidence of depression. Trials do not support the efficacy of selective serotonin reuptake inhibitors (SSRIs) for CLBP. However, depression is common among patients with chronic pain and should be appropriately treated. CBT is based on evidence that psychological and social factors, as well as somatic pathology, are important in the genesis of chronic pain and disability; CBT focuses on efforts to identify and modify

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patients’ thinking about their condition. In one randomized trial, CBT reduced disability and pain in patients with CLBP. Such behavioral treatments appear to provide benefits similar in magnitude to exercise therapy. Back pain is the most frequent reason for seeking complementary and alternative treatments, most commonly spinal manipulation, acupuncture, and massage. The value of these approaches remains unclear, however. Biofeedback has not been studied rigorously. There is no convincing evidence that either spinal manipulation, TENS, laser therapy, or ultrasound are effective in treating CLBP. Rigorous trials of acupuncture suggest that true acupuncture is not superior to sham acupuncture, but that both may offer an advantage over routine care. Whether this is due entirely to placebo effects provided even by sham acupuncture is uncertain. Some trials of massage therapy have been encouraging for short-term relief only. Various injections, including epidural glucocorticoid injections, facet joint injections, and trigger point injections, have been used for treating CLBP. However, in the absence of radiculopathy, there is no clear evidence that these approaches are effective. Injection studies are sometimes used diagnostically to help determine the anatomic source of back pain. Pain relief following a glucocorticoid and anesthetic injection into a facet is commonly used as evidence that the facet joint is the pain source; however, the possibility that the response was a placebo effect or due to systemic absorption of the glucocorticoids is difficult to exclude. Another category of intervention for CLBP is electrothermal and radiofrequency therapy. Intradiskal therapy has been proposed using both types of energy to thermocoagulate and destroy nerves in the intervertebral disk, using specially designed catheters or electrodes. Current evidence does not support the use of discography to identify a specific disk as the pain source, or the use of intradiskal therapy for CLBP. Radiofrequency denervation is sometimes used to destroy nerves that are thought to mediate pain, and this technique has been used for facet joint pain (with the target nerve being the medial branch of the primary dorsal ramus), for back pain thought to arise from the intervertebral disk (ramus communicans), and radicular back pain (dorsal root ganglia). A few small trials have produced conflicting results for facet joint and diskogenic pain. A trial in patients with chronic radicular pain found no difference between radiofrequency denervation of the dorsal root ganglia and sham treatment. These interventional therapies have not been studied in sufficient detail to draw firm conclusions regarding their value for CLBP. Surgical intervention for CLBP without radiculopathy has been evaluated in a number of randomized trials. The case for fusion surgery for CLBP without radiculopathy is weak. While some studies have shown modest benefit, there has been no benefit when compared to an active medical treatment arm, often including highly structured, rigorous rehabilitation combined with CBT. The use of BMP instead of iliac crest graft for the fusion was shown to increase hospital costs and length of stay, but not improve clinical outcomes. Guidelines suggest that referral for an opinion on spinal fusion be considered for people who have completed an optimal nonsurgical treatment program (including combined physical and psychological treatment) and who have persistent severe back pain for which they would consider surgery. Lumbar disk replacement with prosthetic disks is U.S. Food and Drug Administration approved for uncomplicated patients needing single-level surgery at the L3-S1 levels. The disks are generally designed as metal plates with a polyethylene cushion sandwiched in between. The trials that led to approval of these devices were not blinded. When compared to spinal fusion, the artificial disks were “not inferior.” Serious complications are somewhat more likely with the artificial disk. This treatment remains controversial for CLBP. Intensive multidisciplinary rehabilitation programs can include daily or frequent physical therapy, exercise, CBT, a workplace evaluation, and other interventions. For patients who have not responded to other approaches, such programs appear to offer some benefit. Systematic reviews suggest that the evidence is limited and benefits are limited.

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Some observers have raised concerns that CLBP may often be overtreated. For CLBP without radiculopathy, multiple guidelines explicitly recommend against use of SSRIs, any type of injection, TENS, lumbar supports, traction, ulrtaradiofrequency facet joint denervation, intradiskal electrothermal therapy, or intradiskal radiofrequency thermocoagulation. On the other hand, exercise therapy and treatment of depression appear to be useful and underused.

PAIN IN THE NECK AND SHOULDER

Neck pain, which usually arises from diseases of the cervical spine and soft tissues of the neck, is common. Neck pain arising from the cervical spine is typically precipitated by movement and may be accompanied by focal tenderness and limitation of motion. Many of the prior comments made regarding causes of low back pain also apply to disorders of the cervical spine. The text below will emphasize differences. Pain arising from the brachial plexus, shoulder, or peripheral nerves can be confused with cervical spine disease (Table 14-4), but the history and examination usually identify a more distal origin for the pain. When the site of nerve tissue injury is unclear, EMG studies can localize the lesion. Cervical spine trauma, disk disease, or spondylosis with intervertebral foraminal narrowing may be asymptomatic or painful and can produce a myelopathy, radiculopathy, or both. The same risk factors for serious causes of low back pain also apply to neck pain with the additional feature that neurologic signs of myelopathy (incontinence, sensory level, spastic legs) may also occur. Lhermitte’s sign, an electrical shock down the spine with neck flexion, suggests involvement of the cervical spinal cord.

Back and Neck Pain

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LOW BACK PAIN WITH RADICULOPATHY A common cause of back pain with radiculopathy is a herniated disk affecting the nerve root and producing back pain with radiation down the leg. The term sciatica is used when the leg pain radiates posteriorly in a sciatic or L5/S1 distribution. The prognosis for acute low back and leg pain with radiculopathy due to disk herniation is generally favorable, with most patients showing substantial improvement over months. Serial imaging studies suggest spontaneous regression of the herniated portion of the disk in two-thirds of patients over 6 months. Nonetheless, there are several important treatment options that provide symptomatic relief while the healing process unfolds. Resumption of normal activity is recommended. Randomized trial evidence suggests that bed rest is ineffective for treating sciatica as well as back pain alone. Acetaminophen and NSAIDs are useful for pain relief, although severe pain may require short courses of opioid analgesics. Opioids are superior for acute pain relief in the emergency room. Epidural glucocorticoid injections have a role in providing symptom relief for acute lumbar radiculopathy due to a herniated disk. However, there does not appear to be a benefit in terms of reducing subsequent surgical interventions. A brief course of high dose oral glucocorticoids for 5 days followed by a rapid taper >5 days can be helpful for some patients with acute disk-related radiculopathy, although this specific regimen has not been studied rigorously. Diagnostic nerve root blocks have been advocated to determine if pain originates from a specific nerve root. However, improvement may result even when the nerve root is not responsible for the pain; this may occur as a placebo effect, from a pain-generating lesion located distally along the peripheral nerve, or from effects of systemic absorption. Urgent surgery is recommended for patients who have evidence of CES or spinal cord compression, generally manifest as combinations of bowel or bladder dysfunction, diminished sensation in a saddle distribution, a sensory level on the trunk, and bilateral leg weakness or spasticity. Surgical intervention is also indicated for patients with progressive motor weakness due to nerve root injury demonstrated on clinical examination or EMG. Surgery is also an important option for patients who have disabling radicular pain despite optimal conservative treatment. Because patients with a herniated disk and sciatica generally experience rapid improvement over weeks, most experts do not recommend considering surgery unless the patient has failed to respond to a minimum of 6–8 weeks of nonsurgical management. For patients who have not improved, randomized trials indicate that, compared to nonsurgical treatment, surgery results in more rapid pain relief. However, after 2 years of follow-up, patients appear to have similar pain relief and functional improvement with or without surgery. Thus, both treatment approaches are reasonable, and patient preferences and needs (e.g., rapid return to employment) strongly influence decision making. Some patients will want the fastest possible relief and find surgical risks acceptable. Others will be more risk-averse, more tolerant of symptoms and will choose watchful waiting, especially if they understand that improvement is likely in the end. The usual surgical procedure is a partial hemilaminectomy with excision of the prolapsed disk (diskectomy). Minimally invasive techniques have gained in popularity in recent years, but preliminary evidence suggests they may be less effective than standard surgical techniques, with more residual back pain, leg pain, and higher rates of rehospitalization. Fusion of the involved lumbar segments should be considered only if significant spinal instability is present (i.e., degenerative spondylolisthesis). The costs associated

with lumbar interbody fusion have increased dramatically in recent years. There are no large prospective, randomized trials comparing fusion to other types of surgical intervention. In one study, patients with persistent low back pain despite an initial diskectomy fared no better with spine fusion than with a conservative regimen of cognitive intervention and exercise. Artificial disks are used in Europe; their utility remains controversial in the United States.

■■TRAUMA TO THE CERVICAL SPINE

Trauma to the cervical spine (fractures, subluxation) places the spinal cord at risk for compression. Motor vehicle accidents, violent crimes, or falls account for 87% of cervical spinal cord injuries (Chap. 434). Immediate immobilization of the neck is essential to minimize further spinal cord injury from movement of unstable cervical spine segments. The decision to obtain imaging should be based on the nature of the injury. The National Emergency X-Radiography Utilization Study (NEXUS) low-risk criteria established that normally alert patients without palpation tenderness in the midline; intoxication; neurologic deficits; or painful distracting injuries were very unlikely to have sustained a clinically significant traumatic injury to the cervical spine. The Canadian C-spine rule recommends that imaging should be obtained following neck region trauma if the patient is >65 years old or has limb paresthesias or if there was a dangerous mechanism for the injury (e.g., bicycle collision with tree or parked car, fall from height >3 feet or five stairs, diving accident). These guidelines are helpful but must be tailored to individual circumstances; for example, patients with advanced osteoporosis, glucocorticoid use, or cancer may warrant imaging after even mild trauma. A CT scan is the diagnostic procedure of choice for detection of acute fractures following severe trauma; plain x-rays can be used for lesser degrees of trauma. When traumatic injury to the vertebral arteries or cervical spinal cord is suspected, visualization by MRI with magnetic resonance angiography is preferred. Whiplash injury is due to rapid flexion and extension of the neck, usually from automobile accidents. The exact mechanism of injury is unclear. This diagnosis should not be applied to patients with fractures, disk herniation, head injury, focal neurologic findings, or altered consciousness. Up to 50% of persons reporting whiplash injury acutely have persistent neck pain 1 year later. When personal compensation for pain and suffering was removed from the Australian health care system, the prognosis for recovery at 1 year improved. Imaging of the cervical spine is not cost-effective acutely but is useful to detect disk herniations when symptoms persist for >6 weeks following the injury. Severe initial symptoms have been associated with a poor long-term outcome.

■■CERVICAL DISK DISEASE

Degenerative cervical disk disease is very common and usually asymptomatic. Herniation of a lower cervical disk is a common cause of pain or tingling in the neck, shoulder, arm, or hand. Neck pain, stiffness, and a range of motion limited by pain are the usual manifestations.

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TABLE 14-4  Cervical Radiculopathy: Neurologic Features EXAMINATION FINDINGS

PART 2

CERVICAL NERVE ROOTS C5

REFLEX Biceps

C6

Biceps

C7

Triceps

C8

Finger flexors

Cardinal Manifestations and Presentation of Diseases

T1

Finger flexors

SENSORY Lateral deltoid

MOTOR Rhomboidsa (elbow extends backward with hand on hip) Infraspinatusa (arm rotates externally with elbow flexed at the side) Deltoida (arm raised laterally 30–45° from the side) Thumb/index finger; Bicepsa (arm flexed at the elbow in supination) Dorsal hand/lateral forearm Pronator teres (forearm pronated) Middle fingers Tricepsa (forearm extension, flexed at elbow) Dorsal forearm Palmar surface of little finger Medial hand and forearm Axilla and medial arm

Wrist/finger extensorsa Abductor pollicis brevis (abduction of thumb) First dorsal interosseous (abduction of index finger) Abductor digiti minimi (abduction of little finger) Abductor pollicis brevis (abduction of thumb) First dorsal interosseous (abduction of index finger) Abductor digiti minimi (abduction of little finger)

PAIN DISTRIBUTION Lateral arm, medial scapula

Lateral forearm, thumb/index fingers Posterior arm, dorsal forearm, dorsal hand Fourth and fifth fingers, medial hand and forearm

Medial arm, axilla

These muscles receive the majority of innervation from this root.

a

Herniated cervical disks are responsible for ~25% of cervical radiculopathies. Extension and lateral rotation of the neck narrow the ipsilateral intervertebral foramen and may reproduce radicular symptoms (Spurling’s sign). In young adults, acute nerve root compression from a ruptured cervical disk is often due to trauma. Cervical disk herniations are usually posterolateral near the lateral recess. Typical patterns of reflex, sensory, and motor changes that accompany cervical nerve root lesions are summarized in Table 14-4. Although the classic patterns are clinically helpful, there are numerous exceptions because (1) there is overlap in sensory function between adjacent nerve roots, (2) symptoms and signs may be evident in only part of the injured nerve root territory, and (3) the location of pain is the most variable of the clinical features.

■■CERVICAL SPONDYLOSIS

Osteoarthritis of the cervical spine may produce neck pain that radiates into the back of the head, shoulders, or arms, or may be the source of headaches in the posterior occipital region (supplied by the C2-C4 nerve roots). Osteophytes, disk protrusions, or hypertrophic facet or uncovertebral joints may alone or in combination compress one or several nerve roots at the intervertebral foramina; these causes together account for 75% of cervical radiculopathies. The roots most commonly affected are C7 and C6. Narrowing of the spinal canal by osteophytes, ossification of the posterior longitudinal ligament (OPLL), or a large central disk may compress the cervical spinal cord and produce signs of myelopathy alone or radiculopathy with myelopathy (myeloradiculopathy). When little or no neck pain accompanies cervical cord involvement, other diagnoses to be considered include amyotrophic lateral sclerosis (Chap. 429), multiple sclerosis (Chap. 436), spinal cord tumors, or syringomyelia (Chap. 434). Cervical spondylotic myelopathy should be considered even when the patient presents with symptoms or spinal cord signs in the legs only. MRI is the study of choice to define soft tissues in the cervical region including the spinal cord, whereas plain CT is optimal to identify bone pathology including foraminal, lateral recess, or spinal canal stenosis. With spondylotic myelopathy focal enhancement by MRI, sometimes in a characteristic “pancake pattern”, may be present at the site of maximal cord compression. There is no evidence to support prophylactic surgery for asymptomatic cervical spinal stenosis unaccompanied by myelopathic signs or abnormal spinal cord findings on MR imaging, except in the setting of dynamic instability (see spondylolisthesis above). If the patient has postural neck pain, a prior history of whiplash or other spine/head injury, a Lhermitte sign, or preexisting listhesis at the stenotic segment on cervical MRI, or CT, then cervical spine flexion-extension x-rays are indicated to look for dynamic instability. Surgical intervention is

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not recommended for patients with listhesis alone, unaccompanied by dynamic instability.

■■OTHER CAUSES OF NECK PAIN

RA (Chap. 351) of the cervical facet joints produces neck pain, stiffness, and limitation of motion. Synovitis of the atlantoaxial joint (C1-C2; Fig. 14-2) may damage the transverse ligament of the atlas, producing forward displacement of the atlas on the axis (atlantoaxial subluxation). Radiologic evidence of atlantoaxial subluxation occurs in up to 30% of patients with RA and plain x-ray films of the neck should be routinely performed preoperatively to assess the risk of neck hyperextension in patients requiring intubation. The degree of subluxation correlates with the severity of erosive disease. When subluxation is present, careful assessment is important to identify early signs of myelopathy that could be a harbinger of life-threatening spinal cord compression. Surgery should be considered when myelopathy or spinal instability is present. Ankylosing spondylitis is another cause of neck pain and less commonly atlantoaxial subluxation. Acute herpes zoster can present as acute posterior occipital or neck pain prior to the outbreak of vesicles. Neoplasms metastatic to the cervical spine, infections (osteomyelitis and epidural abscess), and metabolic bone diseases may be the cause of neck pain, as discussed above. Neck pain may also be referred from the heart with coronary artery ischemia (cervical angina syndrome).

■■THORACIC OUTLET SYNDROMES

The thoracic outlet contains the first rib, the subclavian artery and vein, the brachial plexus, the clavicle, and the lung apex. Injury to these structures may result in postural or movement-induced pain around the shoulder and supraclavicular region, classified as follows. True neurogenic thoracic outlet syndrome (TOS) is an uncommon disorder resulting from compression of the lower trunk of the brachial plexus or ventral rami of the C8 or T1 nerve roots, caused most often by an anomalous band of tissue connecting an elongate transverse process at C7 with the first rib. Pain is mild or may be absent. Signs include weakness and wasting of intrinsic muscles of the hand and diminished sensation on the palmar aspect of the fifth digit. An anteroposterior cervical spine x-ray will show an elongate C7 transverse process (an anatomic marker for the anomalous cartilaginous band), and EMG and NCSs confirm the diagnosis. Treatment consists of surgical resection of the anomalous band. The weakness and wasting of intrinsic hand muscles typically does not improve, but surgery halts the insidious progression of weakness. Arterial TOS results from compression of the subclavian artery by a cervical rib, resulting in poststenotic dilatation of the artery and in some cases secondary thrombus formation. Blood pressure is reduced

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Pain from injury to the brachial plexus or peripheral nerves of the arm can occasionally mimic referred pain of cervical spine origin including cervical radiculopathy. Neoplastic infiltration of the lower trunk of the brachial plexus may produce shoulder or supraclavicular pain radiating down the arm, numbness of the fourth and fifth fingers or medial forearm, and weakness of intrinsic hand muscles innervated by the lower trunk and medial cord of the brachial plexus. Delayed radiation injury may produce weakness in the upper arm or numbness of the lateral forearm or arm due to involvement of the upper trunk and lateral cord of the plexus. Pain is less common and less severe than with neoplastic infiltration. A Pancoast tumor of the lung (Chap. 74) is another cause and should be considered, especially when a concurrent Horner’s syndrome is present. Suprascapular neuropathy may produce severe shoulder pain, weakness, and wasting of the supraspinatus and infraspinatus muscles. Acute brachial neuritis is often confused with radiculopathy; the acute onset of severe shoulder or scapular pain is followed typically over days by weakness of the proximal arm and shoulder girdle muscles innervated by the upper brachial plexus. The onset may be preceded by an infection, vaccination, or minor surgical procedure. The long thoracic nerve may be affected, resulting in a winged scapula. Brachial neuritis may also present as an isolated paralysis of the diaphragm with or without involvement of other nerves of the upper limb. Recovery may take up to 3 years, and full functional recovery can be expected in the majority of patients. Occasional cases of carpal tunnel syndrome produce pain and paresthesias extending into the forearm, arm, and shoulder resembling a C5 or C6 root lesion. Lesions of the radial or ulnar nerve can also mimic radiculopathy, at C7 or C8, respectively. EMG and NCSs can accurately localize lesions to the nerve roots, brachial plexus, or peripheral nerves. For further discussion of peripheral nerve disorders, see Chap. 438.

■■SHOULDER

Pain arising from the shoulder can on occasion mimic pain from the spine. If symptoms and signs of radiculopathy are absent, then the differential diagnosis includes mechanical shoulder pain (tendonitis, bursitis, rotator cuff tear, dislocation, adhesive capsulitis, or rotator cuff impingement under the acromion) and referred pain (subdiaphragmatic irritation, angina, Pancoast tumor). Mechanical pain is often worse at night, associated with local shoulder tenderness and aggravated by passive abduction, internal rotation, or extension of the arm. Demonstrating normal passive full range of motion of the arm at the shoulder without worsening the usual pain can help exclude mechanical shoulder pathology as a cause of neck region pain. Pain from shoulder disease may radiate into the arm or hand, but focal neurologic signs (sensory, motor, or reflex changes) are absent.

■■GLOBAL CONSIDERATIONS

Many of the considerations described above for LBP also apply to neck pain. Neck pain was ranked #21 as a cause of DALYs in the Global Burden of Diseases Study 2010,

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TREATMENT

Neck Pain without Radiculopathy The evidence regarding treatment for neck pain is less comprehensive than that for low back pain, but the approach is remarkably similar in many respects. As with low back pain, spontaneous improvement is the norm for acute neck pain. The usual goals of therapy are to promote a rapid return to normal function and provide pain relief while healing proceeds. Acute neck pain is often treated with a combination of NSAIDs, acetaminophen, cold packs, or heat while awaiting spontaneous recovery. For patients kept awake by symptoms, cyclobenzaprine (5–10 mg) at night can help relieve muscle spasm and promote drowsiness. For patients with neck pain unassociated with trauma, supervised exercise with or without mobilization appears to be effective. Exercises often include shoulder rolls and neck stretches. The evidence in support of nonsurgical treatments for whiplashassociated disorders is generally of limited quality and neither supports nor refutes the common treatments used for symptom relief. Gentle mobilization of the cervical spine combined with exercise programs may be beneficial. Evidence is insufficient to recommend the use of cervical traction, TENS, ultrasound, electromagnetic therapy, trigger point injections, botulinum toxin injections, tricyclic antidepressants, and SSRIs for acute or chronic neck pain. Some patients obtain modest pain relief using a soft neck collar; there is little risk or cost. Massage can produce temporary pain relief. For patients with chronic neck pain, supervised exercise programs can provide symptom relief and improve function. Acupuncture provided short-term benefit for some patients when compared to a sham procedure and is an option. Spinal manipulation alone has not been shown to be effective and carries a risk for injury. Surgical treatment for chronic neck pain without radiculopathy or spine instability is not recommended.

Back and Neck Pain

■■BRACHIAL PLEXUS AND NERVES

accounting for ~40% of the total global DALYs due to LBP. In general, neck pain rankings were also higher in developed regions of the world.

CHAPTER 14

in the affected limb, and signs of emboli may be present in the hand. Neurologic signs are absent. Ultrasound can confirm the diagnosis noninvasively. Treatment is with thrombolysis or anticoagulation (with or without embolectomy) and surgical excision of the cervical rib compressing the subclavian artery. Venous TOS is due to subclavian vein thrombosis resulting in swelling of the arm and pain. The vein may be compressed by a cervical rib or anomalous scalene muscle. Venography is the diagnostic test of choice. Disputed TOS accounts for 95% of patients diagnosed with TOS; chronic arm and shoulder pain are prominent and of unclear cause. The lack of sensitive and specific findings on physical examination or specific markers for this condition results in diagnostic uncertainty. The role of surgery in disputed TOS is controversial. Major depression, chronic symptoms, work-related injury, and diffuse arm symptoms predict poor surgical outcomes. Multidisciplinary pain management is a conservative approach, although treatment is often unsuccessful.

TREATMENT

Neck Pain with Radiculopathy The natural history of neck pain with acute radiculopathy due to disk disease is favorable, and many patients will improve without specific therapy. Although there are no randomized trials of NSAIDs for neck pain, a course of NSAIDs, acetaminophen, or both, with or without muscle relaxants, and avoidance of activities that trigger symptoms are reasonable as initial therapy. Gentle supervised exercise and avoidance of inactivity are reasonable as well. A short course of high dose oral glucocorticoids with a rapid taper, or epidural steroids administered under imaging guidance can be effective for acute or subacute disk-related cervical radiculopathy, but have not been subjected to rigorous trials. The risk of injection complications is higher in the neck than the low back; vertebral artery dissection, dural puncture, and embolism from injection particles in the vertebral arteries have all been reported. Opioid analgesics can be used in the emergency room and for short courses as an outpatient. Soft cervical collars can be modestly helpful by limiting spontaneous and reflex neck movements that exacerbate pain; hard collars are in general poorly tolerated. If cervical radiculopathy is due to bony compression from cervical spondylosis with foraminal narrowing, periodic follow-up to assess for progression is indicated and consideration of surgical decompression is reasonable. Surgical treatment can produce rapid pain relief, although it is unclear whether long-term outcomes are improved over nonsurgical therapy. Indications for cervical disk surgery include a progressive motor deficit due to nerve root compression, functionally limiting pain that fails to respond to conservative management, or spinal cord compression.

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Surgical treatments include anterior cervical diskectomy alone, laminectomy with diskectomy, or diskectomy with fusion. The risk of subsequent radiculopathy or myelopathy at cervical segments adjacent to a fusion is ~3% per year and 26% per decade. Although this risk is sometimes portrayed as a late complication of surgery, it may also reflect the natural history of degenerative cervical disk disease.

■■FURTHER READING

PART 2 Cardinal Manifestations and Presentation of Diseases

Agency for Healthcare Research and Quality (AHRQ): Noninvasive treatments for low back pain. AHRQ Publication No. 16-EHC004-EF. February 2016, https://effectivehealthcare.ahrq.gov/ehc/ products/553/2178/back-pain-treatment-report-160229.pdf. Benzon HT et al: Improving the safety of epidural steroid injections. JAMA 313:1713, 2015. Friedly JL et al: A randomized trial of epidural glucocorticoid injections for spinal stenosis. N Engl J Med 371:11, 2014. Goldberg H et al: Oral steroids for acute radiculopathy due to a herniated lumbar disk. JAMA 313:1915, 2015. Hoy DG et al: Reflecting on the global burden of musculoskeletal conditions: Lessons learnt from the global burden of disease 2010 study and the next steps forward. Ann Rheum Dis 74:4, 2015. Katz JN, Harris MB: Clinical practice. Lumbar spinal stenosis. N Engl J Med 358:818, 2008. Lamb SE et al: Group cognitive behavioural treatment for low-back pain in primary care: A randomised controlled trial and cost-effectiveness analysis. Lancet 375:916, 2010. Malmivaara A et al: The treatment of acute low back pain—Bed rest, exercises, or ordinary activity? N Engl J Med 332:351, 1995. Melanica J et al: Spinal stenosis. Handb Clin Neurol 109:541, 2014. Serinken M et al: Comparison of intravenous morphine versus paracetamol in sciatica: A randomized placebo controlled trial. Acad Emerg Med 23:674, 2016. Zygourakis CC et al: Geographic and hospital variation in cost of lumbar laminectomy and lumbar fusion for degenerative conditions. Neurosurgery 81:331, 2017.

Section 2  Alterations in Body Temperature

15

Fever

Charles A. Dinarello, Reuven Porat

Body temperature is controlled by the hypothalamus. Neurons in both the preoptic anterior hypothalamus and the posterior hypothalamus receive two kinds of signals: one from peripheral nerves that transmit information from warmth/cold receptors in the skin and the other from the temperature of the blood bathing the region. These two types of signals are integrated by the thermoregulatory center of the hypothalamus to maintain normal temperature. In a neutral temperature environment, the human metabolic rate produces more heat than is necessary to maintain the core body temperature in the range of 36.5–37.5°C (97.7–99.5°F). A normal body temperature is ordinarily maintained despite environmental variations because the hypothalamic thermoregulatory center balances the excess heat production derived from metabolic activity in muscle and the liver with heat dissipation from the skin and lungs. According to studies of healthy individuals 18–40 years of age, the mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F), with low levels at 6 a.m. and higher levels at 4–6 p.m. The maximal normal oral temperature is 37.2°C (98.9°F) at 6 a.m. and 37.7°C (99.9°F) at 4 p.m.; these values define the 99th percentile for healthy individuals. In

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light of these studies, an a.m. temperature of >37.2°C (>98.9°F) or a p.m. temperature of >37.7°C (>99.9°F) would define a fever. The normal daily temperature variation, also called the circadian rhythm, is typically 0.5°C (0.9°F). However, in some individuals recovering from a febrile illness, this daily variation can be as great as 1.0°C. During a febrile illness, the diurnal variation is usually maintained, but at higher, febrile levels. The daily temperature variation appears to be fixed in early childhood; in contrast, elderly individuals can exhibit a reduced ability to develop fever, with only a modest fever even in severe infections. Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings. The lower oral readings are probably attributable to mouth breathing, which is a factor in patients with respiratory infections and rapid breathing. Lower-esophageal temperatures closely reflect core temperature. Tympanic membrane thermometers measure radiant heat from the tympanic membrane and nearby ear canal and display that absolute value (unadjusted mode) or a value automatically calculated from the absolute reading on the basis of nomograms relating the radiant temperature measured to actual core temperatures obtained in clinical studies (adjusted mode). These measurements, although convenient, may be more variable than directly determined oral or rectal values. Studies in adults show that readings are lower with unadjusted-mode than with adjusted-mode tympanic membrane thermometers and that unadjusted-mode tympanic membrane values are 0.8°C (1.6°F) lower than rectal temperatures. In women who menstruate, the a.m. temperature is generally lower during the 2 weeks before ovulation; it then rises by ~0.6°C (1°F) with ovulation and stays at that level until menses occur. During the luteal phase, the amplitude of the circadian rhythm remains the same.

FEVER VERSUS HYPERTHERMIA

Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point (e.g., from 37°C to 39°C). This shift of the set point from “normothermic” to febrile levels very much resembles the resetting of the home thermostat to a higher level in order to raise the ambient temperature in a room. Once the hypothalamic set point is raised, neurons in the vasomotor center are activated and vasoconstriction commences. The individual first notices vasoconstriction in the hands and feet. Shunting of blood away from the periphery to the internal organs essentially decreases heat loss from the skin, and the person feels cold. For most fevers, body temperature increases by 1–2°C. Shivering, which increases heat production from the muscles, may begin at this time; however, shivering is not required if mechanisms of heat conservation raise blood temperature sufficiently. Nonshivering heat production from the liver also contributes to increasing core temperature. Behavioral adjustments (e.g., putting on more clothing or bedding) help raise body temperature by decreasing heat loss. The processes of heat conservation (vasoconstriction) and heat production (shivering and increased nonshivering thermogenesis) continue until the temperature of the blood bathing the hypothalamic neurons matches the new “thermostat setting.” Once that point is reached, the hypothalamus maintains the temperature at the febrile level by the same mechanisms of heat balance that function in the afebrile state. When the hypothalamic set point is again reset downward (in response to either a reduction in the concentration of pyrogens or the use of antipyretics), the processes of heat loss through vasodilation and sweating are initiated. Loss of heat by sweating and vasodilation continues until the blood temperature at the hypothalamic level matches the lower setting. Behavioral changes (e.g., removal of clothing) facilitate heat loss. A fever of >41.5°C (>106.7°F) is called hyperpyrexia. This extraordinarily high fever can develop in patients with severe infections but most commonly occurs in patients with central nervous system (CNS) hemorrhages. In the preantibiotic era, fever due to a variety of infectious diseases rarely exceeded 106°F, and there has been speculation that this natural “thermal ceiling” is mediated by neuropeptides functioning as central antipyretics. In rare cases, the hypothalamic set point is elevated as a result of local trauma, hemorrhage, tumor, or intrinsic hypothalamic malfunction. The term hypothalamic fever is sometimes used to describe elevated

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■■PYROGENS

The term pyrogen (Greek pyro, “fire”) is used to describe any substance that causes fever. Exogenous pyrogens are derived from outside the patient; most are microbial products, microbial toxins, or whole microorganisms (including viruses). The classic example of an exogenous pyrogen is the lipopolysaccharide (endotoxin) produced by all gram-negative bacteria. Pyrogenic products of gram-positive organisms include the enterotoxins of Staphylococcus aureus and the groups A and B streptococcal toxins, also called superantigens. One staphylococcal toxin of clinical importance is that associated with isolates of S. aureus from patients with toxic shock syndrome. These products of staphylococci and streptococci cause fever in experimental animals when injected intravenously at concentrations of 1–10 μg/kg. Endotoxin is a highly pyrogenic molecule in humans: when injected intravenously into volunteers, a dose of 2–3 ng/kg produces fever, leukocytosis, acute-phase proteins, and generalized symptoms of malaise.

■■PYROGENIC CYTOKINES

Cytokines are small proteins (molecular mass, 10,000–20,000 Da) that regulate immune, inflammatory, and hematopoietic processes. For example, the elevated leukocytosis seen in several infections with an absolute neutrophilia is attributable to the cytokines interleukin (IL) 1 and IL-6. Some cytokines also cause fever; formerly referred to as endogenous pyrogens, they are now called pyrogenic cytokines. The pyrogenic cytokines include IL-1, IL-6, tumor necrosis factor (TNF), and ciliary neurotropic factor, a member of the IL-6 family. Fever is a prominent side effect of interferon α therapy. Each pyrogenic cytokine is encoded by a separate gene, and each has been shown to cause fever in laboratory animals and in humans. When injected into humans at low doses (10–100 ng/kg), IL-1 and TNF produce fever; in contrast, for IL-6, a dose of 1–10 μg/kg is required for fever production. A wide spectrum of bacterial and fungal products induce the synthesis and release of pyrogenic cytokines. However, fever can be a manifestation of disease in the absence of microbial infection. For example, inflammatory processes such as pericarditis, trauma, stroke, and routine immunizations induce the production of IL-1, TNF, and/or

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■■ELEVATION OF THE HYPOTHALAMIC SET POINT BY CYTOKINES

During fever, levels of prostaglandin E2 (PGE2) are elevated in hypothalamic tissue and the third cerebral ventricle. The concentrations of PGE2 are highest near the circumventricular vascular organs (organum vasculosum of lamina terminalis)—networks of enlarged capillaries surrounding the hypothalamic regulatory centers. Destruction of these organs reduces the ability of pyrogens to produce fever. Most studies in animals have failed to show, however, that pyrogenic cytokines pass from the circulation into the brain itself. Thus, it appears that both exogenous pyrogens and pyrogenic cytokines interact with the endothelium of these capillaries and that this interaction is the first step in initiating fever—i.e., in raising the set point to febrile levels. The key events in the production of fever are illustrated in Fig. 15-1. Myeloid and endothelial cells are the primary cell types that produce pyrogenic cytokines. Pyrogenic cytokines such as IL-1, IL-6, and TNF are released from these cells and enter the systemic circulation. Although these circulating cytokines lead to fever by inducing the synthesis of PGE2, they also induce PGE2 in peripheral tissues. The increase in PGE2 in the periphery accounts for the nonspecific myalgias and arthralgias that often accompany fever. It is thought that some systemic PGE2 escapes destruction by the lung and gains access to the hypothalamus via the internal carotid. However, it is the elevation of PGE2 in the brain that starts the process of raising the hypothalamic set point for core temperature. There are four receptors for PGE2, and each signals the cell in different ways. Of the four receptors, the third (EP-3) is essential for fever: when the gene for this receptor is deleted in mice, no fever follows the injection of IL-1 or endotoxin. Deletion of the other PGE2 receptor genes leaves the fever mechanism intact. Although PGE2 is essential for fever, it is not a neurotransmitter. Rather, the release of PGE2 from the brain side of the hypothalamic endothelium triggers the PGE2 receptor on glial cells, and this stimulation results in the rapid release of cyclic adenosine 5′-monophosphate (cAMP), which is a neurotransmitter. As shown in Fig. 15-1, the release of cAMP from glial cells activates neuronal endings from the thermoregulatory center that extend into the area. The elevation of cAMP is thought to account for changes in the hypothalamic set point either directly or indirectly (by inducing the release of neurotransmitters). Distinct receptors for microbial products are located on the hypothalamic endothelium. These receptors are called Toll-like receptors and are similar in many ways to IL-1 receptors. IL-1 receptors and Toll-like receptors share the same signal-transducing mechanism. Thus, the direct activation of Toll-like receptors or IL-1 receptors results in PGE2 production and fever. Infection, microbial toxins, mediators of inflammation, immune reactions

Microbial toxins

Fever

PATHOGENESIS OF FEVER

IL-6; individually or in combination, these cytokines trigger the hypothalamus to raise the set point to febrile levels.

CHAPTER 15

temperature caused by abnormal hypothalamic function. However, most patients with hypothalamic damage have subnormal, not supranormal, body temperatures. Although most patients with elevated body temperature have fever, there are circumstances in which elevated temperature represents not fever but hyperthermia (heat stroke). Hyperthermia is characterized by an uncontrolled increase in body temperature that exceeds the body’s ability to lose heat. The setting of the hypothalamic thermoregulatory center is unchanged. In contrast to fever in infections, hyperthermia does not involve pyrogenic molecules. Exogenous heat exposure and endogenous heat production are two mechanisms by which hyperthermia can result in dangerously high internal temperatures. Excessive heat production can easily cause hyperthermia despite physiologic and behavioral control of body temperature. For example, work or exercise in hot environments can produce heat faster than peripheral mechanisms can lose it. For a detailed discussion of hyperthermia, see Chap. 455. It is important to distinguish between fever and hyperthermia since hyperthermia can be rapidly fatal and characteristically does not respond to antipyretics. In an emergency situation, however, making this distinction can be difficult. For example, in systemic sepsis, fever (hyperpyrexia) can be rapid in onset, and temperatures can exceed 40.5°C (104.9°F). Hyperthermia is often diagnosed on the basis of the events immediately preceding the elevation of core temperature—e.g., heat exposure or treatment with drugs that interfere with thermoregulation. In patients with heat stroke syndromes and in those taking drugs that block sweating, the skin is hot but dry, whereas in fever the skin can be cold as a consequence of vasoconstriction. Antipyretics do not reduce the elevated temperature in hyperthermia, whereas in fever—and even in hyperpyrexia—adequate doses of either aspirin or acetaminophen usually result in some decrease in body temperature.

Fever Heat conservation, heat production

Monocytes/macrophages, endothelial cells, others

Cyclic AMP PGE2

Pyrogenic cytokines IL-1, IL-6, TNF, IFN

Elevated thermoregulatory set point

Hypothalamic endothelium

Circulation

FIGURE 15-1  Chronology of events required for the induction of fever. AMP, adenosine 5′-monophosphate; IFN, interferon; IL, interleukin; PGE2, prostaglandin E2; TNF, tumor necrosis factor.

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■■PRODUCTION OF CYTOKINES IN THE CNS

TREATMENT

Cytokines produced in the brain may account for the hyperpyrexia of CNS hemorrhage, trauma, or infection. Viral infections of the CNS induce microglial and possibly neuronal production of IL-1, TNF, and IL-6. In experimental animals, the concentration of a cytokine required to cause fever is several orders of magnitude lower with direct injection into the brain substance or brain ventricles than with systemic injection. Therefore, cytokines produced in the CNS can raise the hypothalamic set point, bypassing the circumventricular organs. CNS cytokines likely account for the hyperpyrexia of CNS hemorrhage, trauma, or infection.

Fever

PART 2 Cardinal Manifestations and Presentation of Diseases

THE DECISION TO TREAT FEVER Most fevers are associated with self-limited infections, such as common viral diseases. The use of antipyretics is not contraindicated in these infections: no significant clinical evidence indicates either that antipyretics delay the resolution of viral or bacterial infections or that fever facilitates recovery from infection or acts as an adjuvant to the immune system. In short, treatment of fever and its symptoms with routine antipyretics does no harm and does not slow the resolution of common viral and bacterial infections. However, in bacterial infections, the withholding of antipyretic therapy can be helpful in evaluating the effectiveness of a particular antibiotic, especially in the absence of positive cultures of the infecting organism, and the routine use of antipyretics can mask an inadequately treated bacterial infection. Withholding antipyretics in some cases may facilitate the diagnosis of an unusual febrile disease. Temperature–pulse dissociation (relative bradycardia) occurs in typhoid fever, brucellosis, leptospirosis, some drug-induced fevers, and factitious fever. As stated earlier, in newborns, elderly patients, patients with chronic liver or kidney failure, and patients taking glucocorticoids, fever may not be present despite infection. Hypothermia can develop in patients with septic shock. Some infections have characteristic patterns in which febrile episodes are separated by intervals of normal temperature. For example, Plasmodium vivax causes fever every third day, whereas fever occurs every fourth day with Plasmodium malariae. Another relapsing fever is related to Borrelia infection, with days of fever followed by a several-day afebrile period and then a relapse into additional days of fever. In the Pel-Ebstein pattern, fever lasting 3–10 days is followed by afebrile periods of 3–10 days; this pattern can be classic for Hodgkin’s disease and other lymphomas. In cyclic neutropenia, fevers occur every 21 days and accompany the neutropenia. There is no periodicity of fever in patients with familial Mediterranean fever. However, these patterns have limited or no diagnostic value compared with specific and rapid laboratory tests.

APPROACH TO THE PATIENT

Fever PHYSICAL EXAMINATION The chronology of events preceding fever, including exposure to other infected individuals or to vectors of disease, should be ascertained. Electronic devices for measuring oral, tympanic membrane, or rectal temperatures are reliable, but the same site should be used consistently to monitor a febrile disease. Moreover, physicians should be aware that newborns, elderly patients, patients with chronic hepatic or renal failure, and patients taking glucocorticoids or being treated with an anticytokine may have active infection in the absence of fever because of a blunted febrile response. LABORATORY TESTS The workup should include a complete blood count; a differential count should be performed manually or with an instrument sensitive to the identification of juvenile or band forms, toxic granulations, and Döhle bodies, which are suggestive of bacterial infection. Neutropenia may be present with some viral infections. Measurement of circulating cytokines in patients with fever is not helpful since levels of cytokines such as IL-1 and TNF in the circulation often are below the detection limit of the assay or do not coincide with fever. However, in patients with low-grade fevers or with suspected occult disease, the most valuable measurements are the C-reactive protein (CRP) level and the erythrocyte sedimentation rate. These markers of inflammatory processes are particularly helpful in detecting occult disease. Measurement of circulating IL-6, which induces CRP, can be useful. However, whereas IL-6 levels may vary during a febrile disease, CRP levels remain elevated. Acute-phase reactants are discussed in Chap. 297. FEVER IN PATIENTS RECEIVING ANTICYTOKINE THERAPY Patients receiving long-term treatment with anticytokine-based regimens are at increased risk of infection because of lowered host defenses. For example, latent Mycobacterium tuberculosis infection can disseminate in patients receiving anti-TNF therapy. With the increasing use of anticytokines to reduce the activity of IL-1, IL-6, IL-12, IL-17, or TNF in patients with Crohn’s disease, rheumatoid arthritis, or psoriasis, the possibility that these therapies blunt the febrile response should be kept in mind. The blocking of cytokine activity has the distinct clinical drawback of lowering the level of host defenses against both routine bacterial and opportunistic infections such as M. tuberculosis and fungal infections. The use of monoclonal antibodies to reduce IL-17 in psoriasis increases the risk of systemic candidiasis. In nearly all reported cases of infection associated with anticytokine therapy, fever is among the presenting signs. However, the extent to which the febrile response is blunted in these patients remains unknown. Therefore, low-grade fever in patients receiving anticytokine therapies is of considerable concern. The physician should conduct an early and rigorous diagnostic evaluation in these cases. The febrile response is also blunted in patients receiving chronic glucocorticoid therapy or anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (NSAIDs).

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ANTICYTOKINE THERAPY TO REDUCE FEVER IN AUTOIMMUNE AND AUTOINFLAMMATORY DISEASES Recurrent fever is documented at some point in most autoimmune diseases and nearly all autoinflammatory diseases. Although fever can be a manifestation of autoimmune diseases, recurrent fevers are characteristic of autoinflammatory diseases (Table 15-1), including uncommon diseases such as adult and juvenile Still’s disease, familial Mediterranean fever, and hyper-IgD syndrome but also common diseases such as idiopathic pericarditis and gout. In addition to recurrent fevers, neutrophilia and serosal inflammation characterize autoinflammatory diseases. The fevers associated with these illnesses are dramatically reduced by blocking of IL-1 activity with anakinra or canakinumab. Anticytokines therefore reduce fever in TABLE 15-1  Autoinflammatory Diseases in Which Fever Is Characteristic Adult and juvenile Still’s disease Cryopyrin-associated periodic syndromes (CAPS) Familial Mediterranean fever Hyper-IgD syndrome Behçet’s syndrome Macrophage activation syndrome Normocomplementemic urticarial vasculitis Antisynthetase myositis PAPAa syndrome Blau syndrome Gouty arthritis a

Pyogenic arthritis, pyoderma gangrenosum, and acne.

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autoimmune and autoinflammatory diseases. Although fevers in autoinflammatory diseases are mediated by IL-1β, patients also respond to antipyretics.

■■FURTHER READING

Dinarello CA et al: Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nature Rev 11:633, 2012. Kullenberg T et al: Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology 55:1499, 2016.

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Elaine T. Kaye, Kenneth M. Kaye

The acutely ill patient with fever and rash often presents a diagnostic challenge for physicians, yet the distinctive appearance of an eruption in concert with a clinical syndrome can facilitate a prompt diagnosis and the institution of life-saving therapy or critical infection-control interventions. Representative images of many of the rashes discussed in this chapter are included in Chap. A1.

APPROACH TO THE PATIENT

Fever and Rash A thorough history of patients with fever and rash includes the following relevant information: immune status, medications taken within the previous month, specific travel history, immunization status, exposure to domestic pets and other animals, history of animal (including arthropod) bites, recent dietary exposures, existence of cardiac abnormalities, presence of prosthetic material, recent exposure to ill individuals, and sexual exposures. The history should also include the site of onset of the rash and its direction and rate of spread. A thorough physical examination entails close attention to the rash, with an assessment and precise definition of its salient features. First, it is critical to determine what type of lesions make up the eruption. Macules are flat lesions defined by an area of changed color (i.e., a blanchable erythema). Papules are raised, solid lesions 5 mm in diameter with a flat, plateau-like surface; and nodules are lesions >5 mm in diameter with a more rounded configuration. Wheals (urticaria, hives) are papules or plaques that are pale pink and may appear annular (ringlike) as they enlarge; classic (nonvasculitic) wheals are transient, lasting only 24 h in any defined area. Vesicles (5 mm) are circumscribed, elevated lesions containing fluid. Pustules are raised lesions containing purulent exudate; vesicular processes such as varicella or herpes simplex may evolve to pustules. Nonpalpable purpura is a flat lesion that is due to bleeding into the skin. If 3 mm, they are termed ecchymoses. Palpable purpura is a raised lesion that is due to inflammation of the vessel wall (vasculitis) with subsequent hemorrhage. An ulcer is a defect in the skin extending at least into the upper layer of the dermis, and an eschar (tâche noire) is a necrotic lesion covered with a black crust. Other pertinent features of rashes include their configuration (i.e., annular or target), the arrangement of their lesions, and their distribution (i.e., central or peripheral). For further discussion, see Chaps. 52, 54, 117, and 124.

Fever and Rash

REGIMENS FOR THE TREATMENT OF FEVER The objectives in treating fever are first to reduce the elevated hypothalamic set point and second to facilitate heat loss. Reducing fever with antipyretics also reduces systemic symptoms of headache, myalgias, and arthralgias. Oral aspirin and NSAIDs effectively reduce fever but can adversely affect platelets and the gastrointestinal tract. Therefore, acetaminophen is preferred as an antipyretic. In children, acetaminophen or oral ibuprofen must be used because aspirin increases the risk of Reye’s syndrome. If the patient cannot take oral antipyretics, parenteral preparations of NSAIDs and rectal suppositories of various antipyretics can be used. Treatment of fever in some patients is highly recommended. Fever increases the demand for oxygen (i.e., for every increase of 1°C over 37°C, there is a 13% increase in oxygen consumption) and can aggravate the condition of patients with preexisting impairment of cardiac, pulmonary, or CNS function. Children with a history of febrile or nonfebrile seizure should be aggressively treated to reduce fever. However, it is unclear what triggers the febrile seizure, and there is no correlation between absolute temperature elevation and onset of a febrile seizure in susceptible children. In hyperpyrexia, the use of cooling blankets facilitates the reduction of temperature; however, cooling blankets should not be used without oral antipyretics. In hyperpyretic patients with CNS disease or trauma (CNS bleeding), reducing core temperature mitigates the detrimental effects of high temperature on the brain. For a discussion of treatment for hyperthermia, see Chap. 455.

Fever and Rash

CHAPTER 16

MECHANISMS OF ANTIPYRETIC AGENTS The reduction of fever by lowering of the elevated hypothalamic set point is a direct function of reduction of the PGE2 level in the thermoregulatory center. The synthesis of PGE2 depends on the constitutively expressed enzyme cyclooxygenase. The substrate for cyclooxygenase is arachidonic acid released from the cell membrane, and this release is the rate-limiting step in the synthesis of PGE2. Therefore, inhibitors of cyclooxygenase are potent antipyretics. The antipyretic potency of various drugs is directly correlated with the inhibition of brain cyclooxygenase. Acetaminophen is a poor cyclooxygenase inhibitor in peripheral tissue and lacks noteworthy anti-inflammatory activity; in the brain, however, acetaminophen is oxidized by the p450 cytochrome system, and the oxidized form inhibits cyclooxygenase activity. Moreover, in the brain, the inhibition of another enzyme, COX-3, by acetaminophen may account for the antipyretic effect of this agent. However, COX-3 is not found outside the CNS. Oral aspirin and acetaminophen are equally effective in reducing fever in humans. NSAIDs such as ibuprofen and specific inhibitors of COX-2 also are excellent antipyretics. Chronic, high-dose therapy with antipyretics such as aspirin or any NSAID does not reduce normal core body temperature. Thus, PGE2 appears to play no role in normal thermoregulation. As effective antipyretics, glucocorticoids act at two levels. First, similar to the cyclooxygenase inhibitors, glucocorticoids reduce PGE2 synthesis by inhibiting the activity of phospholipase A2, which is needed to release arachidonic acid from the cell membrane. Second, glucocorticoids block the transcription of the mRNA for the pyrogenic cytokines. Limited experimental evidence indicates that ibuprofen and COX-2 inhibitors reduce IL-1-induced IL-6 production and may contribute to the antipyretic activity of NSAIDs.

16

105

■■CLASSIFICATION OF RASH

This chapter reviews rashes that reflect systemic disease, but it does not include localized skin eruptions (i.e., cellulitis, impetigo) that may also be associated with fever (Chap. 124). The chapter is not intended to be all-inclusive, but it covers the most important and most common diseases associated with fever and rash. Rashes are classified herein on the basis of lesion morphology and distribution. For practical purposes, this classification system is based on the most typical disease presentations. However, morphology may vary as rashes evolve, and the presentation of diseases with rashes is subject to many variations (Chap. 54). For instance, the classic petechial rash of Rocky Mountain spotted fever (Chap. 182) may initially consist of blanchable erythematous macules distributed peripherally; at times, however, the rash associated with this disease may not be predominantly acral, or no rash may develop at all.

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106

Diseases with fever and rash may be classified by type of eruption: centrally distributed maculopapular, peripheral, confluent desquamative erythematous, vesiculobullous, urticaria-like, nodular, purpuric, ulcerated, or with eschars. Diseases are listed by these categories in Table 16-1, and many are highlighted in the text. However, for a more detailed discussion of each disease associated with a rash, the reader is referred to the chapter dealing with that specific disease. (Reference chapters are cited in the text and listed in Table 16-1.)

■■CENTRALLY DISTRIBUTED MACULOPAPULAR ERUPTIONS PART 2 Cardinal Manifestations and Presentation of Diseases

Centrally distributed rashes, in which lesions are primarily truncal, are the most common type of eruption. The rash of rubeola (measles) starts at the hairline 2–3 days into the illness and moves down the body, typically sparing the palms and soles (Chap. 200). It begins as discrete erythematous lesions, which become confluent as the rash spreads. Koplik’s spots (1- to 2-mm white or bluish lesions with an erythematous halo on the buccal mucosa) are pathognomonic for measles and are generally seen during the first 2 days of symptoms. They should not be confused with Fordyce’s spots (ectopic sebaceous glands), which have no erythematous halos and are found in the mouth of healthy individuals. Koplik’s spots may briefly overlap with the measles exanthem. Rubella (German measles) also spreads from the hairline downward; unlike that of measles, however, the rash of rubella tends to clear from originally affected areas as it migrates, and it may be pruritic (Chap. 201). Forchheimer spots (palatal petechiae) may develop but are nonspecific because they also develop in infectious mononucleosis (Chap. 189), scarlet fever (Chap. 143), and Zika virus infection (Chap. 204). Postauricular and suboccipital adenopathy and arthritis are common among adults with rubella. Exposure of pregnant women to ill individuals should be avoided, as rubella causes severe congenital abnormalities. Numerous strains of enteroviruses (Chap. 199), primarily echoviruses and coxsackieviruses, cause nonspecific syndromes of fever and eruptions that may mimic rubella or measles. Patients with infectious mononucleosis caused by Epstein-Barr virus (Chap. 189) or with primary HIV infection (Chap. 197) may exhibit pharyngitis, lymphadenopathy, and a nonspecific maculopapular exanthem. The rash of erythema infectiosum (fifth disease), which is caused by human parvovirus B19, primarily affects children 3–12 years old; it develops after fever has resolved as a bright blanchable erythema on the cheeks (“slapped cheeks”) with perioral pallor (Chap. 192). A more diffuse rash (often pruritic) appears the next day on the trunk and extremities and then rapidly develops into a lacy reticular eruption that may wax and wane (especially with temperature change) over 3 weeks. Adults with fifth disease often have arthritis, and fetal hydrops can develop in association with this condition in pregnant women. Exanthem subitum (roseola) is caused by human herpesvirus 6 and is most common among children 5 min (from 60 to 360 s) of an upright tilt on a tilt table. B. The same tracing expanded to show 80 s of the episode (from 80 to 200 s). BP, blood pressure; bpm, beats per minute; HR, heart rate.

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126

TABLE 18-2  Causes of Syncope A.  Neurally Mediated Syncope

PART 2 Cardinal Manifestations and Presentation of Diseases

  Vasovagal syncope   Provoked fear, pain, anxiety, intense emotion, sight of blood, unpleasant sights and odors, orthostatic stress   Situational reflex syncope   Pulmonary    Cough syncope, wind instrument player’s syncope, weightlifter’s syncope, “mess trick”a and “fainting lark,”b sneeze syncope, airway instrumentation   Urogenital    Postmicturition syncope, urogenital tract instrumentation, prostatic massage   Gastrointestinal    Swallow syncope, glossopharyngeal neuralgia, esophageal stimulation, gastrointestinal tract instrumentation, rectal examination, defecation syncope   Cardiac     Bezold-Jarisch reflex, cardiac outflow obstruction   Carotid sinus     Carotid sinus sensitivity, carotid sinus massage   Ocular     Ocular pressure, ocular examination, ocular surgery B.  Orthostatic Hypotension  Primary autonomic failure due to idiopathic central and peripheral neurodegenerative diseases—the “synucleinopathies”    Lewy body diseases    Parkinson’s disease    Lewy body dementia    Pure autonomic failure    Multiple system atrophy (Shy-Drager syndrome)   Secondary autonomic failure due to autonomic peripheral neuropathies   Diabetes    Hereditary amyloidosis (familial amyloid polyneuropathy)   Primary amyloidosis (AL amyloidosis; immunoglobulin light chain associated)   Hereditary sensory and autonomic neuropathies (HSAN) (especially type III—familial dysautonomia)    Idiopathic immune-mediated autonomic neuropathy    Autoimmune autonomic ganglionopathy   Sjögren’s syndrome    Paraneoplastic autonomic neuropathy   HIV neuropathy   Postprandial hypotension   Iatrogenic (drug-induced)   Volume depletion C. Cardiac Syncope  Arrhythmias    Sinus node dysfunction   Atrioventricular dysfunction   Supraventricular tachycardias   Ventricular tachycardias   Inherited channelopathies   Cardiac structural disease   Valvular disease   Myocardial ischemia    Obstructive and other cardiomyopathies   Atrial myxoma    Pericardial effusions and tamponade a Hyperventilation for ~1 min, followed by sudden chest compression. bHyperventilation (~20 breaths) in a squatting position, rapid rise to standing, then Valsalva.

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■■ORTHOSTATIC HYPOTENSION

Orthostatic hypotension, defined as a reduction in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 min of standing or head-up tilt on a tilt table, is a manifestation of sympathetic vasoconstrictor (autonomic) failure (Fig. 18-4). In many (but not all) cases, there is no compensatory increase in heart rate despite hypotension; with partial autonomic failure, heart rate may increase to some degree but is insufficient to maintain cardiac output. A variant of orthostatic hypotension is “delayed” orthostatic hypotension, which occurs beyond 3 min of standing; this may reflect a mild or early form of sympathetic adrenergic dysfunction. In some cases, orthostatic hypotension occurs within 15 s of standing (so-called “initial” orthostatic hypotension), a finding that may reflect a transient mismatch between cardiac output and peripheral vascular resistance and does not represent autonomic failure. Characteristic symptoms of orthostatic hypotension include light-headedness, dizziness, and presyncope (near-faintness) occurring in response to sudden postural change. However, symptoms may be absent or nonspecific, such as generalized weakness, fatigue, cognitive slowing, leg buckling, or headache. Visual blurring may occur, likely due to retinal or occipital lobe ischemia. Neck pain, typically in the suboccipital, posterior cervical, and shoulder region (the “coat-hanger headache”), most likely due to neck muscle ischemia, may be the only symptom. Patients may report orthostatic dyspnea (thought to reflect ventilation-perfusion mismatch due to inadequate perfusion of ventilated lung apices) or angina (attributed to impaired myocardial perfusion even with normal coronary arteries). Symptoms may be exacerbated by exertion, prolonged standing, increased ambient temperature, or meals. Syncope is usually preceded by warning symptoms, but may occur suddenly, suggesting the possibility of a seizure or cardiac cause. Supine hypertension is common in patients with orthostatic hypotension due to autonomic failure, affecting >50% of patients in some series. Orthostatic hypotension may present after initiation of therapy for hypertension, and supine hypertension may follow treatment of orthostatic hypotension. However, in other cases, the association of the two conditions is unrelated to therapy; it may in part be explained by baroreflex dysfunction in the presence of residual sympathetic outflow, particularly in patients with central autonomic degeneration.

Causes of Neurogenic Orthostatic Hypotension  Causes

of neurogenic orthostatic hypotension include central and peripheral autonomic nervous system dysfunction (Chap. 432). Autonomic dysfunction of other organ systems (including the bladder, bowels, sexual organs, and sudomotor system) of varying severity frequently accompanies orthostatic hypotension in these disorders (Table 18-2). The primary autonomic degenerative disorders are multiple system atrophy (Shy-Drager syndrome; Chap. 432), Parkinson’s disease (Chap. 427), dementia with Lewy bodies (Chap. 426), and pure autonomic failure (Chap. 432). These are often grouped together as “synucleinopathies” due to the presence of α-synuclein, a small protein that aggregates predominantly in the cytoplasm of neurons in the Lewy body disorders (Parkinson’s disease, dementia with Lewy bodies, and pure autonomic failure) and in the glia in multiple system atrophy. Peripheral autonomic dysfunction may also accompany smallfiber peripheral neuropathies such as those seen in diabetes mellitus, amyloid, immune-mediated neuropathies, hereditary sensory and autonomic neuropathies (HSAN; particularly HSAN type III, familial dysautonomia) (Chaps. 438 and 439). Less frequently, orthostatic hypotension is associated with the peripheral neuropathies that accompany vitamin B12 deficiency, neurotoxic exposure, HIV and other infections, and porphyria. Patients with autonomic failure and the elderly are susceptible to falls in blood pressure associated with meals. The magnitude of the blood pressure fall is exacerbated by large meals, meals high in carbohydrate, and alcohol intake. The mechanism of postprandial syncope is not fully elucidated.

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pause following the termination of a 127 tachycardic episode is a frequent cause of syncope in patients with the tachy72 cardia-bradycardia syndrome. Medications of several classes may also cause 70 bradyarrhythmias of sufficient severity 70 to cause syncope. Syncope due to bradycardia or asystole is referred to as a Stokes-Adams attack. 65 68 Ventricular tachyarrhythmias frequently cause syncope. The likelihood 200 180 of syncope with ventricular tachycardia is in part dependent on the ventricu150 150 lar rate; rates 5 min (from 60 to include the long QT syndrome, Brugada 360 s) of an upright tilt on a tilt table. B. The same tracing expanded to show 40 s of the episode (from 180 to 220 s). syndrome, and catecholaminergic polyBP, blood pressure; bpm, beats per minute; HR, heart rate. morphic ventricular tachycardia. The long QT syndrome is a genetically hetOrthostatic hypotension is often iatrogenic. Drugs from several erogeneous disorder associated with prolonged cardiac repolarization classes may lower peripheral resistance (e.g., α-adrenoreceptor antago- and a predisposition to ventricular arrhythmias. Syncope and sudden nists used to treat hypertension and prostatic hypertrophy; antihyper- death in patients with long QT syndrome result from a unique polytensive agents of several classes; nitrates and other vasodilators; tricyclic morphic ventricular tachycardia called torsades des pointes that degeneragents and phenothiazines). Iatrogenic volume depletion due to diuresis ates into ventricular fibrillation. The long QT syndrome has been linked and volume depletion due to medical causes (hemorrhage, vomiting, to genes encoding K+ channel α-subunits, K+ channel β-subunits, voltdiarrhea, or decreased fluid intake) may also result in decreased effec- age-gated Na+ channel, and a scaffolding protein, ankyrin B (ANK2). tive circulatory volume, orthostatic hypotension, and syncope. Brugada syndrome is characterized by idiopathic ventricular fibrillation in association with right ventricular electrocardiogram (ECG) abnormalities without structural heart disease. This disorder is also genetiTREATMENT cally heterogeneous, although it is most frequently linked to mutations Orthostatic Hypotension in the Na+ channel α-subunit, SCN5A. Catecholaminergic polymorphic tachycardia is an inherited, genetically heterogeneous disorder associThe first step is to remove reversible causes—usually vasoactive ated with exercise- or stress-induced ventricular arrhythmias, syncope, medications (Table 432-6). Next, nonpharmacologic interventions or sudden death. Acquired QT interval prolongation, most commonly should be introduced. These interventions include patient education due to drugs, may also result in ventricular arrhythmias and syncope. regarding staged moves from supine to upright; warnings about the These disorders are discussed in detail in Chap. 249. hypotensive effects of large meals; instructions about the isometric counterpressure maneuvers that increase intravascular pressure (see Structural Disease  Structural heart disease (e.g., valvular disabove); and raising the head of the bed to reduce supine hyperease, myocardial ischemia, hypertrophic and other cardiomyopathies, tension. Intravascular volume should be expanded by increasing cardiac masses such as atrial myxoma, and pericardial effusions) may dietary fluid and salt. If these nonpharmacologic measures fail, lead to syncope by compromising cardiac output. Structural disease pharmacologic intervention with fludrocortisone acetate and vasomay also contribute to other pathophysiologic mechanisms of syncope. constricting agents such as midodrine, l-dihydroxyphenylserine, For example, cardiac structural disease may predispose to arrhythmoand pseudoephedrine should be introduced. Some patients with genesis; aggressive treatment of cardiac failure with diuretics and/or intractable symptoms require additional therapy with supplemenvasodilators may lead to orthostatic hypotension; and inappropriate tary agents that include pyridostigmine, atomoxetine, yohimbine, reflex vasodilation may occur with structural disorders such as aortic desmopressin acetate (DDAVP), and erythropoietin (Chap. 432). stenosis and hypertrophic cardiomyopathy, possibly provoked by HR (bpm)

BP (mm Hg)

Cardiac (or cardiovascular) syncope is caused by arrhythmias and structural heart disease. These may occur in combination because structural disease renders the heart more vulnerable to abnormal electrical activity.

Arrhythmias  Bradyarrhythmias that cause syncope include those

due to severe sinus node dysfunction (e.g., sinus arrest or sinoatrial block) and atrioventricular (AV) block (e.g., Mobitz type II, high-grade, and complete AV block). The bradyarrhythmias due to sinus node dysfunction are often associated with an atrial tachyarrhythmia, a disorder known as the tachycardia-bradycardia syndrome. A prolonged

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Syncope

■■CARDIAC SYNCOPE

CHAPTER 18

HR (bpm)

74

BP (mm Hg)

75

increased ventricular contractility.

TREATMENT

Cardiac Syncope Treatment of cardiac disease depends on the underlying disorder. Therapies for arrhythmias include cardiac pacing for sinus node disease and AV block, and ablation, antiarrhythmic drugs, and cardioverter-defibrillators for atrial and ventricular tachyarrhythmias. These disorders are best managed by physicians with specialized skills in this area.

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128

APPROACH TO THE PATIENT

Syncope

PART 2 Cardinal Manifestations and Presentation of Diseases

DIFFERENTIAL DIAGNOSIS Syncope is easily diagnosed when the characteristic features are present; however, several disorders with transient real or apparent loss of consciousness may create diagnostic confusion. Generalized and partial seizures may be confused with syncope; however, there are a number of differentiating features. Whereas tonic-clonic movements are the hallmark of a generalized seizure, myoclonic and other movements also may occur in up to 90% of syncopal episodes. Myoclonic jerks associated with syncope may be multifocal or generalized. They are typically arrhythmic and of short duration (5 min and is associated with prolonged postictal drowsiness and disorientation, whereas reorientation occurs almost immediately after a syncopal event. Muscle aches may occur after both syncope and seizures, although they tend to last longer and be more severe following a seizure. Seizures, unlike syncope, are rarely provoked by emotions or pain. Incontinence of urine may occur with both seizures and syncope; however, fecal incontinence occurs very rarely with syncope. Hypoglycemia may cause transient loss of consciousness, typically in individuals with type 1 or type 2 diabetes treated with insulin. The clinical features associated with impending or actual hypoglycemia include tremor, palpitations, anxiety, diaphoresis, hunger, and paresthesias. These symptoms are due to autonomic activation to counter the falling blood glucose. Hunger, in particular, is not a typical premonitory feature of syncope. Hypoglycemia also impairs neuronal function, leading to fatigue, weakness, dizziness, and cognitive and behavioral symptoms. Diagnostic difficulties may occur in individuals in strict glycemic control; repeated hypoglycemia impairs the counterregulatory response and leads to a loss of the characteristic warning symptoms that are the hallmark of hypoglycemia. Patients with cataplexy experience an abrupt partial or complete loss of muscular tone triggered by strong emotions, typically anger or laughter. Unlike syncope, consciousness is maintained throughout the attacks, which typically last between 30 s and 2 min. There are no premonitory symptoms. Cataplexy occurs in 60–75% of patients with narcolepsy. The clinical interview and interrogation of eyewitnesses usually allow differentiation of syncope from falls due to vestibular dysfunction, cerebellar disease, extrapyramidal system dysfunction, and other gait disorders. A diagnosis of syncope can be particularly challenging in patients with dementia who experience repeated falls and are unable to provide a clear history of the episodes. If the fall is accompanied by head trauma, a postconcussive syndrome, amnesia for the precipitating events, and/or the presence of loss of consciousness may also contribute to diagnostic difficulty. Apparent loss of consciousness can be a manifestation of psychiatric disorders such as generalized anxiety, panic disorders, major depression, and somatization disorder. These possibilities should be

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considered in individuals who faint frequently without prodromal symptoms. Such patients are rarely injured despite numerous falls. There are no clinically significant hemodynamic changes concurrent with these episodes. In contrast, transient loss of consciousness due to vasovagal syncope precipitated by fear, stress, anxiety, and emotional distress is accompanied by hypotension, bradycardia, or both. INITIAL EVALUATION The goals of the initial evaluation are to determine whether the transient loss of consciousness was due to syncope; to identify the cause; and to assess risk for future episodes and serious harm (Table 18-1). The initial evaluation should include a detailed history, thorough questioning of eyewitnesses, and a complete physical and neurologic examination. Blood pressure and heart rate should be measured in the supine position and after 3 min of standing to determine whether orthostatic hypotension is present. An ECG should be performed if there is suspicion of syncope due to an arrhythmia or underlying cardiac disease. Relevant electrocardiographic abnormalities include bradyarrhythmias or tachyarrhythmias, AV block, ischemia, old myocardial infarction, long QT syndrome, and bundle branch block. This initial assessment will lead to the identification of a cause of syncope in ~50% of patients and also allows stratification of patients at risk for cardiac mortality. Laboratory Tests  Baseline laboratory blood tests are rarely helpful in identifying the cause of syncope. Blood tests should be performed when specific disorders, e.g., myocardial infarction, anemia, and secondary autonomic failure, are suspected (Table 18-2). Autonomic Nervous System Testing (Chap. 432)  Autonomic testing, including tilt-table testing, can be performed in specialized centers. Autonomic testing is helpful to uncover objective evidence of autonomic failure and also to demonstrate a predisposition to neurally mediated syncope. Autonomic testing includes assessments of parasympathetic autonomic nervous system function (e.g., heart rate variability to deep respiration and a Valsalva maneuver), sympathetic cholinergic function (e.g., thermoregulatory sweat response and quantitative sudomotor axon reflex test), and sympathetic adrenergic function (e.g., blood pressure response to a Valsalva maneuver and a tilt-table test with beat-to-beat blood pressure measurement). The hemodynamic abnormalities demonstrated on the tilt-table test (Figs. 18-3 and 18-4) may be useful in distinguishing orthostatic hypotension due to autonomic failure from the hypotensive bradycardic response of neurally mediated syncope. Similarly, the tilt-table test may help identify patients with syncope due to immediate or delayed orthostatic hypotension. Carotid sinus massage should be considered in patients with symptoms suggestive of carotid sinus syncope and in patients >50 years with recurrent syncope of unknown etiology. This test should only be carried out under continuous ECG and blood pressure monitoring and should be avoided in patients with carotid bruits, plaques, or stenosis. Cardiac Evaluation  ECG monitoring is indicated for patients with a high pretest probability of arrhythmia causing syncope. Patients should be monitored in hospital if the likelihood of a lifethreatening arrhythmia is high, e.g., patients with severe structural or coronary artery disease, nonsustained ventricular tachycardia, trifascicular heart block, prolonged QT interval, Brugada syndrome ECG pattern, or family history of sudden cardiac death (Table 18-1). Outpatient Holter monitoring is recommended for patients who experience frequent syncopal episodes (one or more per week), whereas loop recorders, which continually record and erase cardiac rhythm, are indicated for patients with suspected arrhythmias with low risk of sudden cardiac death. Loop recorders may be external (recommended for evaluation of episodes that occur at a frequency of >1 per month) or implantable (if syncope occurs less frequently). Echocardiography should be performed in patients with a history of cardiac disease or if abnormalities are found on physical

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■■FURTHER READING

Al-Khatib SM et al: Risk stratification for arrhythmic events in patients with asymptomatic pre-excitation: A systematic review for the 2015 ACC/AHA/HRS guideline for the management of adult patients with supraventricular tachycardia: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 67:1624, 2016. Freeman R et al: Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. AutonNeurosci 161:46, 2011. Gibbons CH et al: The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 264:1567, 2017. Sheldon RS, Raj SR: Pacing and vasovagal syncope: Back to our physiologic roots. Clin Auton Res 27:213, 2017. Varosy PD et al: Pacing as a treatment for reflex-mediated (vasovagal, situational, or carotid sinus hypersensitivity) syncope: A systematic review for the 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 70:664, 2017.

19

Dizziness and Vertigo Mark F. Walker, Robert B. Daroff

Dizziness is an imprecise symptom used to describe a variety of common sensations that include vertigo, light-headedness, faintness, and imbalance. Vertigo refers to a sense of spinning or other motion that may be physiological, occurring during or after a sustained head rotation, or pathological, due to vestibular dysfunction. The term lightheadedness is classically applied to presyncopal sensations resulting from brain hypoperfusion but as used by patients has little specificity, as it may also refer to other symptoms such as disequilibrium and imbalance. A challenge to diagnosis is that patients often have difficulty distinguishing among these various symptoms, and the words they choose do not reliably indicate the underlying etiology.

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Dizziness and Vertigo

Psychiatric Evaluation  Screening for psychiatric disorders may be appropriate in patients with recurrent unexplained syncope episodes. Tilt-table testing, with demonstration of symptoms in the absence of hemodynamic change, may be useful in reproducing syncope in patients with suspected psychogenic syncope.

There are many causes of dizziness. Vestibular dizziness (vertigo or imbalance) may be due to peripheral disorders that affect the labyrinths or vestibular nerves, or it may result from disruption of central vestibular pathways. It may be paroxysmal or due to a fixed unilateral or bilateral vestibular deficit. Acute unilateral lesions cause vertigo due to a sudden imbalance in vestibular inputs from the two labyrinths. Bilateral lesions cause imbalance and instability of vision when the head moves (oscillopsia) due to loss of normal vestibular reflexes. Presyncopal dizziness occurs when cardiac dysrhythmia, orthostatic hypotension, medication effects, or another cause leads to brain hypoperfusion. Such presyncopal sensations vary in duration; they may increase in severity until loss of consciousness occurs, or they may resolve before loss of consciousness if the cerebral ischemia is corrected. Faintness and syncope, which are discussed in detail in Chap. 18, should always be considered when one is evaluating patients with brief episodes of dizziness or dizziness that occurs with upright posture. Other causes of dizziness include non-vestibular imbalance and gait disorders (e.g., loss of proprioception from sensory neuropathy, parkinsonism), and anxiety. When evaluating patients with dizziness, questions to consider include the following: (1) Is it dangerous (e.g., arrhythmia, transient ischemic attack/stroke)? (2) Is it vestibular? (3) If vestibular, is it peripheral or central? A careful history and examination often provide sufficient information to answer these questions and determine whether additional studies or referral to a specialist is necessary.

CHAPTER 19

examination or the ECG. Echocardiographic diagnoses that may be responsible for syncope include aortic stenosis, hypertrophic cardiomyopathy, cardiac tumors, aortic dissection, and pericardial tamponade. Echocardiography also has a role in risk stratification based on the left ventricular ejection fraction. Treadmill exercise testing with ECG and blood pressure monitoring should be performed in patients who have experienced syncope during or shortly after exercise. Treadmill testing may help identify exercise-induced arrhythmias (e.g., tachycardia-related AV block) and exercise-induced exaggerated vasodilation. Electrophysiologic studies are indicated in patients with structural heart disease and ECG abnormalities in whom noninvasive investigations have failed to yield a diagnosis. Electrophysiologic studies have low sensitivity and specificity and should only be performed when a high pretest probability exists. Currently, this test is rarely performed to evaluate patients with syncope.

APPROACH TO THE PATIENT

Dizziness HISTORY When a patient presents with dizziness, the first step is to delineate more precisely the nature of the symptom. In the case of vestibular disorders, the physical symptoms depend on whether the lesion is unilateral or bilateral, and whether it is acute or chronic. Vertigo, an illusion of self or environmental motion, implies asymmetry of vestibular inputs from the two labyrinths or in their central pathway that is usually acute. Symmetric bilateral vestibular hypofunction causes imbalance but no vertigo. Because of the ambiguity in patients’ descriptions of their symptoms, diagnosis based simply on symptom characteristics is typically unreliable. Thus, the history should focus closely on other features, including whether this is the first attack, the duration of this and any prior episodes, provoking factors, and accompanying symptoms. Dizziness can be divided into episodes that last for seconds, minutes, hours, or days. Common causes of brief dizziness (seconds) include benign paroxysmal positional vertigo (BPPV) and orthostatic hypotension, both of which typically are provoked by changes in head and body position. Attacks of vestibular migraine and Ménière’s disease often last hours. When episodes are of intermediate duration (minutes), transient ischemic attacks of the posterior circulation should be considered, although migraine and a number of other causes are also possible. Symptoms that accompany vertigo may be helpful in distinguishing peripheral vestibular lesions from central causes. Unilateral hearing loss and other aural symptoms (ear pain, pressure, fullness) typically point to a peripheral cause. Because the auditory pathways quickly become bilateral upon entering the brainstem, central lesions are unlikely to cause unilateral hearing loss, unless the lesion lies near the root entry zone of the auditory nerve. Symptoms such as double vision, numbness, and limb ataxia suggest a brainstem or cerebellar lesion. EXAMINATION Because dizziness and imbalance can be a manifestation of a variety of neurologic disorders, the neurologic examination is important in the evaluation of these patients. Particular focus should be given to assessment of eye movements, vestibular function, and hearing.

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PART 2 Cardinal Manifestations and Presentation of Diseases

The range of eye movements and whether they are equal in each eye should be observed. Peripheral eye movement disorders (e.g., cranial neuropathies, eye muscle weakness) are usually disconjugate (different in the two eyes). One should check pursuit (the ability to follow a smoothly moving target) and saccades (the ability to look back and forth accurately between two targets). Poor pursuit or inaccurate (dysmetric) saccades usually indicate central pathology, often involving the cerebellum. Alignment of the two eyes can be checked with a cover test: while the patient is looking at a target, alternately cover the eyes and observe for corrective saccades. A vertical misalignment may indicate a brainstem or cerebellar lesion. Finally, one should look for spontaneous nystagmus, an involuntary back-andforth movement of the eyes. Nystagmus is most often of the jerk type, in which a slow drift (slow phase) in one direction alternates with a rapid saccadic movement (quick phase or fast phase) in the opposite direction that resets the position of the eyes in the orbits. Except in the case of acute vestibulopathy (e.g., vestibular neuritis), if primary position nystagmus is easily seen in the light, it is probably due to a central cause. Two forms of nystagmus that are characteristic of lesions of the cerebellar pathways are vertical nystagmus with downward fast phases (downbeat nystagmus) and horizontal nystagmus that changes direction with gaze (gaze-evoked nystagmus). By contrast, peripheral lesions typically cause unidirectional horizontal nystagmus. Use of Frenzel eyeglasses (self-illuminated goggles with convex lenses that blur the patient’s vision but allow the examiner to see the eyes greatly magnified) can aid in the detection of peripheral vestibular nystagmus, because they reduce the patient’s ability to use visual fixation to suppress nystagmus. Table 19-1 outlines key findings that help distinguish peripheral from central causes of vertigo. The most useful bedside test of peripheral vestibular function is the head impulse test, in which the vestibuloocular reflex (VOR) is assessed with small-amplitude (~20 degrees) rapid head rotations. While the patient fixates on a target, the head is rotated to the left or right. If the VOR is deficient, the rotation is followed by a catch-up saccade in the opposite direction (e.g., a leftward saccade after a rightward rotation). The head impulse test can identify both unilateral (catch-up saccades after rotations toward the weak side) and bilateral vestibular hypofunction (catch-up saccades after rotations in both directions). All patients with episodic dizziness, especially if provoked by positional change, should be tested with the Dix-Hallpike maneuver. The patient begins in a sitting position with the head turned 45 degrees; holding the back of the head, the examiner then lowers the patient into a supine position with the head extended backward by about 20 degrees while watching the eyes. Posterior canal BPPV can be diagnosed confidently if transient upbeating-torsional nystagmus is seen. If no nystagmus is observed after 15–20 s, the patient is raised to the sitting position, and the procedure is repeated with the head turned to the other side. Again, Frenzel goggles may improve the sensitivity of the test. Dynamic visual acuity is a functional test that can be useful in assessing vestibular function. Visual acuity is measured with the head still and when the head is rotated back and forth by the TABLE 19-1  Features of Peripheral and Central Vertigo •  Nystagmus from an acute peripheral lesion is unidirectional, with fast phases beating away from the ear with the lesion. Nystagmus that changes direction with gaze is due to a central lesion. •  Transient mixed vertical-torsional nystagmus occurs in benign paroxysmal positional vertigo (BPPV), but pure vertical or pure torsional nystagmus is a central sign. •  Nystagmus from a peripheral lesion may be inhibited by visual fixation, whereas central nystagmus is not suppressed. •  Absence of a head impulse sign in a patient with acute prolonged vertigo should suggest a central cause. •  Unilateral hearing loss suggests peripheral vertigo. Findings such as diplopia, dysarthria, and limb ataxia suggest a central disorder.

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examiner (about 1–2 Hz). A drop in visual acuity during head motion of more than one line on a near card or Snellen chart is abnormal and indicates vestibular dysfunction. ANCILLARY TESTING The choice of ancillary tests should be guided by the history and examination findings. Audiometry should be performed whenever a vestibular disorder is suspected. Unilateral sensorineural hearing loss supports a peripheral disorder (e.g., vestibular schwannoma). Predominantly low-frequency hearing loss is characteristic of Ménière’s disease. Electronystagmography or videonystagmography includes recordings of spontaneous nystagmus (if present) and measurement of positional nystagmus. Caloric testing assesses the responses of the two horizontal semicircular canals. The test battery often includes recording of saccades and pursuit to assess central ocular motor function. Neuroimaging is important if a central vestibular disorder is suspected. In addition, patients with unexplained unilateral hearing loss or vestibular hypofunction should undergo magnetic resonance imaging (MRI) of the internal auditory canals, including administration of gadolinium, to rule out a schwannoma.

■■DIFFERENTIAL DIAGNOSIS AND TREATMENT

Treatment of vestibular symptoms should be driven by the underlying diagnosis. Simply treating dizziness with vestibular suppressant medications is often not helpful and may make the symptoms worse and prolong recovery. The diagnostic and specific treatment approaches for the most commonly encountered vestibular disorders are discussed below.

■■ACUTE PROLONGED VERTIGO (VESTIBULAR NEURITIS)

An acute unilateral vestibular lesion causes constant vertigo, nausea, vomiting, oscillopsia (motion of the visual scene), and imbalance. These symptoms are due to a sudden asymmetry of inputs from the two labyrinths or in their central connections, simulating a continuous rotation of the head. Unlike BPPV, continuous vertigo persists even when the head remains still. When a patient presents with an acute vestibular syndrome, the most important question is whether the lesion is central (e.g., a cerebellar or brainstem infarct or hemorrhage), which may be life-threatening, or peripheral, affecting the vestibular nerve or labyrinth (vestibular neuritis). Attention should be given to any symptoms or signs that point to central dysfunction (diplopia, weakness or numbness, dysarthria). The pattern of spontaneous nystagmus, if present, may be helpful (Table 19-1). If the head impulse test is normal, an acute peripheral vestibular lesion is unlikely. A central lesion cannot always be excluded with certainty based on symptoms and examination alone; thus, older patients with vascular risk factors who present with an acute vestibular syndrome should be evaluated for the possibility of stroke even when there are no specific findings that indicate a central lesion. Most patients with vestibular neuritis recover spontaneously, but glucocorticoids can improve outcome if administered within 3 days of symptom onset. Antiviral medications are of no proven benefit and are not typically given unless there is evidence to suggest herpes zoster oticus (Ramsay Hunt syndrome). Vestibular suppressant medications may reduce acute symptoms but should be avoided after the first several days because they may impede central compensation and recovery. Patients should be encouraged to resume a normal level of activity as soon as possible, and directed vestibular rehabilitation therapy may accelerate improvement.

■■BENIGN PAROXYSMAL POSITIONAL VERTIGO

BPPV is a common cause of recurrent vertigo. Episodes are brief (1 month) or chronic (present for >6 months) fatigue, but in only a minority was fatigue the primary reason for seeking medical attention. In a community survey of women in India, 12% reported chronic fatigue. By contrast, the prevalence of chronic fatigue syndrome, as defined by the U.S. Centers for Disease Control and Prevention, is low (Chap. 442).

particularly in the context of hair loss, dry skin, cold intolerance, constipation, and weight gain. Fatigue associated with heat intolerance, sweating, and palpitations is typical of hyperthyroidism. Adrenal insufficiency can also manifest with unexplained fatigue as a primary or prominent symptom, often with anorexia, weight loss, nausea, myalgias, and arthralgias; hyponatremia, hyperkalemia, and hyperpigmentation may be present at time of diagnosis. Mild hypercalcemia can cause fatigue, which may be relatively vague, whereas severe hypercalcemia can lead to lethargy, stupor, and coma. Both hypoglycemia and hyperglycemia can cause lethargy, often in association with confusion; diabetes mellitus, and in particular type 1 diabetes, is also associated with fatigue independent of glucose levels. Fatigue may also accompany Cushing’s disease, hypoaldosteronism, and hypogonadism. Low vitamin D status has also been associated with fatigue.

CHAPTER 20

severity is out of proportion with what would be expected for the associated trigger. Fatigue should be distinguished from muscle weakness, a reduction of neuromuscular power (Chap. 21); most patients complaining of fatigue are not truly weak when direct muscle power is tested. Fatigue is also distinct from somnolence, which refers to sleepiness in the context of disturbed sleep-wake physiology (Chap. 27), and from dyspnea on exertion, although patients may use the word fatigue to describe those symptoms. The task facing clinicians when a patient presents with fatigue is to identify the underlying cause and to develop a therapeutic alliance, the goal of which is to spare patients expensive and fruitless diagnostic workups and steer them toward effective therapy.

Obesity  Obesity is associated with fatigue and sleepiness indepen-

dent of the presence of obstructive sleep apnea. Obese patients undergoing bariatric surgery experience improvement in daytime sleepiness sooner than would be expected if the improvement were solely the result of weight loss and resolution of sleep apnea. A number of other factors common in obese patients are likely contributors as well, including physical inactivity, diabetes, and depression.

Physical Inactivity  Physical inactivity is associated with fatigue, and increasing physical activity can improve fatigue in some patients. Malnutrition  Although fatigue can be a presenting feature of malnutrition, nutritional status may also be an important comorbidity and contributor to fatigue in other chronic illnesses, including cancerassociated fatigue. Infection  Both acute and chronic infections commonly lead to

fatigue as part of the broader infectious syndrome. Evaluation for undiagnosed infection as the cause of unexplained fatigue, and particularly prolonged or chronic fatigue, should be guided by the history, physical examination, and infectious risk factors, with particular attention to risk for tuberculosis, HIV, chronic hepatitis, and endocarditis. Infectious mononucleosis may cause prolonged fatigue that persists for weeks to months following the acute illness, but infection with the Epstein-Barr virus is only very rarely the cause of unexplained chronic fatigue.

Drugs  Many medications, drugs, drug withdrawal, and chronic alcohol use can all lead to fatigue. Medications that are more likely to be causative include antidepressants, antipsychotics, anxiolytics, opiates, antispasticity agents, antiseizure agents, and beta blockers. Cardiovascular and Pulmonary  Fatigue is one of the most taxing symptoms reported by patients with congestive heart failure and chronic obstructive pulmonary disease and negatively affects quality of life. Malignancy  Fatigue, particularly in association with unexplained weight loss, can be a sign of occult malignancy, but cancer is rarely identified in patients with unexplained chronic fatigue in the absence of other telltale signs or symptoms. Cancer-related fatigue is experienced by 40% of patients at the time of diagnosis and by >80% at some time in the disease course. Hematologic  Chronic or progressive anemia may present with

fatigue, sometimes in association with exertional tachycardia and breathlessness. Anemia may also contribute to fatigue in chronic illness. Low serum ferritin in the absence of anemia may also cause fatigue that is reversible with iron replacement.

Systemic

Inflammatory/Rheumatologic

Disorders 

Fatigue is a prominent complaint in many chronic inflammatory disorders, including systemic lupus erythematosus, polymyalgia

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rheumatica, rheumatoid arthritis, inflammatory bowel disease, antineutrophil cytoplasmic antibody (ANCA)—associated vasculitis, sarcoidosis, and Sjögren’s syndrome, but is not usually an isolated symptom. Fatigue is also associated with primary immunodeficiency diseases.

Pregnancy  Fatigue is very commonly reported by women during all stages of pregnancy and postpartum.

PART 2 Cardinal Manifestations and Presentation of Diseases

Disorders of Unclear Cause  Chronic fatigue syndrome (Chap. 442) and fibromyalgia (Chap. 366) incorporate chronic fatigue as part of the syndromic definition when present in association with a number of other inclusion and exclusion criteria, as discussed in the respective chapters. Chronic multisymptom illness, also known as Gulf-War syndrome, is another symptom complex with prominent fatigue; it is most commonly, although not exclusively, observed in veterans of the 1991 Gulf war conflict (Chap. S6). Idiopathic chronic fatigue is used to describe the syndrome of unexplained chronic fatigue in the absence of enough additional clinical features to meet the diagnostic criteria for chronic fatigue syndrome.

APPROACH TO THE PATIENT

Fatigue A detailed history focusing on the quality, pattern, time-course, associated symptoms, and alleviating factors of fatigue is critical to define the syndrome and help direct further evaluation and treatment. It is important to determine if fatigue is the appropriate designation, whether symptoms are acute or chronic, and if the impairment is primarily mental, physical, or a combination of the two. The review of systems should attempt to distinguish fatigue from excessive sleepiness, dyspnea on exertion, exercise intolerance, and muscle weakness. The presence of fever, chills, night sweats, or weight loss should raise suspicion for an occult infection or malignancy. A careful review of prescription, over-the-counter, herbal, and recreational drug and alcohol use is required. Circumstances surrounding the onset of symptoms and potential triggers should be investigated. The social history is important, with attention paid to life stressors, workhours, the social support network, and domestic affairs including a screen for intimate partner violence. Sleep habits and sleep hygiene should be questioned. The impact of fatigue on daily functioning is important to understand the patient’s experience and gauge recovery and the success of treatment. The physical examination of patients with fatigue is guided by the history and differential diagnosis. A detailed mental status examination should be performed with particular attention to symptoms of depression and anxiety. A formal neurologic examination is required to determine whether objective muscle weakness is present. This is usually a straightforward exercise, although occasionally patients with fatigue have difficulty sustaining effort against resistance and sometimes report that generating full power requires substantial mental effort. On confrontational testing, full power can be generated for only a brief period before the patient suddenly gives way to the examiner. This type of weakness is often referred to as breakaway weakness and may or may not be associated with pain. This is contrasted with weakness due to lesions in the motor tracts or lower motor unit, in which the patient’s resistance can be overcome in a smooth and steady fashion and full power can never be generated. Occasionally, a patient may demonstrate fatigable weakness, in which power is full when first tested but becomes weak upon repeat evaluation without interval rest. Fatigable weakness, which usually indicates a problem of neuromuscular transmission, never has the sudden breakaway quality that one occasionally observes in patients with fatigue. If the presence or absence of muscle weakness cannot be determined with the physical examination, electromyography with nerve conductions studies can be a helpful ancillary test. The general physical examination should screen for signs of cardiopulmonary disease, malignancy, lymphadenopathy, organomegaly, infection, liver failure, kidney disease, malnutrition, endocrine

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abnormalities, and connective tissue disease. In patients with associated widespread musculoskeletal pain, assessment of tender points may help to reveal fibromyalgia. Although the diagnostic yield of the general physical examination may be relatively low in the context of evaluation of unexplained chronic fatigue, elucidating the cause of only 2% of cases in one prospective analysis, the yield of a detailed neuropsychiatric and mental status evaluation is likely to be much higher, revealing a potential explanation for fatigue in up to 75–80% of patients in some series. Furthermore, a complete physical examination demonstrates a serious and systematic approach to the patient’s complaint and helps build trust and a therapeutic alliance. Laboratory testing is likely to identify the cause of chronic fatigue in only about 5% of cases. Beyond a few standard screening tests, laboratory evaluation should be guided by the history and physical examination; extensive testing is more likely to lead to false-positive results that require explanation and unnecessary follow-up investigation, and should be avoided in lieu of frequent clinical follow-up. A reasonable approach to screening includes a complete blood count with differential (to screen for anemia, infection, and malignancy), electrolytes (including sodium, potassium, and calcium), glucose, renal function, liver function, and thyroid function. Testing for HIV and adrenal function can also be considered. Published guidelines for chronic fatigue syndrome also recommend an erythrocyte sedimentation rate (ESR) as part of the evaluation for mimics, but unless the value is very high such nonspecific testing in the absence of other features is unlikely to clarify the situation. Routine screening with an antinuclear antibody (ANA) test is also unlikely to be informative in isolation and is frequently positive at low titers in otherwise healthy adults. Additional unfocused studies, such as whole-body imaging scans, are usually not indicated; in addition to their inconvenience, potential risk, and cost, they often reveal unrelated incidental findings that can prolong the workup unnecessarily.

TREATMENT

Fatigue The first priority of treatment is to address the underlying disorder or disorders that account for fatigue, because this can be curative in select contexts and palliative in others. Unfortunately, in many chronic illnesses fatigue may be refractory to traditional diseasemodifying therapies, but it is nevertheless important in such cases to evaluate for other potential contributors, because the cause may be multifactorial. Antidepressant treatment (Chap. 444) may be helpful for treatment of chronic fatigue when symptoms of depression are present and may be most effective as part of a multimodal approach. However, antidepressants can also cause fatigue and should be discontinued if they are not clearly effective. Cognitive-behavioral therapy has also been demonstrated to be helpful in the context of chronic fatigue syndrome as well as cancer-associated fatigue. Both cognitive behavioral therapy and graded exercise therapy, in which physical exercise, most typically walking, is gradually increased with attention to target heart rates to avoid overexertion, were shown to modestly improve walking times and self-reported fatigue measures when compared to standard medical care in patients in the United Kingdom with chronic fatigue. These benefits were maintained after a median follow-up of 2.5 years. Psychostimulants such as amphetamines, modafinil, and armodafinil can help increase alertness and concentration and reduce excessive daytime sleepiness in certain clinical contexts, which may in turn help with symptoms of fatigue in a minority of patients, but they have generally proven to be unhelpful in randomized trials for treating fatigue in posttraumatic brain injury, Parkinson’s disease, cancer, and MS. In patients with low vitamin D status, vitamin D replacement may lead to improvement in fatigue. Development of more effective therapy for fatigue is hampered by limited knowledge of the biologic basis of this symptom, including how fatigue is detected and registered in the nervous system. Proinflammatory cytokines, such as interleukin 1α and 1β, and

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tumor necrosis factor α, might mediate fatigue in some patients. Preliminary data suggests that biological therapies that inhibit IL-1 or other cytokines can help to ameliorate fatigue in some patients with inflammatory conditions in addition to, or as part of, their disease modifying effect; thus, cytokine antagonists represent one possible future approach.

■■PROGNOSIS

David A et al: Tired, weak, or in need of rest: Fatigue among general practice attenders. BMJ 301:1199, 1990. Kroenke K et al: Chronic fatigue in primary care. Prevalence, patient characteristics, and outcome. JAMA 260:929–934, 1988. Roerink ME et al: Interleukin-1 as a mediator of fatigue in disease: A narrative review. J Neuroinflammation 14:16, 2017. Sharpe M et al: Rehabilitative treatments for chronic fatigue syndrome: Long-term follow-up from the PACE trial. Lancet Psychiatry 2:1067, 2015. White PD et al: Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): A randomised trial. Lancet 377:823, 2011.

21

Neurologic Causes of Weakness and Paralysis Michael J. Aminoff

Normal motor function involves integrated muscle activity that is modulated by the activity of the cerebral cortex, basal ganglia, cerebellum, red nucleus, brainstem reticular formation, lateral vestibular nucleus, and spinal cord. Motor system dysfunction leads to weakness or paralysis, discussed in this chapter, or to ataxia (Chap. 431) or abnormal movements (Chap. 428). Weakness is a reduction in the power that can be exerted by one or more muscles. It must be distinguished from increased fatigability (i.e., the inability to sustain the performance of an activity that should be normal for a person of the same age, sex, and size), limitation in function due to pain or articular stiffness, or impaired motor activity because severe proprioceptive sensory loss prevents adequate feedback information about the direction and power of movements. It is also distinct from bradykinesia (in which increased

Neurologic Causes of Weakness and Paralysis

■■FURTHER READING

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CHAPTER 21

Acute fatigue significant enough to require medical evaluation is more likely to lead to an identifiable medical, neurologic, or psychiatric cause than unexplained chronic fatigue. Evaluation of unexplained chronic fatigue most commonly leads to diagnosis of a psychiatric condition or remains unexplained. Identification of a previously undiagnosed serious or life-threatening culprit etiology is rare on longitudinal follow-up in patients with unexplained chronic fatigue. Complete resolution of unexplained chronic fatigue is uncommon, at least over the short term, but multidisciplinary treatment approaches can lead to symptomatic improvements that can substantially improve quality of life.

time is required for full power to be exerted) and apraxia, a disorder of planning and initiating a skilled or learned movement unrelated to a significant motor or sensory deficit (Chap. 26). Paralysis or the suffix “-plegia” indicates weakness so severe that a muscle cannot be contracted at all, whereas paresis refers to less severe weakness. The prefix “hemi-” refers to one-half of the body, “para-” to both legs, and “quadri-” to all four limbs. The distribution of weakness helps to localize the underlying lesion. Weakness from involvement of upper motor neurons occurs particularly in the extensors and abductors of the upper limb and the flexors of the lower limb. Lower motor neuron weakness depends on whether involvement is at the level of the anterior horn cells, nerve root, limb plexus, or peripheral nerve—only muscles supplied by the affected structure are weak. Myopathic weakness is generally most marked in proximal muscles. Weakness from impaired neuromuscular transmission has no specific pattern of involvement. Weakness often is accompanied by other neurologic abnormalities that help indicate the site of the responsible lesion (Table 21-1). Tone is the resistance of a muscle to passive stretch. Increased tone may be of several types. Spasticity is the increase in tone associated with disease of upper motor neurons. It is velocity-dependent, has a sudden release after reaching a maximum (the “clasp-knife” phenomenon), and predominantly affects the antigravity muscles (i.e., upper-limb flexors and lower-limb extensors). Rigidity is hypertonia that is present throughout the range of motion (a “lead pipe” or “plastic” stiffness) and affects flexors and extensors equally; it sometimes has a cogwheel quality that is enhanced by voluntary movement of the contralateral limb (reinforcement). Rigidity occurs with certain extrapyramidal disorders, such as Parkinson’s disease. Paratonia (or gegenhalten) is increased tone that varies irregularly in a manner seemingly related to the degree of relaxation, is present throughout the range of motion, and affects flexors and extensors equally; it usually results from disease of the frontal lobes. Weakness with decreased tone (flaccidity) or normal tone occurs with disorders of motor units. A motor unit consists of a single lower motor neuron and all the muscle fibers that it innervates. Muscle bulk generally is not affected by upper motor neuron lesions, although mild disuse atrophy eventually may occur. By contrast, atrophy is often conspicuous when a lower motor neuron lesion is responsible for weakness and also may occur with advanced muscle disease. Muscle stretch (tendon) reflexes are usually increased with upper motor neuron lesions, but may be decreased or absent for a variable period immediately after onset of an acute lesion. Hyperreflexia is usually—but not invariably—accompanied by loss of cutaneous reflexes (such as superficial abdominals; Chap. 415) and, in particular, by an extensor plantar (Babinski) response. The muscle stretch reflexes are depressed with lower motor neuron lesions directly involving specific reflex arcs. They generally are preserved in patients with myopathic weakness except in advanced stages, when they sometimes are attenuated. In disorders of the neuromuscular junction, reflex responses may be affected by preceding voluntary activity of affected muscles; such activity may lead to enhancement of initially depressed reflexes in Lambert-Eaton myasthenic syndrome and, conversely, to depression of initially normal reflexes in myasthenia gravis (Chap. 440). The distinction of neuropathic (lower motor neuron) from myopathic weakness is sometimes difficult clinically, although distal weakness is likely to be neuropathic, and symmetric proximal weakness myopathic. Fasciculations (visible or palpable twitch within a muscle due to the

TABLE 21-1  Signs That Distinguish the Origin of Weakness SIGN Atrophy Fasciculations Tone Distribution of weakness

UPPER MOTOR NEURON None None Spastic Pyramidal/regional

LOWER MOTOR NEURON Severe Common Decreased Distal/segmental

MYOPATHIC Mild None Normal/decreased Proximal

Muscle stretch reflexes Babinski sign

Hyperactive Present

Hypoactive/absent Absent

Normal/hypoactive Absent

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PSYCHOGENIC None None Variable/paratonia Variable/inconsistent with daily activities Normal Absent

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spontaneous discharge of a motor unit) and early atrophy indicate that weakness is neuropathic.

■■PATHOGENESIS Upper Motor Neuron Weakness  Lesions of the upper motor

PART 2

Corticospinal tract

Hip

Sh Trunk oul der Elb Wr ow i Fin st Th ger um s b

neurons or their descending axons to the spinal cord (Fig. 21-1) produce weakness through decreased activation of lower motor neurons.

Knee

Ankle Toes

Cardinal Manifestations and Presentation of Diseases

ck Ne ro B w Eyelid Nares Lips Tongue Larynx

Red nucleus Reticular nuclei Vestibular nuclei Vestibulospinal tract Reticulospinal tract

Rubrospinal tract Lateral corticospinal tract

In general, distal muscle groups are affected more severely than proximal ones, and axial movements are spared unless the lesion is severe and bilateral. Spasticity is typical but may not be present acutely. Rapid repetitive movements are slowed and coarse, but normal rhythmicity is maintained. With corticobulbar involvement, weakness occurs in the lower face and tongue; extraocular, upper facial, pharyngeal, and jaw muscles are typically spared. Bilateral corticobulbar lesions produce a pseudobulbar palsy: dysarthria, dysphagia, dysphonia, and emotional lability accompany bilateral facial weakness and a brisk jaw jerk. Electromyogram (EMG) (Chap. 438) shows that with weakness of the upper motor neuron type, motor units have a diminished maximal discharge frequency.

Lower Motor Neuron Weakness  This pattern results from dis-

orders of lower motor neurons in the brainstem motor nuclei and the anterior horn of the spinal cord or from dysfunction of the axons of these neurons as they pass to skeletal muscle (Fig. 21-2). Weakness is due to a decrease in the number of muscle fibers that can be activated through a loss of α motor neurons or disruption of their connections to muscle. Loss of γ motor neurons does not cause weakness but decreases tension on the muscle spindles, which decreases muscle tone and attenuates the stretch reflexes. An absent stretch reflex suggests involvement of spindle afferent fibers. When a motor unit becomes diseased, especially in anterior horn cell diseases, it may discharge spontaneously, producing fasciculations. When α motor neurons or their axons degenerate, the denervated muscle fibers also may discharge spontaneously. These single muscle fiber discharges, or fibrillation potentials, cannot be seen but can be recorded with EMG. Weakness leads to delayed or reduced recruitment of motor units, with fewer than normal activated at a particular discharge frequency.

Afferent neuron Lateral corticospinal tract Rubrospinal (ventrolateral) tract Ventromedial bulbospinal tracts

FIGURE 21-1  The corticospinal and bulbospinal upper motor neuron pathways. Upper motor neurons have their cell bodies in layer V of the primary motor cortex (the precentral gyrus, or Brodmann’s area 4) and in the premotor and supplemental motor cortex (area 6). The upper motor neurons in the primary motor cortex are somatotopically organized (right side of figure). Axons of the upper motor neurons descend through the subcortical white matter and the posterior limb of the internal capsule. Axons of the pyramidal or corticospinal system descend through the brainstem in the cerebral peduncle of the midbrain, the basis pontis, and the medullary pyramids. At the cervicomedullary junction, most corticospinal axons decussate into the contralateral corticospinal tract of the lateral spinal cord, but 10–30% remain ipsilateral in the anterior spinal cord. Corticospinal neurons synapse on premotor interneurons, but some—especially in the cervical enlargement and those connecting with motor neurons to distal limb muscles—make direct monosynaptic connections with lower motor neurons. They innervate most densely the lower motor neurons of hand muscles and are involved in the execution of learned, fine movements. Corticobulbar neurons are similar to corticospinal neurons but innervate brainstem motor nuclei. Bulbospinal upper motor neurons influence strength and tone but are not part of the pyramidal system. The descending ventromedial bulbospinal pathways originate in the tectum of the midbrain (tectospinal pathway), the vestibular nuclei (vestibulospinal pathway), and the reticular formation (reticulospinal pathway). These pathways influence axial and proximal muscles and are involved in the maintenance of posture and integrated movements of the limbs and trunk. The descending ventrolateral bulbospinal pathways, which originate predominantly in the red nucleus (rubrospinal pathway), facilitate distal limb muscles. The bulbospinal system sometimes is referred to as the extrapyramidal upper motor neuron system. In all figures, nerve cell bodies and axon terminals are shown, respectively, as closed circles and forks.

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γ α Alpha and gamma motor neurons

Motor end plates on voluntary muscle (extrafusal fibers) Muscle spindle (intrafusal fibers) FIGURE 21-2  Lower motor neurons are divided into ` and f types. The larger α motor neurons are more numerous and innervate the extrafusal muscle fibers of the motor unit. Loss of α motor neurons or disruption of their axons produces lower motor neuron weakness. The smaller, less numerous γ motor neurons innervate the intrafusal muscle fibers of the muscle spindle and contribute to normal tone and stretch reflexes. The α motor neuron receives direct excitatory input from corticomotoneurons and primary muscle spindle afferents. The α and γ motor neurons also receive excitatory input from other descending upper motor neuron pathways, segmental sensory inputs, and interneurons. The α motor neurons receive direct inhibition from Renshaw cell interneurons, and other interneurons indirectly inhibit the α and γ motor neurons. A muscle stretch (tendon) reflex requires the function of all the illustrated structures. A tap on a tendon stretches muscle spindles (which are tonically activated by γ motor neurons) and activates the primary spindle afferent neurons. These neurons stimulate the α motor neurons in the spinal cord, producing a brief muscle contraction, which is the familiar tendon reflex.

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Neuromuscular Junction Weakness  Disorders of the neuro-

muscular junctions produce weakness of variable degree and distribution. The number of muscle fibers that are activated varies over time, depending on the state of rest of the neuromuscular junctions. Strength is influenced by preceding activity of the affected muscle. In myasthenia gravis, for example, sustained or repeated contractions of affected muscle decline in strength despite continuing effort (Chap. 440). Thus, fatigable weakness is suggestive of disorders of the neuromuscular junction, which cause functional loss of muscle fibers due to failure of their activation.

nizable organic basis. It tends to be variable, inconsistent, and with a pattern of distribution that cannot be explained on a neuroanatomic basis. On formal testing, antagonists may contract when the patient is supposedly activating the agonist muscle. The severity of weakness is out of keeping with the patient’s daily activities.

Paraparesis  Acute paraparesis is caused most commonly by an

intraspinal lesion, but its spinal origin may not be recognized initially if the legs are flaccid and areflexic. Usually, however, there is sensory loss in the legs with an upper level on the trunk, a dissociated sensory ■■DISTRIBUTION OF WEAKNESS loss suggestive of a central cord syndrome (Chap. 434), or hyperreflexia Hemiparesis  Hemiparesis results from an upper motor neuron in the legs with normal reflexes in the arms. Imaging the spinal cord lesion above the midcervical spinal cord; most such lesions are above (Fig. 21-3) may reveal compressive lesions, infarction (proprioception the foramen magnum. The presence of other neurologic deficits helps usually is spared), arteriovenous fistulas or other vascular anomalies, localize the lesion. Thus, language disorders, for example, point to a or transverse myelitis (Chap. 434). cortical lesion. Homonymous visual field defects reflect either a cortical Diseases of the cerebral hemispheres that produce acute paraparesis include anterior cerebral artery ischemia (shoulder shrug also is affected), superior sagittal sinus or cortical venous DISTRIBUTION OF WEAKNESS thrombosis, and acute hydrocephalus. Paraparesis may result from a cauda Paraparesis Hemiparesis Quadriparesis Monoparesis Distal Proximal Restricted equina syndrome, for example, after trauma to the low back, a midline disk herniation, or an intraspinal tumor. Alert The sphincters are commonly affected, whereas hip flexion often is spared, as is Yes No UMN signs UMN signs sensation over the anterolateral thighs. LMN signs* LMN signs* Rarely, paraparesis is caused by a rapidly evolving anterior horn cell disease Cerebral signs (such as poliovirus or West Nile virus infection), peripheral neuropathy (such as Guillain-Barré syndrome; Chap. 439), Yes No UMN signs LMN signs* or myopathy (Chap. 441). Subacute or chronic spastic paraparesis is EMG and NCS caused by upper motor neuron disease. When associated with lower-limb sensory loss and sphincter involvement, a UMN pattern LMN pattern Myopathic pattern chronic spinal cord disorder should be considered (Chap. 434). If hemispheric signs are present, a parasagittal menAnterior horn, Muscle or Brain CT ‡ ingioma or chronic hydrocephalus is Spinal MRI root, or peripheral neuromuscular † or MRI nerve disease junction disease likely. The absence of spasticity in a long-standing paraparesis suggests or signs of myopathy * a lower motor neuron or myopathic † If no abnormality detected, consider spinal MRI. etiology. ‡ If no abnormality detected, consider myelogram or brain MRI. Investigations typically begin with spinal MRI, but when upper motor neuron FIGURE 21-3  An algorithm for the initial workup of a patient with weakness. CT, computed tomography; EMG, signs are associated with drowsiness, electromyography; LMN, lower motor neuron; MRI, magnetic resonance imaging; NCS, nerve conduction studies; confusion, seizures, or other hemispheric UMN, upper motor neuron.

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Neurologic Causes of Weakness and Paralysis

Psychogenic Weakness  Weakness may occur without a recog-

137

CHAPTER 21

Myopathic Weakness  Myopathic weakness is produced by a decrease in the number or contractile force of muscle fibers activated within motor units. With muscular dystrophies, inflammatory myopathies, or myopathies with muscle fiber necrosis, the number of muscle fibers is reduced within many motor units. On EMG, the size of each motor unit action potential is decreased, and motor units must be recruited more rapidly than normal to produce the desired power. Some myopathies produce weakness through loss of contractile force of muscle fibers or through relatively selective involvement of type II (fast) fibers. These myopathies may not affect the size of individual motor unit action potentials and are detected by a discrepancy between the electrical activity and force of a muscle.

or a subcortical hemispheric lesion. A “pure motor” hemiparesis of the face, arm, and leg often is due to a small, discrete lesion in the posterior limb of the internal capsule, cerebral peduncle in the midbrain, or upper pons. Some brainstem lesions produce “crossed paralyses,” consisting of ipsilateral cranial nerve signs and contralateral hemiparesis (Chap. 419). The absence of cranial nerve signs or facial weakness suggests that a hemiparesis is due to a lesion in the high cervical spinal cord, especially if associated with the Brown-Séquard syndrome (Chap. 434). Acute or episodic hemiparesis usually results from focal structural lesions, particularly rapidly expanding lesions, or an inflammatory process. Subacute hemiparesis that evolves over days or weeks may relate to subdural hematoma, infectious or inflammatory disorders (e.g., cerebral abscess, fungal granuloma or meningitis, parasitic infection, multiple sclerosis, sarcoidosis), or primary or metastatic neoplasms. AIDS may present with subacute hemiparesis due to toxoplasmosis or primary central nervous system (CNS) lymphoma. Chronic hemiparesis that evolves over months usually is due to a neoplasm or vascular malformation, a chronic subdural hematoma, or a degenerative disease. Investigation of hemiparesis (Fig. 21-3) of acute origin starts with a computed tomography (CT) scan of the brain and laboratory studies. If the CT is normal, or in subacute or chronic cases of hemiparesis, magnetic resonance imaging (MRI) of the brain and/or cervical spine (including the foramen magnum) is performed, depending on the clinical accompaniments.

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138

TABLE 21-2  Causes of Episodic Generalized Weakness

PART 2 Cardinal Manifestations and Presentation of Diseases

1. Electrolyte disturbances, e.g., hypokalemia, hyperkalemia, hypercalcemia, hypernatremia, hyponatremia, hypophosphatemia, hypermagnesemia 2.  Muscle disorders a.  Channelopathies (periodic paralyses) b. Metabolic defects of muscle (impaired carbohydrate or fatty acid utilization; abnormal mitochondrial function) 3.  Neuromuscular junction disorders a.  Myasthenia gravis b.  Lambert-Eaton myasthenic syndrome 4.  Central nervous system disorders a.  Transient ischemic attacks of the brainstem b.  Transient global cerebral ischemia c.  Multiple sclerosis 5.  Lack of voluntary effort a. Anxiety b.  Pain or discomfort c.  Somatization disorder

signs, brain MRI should also be performed, sometimes as the initial investigation. Electrophysiologic studies are diagnostically helpful when clinical findings suggest an underlying neuromuscular disorder.

Quadriparesis or Generalized Weakness  Generalized weak-

ness may be due to disorders of the CNS or the motor unit. Although the terms often are used interchangeably, quadriparesis is commonly used when an upper motor neuron cause is suspected, and generalized weakness is used when a disease of the motor units is likely. Weakness from CNS disorders usually is associated with changes in consciousness or cognition and accompanied by spasticity, hyperreflexia, and sensory disturbances. Most neuromuscular causes of generalized weakness are associated with normal mental function, hypotonia, and hypoactive muscle stretch reflexes. The major causes of intermittent weakness are listed in Table 21-2. A patient with generalized fatigability without objective weakness may have the chronic fatigue syndrome (Chap. 442). Quadriparesis with onset over minutes may result from disorders of upper motor neurons (such as from anoxia, hypotension, brainstem or cervical cord ischemia, trauma, and systemic metabolic abnormalities) or muscle (electrolyte disturbances, certain inborn errors of muscle energy metabolism, toxins, and periodic paralyses). Onset over hours to weeks may, in addition to these disorders, be due to lower motor neuron disorders such as Guillain-Barré syndrome (Chap. 439). In obtunded patients, evaluation begins with a CT scan of the brain. If upper motor neuron signs are present but the patient is alert, the initial test is usually an MRI of the cervical cord. If weakness is lower motor neuron, myopathic, or uncertain in origin, the clinical approach begins with blood studies to determine the level of muscle enzymes and electrolytes and with EMG and nerve conduction studies.

ACUTE QUADRIPARESIS 

Quadriparesis due to upper motor neuron disease may develop over weeks to years from chronic myelopathies, multiple sclerosis, brain or spinal tumors, chronic subdural hematomas, and various metabolic, toxic, and infectious disorders. It may also result from lower motor neuron disease, a chronic neuropathy (in which weakness is often most profound distally), or myopathic weakness (typically proximal). When quadriparesis develops acutely in obtunded patients, evaluation begins with a CT scan of the brain. If upper motor neuron signs have developed acutely but the patient is alert, the initial test is usually an MRI of the cervical cord. When onset has been gradual, disorders of the cerebral hemispheres, brainstem, and cervical spinal cord can usually be distinguished clinically, and imaging is directed first at the clinically suspected site of pathology. If weakness is lower motor neuron, myopathic, or uncertain in origin, laboratory studies to determine

SUBACUTE OR CHRONIC QUADRIPARESIS 

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the levels of muscle enzymes and electrolytes, and EMG and nerve conduction studies help to localize the pathologic process.

Monoparesis  Monoparesis usually is due to lower motor neuron

disease, with or without associated sensory involvement. Upper motor neuron weakness occasionally presents as a monoparesis of distal and nonantigravity muscles. Myopathic weakness rarely is limited to one limb. If weakness is predominantly distal and of upper motor neuron type and is not associated with sensory impairment or pain, focal cortical ischemia is likely (Chap. 420); diagnostic possibilities are similar to those for acute hemiparesis. Sensory loss and pain usually accompany acute lower motor neuron weakness; the weakness commonly localizes to a single nerve root or peripheral nerve, but occasionally reflects plexus involvement. If lower motor neuron weakness is likely, evaluation begins with EMG and nerve conduction studies.

ACUTE MONOPARESIS 

SUBACUTE OR CHRONIC MONOPARESIS  Weakness and atrophy that develop over weeks or months are usually of lower motor neuron origin. When associated with sensory symptoms, a peripheral cause (nerve, root, or plexus) is likely; otherwise, anterior horn cell disease should be considered. In either case, an electrodiagnostic study is indicated. If weakness is of the upper motor neuron type, a discrete cortical (precentral gyrus) or cord lesion may be responsible, and appropriate imaging is performed.

Distal Weakness  Involvement of two or more limbs distally suggests lower motor neuron or peripheral nerve disease. Acute distal lower-limb weakness results occasionally from an acute toxic polyneuropathy or cauda equina syndrome. Distal symmetric weakness usually develops over weeks, months, or years and, when associated with numbness, is due to peripheral neuropathy (Chap. 438). Anterior horn cell disease may begin distally but is typically asymmetric and without accompanying numbness (Chap. 429). Rarely, myopathies present with distal weakness (Chap. 441). Electrodiagnostic studies help localize the disorder (Fig. 21-3). Proximal Weakness  Myopathy often produces symmetric weakness of the pelvic or shoulder girdle muscles (Chap. 441). Diseases of the neuromuscular junction, such as myasthenia gravis (Chap. 440), may present with symmetric proximal weakness often associated with ptosis, diplopia, or bulbar weakness and fluctuating in severity during the day. In anterior horn cell disease, proximal weakness is usually asymmetric, but it may be symmetric if familial. Numbness does not occur with any of these diseases. The evaluation usually begins with determination of the serum creatine kinase level and electrophysiologic studies. Weakness in a Restricted Distribution  Weakness may not

fit any of these patterns, being limited, for example, to the extraocular, hemifacial, bulbar, or respiratory muscles. If it is unilateral, restricted weakness usually is due to lower motor neuron or peripheral nerve disease, such as in a facial palsy. Weakness of part of a limb is commonly due to a peripheral nerve lesion such as an entrapment neuropathy. Relatively symmetric weakness of extraocular or bulbar muscles frequently is due to a myopathy (Chap. 441) or neuromuscular junction disorder (Chap. 440). Bilateral facial palsy with areflexia suggests Guillain-Barré syndrome (Chap. 439). Worsening of relatively symmetric weakness with fatigue is characteristic of neuromuscular junction disorders. Asymmetric bulbar weakness usually is due to motor neuron disease. Weakness limited to respiratory muscles is uncommon and usually is due to motor neuron disease, myasthenia gravis, or polymyositis/dermatomyositis (Chap. 358).

■■FURTHER READING

Brazis P, Masdeu JC, Biller J: Localization in Clinical Neurology, 7th ed. Philadelphia, Lippincott William & Wilkins, 2016. Campbell WW: DeJong’s The Neurological Examination, 7th ed. Philadelphia, Lippincott William & Wilkins, 2012. Guarantors of Brain: Aids to the Examination of the Peripheral Nervous System, 4th ed. Edinburgh, Saunders, 2000.

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Michael J. Aminoff

■■POSITIVE AND NEGATIVE SYMPTOMS

Abnormal sensory symptoms can be divided into two categories: positive and negative. The prototypical positive symptom is tingling (pins and needles); other positive sensory phenomena include itch and altered sensations that are described as pricking, bandlike, lightninglike shooting feelings (lancinations), aching, knifelike, twisting, drawing, pulling, tightening, burning, searing, electrical, or raw feelings. Such symptoms are often painful. Positive phenomena usually result from trains of impulses generated at sites of lowered threshold or heightened excitability along a peripheral or central sensory pathway. The nature and severity of the abnormal sensation depend on the number, rate, timing, and distribution of ectopic impulses and the type and function of nervous tissue in which they arise. Because positive phenomena represent excessive activity in sensory pathways, they are not necessarily associated with a sensory deficit (loss) on examination. Negative phenomena represent loss of sensory function and are characterized by diminished or absent feeling that often is experienced as numbness and by abnormal findings on sensory examination. In disorders affecting peripheral sensation, at least one-half the afferent axons innervating a particular site are probably lost or functionless before a sensory deficit can be demonstrated by clinical examination. If the rate of loss is slow, however, lack of cutaneous feeling may be unnoticed by the patient and difficult to demonstrate on examination, even though few sensory fibers are functioning; if it is rapid, both positive and negative phenomena are usually conspicuous. Subclinical degrees of sensory dysfunction may be revealed by sensory nerve conduction studies or somatosensory-evoked potentials. Whereas sensory symptoms may be either positive or negative, sensory signs on examination are always a measure of negative phenomena.

■■TERMINOLOGY

Paresthesias and dysesthesias are general terms used to denote positive sensory symptoms. The term paresthesias typically refers to tingling or pins-and-needles sensations but may include a wide variety of other abnormal sensations, except pain; it sometimes implies that the abnormal sensations are perceived spontaneously. The more general term dysesthesias denotes all types of abnormal sensations, including painful ones, regardless of whether a stimulus is evident. Another set of terms refers to sensory abnormalities found on examination. Hypesthesia or hypoesthesia refers to a reduction of cutaneous sensation to a specific type of testing such as pressure, light touch, and warm or cold stimuli; anesthesia, to a complete absence of skin sensation to the same stimuli plus pinprick; and hypalgesia or analgesia, to reduced or absent pain perception (nociception). Hyperesthesia means pain or increased sensitivity in response to touch. Similarly, allodynia describes the situation in which a nonpainful stimulus, once perceived, is experienced as painful, even excruciating. An example is elicitation of a painful sensation by application of a vibrating tuning fork. Hyperalgesia denotes severe pain in response to a mildly noxious stimulus, and hyperpathia, a broad term, encompasses all the phenomena described by hyperesthesia, allodynia, and hyperalgesia. With hyperpathia, the

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139

■■ANATOMY OF SENSATION

Cutaneous receptors are classified by the type of stimulus that optimally excites them. They consist of naked nerve endings (nociceptors, which respond to tissue-damaging stimuli, and thermoreceptors, which respond to noninjurious thermal stimuli) and encapsulated terminals (several types of mechanoreceptor, activated by physical deformation of the skin). Each type of receptor has its own set of sensitivities to specific stimuli, size and distinctness of receptive fields, and adaptational qualities. Afferent fibers in peripheral nerve trunks traverse the dorsal roots and enter the dorsal horn of the spinal cord (Fig. 22-1). From there, the polysynaptic projections of the smaller fibers (unmyelinated and small myelinated), which subserve mainly nociception, itch, temperature sensibility, and touch, cross and ascend in the opposite anterior and lateral columns of the spinal cord, through the brainstem, to the ventral posterolateral (VPL) nucleus of the thalamus and ultimately project to the postcentral gyrus of the parietal cortex and other cortical areas (Chap. 10). This is the spinothalamic pathway or anterolateral system. The larger fibers, which subserve tactile and position sense and kinesthesia, project rostrally in the posterior and posterolateral columns on the same side of the spinal cord and make their first synapse in the gracile or cuneate nucleus of the lower medulla. Axons of second-order neurons decussate and ascend in the medial lemniscus located medially in the medulla and in the tegmentum of the pons and midbrain and synapse in the VPL nucleus; third-order neurons project to parietal cortex as well as to other cortical areas. This large-fiber system is referred to as the posterior column–medial lemniscal pathway (lemniscal, for short). Although the fiber types and functions that make up the spinothalamic and lemniscal systems are relatively well known, many other fibers, particularly those associated with touch, pressure, and position sense, ascend in a diffusely distributed pattern both ipsilaterally and contralaterally in the anterolateral quadrants of the spinal cord. This explains why a complete lesion of the posterior columns of the spinal cord may be associated with little sensory deficit on examination. Nerve conduction studies and nerve biopsy are important means of investigating the peripheral nervous system, but they do not evaluate the function or structure of cutaneous receptors and free nerve endings or of unmyelinated or thinly myelinated nerve fibers in the nerve trunks. Skin biopsy can be used to evaluate these structures in the dermis and epidermis.

CHAPTER 22

Normal somatic sensation reflects a continuous monitoring process, little of which reaches consciousness under ordinary conditions. By contrast, disordered sensation, particularly when experienced as painful, is alarming and dominates the patient’s attention. Physicians should be able to recognize abnormal sensations by how they are described, know their type and likely site of origin, and understand their implications. Pain is considered separately in Chap. 10.

threshold for a sensory stimulus is increased and perception is delayed, but once felt, it is unduly painful. Disorders of deep sensation arising from muscle spindles, tendons, and joints affect proprioception (position sense). Manifestations include imbalance (particularly with eyes closed or in the dark), clumsiness of precision movements, and unsteadiness of gait, which are referred to collectively as sensory ataxia. Other findings on examination usually, but not invariably, include reduced or absent joint position and vibratory sensibility and absent deep tendon reflexes in the affected limbs. The Romberg sign is positive, which means that the patient sways markedly or topples when asked to stand with feet close together and eyes closed. In severe states of deafferentation involving deep sensation, the patient cannot walk or stand unaided or even sit unsupported. Continuous involuntary movements (pseudoathetosis) of the outstretched hands and fingers occur, particularly with eyes closed.

Numbness, Tingling, and Sensory Loss

22

Numbness, Tingling, and Sensory Loss

■■CLINICAL EXAMINATION OF SENSATION

The main components of the sensory examination are tests of primary sensation (pain, touch, vibration, joint position, and thermal sensation) (Table 22-1). The examiner must depend on patient responses, and this complicates interpretation. Further, examination may be limited in some patients. In a stuporous patient, for example, sensory examination is reduced to observing the briskness of withdrawal in response to a pinch or another noxious stimulus. Comparison of responses on the two sides of the body is essential. In an alert but uncooperative patient, it may not be possible to examine cutaneous sensation, but some idea of proprioceptive function may be gained by noting the patient’s best performance of movements requiring balance and precision.

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140 Leg

Trunk

Post-central cortex Arm

Thalamus

Face

Some patients present with sensory symptoms that do not fit an anatomic localization and are accompanied by either no abnormalities or gross inconsistencies on examination. The examiner should consider whether the sensory symptoms are a disguised request for help with psychologic or situational problems. Sensory examination of a patient who has no neurologic complaints can be brief and consist of pinprick, touch, and vibration testing in the hands and feet plus evaluation of stance and gait, including the Romberg maneuver (Chap. V6). Evaluation of stance and gait also tests the integrity of motor and cerebellar systems.

PART 2 Cardinal Manifestations and Presentation of Diseases

Primary Sensation  The sense of pain usually is tested with a clean pin, which is then discarded. The patient Internal is asked to close the eyes and focus on the pricking or capsule unpleasant quality of the stimulus, not just the pressure Ventral or touch sensation elicited. Areas of hypalgesia should be posterolateral mapped by proceeding radially from the most hypalgesic nucleus of site. Temperature sensation to both hot and cold is best thalamus tested with small containers filled with water of the desired MIDBRAIN temperature. An alternative way to test cold sensation is to touch a metal object, such as a tuning fork at room temperature, to the skin. For testing warm temperatures, the tuning fork or another metal object may be held under warm water of the desired temperature and then used. The Principal sensory PONS appreciation of both cold and warmth should be tested nucleus of V because different receptors respond to each. Touch usually Medial lemniscus is tested with a wisp of cotton or a fine camel hair brush, minimizing pressure on the skin. In general, it is better to avoid testing touch on hairy skin because of the profusion Nucleus of funiculus gracilis of the sensory endings that surround each hair follicle. The Nucleus of patient is tested with the eyes closed and should indicate MEDULLA funiculus cuneatus as soon as the stimulus is perceived, indicating its location. Spinothalamic tract Joint position testing is a measure of proprioception. Nucleus of With the patient’s eyes closed, joint position is tested in spinal tract V the distal interphalangeal joint of the great toe and finPosterior column gers. The digit is held by its sides, distal to the joint being fibers tested, and moved passively while more proximal joints are stabilized—the patient indicates the change in position or SPINAL CORD direction of movement. If errors are made, more proximal joints are tested. A test of proximal joint position sense, priSpinothalamic tract marily at the shoulder, is performed by asking the patient to bring the two index fingers together with arms extended and eyes closed. Normal individuals can do this accurately, FIGURE 22-1  The main somatosensory pathways. The spinothalamic tract (pain, thermal with errors of 1 cm or less. sense) and the posterior column–lemniscal system (touch, pressure, joint position) are shown. The sense of vibration is tested with an oscillating tuning Offshoots from the ascending anterolateral fasciculus (spinothalamic tract) to nuclei in the fork that vibrates at 128 Hz. Vibration is tested over bony medulla, pons, and mesencephalon and nuclear terminations of the tract are indicated. (From AH Ropper, MA Samuels: Adams and Victor’s Principles of Neurology, 9th ed. New York, McGraw- points, beginning distally; in the feet, it is tested over the dorsal surface of the distal phalanx of the big toes and at Hill, 2009.) the malleoli of the ankles, and in the hands, it is tested In patients with sensory complaints, testing should begin in the dorsally at the distal phalanx of the fingers. If abnormalities are found, center of the affected region and proceed radially until sensation is per- more proximal sites should be examined. Vibratory thresholds at the ceived as normal. The distribution of any abnormality is defined and same site in the patient and the examiner may be compared for control compared to root and peripheral nerve territories (Figs. 22-2 and 22-3). purposes. TABLE 22-1  Testing Primary Sensation SENSE Pain Temperature, heat Temperature, cold Touch

TEST DEVICE Pinprick Warm metal object Cold metal object Cotton wisp, fine brush

Vibration

Tuning fork, 128 Hz

Joint position

Passive movement of specific joints

ENDINGS ACTIVATED Cutaneous nociceptors Cutaneous thermoreceptors for hot Cutaneous thermoreceptors for cold Cutaneous mechanoreceptors, also naked endings Mechanoreceptors, especially pacinian corpuscles Joint capsule and tendon endings, muscle spindles

FIBER SIZE MEDIATING Small Small Small Large and small

CENTRAL PATHWAY SpTh, also D SpTh SpTh Lem, also D and SpTh

Large

Lem, also D

Large

Lem, also D

Abbreviations: D, diffuse ascending projections in ipsilateral and contralateral anterolateral columns; Lem, posterior column and lemniscal projection, ipsilateral; SpTh, spinothalamic projection, contralateral.

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141 I

} occipital nerves

Greater Lesser n.

II

Great auricular n. III

Great auricular n.

Ant. cut. n. of neck

Ant. cut. n. of neck C5 C6

Supraclavicular n’s. Axillary n. (circumflex)

Ant. Lat.

cut.

rami of thor.

rami

n’s.

Ilioinguinal n.

Med. cut. n. of arm & intercostobrachial n.

Med. cut. n. of forearm

Femoral branch of genitofemoral n. (lumbo-inguinal n.)

Iliohypogastric n.

Radial n.

Genital branch of genitofem. n.

Median n.

Ulnar n.

Dorsal n. of penis

Lat. cut. n. of thigh Intermed. & med. cut. n’s. of thigh (from femoral n.)

Post cut. n. of arm (from radial n.) Lower Lat. cut. of arm (from radial n.) Iliohypogastric n.

Obturator n. Lat. cut. n. of calf (from common peroneal n.)

Superficial peroneal n. (from common peroneal n.)

Deep peroneal n. (from common peroneal n.)

Post cut. n. of thigh

Lat. cut. n.of calf (from common femoral n.)

Sural n. (from tibial n.)

Lat. cut. n. of forearm (from musculocut n.)

Med. cut. n. of forearm

Radial n.

Ulnar n. Inf. lat. cluneal n’s. Median n. Obturator n.

Med. cut. n. of thigh (from femoral n.) Lat. plantar n.

Saphenous n. (from femoral n.)

Med. plantar n.

Lat. plantar n. Superficial peroneal n.

Superficial peroneal n. (from common peroneal n.) Sural n. (from tibial n.)

Med. & lat. plantar n’s. (from posttibial n.)

Post. cut. n. of forearm (from radial n.)

Inf. med. n. of thigh

Scrotal branch of perineal n.

Saphenous n. (from femoral n.)

Med. cut. n. of arm & intercostobrachial n.

L1

S1 Post. rami of lumbar sacral & coccygeal n’s.

Inf. med. cluneal n.

Supraclavicular n’s.

Numbness, Tingling, and Sensory Loss

Lat. cut. of forearm (from musculocut. n.)

T2 3 4 5 6 7 8 9 10 11 12

T1 Post. cut. rami Lat. of cut. thor.rami n’s.

CHAPTER 22

Lower lat. cut. n. of arm (from radial n.)

cut.

T2 3 4 5 6 7 8 9 10 11 12

Axillary n. (circumflex)

Saphenous n. Calcanean branches of tibial & sural n’s.

Sural n.

Calcanean branches of sural & tibial n’s.

FIGURE 22-2  The cutaneous fields of peripheral nerves. (Reproduced by permission from W Haymaker, B Woodhall: Peripheral Nerve Injuries, 2nd ed. Philadelphia, Saunders, 1953.)

Quantitative Sensory Testing  Effective sensory testing devices are commercially available. Quantitative sensory testing is particularly useful for serial evaluation of cutaneous sensation in clinical trials. Threshold testing for touch and vibratory and thermal sensation is the most widely used application.

C2 C3 C3 C4

T2

T2 T4

C6

T8

T10

T10

T12 L1 L L3 2 S1 S2

L1 C8

C5

T8

T12 C7

Cortical Sensation  The most commonly used tests of cortical

T6

T6

T1

C4

T4

C5

S5 S4

T2 T1 C6 C8

C7

S3

L2 S2 L3 L3 L4 L5

S1

L4

L5

L5

S1

FIGURE 22-3  Distribution of the sensory spinal roots on the surface of the body (dermatomes). (From D Sinclair: Mechanisms of Cutaneous Sensation. Oxford, UK, Oxford University Press, 1981; with permission from Dr. David Sinclair.)

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function are two-point discrimination, touch localization, and bilateral simultaneous stimulation and tests for graphesthesia and stereognosis. Abnormalities of these sensory tests, in the presence of normal primary sensation in an alert cooperative patient, signify a lesion of the parietal cortex or thalamocortical projections. If primary sensation is altered, these cortical discriminative functions usually will be abnormal also. Comparisons should always be made between analogous sites on the two sides of the body because the deficit with a specific parietal lesion is likely to be unilateral. Two-point discrimination is tested with special calipers, the points of which may be set from 2 mm to several centimeters apart and then applied simultaneously to the test site. On the fingertips, a normal individual can distinguish about a 3-mm separation of points. Touch localization is performed by light pressure for an instant with the examiner’s fingertip or a wisp of cotton wool; the patient, whose eyes are closed, is required to identify the site of touch. Bilateral simultaneous stimulation at analogous sites (e.g., the dorsum of both hands) can be carried out to determine whether the perception of touch is extinguished consistently on one side (extinction or neglect). Graphesthesia refers to the capacity to recognize, with eyes closed, letters or numbers drawn by the examiner’s fingertip on the palm of the hand. Once again, interside comparison is of prime importance. Inability to recognize numbers or letters is termed agraphesthesia.

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Stereognosis refers to the ability to identify common objects by palpation, recognizing their shape, texture, and size. Common standard objects such as keys, paper clips, and coins are best used. Patients with normal stereognosis should be able to distinguish a dime from a penny and a nickel from a quarter without looking. Patients should feel the object with only one hand at a time. If they are unable to identify it in one hand, it should be placed in the other for comparison. Individuals who are unable to identify common objects and coins in one hand but can do so in the other are said to have astereognosis of the abnormal hand.

■■LOCALIZATION OF SENSORY ABNORMALITIES

PART 2 Cardinal Manifestations and Presentation of Diseases

Sensory symptoms and signs can result from lesions at many different levels of the nervous system from the parietal cortex to the peripheral sensory receptor. Noting their distribution and nature is the most important way to localize their source. Their extent, configuration, symmetry, quality, and severity are the key observations. Dysesthesias without sensory findings by examination may be difficult to interpret. To illustrate, tingling dysesthesias in an acral distribution (hands and feet) can be systemic in origin, for example, secondary to hyperventilation, or induced by a medication such as acetazolamide. Distal dysesthesias can also be an early event in an evolving polyneuropathy or may herald a myelopathy, such as from vitamin B12 deficiency. Sometimes, distal dysesthesias have no definable basis. In contrast, dysesthesias that correspond in distribution to that of a particular peripheral nerve structure denote a lesion at that site. For instance, dysesthesias restricted to the fifth digit and the adjacent onehalf of the fourth finger on one hand reliably point to disorder of the ulnar nerve, most commonly at the elbow.

Nerve and Root  In focal nerve trunk lesions, sensory abnor-

malities are readily mapped and generally have discrete boundaries (Figs. 22-2 and 22-3). Root (“radicular”) lesions frequently are accompanied by deep, aching pain along the course of the related nerve trunk. With compression of a fifth lumbar (L5) or first sacral (S1) root, as from a ruptured intervertebral disk, sciatica (radicular pain relating to the sciatic nerve trunk) is a common manifestation (Chap. 14). With a lesion affecting a single root, sensory deficits may be minimal or absent because adjacent root territories overlap extensively. Isolated mononeuropathies may cause symptoms beyond the territory supplied by the affected nerve, but abnormalities on examination typically are confined to appropriate anatomic boundaries. In multiple mononeuropathies, symptoms and signs occur in discrete territories supplied by different individual nerves and—as more nerves are affected—may simulate a polyneuropathy if deficits become confluent. With polyneuropathies, sensory deficits are generally graded, distal, and symmetric in distribution (Chap. 438). Dysesthesias, followed by numbness, begin in the toes and ascend symmetrically. When dysesthesias reach the knees, they usually also have appeared in the fingertips. The process is nerve length–dependent, and the deficit is often described as “stocking-glove” in type. Involvement of both hands and feet also occurs with lesions of the upper cervical cord or the brainstem, but an upper level of the sensory disturbance may then be found on the trunk and other evidence of a central lesion may be present, such as sphincter involvement or signs of an upper motor neuron lesion (Chap. 21). Although most polyneuropathies are pansensory and affect all modalities of sensation, selective sensory dysfunction according to nerve fiber size may occur. Small-fiber polyneuropathies are characterized by burning, painful dysesthesias with reduced pinprick and thermal sensation but with sparing of proprioception, motor function, and deep tendon reflexes. Touch is involved variably; when it is spared, the sensory pattern is referred to as exhibiting sensory dissociation. Sensory dissociation may occur also with spinal cord lesions. Large-fiber polyneuropathies are characterized by vibration and position sense deficits, imbalance, absent tendon reflexes, and variable motor dysfunction but preservation of most cutaneous sensation. Dysesthesias, if present at all, tend to be tingling or bandlike in quality. Sensory neuronopathy (or ganglionopathy) is characterized by widespread but asymmetric sensory loss occurring in a non-lengthdependent manner so that it may occur proximally or distally and in

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the arms, legs, or both. Pain and numbness progress to sensory ataxia and impairment of all sensory modalities with time. This condition is usually paraneoplastic or idiopathic in origin (Chaps. 90 and 438) or related to an autoimmune disease, particularly Sjögren’s syndrome.

Spinal Cord  (See also Chap. 434) If the spinal cord is transected,

all sensation is lost below the level of transection. Bladder and bowel function also are lost, as is motor function. Lateral hemisection of the spinal cord produces the Brown-Séquard syndrome, with absent pain and temperature sensation contralaterally and loss of proprioceptive sensation and power ipsilaterally below the lesion (see Figs. 22-1 and 434-1); ipsilateral pain or hyperesthesia may also occur. Numbness or paresthesias in both feet may arise from a spinal cord lesion; this is especially likely when the upper level of the sensory loss extends to the trunk. When all extremities are affected, the lesion is probably in the cervical region or brainstem unless a peripheral neuropathy is responsible. The presence of upper motor neuron signs (Chap. 21) supports a central lesion; a hyperesthetic band on the trunk may suggest the level of involvement. A dissociated sensory loss can reflect spinothalamic tract involvement in the spinal cord, especially if the deficit is unilateral and has an upper level on the torso. Bilateral spinothalamic tract involvement occurs with lesions affecting the center of the spinal cord, such as in syringomyelia. There is a dissociated sensory loss with impairment of pinprick and temperature appreciation but relative preservation of light touch, position sense, and vibration appreciation. Dysfunction of the posterior columns in the spinal cord or of the posterior root entry zone may lead to a bandlike sensation around the trunk or a feeling of tight pressure in one or more limbs. Flexion of the neck sometimes leads to an electric shock–like sensation that radiates down the back and into the legs (Lhermitte’s sign) in patients with a cervical lesion affecting the posterior columns, such as from multiple sclerosis, cervical spondylosis, or recent irradiation to the cervical region.

Brainstem  Crossed patterns of sensory disturbance, in which one

side of the face and the opposite side of the body are affected, localize to the lateral medulla. Here a small lesion may damage both the ipsilateral descending trigeminal tract and the ascending spinothalamic fibers subserving the opposite arm, leg, and hemitorso (see “Lateral medullary syndrome” in Fig. 419-7). A lesion in the tegmentum of the pons and midbrain, where the lemniscal and spinothalamic tracts merge, causes pansensory loss contralaterally.

Thalamus  Hemisensory disturbance with tingling numbness from head to foot is often thalamic in origin but also can arise from the anterior parietal region. If abrupt in onset, the lesion is likely to be due to a small stroke (lacunar infarction), particularly if localized to the thalamus. Occasionally, with lesions affecting the VPL nucleus or adjacent white matter, a syndrome of thalamic pain, also called Déjerine-Roussy syndrome, may ensue. The persistent, unrelenting unilateral pain often is described in dramatic terms. Cortex  With lesions of the parietal lobe involving either the cortex or the subjacent white matter, the most prominent symptoms are contralateral hemineglect, hemi-inattention, and a tendency not to use the affected hand and arm. On cortical sensory testing (e.g., two-point discrimination, graphesthesia), abnormalities are often found but primary sensation is usually intact. Anterior parietal infarction may present as a pseudothalamic syndrome with contralateral loss of primary sensation from head to toe. Dysesthesias or a sense of numbness and, rarely, a painful state may also occur. Focal Sensory Seizures  These seizures generally are due to

lesions in the area of the postcentral or precentral gyrus. The principal symptom of focal sensory seizures is tingling, but additional, more complex sensations may occur, such as a rushing feeling, a sense of warmth, or a sense of movement without detectable motion. Symptoms typically are unilateral; commonly begin in the arm or hand, face, or foot; and often spread in a manner that reflects the cortical

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representation of different bodily parts, as in a Jacksonian march. Their duration is variable; seizures may be transient, lasting only for seconds, or persist for an hour or more. Focal motor features may supervene, often becoming generalized with loss of consciousness and tonic-clonic jerking.

Psychogenic Symptoms  Sensory symptoms may have a psycho-

Brazis P, Masdeu JC, Biller J: Localization in Clinical Neurology, 7th ed. Philadelphia, Lippincott William & Wilkins, 2016. Campbell WW: DeJong’s The Neurological Examination, 7th ed. Philadelphia, Lippincott William & Wilkins, 2012.

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■■FURTHER READING

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CHAPTER 23

genic basis. Such symptoms may be generalized or have an anatomic boundary that is difficult to explain neurologically, for example, circumferentially at the groin or shoulder or around a specific joint. Pain is common, but the nature and intensity of any sensory disturbances are variable. The diagnosis should not be one of exclusion but based on suggestive findings that are otherwise difficult to explain, such as midline splitting of impaired vibration, pinprick, or light touch appreciation; variability or poor reproducibility of sensory deficits; or normal performance of tasks requiring sensory input that is seemingly abnormal on formal testing, such as good performance with eyes closed of the finger-to-nose test despite an apparent loss of position sense in the upper limb. The side with abnormal sensation may be confused when the limbs are placed in an unusual position, such as crossed behind the back. Sensory complaints should not be regarded as psychogenic simply because they are unusual.

adjustments maintain standing balance: long latency responses are measurable in the leg muscles, beginning 110 milliseconds after a perturbation. Forward motion of the center of mass provides propulsive force for stepping, but failure to maintain the center of mass within stability limits results in falls. The anatomic substrate for dynamic balance has not been well defined, but the vestibular nucleus and midline cerebellum contribute to balance control in animals. Patients with damage to these structures have impaired balance while standing and walking. Standing balance depends on good-quality sensory information about the position of the body center with respect to the environment, support surface, and gravitational forces. Sensory information for postural control is primarily generated by the visual system, the vestibular system, and proprioceptive receptors in the muscle spindles and joints. A healthy redundancy of sensory afferent information is generally available, but loss of two of the three pathways is sufficient to compromise standing balance. Balance disorders in older individuals sometimes result from multiple insults in the peripheral sensory systems (e.g., visual loss, vestibular deficit, peripheral neuropathy) that critically degrade the quality of afferent information needed for balance stability. Older patients with cognitive impairment appear to be particularly prone to falls and injury. There is a growing body of literature on the use of attentional resources to manage gait and balance. Walking is generally considered to be unconscious and automatic, but the ability to walk while attending to a cognitive task (dual-task walking) may be compromised in the elderly. Older patients with deficits in executive function may have particular difficulty in managing the attentional resources needed for dynamic balance when distracted.

DISORDERS OF GAIT

23

Gait Disorders, Imbalance, and Falls Jessica M. Baker, Lewis R. Sudarsky

PREVALENCE, MORBIDITY, AND MORTALITY

Gait and balance problems are common in the elderly and contribute to the risk of falls and injury. Gait disorders have been described in 15% of individuals aged >65. By age 80 one person in four will use a mechanical aid to assist with ambulation. Among those aged ≥85, the prevalence of gait abnormality approaches 40%. In epidemiologic studies, gait disorders are consistently identified as a major risk factor for falls and injury.

Disorders of gait may be attributed to neurological and non-neurological causes, though significant overlap often exists. The antalgic gait results from avoidance of pain associated with weight-bearing and is commonly seen in osteoarthritis. Asymmetry is a common feature of gait disorders due to contractures and other orthopedic deformities. Impaired vision rounds out the list of common non-neurological causes of gait disorders. Neurologic gait disorders are disabling and equally important to address. The heterogeneity of gait disorders observed in clinical practice reflects the large network of neural systems involved in the task. Walking is vulnerable to neurologic disease at every level. Gait disorders have been classified descriptively on the basis of abnormal physiology and biomechanics. One problem with this approach is that many failing gaits look fundamentally similar. This overlap reflects common patterns of adaptation to threatened balance stability and declining performance. The gait disorder observed clinically must be viewed as the product of a neurologic deficit and a functional adaptation. Unique features of the failing gait are often overwhelmed by the adaptive response. Some common patterns of abnormal gait are summarized next. Gait disorders can also be classified by etiology (Table 23-1).

ANATOMY AND PHYSIOLOGY

An upright bipedal gait depends on the successful integration of postural control and locomotion. These functions are widely distributed in the central nervous system. The biomechanics of bipedal walking are complex, and the performance is easily compromised by a neurologic deficit at any level. Command and control centers in the brainstem, cerebellum, and forebrain modify the action of spinal pattern generators to promote stepping. While a form of “fictive locomotion” can be elicited from quadrupedal animals after spinal transection, this capacity is limited in primates. Step generation in primates is dependent on locomotor centers in the pontine tegmentum, midbrain, and subthalamic region. Locomotor synergies are executed through the reticular formation and descending pathways in the ventromedial spinal cord. Cerebral control provides a goal and purpose for walking and is involved in avoidance of obstacles and adaptation of locomotor programs to context and terrain. Postural control requires the maintenance of the center of mass over the base of support through the gait cycle. Unconscious postural

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TABLE 23-1  Etiology of Gait Disorders ETIOLOGY Sensory deficits Myelopathy Multiple infarcts Parkinsonism Cerebellar degeneration Hydrocephalus Toxic/metabolic causes Psychogenic causes Other Unknown causes Total

NO. OF CASES 22 20 18 14 8 8 3 4 6 17 120

PERCENT 18.3 16.7 15.0 11.7 6.7 6.7 2.5 3.3 5.0 14.2 100

Source: Reproduced with permission from J Masdeu et al: Gait Disorders of Aging. Lippincott Raven, 1997.

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■■CAUTIOUS GAIT

The term cautious gait is used to describe the patient who walks with an abbreviated stride, widened base and lowered center of mass, as if walking on a slippery surface. This disorder is both common and nonspecific. It is, in essence, an adaptation to a perceived postural threat. There may be an associated fear of falling. This disorder can be observed in more than one-third of older patients with gait impairment. Physical therapy often improves walking to the degree that follow-up observation may reveal a more specific underlying disorder.

■■STIFF-LEGGED GAIT PART 2 Cardinal Manifestations and Presentation of Diseases

Spastic gait is characterized by stiffness in the legs, an imbalance of muscle tone, and a tendency to circumduct and scuff the feet. The disorder reflects compromise of corticospinal command and overactivity of spinal reflexes. The patient may walk on the toes. In extreme instances, the legs cross due to increased tone in the adductors (“scissoring” gait). Upper motor neuron signs are present on physical examination. The disorder may be cerebral or spinal in origin. Myelopathy from cervical spondylosis is a common cause of spastic or spastic-ataxic gait in the elderly. Demyelinating disease and trauma are the leading causes of myelopathy in younger patients. In chronic progressive myelopathy of unknown cause, a workup with laboratory and imaging tests may establish a diagnosis. A structural lesion, such as a tumor or a spinal vascular malformation, should be excluded with appropriate testing. Spinal cord disorders are discussed in detail in Chap. 434. With cerebral spasticity, asymmetry is common, the upper extremities are usually involved, and dysarthria is often an associated feature. Common causes include vascular disease (stroke), multiple sclerosis, motor neuron disease, and perinatal nervous system injury (cerebral palsy). Other stiff-legged gaits include dystonia (Chap. 428) and stiffperson syndrome (Chap. 90). Dystonia is a disorder characterized by sustained muscle contractions resulting in repetitive twisting movements and abnormal posture. It often has a genetic basis. Dystonic spasms can produce plantar flexion and inversion of the feet, sometimes with torsion of the trunk. In autoimmune stiff-person syndrome, exaggerated lordosis of the lumbar spine and overactivation of antagonist muscles restrict trunk and lower-limb movement and result in a wooden or fixed posture.

■■PARKINSONISM, FREEZING GAIT, AND OTHER MOVEMENT DISORDERSS

Parkinson’s disease (Chap. 427) is common, affecting 1% of the population >55 years of age. The stooped posture and shuffling gait are characteristic and distinctive features. Patients sometimes accelerate (festinate) with walking, display retropulsion, or exhibit a tendency to turn en bloc. The step-to-step variability of the parkinsonian gait also contributes to fall risk. Dopamine replacement improves step length, arm swing, turning speed, and gait initiation. There is increasing evidence that deficits in cholinergic circuits in the pedunculopontine nucleus and cortex contribute to the gait disorder of Parkinson’s disease. Cholinesterase inhibitors such as donepezil and rivastigmine have been shown in early studies to significantly decrease gait variability, instability, and fall frequency, even in the absence of cognitive impairment, perhaps through improvement in attention. Freezing is defined as a brief, episodic absence of forward progression of the feet, despite the intention to walk. Freezing may be triggered by approaching a narrow doorway or crowd, may be overcome by visual cueing, and contributes to fall risk. Gait freezing is present in approximately one-quarter of Parkinson’s patients within 5 years of onset, and its frequency increases further over time. In treated patients, an end-of-dose gait freezing is a common problem that may improve with more frequent administration of dopaminergic drugs, or with use of monoamine oxidase type B inhibitors such as rasagiline or selegiline (Chap. 427). Freezing of gait is also common in other neurodegenerative disorders associated with parkinsonism, including progressive supranuclear palsy (PSP), multiple-system atrophy, and corticobasal degeneration.

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Patients with these disorders frequently present with axial stiffness, postural instability, and a shuffling, freezing gait while lacking the characteristic pill-rolling tremor of Parkinson’s disease. The gait of PSP is typically more erect compared with the stooped posture of typical Parkinson’s disease, and falls within the first year also suggest the possibility of, PSP. Hyperkinetic movement disorders also produce characteristic and recognizable disturbances in gait. In Huntington’s disease (Chap. 428), the unpredictable occurrence of choreic movements gives the gait a dancing quality. Tardive dyskinesia is the cause of many odd, stereotypic gait disorders seen in patients chronically exposed to antipsychotics and other drugs that block the D2 dopamine receptor. Orthostatic tremor is a high frequency, low amplitude tremor predominantly involving the lower extremities. Patients often report shakiness or unsteadiness on standing, and improvement with sitting or walking. Falls are common. The tremor is often only appreciable by palpating the legs while standing.

■■FRONTAL GAIT DISORDER

Frontal gait disorder, also known as higher level gait disorder, is common in the elderly and has a variety of causes. The term is used to describe a shuffling, freezing gait with imbalance, and other signs of higher cerebral dysfunction. Typical features include a wide base of support, a short stride, shuffling along the floor, and difficulty with starts and turns. Many patients exhibit a difficulty with gait initiation that is descriptively characterized as the “slipping clutch” syndrome or gait ignition failure. The term lower-body parkinsonism is also used to describe such patients. Strength is generally preserved, and patients are able to make stepping movements when not standing and maintaining their balance at the same time. This disorder is best considered a higher-level motor control disorder, as opposed to an apraxia (Chap. 26), though the term gait apraxia persists in the literature. The most common cause of frontal gait disorder is vascular disease, particularly subcortical small-vessel disease in the deep frontal white matter and centrum ovale. Over three-quarters of patients with subcortical vascular dementia demonstrate gait abnormalities; decreased arm swing and a stooped posture are particularly prevalent features. The clinical syndrome also includes dysarthria, pseudobulbar affect (emotional disinhibition), increased tone, and hyperreflexia in the lower limbs. Normal pressure (communicating) hydrocephalus (NPH) in adults also presents with a similar gait disorder. Other features of the diagnostic triad (mental changes, incontinence) may be absent in a substantial number of patients. MRI demonstrates ventricular enlargement, an enlarged flow void about the aqueduct, periventricular white-matter change, and high-convexity tightness (disproportionate widening of the sylvian fissures versus the cortical sulci). A lumbar puncture or dynamic test is necessary to confirm a diagnosis of NPH. Neurodegenerative dementias and mass lesions of the frontal lobes cause a similar clinical picture and can be differentiated from vascular disease and hydrocephalus by neuroimaging.

■■CEREBELLAR GAIT ATAXIA

Disorders of the cerebellum have a dramatic impact on gait and balance. Cerebellar gait ataxia is characterized by a wide base of support, lateral instability of the trunk, erratic foot placement, and decompensation of balance when attempting to walk on a narrow base. Difficulty maintaining balance when turning is often an early feature. Patients are unable to walk tandem heel to toe and display truncal sway in narrow-based or tandem stance. They show considerable variation in their tendency to fall in daily life. Causes of cerebellar ataxia in older patients include stroke, trauma, tumor, and neurodegenerative disease such as multiple-system atrophy (Chap. 432) and various forms of hereditary cerebellar degeneration (Chap. 431). A short expansion at the site of the fragile X mutation (fragile X pre-mutation) has been associated with gait ataxia in older men. Alcohol causes an acute and chronic cerebellar ataxia. In patients with ataxia due to cerebellar degeneration, MRI demonstrates the extent and topography of cerebellar atrophy.

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TABLE 23-2  Features of Cerebellar Ataxia, Sensory Ataxia, and Frontal Gait Disorders FEATURE Base of support Velocity Stride Romberg test

Falls

SENSORY ATAXIA Narrow base, looks down Slow Regular with path deviation Unsteady, falls +/–

FRONTAL GAIT Wide-based Very slow Short, shuffling +/– Normal

Normal Unsteady +

Normal +/– +++

Late event

Frequent

Hesitant Hesitant, multistep ++++ Poor postural synergies rising from a chair Frequent

As reviewed earlier in this chapter, balance depends on high-quality afferent information from the visual and the vestibular systems and proprioception. When this information is lost or degraded, balance during locomotion is impaired and instability results. The sensory ataxia of tabetic neurosyphilis is a classic example. The contemporary equivalent is the patient with neuropathy affecting large fibers. Vitamin B12 deficiency is a treatable cause of large-fiber sensory loss in the spinal cord and peripheral nervous system. Joint position and vibration sense are diminished in the lower limbs. The stance in such patients is destabilized by eye closure; they often look down at their feet when walking and do poorly in the dark. Table 23-2 compares sensory ataxia with cerebellar ataxia and frontal gait disorder.

■■NEUROMUSCULAR DISEASE

Patients with neuromuscular disease often have an abnormal gait, occasionally as a presenting feature. With distal weakness (peripheral neuropathy), the step height is increased to compensate for foot drop, and the sole of the foot may slap on the floor during weight acceptance, termed the steppage gait. Patients with myopathy or muscular dystrophy more typically exhibit proximal weakness. Weakness of the hip girdle may result in some degree of excess pelvic sway during locomotion. The stooped posture of lumbar spinal stenosis ameliorates pain from the compression of the cauda equina occurring with a more upright posture while walking, and may mimic early parkinsonism.

■■TOXIC AND METABOLIC DISORDERS

Chronic toxicity from medications and metabolic disturbances can impair motor function and gait. Examination may reveal mental status changes, asterixis or myoclonus. Static equilibrium is disturbed, and such patients are easily thrown off balance. Disequilibrium is particularly evident in patients with chronic renal disease and those with hepatic failure, in whom asterixis may impair postural support. Sedative drugs, especially neuroleptics and long-acting benzodiazepines, affect postural control and increase the risk for falls. These disorders are especially important to recognize because they are often treatable.

■■FUNCTIONAL GAIT DISORDER

Functional disorders (formerly “psychogenic”) are common in neurologic practice, and the presentation often involves gait. The hallmark of a functional gait disorder is an internal inconsistency of deficits that may be incompatible with a neurological deficit. For example, odd gyrations of posture with wastage of muscular energy (astasia–abasia) appear superficially unsteady, yet in reality require significant postural control. Falls are rare, and there are often discrepancies between examination findings and the patient’s functional status. Extreme slow motion, an inappropriately overcautious gait, and dramatic fluctuations over time may improve with distraction, keeping in mind that numerous organic neurological diseases are also paroxysmal in nature. Preceding stress or trauma is variably present, and its absence no longer precludes the diagnosis of a functional neurological disorder. Functional gait disorders are among the most dramatic encountered, and should be differentiated from the slowness and psychomotor retardation seen in certain patients with major depression.

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APPROACH TO THE PATIENT

Slowly Progressive Disorder of Gait When reviewing the history, it is helpful to inquire about the onset and progression of disability. Initial awareness of an unsteady gait often follows a fall. Stepwise evolution or sudden progression suggests vascular disease. Gait disorder may be associated with urinary urgency and incontinence, particularly in patients with cervical spine disease or hydrocephalus. It is always important to review the use of alcohol and medications that affect gait and balance. Information on localization derived from the neurologic examination can be helpful in narrowing the list of possible diagnoses. Gait observation provides an immediate sense of the patient’s degree of disability. Arthritic and antalgic gaits are recognized by observation, though neurologic and orthopedic problems may coexist. Characteristic patterns of abnormality are sometimes seen, though, as stated previously, failing gaits often look fundamentally similar. Cadence (steps per minute), velocity, and stride length can be recorded by timing a patient over a fixed distance. Watching the patient rise from a chair provides a good functional assessment of balance. Brain imaging studies may be informative in patients with an undiagnosed disorder of gait. MRI is sensitive for cerebral lesions of vascular or demyelinating disease and is a good screening test for occult hydrocephalus. Patients with recurrent falls are at risk for subdural hematoma. As mentioned earlier, many elderly patients with gait and balance difficulty have white matter abnormalities in the periventricular region and centrum semiovale. While these lesions may be an incidental finding, a substantial burden of white matter disease will ultimately impact cerebral control of locomotion.

Gait Disorders, Imbalance, and Falls

■■SENSORY ATAXIA

CHAPTER 23

Heel → shin Initiation Turns Postural instability

CEREBELLAR ATAXIA Wide-based Variable Irregular, lurching +/– Abnormal

DISORDERS OF BALANCE ■■DEFINITION, ETIOLOGY, AND MANIFESTATIONS

Balance is the ability to maintain equilibrium—a dynamic state in which one’s center of mass is controlled with respect to the lower extremities, gravity and the support surface despite external perturbations. The reflexes required to maintain upright posture require input from cerebellar, vestibular, and somatosensory systems; the premotor cortex, corticospinal and reticulospinal tracts mediate output to axial and proximal limb muscles. These responses are physiologically complex, and the anatomic representation they entail is not well understood. Failure can occur at any level and presents as difficulty maintaining posture while standing and walking. The history and physical examination may differentiate underlying causes of imbalance. Patients with cerebellar ataxia do not generally complain of dizziness, though balance is visibly impaired. Neurologic examination reveals a variety of cerebellar signs. Postural compensation may prevent falls early on, but falls are inevitable with disease progression. The progression of neurodegenerative ataxia is often measured by the number of years to loss of stable ambulation. Vestibular disorders (Chap. 19) have symptoms and signs that fall into three categories: (1) vertigo (the subjective inappropriate perception or illusion of movement); (2) nystagmus (involuntary eye

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PART 2 Cardinal Manifestations and Presentation of Diseases

movements); and (3) impaired standing balance. Not every patient has all manifestations. Patients with vestibular deficits related to ototoxic drugs may lack vertigo or obvious nystagmus, but their balance is impaired on standing and walking, and they cannot navigate in the dark. Laboratory testing is available to investigate vestibular deficits. Somatosensory deficits also produce imbalance and falls. There is often a subjective sense of insecure balance and fear of falling. Postural control is compromised by eye closure (Romberg’s sign); these patients also have difficulty navigating in the dark. A dramatic example is provided by the patient with autoimmune subacute sensory neuropathy, which is sometimes a paraneoplastic disorder (Chap. 90). Compensatory strategies enable such patients to walk in the virtual absence of proprioception, but the task requires active visual monitoring. Patients with higher-level disorders of equilibrium have difficulty maintaining balance in daily life and may present with falls. Their awareness of balance impairment may be reduced. Patients taking sedating medications are in this category.

■■FALLS

Falls are common in the elderly; over one-third of people aged >65 who are living in the community fall each year. This number is even higher in nursing homes and hospitals. Elderly people are not only at higher risk for falls, but are more likely to suffer serious complications due to medical comorbidities such as osteoporosis. Hip fractures result in hospitalization, can lead to nursing home admission, and are associated with an increased mortality risk in the subsequent year. Falls may result in brain or spinal injury, the history of which may be difficult for the patient to provide. The proportion of spinal cord injuries due to falls in individuals aged >65 years has doubled in the last decade, perhaps due to increasing activity in this age group. Some falls result in a prolonged time lying on the ground; fractures and CNS injury are a particular concern in this context. For each person who is physically disabled, there are others whose functional independence is limited by anxiety and fear of falling. Nearly one in five elderly individuals voluntarily restricts his or her activity because of fear of falling. With loss of ambulation, the quality of life diminishes, and rates of morbidity and mortality increase.

■■RISK FACTORS FOR FALLS

Risk factors for falls may be intrinsic (e.g., gait and balance disorders) or extrinsic (e.g., polypharmacy, and environmental factors); some risk factors are modifiable. The presence of multiple risk factors is associated with a substantially increased risk of falls. (Table 23-3) summarizes a meta-analysis of studies establishing the principal risk factors for falls. Polypharmacy (use of four or more prescription medications) has also been identified as an important risk factor.

■■ASSESSMENT OF THE PATIENT WITH FALLS

The most productive approach is to identify the high-risk patient prospectively, before there is a serious injury. All community-dwelling TABLE 23-3  Meta-Analysis of Risk Factors for Falls in Older Persons RISK FACTOR Muscle weakness History of falls Gait deficit Balance deficit Use assistive device Visual deficit Arthritis Impaired ADL Depression Cognitive impairment Age >80 years

MEAN RR (OR) 4.4 3.0 2.9 2.9 2.6 2.5 2.4 2.3 2.2 1.8 1.7

RANGE 1.5–10.3 1.7–7.0 1.3–5.6 1.6–5.4 1.2–4.6 1.6–3.5 1.9–2.9 1.5–3.1 1.7–2.5 1.0–2.3 1.1–2.5

Abbreviations: ADL, activity of daily living; OR, odds ratio from retrospective studies; RR, relative risk from prospective studies. Source: Reproduced with permission from Guideline for the Prevention of Falls in Older Persons. J Am Geriatr Soc 49:664, 2001.

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adults should be asked about falls at least annually. The Timed Up and Go (“TUG”) test involves timing a patient as they stand up from a chair, walk 10 ft, turn, then sit down. Patients with a history of falls, or those requiring >12 s to complete the TUG test, are high risk for falls and should undergo further assessment.

History  The history surrounding a fall is often problematic or incomplete, and the underlying mechanism or cause may be difficult to establish in retrospect. Patients should be queried about any provoking factors (including head turn, standing) or prodromal symptoms, such as dizziness, vertigo, pre-syncopal symptoms or focal weakness. A history of baseline mobility and medical comorbidities should be elicited. Patients at particular risk include those with mental status changes or dementia. Medications should be reviewed, with particular attention to neuroleptics, benzodiazepines, anti-depressants, anti-arrhythmics, and diuretics, all of which are associated with an increased risk of falls. It is equally important to distinguish mechanical falls (those caused by tripping or slipping) due to purely extrinsic or environmental factors from those in which a modifiable intrinsic factor contributes. Recurrent falls may indicate an underlying gait or balance disorder. Falls associated with loss of consciousness (syncope, seizure) may require appropriate cardiac or neurological evaluation and intervention (Chaps. 18 and 418), though a patient’s report of change in consciousness may be unreliable. Physical Examination  Examination of the patient with falls should include a basic cardiac examination, including orthostatic blood pressure if indicated by history, and observation of any orthopedic abnormalities. Mental status is easily assessed while obtaining a history from the patient; the remainder of the neurological examination should include visual acuity, strength and sensation in the lower extremities, muscle tone, and cerebellar function, with particular attention to gait and balance as described earlier in this chapter. Fall Patterns  The description of a fall event may provide further clues to the underlying etiology. While there is no standard nosology of falls, some common clinical patterns may emerge and provide a clue. DROP ATTACKS AND COLLAPSING FALLS  Drop attacks and collapsing falls are associated with a sudden loss of postural tone. Patients may report that their legs just “gave out” underneath them, or that they “collapsed in a heap.” Syncope or orthostatic hypotension may be a factor in some such falls. Neurological causes are relatively rare, but include atonic seizures, myoclonus and intermittent obstruction of the foramen of Monro by a colloid cyst of the third ventricle causing acute obstructive hydrocephalus. An emotional trigger suggests cataplexy. While collapsing falls are more common among older patients with vascular risk factors, drop attacks should not be confused with vertebrobasilar ischemic attacks. TOPPLING FALLS  Some patients maintain tone in antigravity muscles but fall over like a tree trunk, as if postural defenses had disengaged. Causes include cerebellar pathology and lesions of the vestibular system. There may be a consistent direction to such falls. Toppling falls are an early feature of PSP, and a late feature of Parkinson’s disease, once postural instability has developed. Thalamic lesions causing truncal instability (thalamic astasia) may also contribute to this type of fall.

Freezing of gait is seen in Parkinson’s disease and related disorders. The feet stick to the floor and the center of mass keeps moving, resulting in a disequilibrium from which the patient has difficulty recovering, resulting in a forward fall. Similarly, patients with Parkinson’s disease and festinating gait may find their feet unable to keep up and may thus fall forward.

FALLS DUE TO GAIT FREEZING 

FALLS RELATED TO SENSORY LOSS  Patients with somatosensory, visual, or vestibular deficits are prone to falls. These patients have particular difficulty dealing with poor illumination or walking on uneven ground. They often report subjective imbalance, apprehension, and fear of falling. These patients may be especially responsive to a rehabilitation-based intervention. FALLS RELATED TO WEAKNESS  Patients who lack strength in antigravity muscles have difficulty rising from a chair or maintaining their balance

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after a perturbation. These patients are often unable to get up after a fall and may have to remain on the floor for a prolonged period until help arrives. If due to deconditioning, this is often treatable. Resistance strength training can increase muscle mass and leg strength, even for people in their eighties and nineties.

TREATMENT

Interventions to Reduce the Risk of Falls and Injury

American Geriatrics Society, British Geriatrics Society, American Academy of Orthopedic Surgeons Panel on Falls Prevention: Guideline for the Prevention of Falls in Older Persons. J Am Geriatr Soc 49:664, 2001. Nutt JG: Classification of Gait and Balance Disorders. Adv Neurol 87:135, 2001. Pirker W, Katzenschlager R: Gait disorders in adults and the elderly. Wien Klin Wochenschr 129:81, 2017.

24

Confusion and Delirium

S. Andrew Josephson, Bruce L. Miller

Confusion, a mental and behavioral state of reduced comprehension, coherence, and capacity to reason, is one of the most common problems encountered in medicine, accounting for a large number of emergency department visits, hospital admissions, and inpatient consultations. Delirium, a term used to describe an acute confusional state, remains a major cause of morbidity and mortality, costing billions of dollars yearly in health care costs in the United States alone. Despite increased efforts targeting awareness of this condition, delirium often goes unrecognized in the face of evidence that it is usually the cognitive manifestation of serious underlying medical or neurologic illness.

■■CLINICAL FEATURES OF DELIRIUM

A multitude of terms are used to describe patients with delirium, including encephalopathy, acute brain failure, acute confusional state, and postoperative or intensive care unit (ICU) psychosis. Delirium has many clinical manifestations, but it is defined as a relatively acute decline in

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■■FURTHER READING

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Efforts should be made to define the etiology of the gait disorder and the mechanism underlying the falls by a given patient. Orthostatic changes in blood pressure and pulse should be recorded. Rising from a chair and walking should be evaluated for safety. Specific treatment may be possible once a diagnosis is established. Therapeutic intervention is often recommended for older patients at substantial risk for falls, even if no neurologic disease is identified. A home visit to look for environmental hazards can be helpful. A variety of modifications may be recommended to improve safety, including improved lighting and the installation of grab bars and nonslip surfaces. Rehabilitative interventions aim to improve muscle strength and balance stability and to make the patient more resistant to injury. High-intensity resistance strength training with weights and machines is useful to improve muscle mass, even in frail older patients. Improvements realized in posture and gait should translate to reduced risk of falls and injury. Sensory balance training is another approach to improving balance stability. Measurable gains can be made in a few weeks of training, and benefits can be maintained over 6 months by a 10- to 20-min home exercise program. This strategy is particularly successful in patients with vestibular and somatosensory balance disorders. A Tai Chi exercise program has been demonstrated to reduce the risk of falls and injury in patients with Parkinson’s disease.

cognition that fluctuates over hours or days. The hallmark of delirium is a deficit of attention, although all cognitive domains—including memory, executive function, visuospatial tasks, and language—are variably involved. Associated symptoms that may be present in some cases include altered sleep-wake cycles, perceptual disturbances such as hallucinations or delusions, affect changes, and autonomic findings that include heart rate and blood pressure instability. Delirium is a clinical diagnosis that is made only at the bedside. Two subtypes have been described—hyperactive and hypoactive—based on differential psychomotor features. The cognitive syndrome associated with severe alcohol withdrawal (i.e., “delirium tremens”) remains the classic example of the hyperactive subtype, featuring prominent hallucinations, agitation, and hyperarousal, often accompanied by life-threatening autonomic instability. In striking contrast is the hypoactive subtype, exemplified by benzodiazepine intoxication, in which patients are withdrawn and quiet, with prominent apathy and psychomotor slowing. This dichotomy between subtypes of delirium is a useful construct, but patients often fall somewhere along a spectrum between the hyperactive and hypoactive extremes, sometimes fluctuating from one to the other. Therefore, clinicians must recognize this broad range of presentations of delirium to identify all patients with this potentially reversible cognitive disturbance. Hyperactive patients are often easily recognized by their characteristic severe agitation, tremor, hallucinations, and autonomic instability. Patients who are quietly hypoactive are more often overlooked on the medical wards and in the ICU. The reversibility of delirium is emphasized because many etiologies, such as infection and medication effects, can be treated easily. The longterm cognitive consequences of delirium remain largely unknown. Some episodes of delirium continue for weeks, months, or even years. The persistence of delirium in some patients and its high recurrence rate may be due to inadequate initial treatment of the underlying etiology. In other instances, delirium appears to cause permanent neuronal damage and cognitive decline; therefore prevention strategies are important to implement. Even if an episode of delirium completely resolves, there may be lingering effects of the disorder; a patient’s recall of events after delirium varies widely, ranging from complete amnesia to repeated re-experiencing of the frightening period of confusion, similar to what is seen in patients with posttraumatic stress disorder.

■■RISK FACTORS

An effective primary prevention strategy for delirium begins with identification of high-risk patients, including those preparing for elective surgery or being admitted to the hospital. Multiple validated scoring systems have been developed as a screen for asymptomatic patients, many of which emphasize well-established risk factors for delirium. The two most consistently identified risk factors are older age and baseline cognitive dysfunction. Individuals who are aged >65 or exhibit low scores on standardized tests of cognition develop delirium upon hospitalization at a rate approaching 50%. Whether age and baseline cognitive dysfunction are truly independent risk factors is uncertain. Other predisposing factors include sensory deprivation, such as preexisting hearing and visual impairment, as well as indices for poor overall health, including baseline immobility, malnutrition, and underlying medical or neurologic illness. In-hospital risks for delirium include the use of bladder catheterization, physical restraints, sleep and sensory deprivation, and the addition of three or more new medications. Avoiding such risks remains a key component of delirium prevention as well as treatment. Surgical and anesthetic risk factors for the development of postoperative delirium include procedures such as those involving cardiopulmonary bypass, inadequate or excessive treatment of pain in the immediate postoperative period, and perhaps specific agents such as inhalational anesthetics. The relationship between delirium and dementia (Chap. 25) is complicated by significant overlap between the two conditions, and it is not always simple to distinguish between them. Dementia and preexisting cognitive dysfunction serve as major risk factors for delirium, and at

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least two-thirds of cases of delirium occur in patients with coexisting underlying dementia. A form of dementia with parkinsonism, dementia with Lewy bodies, is characterized by a fluctuating course, prominent visual hallucinations, parkinsonism, and an attentional deficit that clinically resembles hyperactive delirium; patients with this condition are particularly vulnerable to delirium. Delirium in the elderly often reflects an insult to a brain that is vulnerable due to an underlying neurodegenerative condition. Therefore, the development of delirium sometimes heralds the onset of a previously unrecognized brain disorder, and after the acute delirious episode has cleared, careful screening for an underlying condition should occur in the outpatient setting.

PART 2

■■EPIDEMIOLOGY

Cardinal Manifestations and Presentation of Diseases

Delirium is common, but its reported incidence has varied widely with the criteria used to define this disorder. Estimates of delirium in hospitalized patients range from 10 to >50%, with higher rates reported for elderly patients and patients undergoing hip surgery. Older patients in the ICU have especially high rates of delirium that approach 75%. The condition is not recognized in up to one-third of delirious inpatients, and the diagnosis is especially problematic in the ICU environment, where cognitive dysfunction is often difficult to appreciate in the setting of serious systemic illness and sedation. Delirium in the ICU should be viewed as an important manifestation of organ dysfunction not unlike liver, kidney, or heart failure. Outside the acute hospital setting, delirium occurs in nearly one-quarter of patients in nursing homes and in 50–80% of those at the end of life. These estimates emphasize the remarkably high frequency of this cognitive syndrome in older patients, a population that continues to grow. An episode of delirium was previously viewed as a transient condition that carried a benign prognosis. It is now recognized as a disorder with substantial morbidity and mortality, and that often represents the first manifestation of a serious underlying illness. Estimates of inhospital mortality rates among delirious patients range from 25 to 33%, similar to mortality rates due to sepsis. Patients with an in-hospital episode of delirium have a fivefold higher mortality rate in the months after their illness compared with age-matched nondelirious hospitalized patients. Delirious hospitalized patients also have a longer length of stay, are more likely to be discharged to a nursing home, and are more likely to experience subsequent episodes of delirium and cognitive decline; as a result, this condition has an enormous economic cost.

■■PATHOGENESIS

The pathogenesis and anatomy of delirium are incompletely understood. The attentional deficit that serves as the neuropsychological hallmark of delirium has a diffuse localization within the brainstem, thalamus, prefrontal cortex, and parietal lobes. Rarely, focal lesions such as ischemic strokes have led to delirium in otherwise healthy persons; right parietal and medial dorsal thalamic lesions have been reported most commonly, pointing to the importance of these areas in delirium pathogenesis. In most cases, however, delirium results from widespread disturbances in cortical and subcortical regions of the brain. Electroencephalogram (EEG) usually reveals symmetric slowing, a nonspecific finding that supports diffuse cerebral dysfunction. Multiple neurotransmitter abnormalities, proinflammatory factors, and specific genes likely play a role in the pathogenesis of delirium. Deficiency of acetylcholine may play a key role, and medications with anticholinergic properties can commonly precipitate delirium. As noted above, patients with preexisting dementia are particularly susceptible to episodes of delirium. Alzheimer’s disease, dementia with Lewy bodies, and Parkinson’s disease dementia are all associated with cholinergic deficiency due to degeneration of acetylcholine-producing neurons in the basal forebrain. In addition, other neurotransmitters are also likely to be involved in this diffuse cerebral disorder. For example, increases in dopamine can lead to delirium, and patients with Parkinson’s disease treated with dopaminergic medications can develop a delirium-like state that features visual hallucinations, fluctuations, and confusion. Not all individuals exposed to the same insult will develop signs of delirium. A low dose of an anticholinergic medication may have no

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cognitive effects on a healthy young adult but produce a florid delirium in an elderly person with known underlying dementia, although even healthy young persons develop delirium with very high doses of anticholinergic medications. This concept of delirium developing as the result of an insult in predisposed individuals is currently the most widely accepted pathogenic construct. Therefore, if a previously healthy individual with no known history of cognitive illness develops delirium in the setting of a relatively minor insult such as elective surgery or hospitalization, an unrecognized underlying neurologic illness such as a neurodegenerative disease, multiple previous strokes, or another diffuse cerebral cause should be considered. In this context, delirium can be viewed as a “stress test for the brain” whereby exposure to known inciting factors such as systemic infection and offending drugs can unmask a decreased cerebral reserve and herald a serious underlying and potentially treatable illness.

APPROACH TO THE PATIENT

Delirium Because the diagnosis of delirium is clinical and is made at the bedside, a careful history and physical examination are necessary in evaluating patients with possible confusional states. Screening tools can aid physicians and nurses in identifying patients with delirium, including the Confusion Assessment Method (CAM); the Nursing Delirium Screening Scale (NuDESC); the Organic Brain Syndrome Scale; the Delirium Rating Scale; and, in the ICU, the ICU version of the CAM and the Delirium Detection Score. Using the wellvalidated CAM, a diagnosis of delirium is made if there is (1) an acute onset and fluctuating course and (2) inattention accompanied by either (3) disorganized thinking or (4) an altered level of consciousness (Table 24-1). These scales may not identify the full spectrum of patients with delirium, and all patients who are acutely confused should be presumed delirious regardless of their presentation due to the wide variety of possible clinical features. A course that fluctuates over hours or days and may worsen at night (termed sundowning) is typical but not essential for the diagnosis. Observation will usually reveal an altered level of consciousness or a deficit of attention. Other features that are sometimes present include

TABLE 24-1  The Confusion Assessment Method (CAM) Diagnostic Algorithma The diagnosis of delirium requires the presence of features 1 and 2 and either feature 3 or 4. Feature 1. Acute Onset and Fluctuating Course This feature is satisfied by positive responses to the following questions: Is there evidence of an acute change in mental status from the patient’s baseline? Did the (abnormal) behavior fluctuate during the day, that is, tend to come and go, or did it increase and decrease in severity? Feature 2. Inattention This feature is satisfied by a positive response to the following question: Did the patient have difficulty focusing attention, for example, being easily distractible, or have difficulty keeping track of what was being said? Feature 3. Disorganized Thinking This feature is satisfied by a positive response to the following question: Was the patient’s thinking disorganized or incoherent, such as rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject? Feature 4. Altered Level of Consciousness This feature is satisfied by any answer other than “alert” to the following question: Overall, how would you rate the patient’s level of consciousness: alert (normal), vigilant (hyperalert), lethargic (drowsy, easily aroused), stupor (difficult to arouse), or coma (unarousable)? a Information is usually obtained from a reliable reporter, such as a family member, caregiver, or nurse.

Source: Modified from SK Inouye et al: Clarifying confusion: The Confusion Assessment Method. A new method for detection of delirium. Ann Intern Med 113:941, 1990.

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alteration of sleep-wake cycles, thought disturbances such as hallucinations or delusions, autonomic instability, and changes in affect.

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PHYSICAL EXAMINATION The general physical examination in a delirious patient should include careful screening for signs of infection such as fever, tachypnea, pulmonary consolidation, heart murmur, and meningismus. The patient’s fluid status should be assessed; both dehydration and fluid overload with resultant hypoxemia have been associated with delirium, and each is usually easily rectified. The appearance of the skin can be helpful, showing jaundice in hepatic encephalopathy, cyanosis in hypoxemia, or needle tracks in patients using intravenous drugs. The neurologic examination requires a careful assessment of mental status. Patients with delirium often present with a fluctuating course; therefore, the diagnosis can be missed when one relies on a single time point of evaluation. For patients who worsen in the evening (sundowning), assessment only during morning rounds may be falsely reassuring. An altered level of consciousness ranging from hyperarousal to lethargy to coma is present in most patients with delirium and can be assessed easily at the bedside. In a patient with a relatively normal level of consciousness, a screen for an attentional deficit is in order, because this deficit is the classic neuropsychological hallmark

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HISTORY It may be difficult to elicit an accurate history in delirious patients who have altered levels of consciousness or impaired attention. Information from a collateral source such as a spouse or another family member is therefore invaluable. The three most important pieces of history are the patient’s baseline cognitive function, the time course of the present illness, and current medications. Premorbid cognitive function can be assessed through the collateral source or, if needed, via a review of outpatient records. Delirium by definition represents a change that is relatively acute and usually developing over hours to days, from a cognitive baseline. An acute confusional state is nearly impossible to diagnose without some knowledge of baseline cognitive function. Without this information, many patients with dementia or longstanding depression may be mistaken as delirious during a single initial evaluation. Patients with a more hypoactive, apathetic presentation with psychomotor slowing may be identified as being different from baseline only through conversations with family members. A number of validated instruments have been shown to diagnose cognitive dysfunction accurately using a collateral source, including the modified Blessed Dementia Rating Scale and the Clinical Dementia Rating (CDR). Baseline cognitive impairment is common in patients with delirium. Even when no such history of cognitive impairment is elicited, there should still be a high suspicion for a previously unrecognized underlying neurologic disorder. Establishing the time course of cognitive change is important not only to make a diagnosis of delirium but also to correlate the onset of the illness with potentially treatable etiologies such as recent medication changes or symptoms of systemic infection. Medications remain a common cause of delirium, especially compounds with anticholinergic or sedative properties. It is estimated that nearly one-third of all cases of delirium are secondary to medications, especially in the elderly. Medication histories should include all prescription as well as over-the-counter and herbal substances taken by the patient and any recent changes in dosing or formulation, including substitution of generics for brand-name medications. Other important elements of the history include screening for symptoms of organ failure or systemic infection, which often contributes to delirium in the elderly. A history of illicit drug use, alcoholism, or toxin exposure is common in younger delirious patients. Finally, asking the patient and collateral source about other symptoms that may accompany delirium, such as depression, may help identify potential therapeutic targets.

of delirium. Attention can be assessed while taking a history from the patient. Tangential speech, a fragmentary flow of ideas, or inability to follow complex commands often signifies an attentional problem. There are formal neuropsychological tests to assess attention, but a simple bedside test of digit span forward is quick and fairly sensitive. In this task, patients are asked to repeat successively longer random strings of digits beginning with two digits in a row, said to the patient at one per second intervals. Healthy adults can repeat a string of five to seven digits before faltering; a digit span of four or less usually indicates an attentional deficit unless hearing or language barriers are present, and many patients with delirium have digit spans of three or fewer digits. More formal neuropsychological testing can be helpful in assessing a delirious patient, but it is usually too cumbersome and timeconsuming in the inpatient setting. A Mini-Mental State Examination (MMSE) provides information regarding orientation, language, and visuospatial skills (Chap. 25); however, performance of many tasks on the MMSE, including the spelling of “world” backward and serial subtraction of digits, will be impaired by delirious patients’ attentional deficits, rendering the test unreliable. The remainder of the screening neurologic examination should focus on identifying new focal neurologic deficits. Focal strokes or mass lesions in isolation are rarely the cause of delirium, but patients with underlying extensive cerebrovascular disease or neurodegenerative conditions may not be able to cognitively tolerate even relatively small new insults. Patients should be screened for other signs of neurodegenerative conditions such as parkinsonism, which is seen not only in idiopathic Parkinson’s disease but also in other dementing conditions including Alzheimer’s disease, dementia with Lewy bodies, and progressive supranuclear palsy. The presence of multifocal myoclonus or asterixis on the motor examination is nonspecific but usually indicates a metabolic or toxic etiology of the delirium. ETIOLOGY Some etiologies can be easily discerned through a careful history and physical examination, whereas others require confirmation with laboratory studies, imaging, or other ancillary tests. A large, diverse group of insults can lead to delirium, and the cause in many patients is multifactorial. Common etiologies are listed in Table 24-2. Prescribed, over-the-counter, and herbal medications all can precipitate delirium. Drugs with anticholinergic properties, narcotics, and benzodiazepines are particularly common offenders, but nearly any compound can lead to cognitive dysfunction in a predisposed patient. Whereas an elderly patient with baseline dementia may become delirious upon exposure to a relatively low dose of a medication, in less susceptible individuals delirium occurs only with very high doses of the same medication. This observation emphasizes the importance of correlating the timing of recent medication changes, including dose and formulation, with the onset of cognitive dysfunction. In younger patients, illicit drugs and toxins are common causes of delirium. In addition to more classic drugs of abuse, the recent rise in availability of “bath salts,” synthetic cannabis, methylenedioxymethamphetamine (MDMA, ecstasy), γ-hydroxybutyrate (GHB), and the phencyclidine (PCP)-like agent ketamine has led to an increase in delirious young persons presenting to acute care settings (Chap. 447). Many common prescription drugs such as oral narcotics and benzodiazepines are often abused and readily available on the street. Alcohol abuse leading to high serum levels causes confusion, but more commonly, it is withdrawal from alcohol that leads to a hyperactive delirium (Chap. 445). Alcohol and benzodiazepine withdrawal should be considered in all cases of delirium because even patients who drink only a few servings of alcohol every day can experience relatively severe withdrawal symptoms upon hospitalization. Metabolic abnormalities such as electrolyte disturbances of sodium, calcium, magnesium, or glucose can cause delirium, and

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TABLE 24-2  Common Etiologies of Delirium

PART 2 Cardinal Manifestations and Presentation of Diseases

Toxins Prescription medications: especially those with anticholinergic properties, narcotics, and benzodiazepines Drugs of abuse: alcohol intoxication and alcohol withdrawal, opiates, ecstasy, LSD, GHB, PCP, ketamine, cocaine, “bath salts,” marijuana and its synthetic forms Poisons: inhalants, carbon monoxide, ethylene glycol, pesticides Metabolic Conditions Electrolyte disturbances: hypoglycemia, hyperglycemia, hyponatremia, hypernatremia, hypercalcemia, hypocalcemia, hypomagnesemia Hypothermia and hyperthermia Pulmonary failure: hypoxemia and hypercarbia Liver failure/hepatic encephalopathy Renal failure/uremia Cardiac failure Vitamin deficiencies: B12, thiamine, folate, niacin Dehydration and malnutrition Anemia Infections Systemic infections: urinary tract infections, pneumonia, skin and soft tissue infections, sepsis CNS infections: meningitis, encephalitis, brain abscess Endocrine Conditions Hyperthyroidism, hypothyroidism Hyperparathyroidism Adrenal insufficiency Cerebrovascular Disorders Global hypoperfusion states Hypertensive encephalopathy Focal ischemic strokes and hemorrhages (rare): especially nondominant parietal and thalamic lesions Autoimmune Disorders CNS vasculitis Cerebral lupus Neurologic paraneoplastic and autoimmune encephalitis Seizure-Related Disorders Nonconvulsive status epilepticus Intermittent seizures with prolonged postictal states Neoplastic Disorders Diffuse metastases to the brain Gliomatosis cerebri Carcinomatous meningitis CNS lymphoma Hospitalization Terminal end-of-life delirium Abbreviations: CNS, central nervous system; GHB, γ-hydroxybutyrate; LSD, lysergic acid diethylamide; PCP, phencyclidine.

mild derangements can lead to substantial cognitive disturbances in susceptible individuals. Other common metabolic etiologies include liver and renal failure, hypercarbia and hypoxemia, vitamin deficiencies of thiamine and B12, autoimmune disorders including central nervous system (CNS) vasculitis, and endocrinopathies such as thyroid and adrenal disorders. Systemic infections often cause delirium, especially in the elderly. A common scenario involves the development of an acute cognitive decline in the setting of a urinary tract infection in a patient with baseline dementia. Pneumonia, skin infections such as cellulitis, and frank sepsis also lead to delirium. This so-called septic encephalopathy, often seen in the ICU, is probably due to the release of proinflammatory cytokines and their diffuse cerebral effects. CNS infections such as meningitis, encephalitis, and abscess are less common etiologies of delirium as are cases of autoimmune or

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paraneoplastic encephalitis; however, in light of the high morbidity and mortality rates associated with these conditions when they are not treated, clinicians must always maintain a high index of suspicion. In some susceptible individuals, exposure to the unfamiliar environment of a hospital itself can lead to delirium. This etiology usually occurs as part of a multifactorial delirium and should be considered a diagnosis of exclusion after all other causes have been thoroughly investigated. Many primary prevention and treatment strategies for delirium involve relatively simple methods to address the aspects of the inpatient setting that are most confusing. Cerebrovascular etiologies of delirium are usually due to global hypoperfusion in the setting of systemic hypotension from heart failure, septic shock, dehydration, or anemia. Focal strokes in the right parietal lobe and medial dorsal thalamus rarely can lead to a delirious state. A more common scenario involves a new focal stroke or hemorrhage causing confusion in a patient who has decreased cerebral reserve. In these individuals, it is sometimes difficult to distinguish between cognitive dysfunction resulting from the new neurovascular insult itself and delirium due to the infectious, metabolic, and pharmacologic complications that can accompany hospitalization after stroke. Because a fluctuating course often is seen in delirium, intermittent seizures may be overlooked when one is considering potential etiologies. Both nonconvulsive status epilepticus and recurrent focal or generalized seizures followed by postictal confusion can cause delirium; EEG remains essential for this diagnosis and should be considered whenever the etiology of delirium remains unclear following initial workup. Seizure activity spreading from an electrical focus in a mass or infarct can explain global cognitive dysfunction caused by relatively small lesions. It is extremely common for patients to experience delirium at the end of life in palliative care settings. This condition, sometimes described as terminal restlessness, must be identified and treated aggressively because it is an important cause of patient and family discomfort at the end of life. It should be remembered that these patients also may be suffering from more common etiologies of delirium such as systemic infection. LABORATORY AND DIAGNOSTIC EVALUATION A cost-effective approach allows the history and physical examination to guide further tests. No single algorithm will fit all delirious patients due to the staggering number of potential etiologies, but one stepwise approach is detailed in Table 24-3. If a clear precipitant such as an offending medication is identified, further testing may not be required. If, however, no likely etiology is uncovered with initial evaluation, an aggressive search for an underlying cause should be initiated. Basic screening labs, including a complete blood count, electrolyte panel, and tests of liver and renal function, should be obtained in all patients with delirium. In elderly patients, screening for systemic infection, including chest radiography, urinalysis and culture, and possibly blood cultures, is important. In younger individuals, serum and urine drug and toxicology screening may be appropriate earlier in the workup. Additional laboratory tests addressing other autoimmune, endocrinologic, metabolic, and infectious etiologies should be reserved for patients in whom the diagnosis remains unclear after initial testing. Multiple studies have demonstrated that brain imaging in patients with delirium is often unhelpful. If, however, the initial workup is unrevealing, most clinicians quickly move toward imaging of the brain to exclude structural causes. A noncontrast computed tomography (CT) scan can identify large masses and hemorrhages but is otherwise unlikely to help determine an etiology of delirium. The ability of magnetic resonance imaging (MRI) to identify most acute ischemic strokes as well as to provide neuroanatomic detail that gives clues to possible infectious, inflammatory, neurodegenerative, and neoplastic conditions makes it the test of choice. Because MRI

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TABLE 24-3  Stepwise Evaluation of a Patient with Delirium Initial Evaluation  istory with special attention to medications (including over-the-counter and H herbals) General physical examination and neurologic examination Complete blood count Electrolyte panel including calcium, magnesium, phosphorus Liver function tests, including albumin Renal function tests

Second-tier Further Evaluation Vitamin levels: B12, folate, thiamine Endocrinologic laboratories: thyroid-stimulating hormone (TSH) and free T4; cortisol Serum ammonia Sedimentation rate Autoimmune serologies: antinuclear antibodies (ANA), complement levels; p-ANCA, c-ANCA, consider paraneoplastic/autoimmune encephalitis serologies Infectious serologies: rapid plasmin reagin (RPR); fungal and viral serologies if high suspicion; HIV antibody Lumbar puncture (if not already performed) Brain MRI with and without gadolinium (if not already performed) Abbreviations: c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody; CNS, central nervous system; CT, computed tomography; MRI, magnetic resonance imaging; p-ANCA, perinuclear antineutrophil cytoplasmic antibody.

techniques are limited by availability, speed of imaging, patient’s cooperation, and contraindications, many clinicians begin with CT scanning and proceed to MRI if the etiology of delirium remains elusive. Lumbar puncture (LP) must be obtained immediately after neuroimaging for all patients in whom CNS infection is suspected. Spinal fluid examination can also be useful in identifying inflammatory and neoplastic conditions. As a result, LP should be considered in any delirious patient with a negative workup. EEG remains invaluable if seizures are considered or if there is no cause readily identified.

TREATMENT

Delirium Management of delirium begins with treatment of the underlying inciting factor (e.g., patients with systemic infections should be given appropriate antibiotics, and underlying electrolyte disturbances judiciously corrected). These treatments often lead to prompt resolution of delirium. Blindly targeting the symptoms of delirium pharmacologically only serves to prolong the time patients remain in the confused state and may mask important diagnostic information. Relatively simple methods of supportive care can be highly effective. Reorientation by the nursing staff and family combined with visible clocks, calendars, and outside-facing windows can reduce

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Systemic infection screen   Urinalysis and culture   Chest radiograph   Blood cultures Electrocardiogram Arterial blood gas Serum and/or urine toxicology screen (perform earlier in young persons) Brain imaging with MRI with diffusion and gadolinium (preferred) or CT Suspected CNS infection or other inflammatory disorder: lumbar puncture after brain imaging Suspected seizure-related etiology: electroencephalogram (EEG) (if high suspicion, should be performed immediately)

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First-tier Further Evaluation Guided by Initial Evaluation

confusion. Sensory isolation should be prevented by providing glasses and hearing aids to patients who need them. Sundowning can be addressed to a large extent through vigilance to appropriate sleep-wake cycles. During the day, a well-lit room should be accompanied by activities or exercises to prevent napping. At night, a quiet, dark environment with limited interruptions by staff can assure proper rest. These sleep-wake cycle interventions are especially important in the ICU setting as the usual constant 24-h activity commonly provokes delirium. Attempting to mimic the home environment as much as possible also has been shown to help treat and even prevent delirium. Visits from friends and family throughout the day minimize the anxiety associated with the constant flow of new faces of staff and physicians. Allowing hospitalized patients to have access to home bedding, clothing, and nightstand objects makes the hospital environment less foreign and therefore less confusing. Simple standard nursing practices such as maintaining proper nutrition and volume status as well as managing pain, incontinence and skin breakdown also help alleviate discomfort and resulting confusion. In some instances, patients pose a threat to their own safety or to the safety of staff members, and acute management is required. Bed alarms and personal sitters are more effective and much less disorienting than physical restraints. Chemical restraints should be avoided, but when necessary, very-low-dose typical or atypical antipsychotic medications administered on an as-needed basis can be used; however, there is little evidence that these medications are effective in delirium, and therefore they should be reserved for patients who display severe agitation and significant potential to harm themselves or staff. The recent association of antipsychotic use in the elderly with increased mortality rates underscores the importance of using these medications judiciously and only as a last resort. Benzodiazepines often worsen confusion through their sedative properties. Although many clinicians still use benzodiazepines to treat acute confusion, their use should be limited to cases in which delirium is caused by alcohol or benzodiazepine withdrawal.

■■PREVENTION

In light of the high morbidity associated with delirium and the tremendously increased health care costs that accompany it, development of an effective strategy to prevent delirium in hospitalized patients is extremely important. Successful identification of high-risk patients is the first step, followed by initiation of appropriate interventions. Increasingly, hospitals are using nursing or physician-administered tools to screen for high-risk individuals, triggering simple standardized protocols used to manage risk factors for delirium, including sleepwake cycle reversal, immobility, visual impairment, hearing impairment, sleep deprivation, and dehydration. No specific medications have been definitively shown to be effective for delirium prevention, including trials of cholinesterase inhibitors and antipsychotic agents. Melatonin and its agonist ramelteon have shown some promising results in small preliminary trials. Recent studies in the ICU have focused both on identifying sedatives, such as dexmedetomidine, that are less likely to lead to delirium in critically ill patients and on developing protocols for daily awakenings in which infusions of sedative medications are interrupted and the patient is reorientated by the staff. All hospitals and health care systems should work toward decreasing the incidence of delirium and promptly recognizing and treating the disorder when it occurs.

■■FURTHER READING

Constantin JM et al: Efficacy and safety of sedation with dexmedetomidine in critical care patients: A meta-analysis of randomized controlled trials. Anaesth Crit Care Pain Med 35:7, 2016. Hatta K et al: Preventive effects of ramelteon on delirium: A randomized placebo-controlled trial. JAMA Psychiatry 71:397, 2014. Neufeld KJ et al: Antipsychotic medication for prevention and treatment of delirium in hospitalized adults: A systematic review and meta-analysis. J Am Geriatr Soc 64:705, 2016.

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25

Dementia

through the globus pallidus and thalamus, and damage to these nodes can likewise reproduce the clinical syndrome associated with the corresponding cortical or striatal injuries.

William W. Seeley, Bruce L. Miller

PART 2 Cardinal Manifestations and Presentation of Diseases

Dementia, a syndrome with many causes, affects >5 million people in the United States and results in a total annual health care cost in excess of $250 billion. Dementia is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living. Episodic memory, the ability to recall events specific in time and place, is the cognitive function most commonly lost; 10% of persons aged >70 years and 20–40% of individuals aged >85 years have clinically identifiable memory loss. In addition to memory, dementia may erode other mental faculties, including language, visuospatial, praxis, calculation, judgment, and problem-solving abilities. Neuropsychiatric and social deficits also arise in many dementia syndromes, manifesting as depression, apathy, anxiety, hallucinations, delusions, agitation, insomnia, sleep disturbances, compulsions, or disinhibition. The clinical course may be slowly progressive, as in Alzheimer’s disease (AD); static, as in anoxic encephalopathy; or may fluctuate from day to day or minute to minute, as in dementia with Lewy bodies (DLB). Most patients with AD, the most prevalent form of dementia, begin with episodic memory impairment, although in other dementias, such as frontotemporal dementia (FTD), memory loss is not typically a presenting feature. Focal cerebral disorders are discussed in Chap. 26 and illustrated in a video library in Chap. V2; detailed discussions of AD can be found in Chap. 423; FTD and related disorders in Chap. 424; vascular dementia in Chap. 425; DLB in Chap. 426; Huntington’s disease (HD) in Chap. 428; and prion diseases in Chap. 430.

■■THE CAUSES OF DEMENTIA

The single strongest risk factor for dementia is increasing age. The prevalence of disabling memory loss increases with each decade for those aged >50 and is usually associated with the microscopic changes of AD at autopsy. Yet some centenarians have intact memory function and no evidence of clinically significant dementia. Whether dementia is an inevitable consequence of normal human aging remains controversial. The many causes of dementia are listed in Table 25-1. The frequency of each condition depends on the age group under study, access of the group to medical care, country of origin, and perhaps racial or ethnic

TABLE 25-1  Differential Diagnosis of Dementia Most Common Causes of Dementia Alzheimer’s disease Vascular dementia  Multi-infarct  Diffuse white matter disease (Binswanger’s) Less Common Causes of Dementia Vitamin deficiencies  Thiamine (B1): Wernicke’s encephalopathya  B12 (subacute combined degeneration)a   Nicotinic acid (pellagra)a Endocrine and other organ failure  Hypothyroidisma  Adrenal insufficiency and Cushing’s syndromea   Hypo- and hyperparathyroidisma   Renal failurea   Liver failurea   Pulmonary failurea Chronic infections  HIV  Neurosyphilisa  Papovavirus (JC virus) (progressive multifocal leukoencephalopathy)   Tuberculosis, fungal, and protozoala   Whipple’s diseasea Head trauma and diffuse brain damage   Chronic traumatic encephalopathy   Chronic subdural hematomaa  Postanoxia  Postencephalitis   Normal-pressure hydrocephalusa Intracranial hypotension Neoplastic   Primary brain tumora   Metastatic brain tumora  Paraneoplastic/autoimmune limbic encephalitisa

FUNCTIONAL ANATOMY OF THE DEMENTIAS

Dementia syndromes result from the disruption of specific large-scale neuronal networks; the location and severity of synaptic and neuronal loss combine to produce the clinical features (Chap. 26). Behavior, mood, and attention are modulated by ascending noradrenergic, serotonergic, and dopaminergic pathways, whereas cholinergic signaling is critical for attention and memory functions. The dementias differ in the relative neurotransmitter deficit profiles; accordingly, accurate diagnosis guides effective pharmacologic therapy. AD begins in the entorhinal region of the medial temporal lobe, spreads to the hippocampus, and then moves to lateral and posterior temporal and parietal neocortex, eventually causing a more widespread degeneration. Vascular dementia is associated with focal damage in a variable patchwork of cortical and subcortical regions or white matter tracts that disconnect nodes within distributed networks. In keeping with its anatomy, AD typically presents with episodic memory loss accompanied later by aphasia, executive dysfunction, or navigational problems. In contrast, dementias that begin in frontal or subcortical regions, such as FTD or HD, are less likely to begin with memory problems and more likely to present with difficulties with judgment, mood, executive control, movement, and behavior. Lesions of frontal-striatal1 pathways produce specific and predictable effects on behavior. The dorsolateral prefrontal cortex has connections with a central band of the caudate nucleus. Lesions of either the caudate or dorsolateral prefrontal cortex, or their connecting white matter pathways, may result in executive dysfunction, manifesting as poor organization and planning, decreased cognitive flexibility, and impaired working memory. The lateral orbital frontal cortex connects with the ventromedial caudate, and lesions of this system cause impulsiveness, distractibility, and disinhibition. The anterior cingulate cortex and adjacent medial prefrontal cortex project to the nucleus accumbens, and interruption of this system produces apathy, poverty of speech, emotional blunting, or even akinetic mutism. All corticostriatal systems also include topographically organized projections 1

The striatum comprises the caudate/putamen/nucleus accumbens.

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Alcoholisma PDD/LBD spectrum Drug/medication intoxicationa  

a

Toxic disorders  Drug, medication, and narcotic poisoninga   Heavy metal intoxicationa   Organic toxins Psychiatric   Depression (pseudodementia)a  Schizophreniaa   Conversion disordera Degenerative disorders   Huntington’s disease   Multisystem atrophy   Hereditary ataxias (some forms)  Frontotemporal lobar degeneration spectrum   Multiple sclerosis  Adult Down’s syndrome with Alzheimer’s disease  ALS-parkinsonism-dementia complex of Guam  Prion (Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases) Miscellaneous  Sarcoidosisa  Vasculitisa   CADASIL, etc.   Acute intermittent porphyriaa   Recurrent nonconvulsive seizuresa Additional conditions in children or adolescents  Pantothenate kinase–associated neurodegeneration  Subacute sclerosing panencephalitis  Metabolic disorders (e.g., Wilson’s and Leigh’s diseases, leukodystrophies, lipid storage diseases, mitochondrial mutations)

Potentially reversible dementia.

Abbreviations: ALS, amyotrophic lateral sclerosis; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; LBD, Lewy body disease; PDD, Parkinson’s disease dementia.

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background. AD is the most common cause of dementia in Western countries, accounting for more than half of all patients. Vascular disease is considered the second most frequent cause for dementia and is particularly common in elderly patients or populations with limited access to medical care, where vascular risk factors are undertreated. Often, vascular brain injury is mixed with neurodegenerative disorders, making it difficult, even for the neuropathologist, to estimate the contribution of cerebrovascular disease to the cognitive disorder in an individual patient. Dementias associated with Parkinson’s disease (PD) are common and may develop years after onset of a parkinsonian disorder, as seen with PD-related dementia (PDD), or can occur concurrently with or preceding the motor syndrome, as in DLB. A mixed pathology is common, especially in very old individuals. In patients aged AD

VISUO-SPATIAL (Posterior cortical atrophy-PCA) AD>>LBD>FTLD

PART 2

APHASIC (Primary progressive aphasia- PPA) FTLD>AD

AMNESTIC

Cardinal Manifestations and Presentation of Diseases

(Dementia of the Alzheimer-type-DAT) AD>>>FTLD

FIGURE 26-4  Four focal dementia syndromes and their most likely neuropathologic correlates. AD, Alzheimer’s disease; bvFTD, behavioral variant frontotemporal dementia; DAT, amnestic dementia of the Alzheimer-type; FTLD, frontotemporal lobar degeneration (tau or TDP-43 type); LBD, Lewy body disease; PCA, posterior cortical atrophy syndrome; PPA, primary progressive aphasia.

and object recognition. The anterior temporal lobe atrophy is usually bilateral in semantic dementia whereas it tends to affect mostly the left hemisphere in semantic PPA. Acute onset of the semantic dementia syndrome can be associated with herpes simplex encephalitis.

LIMBIC NETWORK FOR EXPLICIT MEMORY AND AMNESIA

Limbic and paralimbic areas (such as the hippocampus, amygdala, and entorhinal cortex), the anterior and medial nuclei of the thalamus, the medial and basal parts of the striatum, and the hypothalamus collectively constitute a distributed network known as the limbic system. The behavioral affiliations of this network include the coordination of emotion, motivation, autonomic tone, and endocrine function. An additional area of specialization for the limbic network and the one that is of most relevance to clinical practice is that of declarative (explicit) memory for recent episodes and experiences. A disturbance in this function is known as an amnestic state. In the absence of deficits in motivation, attention, language, or visuospatial function, the clinical diagnosis of a persistent global amnestic state is always associated with bilateral damage to the limbic network, usually within the hippocampo-entorhinal complex or the thalamus. Damage to the limbic network does not necessarily destroy memories but interferes with their conscious recall in coherent form. The individual fragments of information remain preserved despite the limbic lesions and can sustain what is known as implicit memory. For example, patients with amnestic states can acquire new motor or perceptual skills even though they may have no conscious knowledge of the experiences that led to the acquisition of these skills. The memory disturbance in the amnestic state is multimodal and includes retrograde and anterograde components. The retrograde amnesia involves an inability to recall experiences that occurred before the onset of the amnestic state. Relatively recent events are more vulnerable to retrograde amnesia than are more remote and more extensively consolidated events. A patient who comes to the emergency room complaining that he cannot remember his or her identity but can remember the events of the previous day almost certainly does not have a neurologic cause of memory disturbance. The second and most important component of the amnestic state is the anterograde amnesia, which indicates an inability to store, retain, and recall new knowledge. Patients with amnestic states cannot remember what they ate a few hours ago or the details of an important event they may have experienced in the recent past. In the acute stages, there also may be a tendency to fill in memory gaps with inaccurate, fabricated, and often implausible information. This is known as confabulation. Patients with the amnestic syndrome forget that they forget and tend to deny the existence of a memory problem when questioned. Confabulation is more common

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in cases where the underlying lesion also interferes with parts of the frontal network, as in the case of the Wernicke-Korsakoff syndrome or traumatic head injury.

■■CLINICAL EXAMINATION

A patient with an amnestic state is almost always disoriented, especially to time, and has little knowledge of current news. The anterograde component of an amnestic state can be tested with a list of four to five words read aloud by the examiner up to five times or until the patient can immediately repeat the entire list without an intervening delay. The next phase of the recall occurs after a period of 5–10 min during which the patient is engaged in other tasks. Amnestic patients fail this phase of the task and may even forget that they were given a list of words to remember. Accurate recognition of the words by multiple choice in a patient who cannot recall them indicates a less severe memory disturbance that affects mostly the retrieval stage of memory. The retrograde component of an amnesia can be assessed with questions related to autobiographical or historic events. The anterograde component of amnestic states is usually much more prominent than the retrograde component. In rare instances, occasionally associated with temporal lobe epilepsy or herpes simplex encephalitis, the retrograde component may dominate. Confusional states caused by toxicmetabolic encephalopathies and some types of frontal lobe damage lead to secondary memory impairments, especially at the stages of encoding and retrieval, even in the absence of limbic lesions. This sort of memory impairment can be differentiated from the amnestic state by the presence of additional impairments in the attention-related tasks described below in the section on the frontal lobes.

■■CAUSES, INCLUDING ALZHEIMER’S DISEASE

Neurologic diseases that give rise to an amnestic state include tumors (of the sphenoid wing, posterior corpus callosum, thalamus, or medial temporal lobe), infarctions (in the territories of the anterior or posterior cerebral arteries), head trauma, herpes simplex encephalitis, Wernicke-Korsakoff encephalopathy, autoimmune limbic encephalitis, and degenerative dementias such as AD and Pick’s disease. The one common denominator of all these diseases is the presence of bilateral lesions within one or more components in the limbic network. Occasionally, unilateral left-sided hippocampal lesions can give rise to an amnestic state, but the memory disorder tends to be transient. Depending on the nature and distribution of the underlying neurologic disease, the patient also may have visual field deficits, eye movement limitations, or cerebellar findings. The most common cause of progressive memory impairments in the elderly is AD. This is why a predominantly amnestic dementia is also known as a dementia of the Alzheimer-type (DAT). A prodromal stage

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The frontal lobes can be subdivided into motor-premotor, dorsolateral prefrontal, medial prefrontal, and orbitofrontal components. The terms frontal lobe syndrome and prefrontal cortex refer only to the last three of these four components. These are the parts of the cerebral cortex that show the greatest phylogenetic expansion in primates, especially in humans. The dorsolateral prefrontal, medial prefrontal, and orbitofrontal areas, along with the subcortical structures with which they are interconnected (i.e., the head of the caudate and the dorsomedial nucleus of the thalamus), collectively make up a large-scale network that coordinates exceedingly complex aspects of human cognition and behavior. The term salience network has been introduced to designate parts of the frontal network and their interactions with adjacent paralimbic cortices of the insula and cingulate gyrus. Impairments of social conduct and empathy seen in neurodegenerative frontal dementias are attributed to pathology of the salience network. The prefrontal network plays an important role in behaviors that require multitasking and the integration of thought with emotion. Cognitive operations impaired by prefrontal cortex lesions often are referred to as “executive functions.” The most common clinical manifestations of damage to the prefrontal network take the form of two relatively distinct syndromes. In the frontal abulic syndrome, the patient shows a loss of initiative, creativity, and curiosity and displays a pervasive emotional blandness, apathy, and lack of empathy. In the frontal disinhibition syndrome, the patient becomes socially disinhibited and shows severe impairments of judgment, insight, foresight, and the ability to mind rules of conduct. The dissociation between intact intellectual function and a total lack of even rudimentary common sense is striking. Despite the preservation of all essential memory functions, the patient cannot learn from experience and continues to display inappropriate behaviors without appearing to feel emotional pain, guilt, or regret when those behaviors repeatedly lead to disastrous consequences. The impairments may emerge only in real-life situations when behavior is under minimal external control and may not be apparent within the structured environment of the medical office. Testing judgment by asking patients what they would do if they detected a fire in a theater or found a stamped and addressed envelope on the road is not very informative because patients who answer these questions wisely in the office may still act very foolishly in real-life settings. The physician must therefore be prepared to make a diagnosis of frontal lobe disease based on historic information alone even when the mental state is quite intact in the office examination.

■■CLINICAL EXAMINATION

The emergence of developmentally primitive reflexes, also known as frontal release signs, such as grasping (elicited by stroking the palm)

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■■CAUSES: TRAUMA, NEOPLASM, AND FRONTOTEMPORAL DEMENTIA

The abulic syndrome tends to be associated with damage in dorsolateral or dorsomedial prefrontal cortex, and the disinhibition syndrome with damage in orbitofrontal or ventromedial cortex. These syndromes tend to arise almost exclusively after bilateral lesions. Unilateral lesions confined to the prefrontal cortex may remain silent until the pathology spreads to the other side; this explains why thromboembolic CVA is an unusual cause of the frontal lobe syndrome. When behavioral syndromes of the frontal network arise in conjunction with asymmetric disease, the lesion tends to be predominantly on the right side of the brain. Common settings for frontal lobe syndromes include head trauma, ruptured aneurysms, hydrocephalus, tumors (including metastases, glioblastoma, and falx or olfactory groove meningiomas), and focal degenerative diseases, especially FTLD. The most prominent neurodegenerative frontal syndrome is known as the behavioral variant of frontotemporal dementia (bvFTD). In many patients with bvFTD the atrophy extends into the anterior temporal lobes. Occasionally, atrophy prodominantly in the right anterior temporal lobe presents with the bvFTD syndrome. The behavioral changes in these patients can range from apathy to shoplifting, compulsive gambling, sexual indiscretions, remarkable lack of common sense, new ritualistic behaviors, and alterations in dietary preferences, usually leading to increased taste for sweets or rigid attachment to specific food items. In many patients with AD, neurofibrillary degeneration eventually spreads to prefrontal cortex and gives rise to components of the frontal lobe syndrome, but almost always on a background of severe memory impairment. Rarely, the bvFTD syndrome can arise in isolation in the context of an atypical form of AD pathology. Lesions in the caudate nucleus or in the dorsomedial nucleus of the thalamus (subcortical components of the prefrontal network) also can produce a frontal lobe syndrome affecting mostly executive functions. This is one reason why the changes in mental state associated with

165

Aphasia, Memory Loss, Hemispatial Neglect, Frontal Syndromes, and Other Cerebral Disorders

THE PREFRONTAL NETWORK FOR EXECUTIVE FUNCTION AND BEHAVIOR

and sucking (elicited by stroking the lips) are seen primarily in patients with large structural lesions that extend into the premotor components of the frontal lobes or in the context of metabolic encephalopathies. The vast majority of patients with prefrontal lesions and frontal lobe behavioral syndromes do not display these reflexes. Damage to the frontal lobe disrupts a variety of attention-related functions, including working memory (the transient online holding and manipulation of information), concentration span, the effortful scanning and retrieval of stored information, the inhibition of immediate but inappropriate responses, and mental flexibility. Digit span (which should be seven forward and five reverse) is decreased, reflecting poor working memory; the recitation of the months of the year in reverse order (which should take 80% of the time, especially later in the night. Less vivid imagery may also be reported after NREM sleep interruptions. Certain disorders may occur during specific sleep stages and are described below under “Parasomnias.” These include sleepwalking, night terrors, and enuresis (bed wetting), which occur most commonly in children during deep (N3) NREM sleep, and REM sleep behavior disorder, which occurs mainly among older men who fail to maintain full paralysis during REM sleep, and often call out, thrash around, or even act out fragments of dreams. All major physiologic systems are influenced by sleep. Blood pressure and heart rate decrease during NREM sleep, particularly during N3 sleep. During REM sleep, bursts of eye movements are associated with large variations in both blood pressure and heart rate mediated by the autonomic nervous system. Cardiac dysrhythmias may occur selectively during REM sleep. Respiratory function also changes. In comparison to relaxed wakefulness, respiratory rate becomes slower but more regular during NREM sleep (especially N3 sleep) and becomes irregular during bursts of eye movements in REM sleep. Decreases in minute ventilation during NREM sleep are out of proportion to the decrease in metabolic rate, resulting in a slightly higher Pco2. Within the brain itself, neurotransmission is supported by ion gradients across the cell membranes of neurons and astrocytes. These ion flows are accompanied by increases in intracellular volume, so that during wake, there is very little extracellular space in the brain. During sleep, intracellular volume is reduced, resulting in increased extracellular space, which has higher calcium and lower potassium concentrations, supporting hyperpolarization and reduced firing of neurons. This expansion of the extracellular space during sleep increases diffusion of substances that accumulate extracellularly, like β-amyloid peptide, enhancing their clearance from the brain via cerebrospinal fluid flow. Recent evidence suggests that lack of adequate sleep may contribute to extracellular accumulation of β-amyloid peptide, a key step in the pathogenesis of Alzheimer’s disease. Endocrine function also varies with sleep. N3 sleep is associated with secretion of growth hormone in men, while sleep in general is associated with augmented secretion of prolactin in both men and women. Sleep has a complex effect on the secretion of luteinizing hormone (LH): during puberty, sleep is associated with increased LH secretion, whereas sleep in postpubertal women inhibits LH secretion in the early follicular phase of the menstrual cycle. Sleep onset (and probably N3 sleep) is associated with inhibition of thyroid-stimulating hormone and of the adrenocorticotropic hormone–cortisol axis, an effect that is superimposed on the prominent circadian rhythms in the two systems. The pineal hormone melatonin is secreted predominantly at night in both day- and night-active species, reflecting the direct modulation of pineal activity by the SCN via the sympathetic nervous system which innervates the pineal gland. Melatonin secretion does not require sleep, but melatonin secretion is inhibited by ambient light, an effect mediated by the neural connection from the retina to the pineal gland via the SCN. Sleep efficiency is highest when sleep coincides with endogenous melatonin secretion. When endogenous melatonin levels are low, such as during the biological day or at the desired bedtime in patients with delayed sleep-wake phase disorder (DSWPD), administration of exogenous melatonin can hasten sleep onset and increase sleep efficiency, but it does not increase sleep efficiency if administered when endogenous melatonin levels are elevated. This may explain why melatonin is often ineffective in the treatment of patients with primary insomnia. On the other hand, patients with sympathetic denervation of the pineal gland, such as occurs in cervical spinal cord injury or in patients with Parkinson’s disease, often have low melatonin levels, and administration of melatonin (3 mg 30 min before bedtime) may help them sleep. Sleep is accompanied by alterations of thermoregulatory function. NREM sleep is associated with an increase in the firing of warmresponsive neurons in the preoptic area and a fall in body temperature; conversely, skin warming without increasing core body temperature has been found to increase NREM sleep. REM sleep is associated with reduced thermoregulatory responsiveness.

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DISORDERS OF SLEEP AND WAKEFULNESS APPROACH TO THE PATIENT

Sleep Disorders

PART 2 Cardinal Manifestations and Presentation of Diseases

Patients may seek help from a physician because of: (1) sleepiness or tiredness during the day; (2) difficulty initiating or maintaining sleep at night (insomnia); or (3) unusual behaviors during sleep itself (parasomnias). Obtaining a careful history is essential. In particular, the duration, severity, and consistency of the symptoms are important, along with the patient’s estimate of the consequences of the sleep disorder on waking function. Information from a bed partner or family member is often helpful because some patients may be unaware of symptoms such as heavy snoring or may underreport symptoms such as falling asleep at work or while driving. Physicians should inquire about when the patient typically goes to bed, when they fall asleep and wake up, whether they awaken during sleep, whether they feel rested in the morning, and whether they nap during the day. Depending on the primary complaint, it may be useful to ask about snoring, witnessed apneas, restless sensations in the legs, movements during sleep, depression, anxiety, and behaviors around the sleep episode. The physical examination may provide evidence of a small airway, large tonsils, or a neurologic or medical disorder that contributes to the main complaint. It is important to remember that, rarely, seizures may occur exclusively during sleep, mimicking a primary sleep disorder; such sleep-related seizures typically occur during episodes of NREM sleep and may take the form of generalized tonic-clonic movements (sometimes with urinary incontinence or tongue biting) or stereotyped movements in partial complex epilepsy (Chap. 418). It is often helpful for the patient to complete a daily sleep log for 1–2 weeks to define the timing and amounts of sleep. When relevant, the log can also include information on levels of alertness, work times, and drug and alcohol use, including caffeine and hypnotics. Polysomnography is necessary for the diagnosis of several disorders such as sleep apnea, narcolepsy, and periodic limb movement disorder (PLMD). A conventional polysomnogram performed in a clinical sleep laboratory allows measurement of sleep stages, respiratory effort and airflow, oxygen saturation, limb movements, heart rhythm, and additional parameters. A home sleep test usually focuses on just respiratory measures and is helpful in patients with a moderate to high likelihood of having obstructive sleep apnea. The multiple sleep latency test (MSLT) is used to measure a patient’s propensity to sleep during the day and can provide crucial evidence for diagnosing narcolepsy and some other causes of sleepiness.

The maintenance of wakefulness test is used to measure a patient’s ability to sustain wakefulness during the daytime and can provide important evidence for evaluating the efficacy of therapies for improving sleepiness in conditions such as narcolepsy and obstructive sleep apnea.

■■EVALUATION OF DAYTIME SLEEPINESS

Up to 25% of the adult population has persistent daytime sleepiness that impairs an individual’s ability to perform optimally in school, at work, while driving, and in other conditions that require alertness. Sleepy students often have trouble staying alert and performing well in school, and sleepy adults struggle to stay awake and focused on their work. More than half of Americans have fallen asleep while driving. An estimated 1.2 million motor vehicle crashes per year are due to drowsy drivers, causing about 20% of all serious crash injuries and deaths. One needn’t fall asleep to have an accident, as the inattention and slowed responses of drowsy drivers are a major contributor. Twenty-four hours of continuous wakefulness impairs reaction time as much as a blood alcohol concentration of 0.10 g/dL (which is legally drunk in all 50 states). Identifying and quantifying sleepiness can be challenging. First, patients may describe themselves as “sleepy,” “fatigued,” or “tired,” and the meanings of these words may differ between patients. For clinical purposes, it is best to use the term “sleepiness” to describe a propensity to fall asleep; whereas “fatigue” is best used to describe a feeling of low physical or mental energy but without a tendency to actually sleep. Sleepiness is usually most evident when the patient is sedentary, whereas fatigue may interfere with more active pursuits. Sleepiness generally occurs with disorders that reduce the quality or quantity of sleep or that interfere with the neural mechanisms of arousal, whereas fatigue is more common in inflammatory disorders such as cancer, multiple sclerosis (Chap. 436), fibromyalgia (Chap. 366), chronic fatigue syndrome (Chap. 442), or endocrine deficiencies such as hypothyroidism (Chap. 376) or Addison’s disease (Chap. 379). Second, sleepiness can affect judgment in a manner analogous to ethanol, such that patients may have limited insight into the condition and the extent of their functional impairment. Finally, patients may be reluctant to admit that sleepiness is a problem because they may have become unfamiliar with feeling fully alert and because sleepiness is sometimes viewed pejoratively as reflecting poor motivation or bad sleep habits. Table 27-1 outlines the diagnostic and therapeutic approach to the patient with a complaint of excessive daytime sleepiness. To determine the extent and impact of sleepiness on daytime function, it is helpful to ask patients about the occurrence of sleep episodes during normal waking hours, both intentional and unintentional. Specific areas to be addressed include the occurrence of inadvertent sleep

TABLE 27-1  Evaluation of the Patient with Excessive Daytime Sleepiness FINDINGS ON HISTORY AND PHYSICAL EXAMINATION Difficulty waking in the morning, rebound sleep on weekends and vacations with improvement in sleepiness Obesity, snoring, hypertension

DIAGNOSTIC EVALUATION Sleep log

DIAGNOSIS Insufficient sleep

Polysomnogram or home sleep test

Obstructive sleep apnea (Chap. 291)

Cataplexy, hypnogogic hallucinations, sleep paralysis

Polysomnogram and multiple sleep latency test

Restless legs, kicking movements during sleep

Assessment for predisposing medical conditions (e.g., iron deficiency or renal failure) Thorough medical history and examination including detailed neurologic examination

Sedating medications, stimulant withdrawal, head trauma, systemic inflammation, Parkinson’s disease and other neurodegenerative disorders, hypothyroidism, encephalopathy

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THERAPY Sleep education and behavioral modification to increase amount of sleep

Continuous positive airway pressure; upper airway surgery (e.g., uvulopalatopharyngoplasty); dental appliance; weight loss Narcolepsy Stimulants (e.g., modafinil, methylphenidate); REM sleep-suppressing antidepressants (e.g., venlafaxine); sodium oxybate Restless legs syndrome Treatment of predisposing condition; dopamine with or without periodic limb agonists (e.g., pramipexole, ropinirole); movements gabapentin; opiates Sleepiness due to a drug or Change medications, treat underlying condition, medical condition consider stimulants

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Insufficient sleep is probably the most common cause of excessive daytime sleepiness. The average adult needs 7.5–8 h of sleep, but on weeknights, the average U.S. adult gets only 6.75 h of sleep. Only 30% of the U.S. adult population reports consistently obtaining sufficient sleep. Insufficient sleep is especially common among shift workers, individuals working multiple jobs, and people in lower socioeconomic groups. Most teenagers need ≥9 h of sleep, but many fail to get enough sleep because of circadian phase delay, plus social pressures to stay up late coupled with early school start times. Late evening light exposure, television viewing, video-gaming, social media, texting, and smartphone use often delay bedtimes despite the fixed, early wake times required for work or school. As is typical with any disorder that causes sleepiness, individuals with chronically insufficient sleep may feel inattentive, irritable, unmotivated, and depressed, and have difficulty with school, work, and driving. Individuals differ in their optimal amount of sleep, and it can be helpful to ask how much sleep the patient obtains on a quiet vacation when he or she can sleep without restrictions. Some patients may think that a short amount of sleep is normal or advantageous, and they may not appreciate their biological need for more sleep, especially if coffee and other stimulants mask the sleepiness. A 2-week sleep log documenting the timing of sleep and daily level of alertness is diagnostically useful and provides helpful feedback for the patient. Healthy Extending sleep to the optimal amount Awake REM on a regular basis can resolve the sleepN1 iness and other symptoms. As with any N2 lifestyle change, extending sleep requires N3 commitment and adjustments, but the improvements in daytime alertness make Narcolepsy this change worthwhile. Awake

■■SLEEP APNEA SYNDROMES

Respiratory dysfunction during sleep is a common, serious cause of excessive daytime sleepiness as well as of disturbed nocturnal sleep. At least 24% of middle-aged men and 9% of middle-aged women in the United States have a reduction or cessation of breathing dozens or more times each night during sleep, with 9% of men and 4% of women doing so

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■■NARCOLEPSY

Narcolepsy is characterized by difficulty sustaining wakefulness, poor regulation of REM sleep, and disturbed nocturnal sleep. All patients with narcolepsy have excessive daytime sleepiness. This sleepiness is usually moderate to severe, and in contrast to patients with disrupted sleep (e.g., sleep apnea), people with narcolepsy usually feel well rested upon awakening and then feel tired throughout much of the day. In addition, they often experience symptoms related to an intrusion of REM sleep characteristics. REM sleep is characterized by dreaming and muscle paralysis, and people with narcolepsy can have: (1) sudden muscle weakness without a loss of consciousness, which is usually triggered by strong emotions (cataplexy; Video 27-1); (2) dream-like hallucinations at sleep onset (hypnagogic hallucinations) or upon awakening (hypnopompic hallucinations); and (3) muscle paralysis upon awakening (sleep paralysis). With severe cataplexy, an individual may be laughing at a joke and then suddenly collapse to the ground, immobile but awake for 1–2 min. With milder episodes, patients may have partial weakness of the face or neck. Narcolepsy is one of the more common causes of chronic sleepiness and affects about 1 in 2000 people in the United States. Narcolepsy typically begins between age 10 and 20; once established, the disease persists for life. Narcolepsy is caused by loss of the hypothalamic neurons that produce the orexin neuropeptides (also known as hypocretins). Research in mice and dogs first demonstrated that a loss of orexin signaling due to null mutations of either the orexin neuropeptides or one of the orexin receptors causes sleepiness and cataplexy nearly identical to that seen in people with narcolepsy. Although genetic mutations rarely cause human narcolepsy, researchers soon discovered that patients with narcolepsy with cataplexy (now called type 1 narcolepsy) have very low or undetectable levels of orexins in their cerebrospinal fluid, and autopsy studies showed a nearly complete loss of the orexinproducing neurons in the hypothalamus. The orexins normally promote long episodes of wakefulness and suppress REM sleep, and thus, loss of orexin signaling results in frequent intrusions of sleep during the usual waking episode, with REM sleep and fragments of REM sleep at any time of day (Fig. 27-3). Patients with narcolepsy but no cataplexy

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■■INSUFFICIENT SLEEP

more than a hundred times per night. These episodes may be due to an occlusion of the airway (obstructive sleep apnea), absence of respiratory effort (central sleep apnea), or a combination of these factors. Failure to recognize and treat these conditions appropriately may lead to impairment of daytime alertness, increased risk of sleep-related motor vehicle crashes, depression, hypertension, myocardial infarction, diabetes, stroke, and increased mortality. Sleep apnea is particularly prevalent in overweight men and in the elderly, yet it is estimated to go undiagnosed in most affected individuals. This is unfortunate because several effective treatments are available. Readers are referred to Chap. 291 for a comprehensive review of the diagnosis and treatment of patients with sleep apnea.

CHAPTER 27

episodes while driving or in other safety-related settings, sleepiness while at work or school (and the relationship of sleepiness to work and school performance), and the effect of sleepiness on social and family life. Standardized questionnaires such as the Epworth Sleepiness Scale are often used clinically to measure sleepiness. Eliciting a history of daytime sleepiness is usually adequate, but objective quantification is sometimes necessary. The MSLT measures a patient’s propensity to sleep under quiet conditions. An overnight polysomnogram should precede the MSLT to establish that the patient has had an adequate amount of good-quality nighttime sleep. The MSLT consists of five 20-min nap opportunities every 2 h across the day. The patient is instructed to try to fall asleep, and the major endpoints are the average latency to sleep and the occurrence of REM sleep during the naps. An average sleep latency across the naps of 90% of people with type 1 narcolepsy, whereas it occurs in only 12–25% of the general population. Researchers now hypothesize that in people with DQB1*06:02, an immune response against influenza, Streptococcus, or other infections may also damage the orexin-producing neurons through a process of molecular mimicry. This mechanism may account for the eight- to twelvefold increase in new cases of narcolepsy among children in Europe who received a particular brand of H1N1 influenza A vaccine (Pandemrix). Traumatic brain injury can also damage orexin-containing neurons, inducing type 2 narcolepsy. On rare occasions, narcolepsy can occur with neurologic disorders such as tumors or strokes that directly damage the orexin-producing neurons in the hypothalamus or their projections.

Diagnosis  Narcolepsy is most commonly diagnosed by the history

of chronic sleepiness plus cataplexy or other symptoms. Many disorders can cause feelings of weakness, but with true cataplexy, patients will describe definite functional weakness (e.g., slurred speech, dropping a cup, slumping into a chair) that has consistent emotional triggers such as heartfelt mirth when laughing at a great joke, happy surprise at unexpectedly seeing a friend, or intense anger. Cataplexy occurs in about half of all narcolepsy patients and is diagnostically very helpful because it occurs in almost no other disorder. In contrast, occasional hypnagogic hallucinations and sleep paralysis occur in about 20% of the general population, and these symptoms are not as diagnostically specific. When narcolepsy is suspected, the diagnosis should be firmly established with a polysomnogram followed the next day by an MSLT. The polysomnogram helps rule out other possible causes of sleepiness such as sleep apnea and establishes that the patient was not sleep deprived the night before, and the MSLT provides essential, objective evidence of sleepiness plus REM sleep dysregulation. Across the five naps of the MSLT, most patients with narcolepsy will fall asleep in 3 months, occurs in about 10% of adults and is more common in women, older adults, people of lower socioeconomic status, and individuals with medical, psychiatric, and substance abuse disorders. Acute or short-term insomnia affects over 30% of adults and is often precipitated by stressful life events such as a major illness or loss, change of occupation, medications, and substance abuse. If the acute insomnia triggers maladaptive behaviors such as increased nocturnal light exposure, frequently checking the clock, or attempting to sleep more by napping, it can lead to chronic insomnia. Most insomnia begins in adulthood, but many patients may be predisposed and report easily disturbed sleep predating the insomnia, suggesting that their sleep is lighter than usual. Clinical studies and animal models indicate that insomnia is associated with activation during sleep of brain areas normally active only during wakefulness. The polysomnogram is rarely used in the evaluation of insomnia, as it typically confirms the patient’s subjective report of long latency to sleep and numerous awakenings but usually adds little new information. Many patients with insomnia have increased fast (beta) activity in the EEG during sleep; this fast activity is normally present only during wakefulness, which may explain why some patients report feeling awake for much of the night. The MSLT is rarely used in the evaluation of insomnia because, despite their feelings of low energy, most people with insomnia do not easily fall asleep during the day, and on the MSLT, their average sleep latencies are usually longer than normal. Many factors can contribute to insomnia, and obtaining a careful history is essential so one can select therapies targeting the underlying factors. The assessment should focus on identifying predisposing, precipitating, and perpetuating factors.

Psychophysiologic Factors  Many patients with insomnia have

negative expectations and conditioned arousal that interfere with sleep. These individuals may worry about their insomnia during the day and have increasing anxiety as bedtime approaches if they anticipate a poor night of sleep. While attempting to sleep, they may frequently check the clock, which only heightens anxiety and frustration. They may find it easier to sleep in a new environment rather than their bedroom, as it lacks the negative associations.

Inadequate Sleep Hygiene  Patients with insomnia sometimes develop counterproductive behaviors that contribute to their insomnia. These can include daytime napping that reduces sleep drive at night; an irregular sleep-wake schedule that disrupts their circadian rhythms; use of wake-promoting substances (e.g., caffeine, tobacco) too close to bedtime; engaging in alerting or stressful activities close to bedtime (e.g., arguing with a partner, work-related emailing and texting while in bed, sleeping with a smartphone or tablet at the bedside); and routinely using the bedroom for activities other than sleep or sex (e.g., TV, work), so the bedroom becomes associated with arousing or stressful feelings.

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Psychiatric Conditions  About 80% of patients with psychiatric

Medications and Drugs of Abuse  A wide variety of psychoac-

Medical Conditions  A large number of medical conditions dis-

rupt sleep. Pain from rheumatologic disorders or a painful neuropathy commonly disrupts sleep. Some patients may sleep poorly because of respiratory conditions such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, congestive heart failure, or restrictive lung disease, and some of these disorders are worse at night in bed due to circadian variations in airway resistance and postural changes that can result in nocturnal dyspnea. Many women experience poor sleep with the hormonal changes of menopause. Gastroesophageal reflux is also a common cause of difficulty sleeping.

Neurologic Disorders  Dementia (Chap. 25) is often associated

with poor sleep, probably due to a variety of factors, including napping during the day, altered circadian rhythms, and perhaps a weakened output of the brain’s sleep-promoting mechanisms. In fact, insomnia and nighttime wandering are some of the most common causes for institutionalization of patients with dementia, because they place a larger burden on caregivers. Conversely, in cognitively intact elderly men, fragmented sleep and poor sleep quality are associated with subsequent cognitive decline. Patients with Parkinson’s disease may sleep poorly due to rigidity, dementia, and other factors. Fatal familial insomnia is a very rare neurodegenerative condition caused by mutations in the prion protein gene, and although insomnia is a common early symptom, most patients present with other obvious neurologic signs such dementia, myoclonus, dysarthria, or autonomic dysfunction.

TREATMENT

Insomnia Treatment of insomnia improves quality of life and can promote long-term health. With improved sleep, patients often report less daytime fatigue, improved cognition, and more energy. Treating the insomnia can also improve the comorbid disease. For example, management of insomnia at the time of diagnosis of major depression often improves the response to antidepressants and reduces the risk of relapse. Sleep loss can heighten the perception of pain, so a similar approach is warranted in acute and chronic pain management. The treatment plan should target all putative contributing factors: establish good sleep hygiene, treat medical disorders, use behavioral therapies for anxiety and negative conditioning, and use pharmacotherapy and/or psychotherapy for psychiatric disorders. Behavioral therapies should be the first-line treatment, followed by judicious use of sleep-promoting medications if needed.

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IMPROVE SLEEP HYGIENE Attention should be paid to improving sleep hygiene and avoiding counterproductive, arousing behaviors before bedtime. Patients should establish a regular bedtime and wake time, even on weekends, to help synchronize their circadian rhythms and sleep patterns. The amount of time allocated for sleep should not be more than their actual total amount of sleep. In the 30 min before bedtime, patients should establish a relaxing “wind-down” routine that can include a warm bath, listening to music, meditation, or other relaxation techniques. The bedroom should be off-limits to computers, televisions, radios, smartphones, videogames, and tablets. Once in bed, patients should try to avoid thinking about anything stressful or arousing such as problems with relationships or work. If they cannot fall asleep within 20 min, it often helps to get out of bed and read or listen to relaxing music in dim light as a form of distraction from any anxiety, but artificial light, including light from a television, cell phone, or computer, should be avoided, because light itself suppresses melatonin secretion and is arousing. Table 27-2 outlines some of the key aspects of good sleep hygiene to improve insomnia.

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tive drugs can interfere with sleep. Caffeine, which has a half-life of 6–9 h, can disrupt sleep for up to 8–14 h, depending on the dose, variations in metabolism, and an individual’s caffeine sensitivity. Insomnia can also result from use of prescription medications too close to bedtime (e.g., antidepressants, stimulants, glucocorticoids, theophylline). Conversely, withdrawal of sedating medications such as alcohol, narcotics, or benzodiazepines can cause insomnia. Alcohol taken just before bed can shorten sleep latency, but it often produces rebound insomnia 2–3 h later as it wears off. This same problem with sleep maintenance can occur with short-acting benzodiazepines such as alprazolam.

TREATMENT OF MEDICAL AND PSYCHIATRIC DISEASE If the history suggests that a medical or psychiatric disease contributes to the insomnia, then it should be addressed by, for example, treating the pain, improving breathing, and switching or adjusting the timing of medications.

CHAPTER 27

disorders have sleep complaints, and about half of all chronic insomnia occurs in association with a psychiatric disorder. Depression is classically associated with early morning awakening, but it can also interfere with the onset and maintenance of sleep. Mania and hypomania can disrupt sleep and often are associated with substantial reductions in the total amount of sleep. Anxiety disorders can lead to racing thoughts and rumination that interfere with sleep and can be very problematic if the patient’s mind becomes active midway through the night. Panic attacks can arise from sleep and need to be distinguished from other parasomnias. Insomnia is common in schizophrenia and other psychoses, often resulting in fragmented sleep, less deep NREM sleep, and sometimes reversal of the day-night sleep pattern.

COGNITIVE BEHAVIORAL THERAPY CBT uses a combination of the techniques above plus additional methods to improve insomnia. A trained therapist may use cognitive psychology techniques to reduce excessive worrying about sleep and to reframe faulty beliefs about the insomnia and its daytime consequences. The therapist may also teach the patient relaxation techniques, such as progressive muscle relaxation or meditation, to reduce autonomic arousal, intrusive thoughts, and anxiety. MEDICATIONS FOR INSOMNIA If insomnia persists after treatment of these contributing factors, pharmacotherapy is often used on a nightly or intermittent basis. A variety of sedatives can improve sleep. Antihistamines, such as diphenhydramine, are the primary active ingredient in most over-the-counter sleep aids. These may be of benefit when used intermittently, but can produce tolerance and anticholinergic side effects such as dry mouth and constipation, which limit their use, particularly in the elderly. Benzodiazepine receptor agonists (BzRAs) are an effective and well-tolerated class of medications for insomnia. BzRAs bind to the GABAA receptor and potentiate the postsynaptic response to GABA. GABAA receptors are found throughout the brain, and BzRAs may TABLE 27-2  Methods to Improve Sleep Hygiene in Insomnia Patients HELPFUL BEHAVIORS Use the bed only for sleep and sex •  If you cannot sleep within 20 min, get out of bed and read or do other relaxing activities in dim light before returning to bed Make quality sleep a priority •  Go to bed and get up at the same time each day •  Ensure a restful environment (comfortable bed, bedroom quiet and dark) Develop a consistent bedtime routine. For example: •  Prepare for sleep with 20–30 min of relaxation (e.g., soft music, meditation, yoga, pleasant reading) •  Take a warm bath

BEHAVIORS TO AVOID Avoid behaviors that interfere with sleep physiology, including: •  Napping, especially after 3:00 pm •  Attempting to sleep too early •  Caffeine after lunchtime In the 2–3 h before bedtime, avoid: •  Heavy eating •  Smoking or alcohol •  Vigorous exercise When trying to fall asleep, avoid: •  Solving problems •  Thinking about life issues •  Reviewing events of the day

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PART 2 Cardinal Manifestations and Presentation of Diseases

globally reduce neural activity and may enhance the activity of specific sleep-promoting GABAergic pathways. Classic BzRAs include lorazepam, triazolam, and clonazepam, whereas newer agents such as zolpidem and zaleplon have more selective affinity for the α1 subunit of the GABAA receptor. Specific BzRAs are often chosen based on the desired duration of action. The most commonly prescribed agents in this family are zaleplon (5–20 mg), with a half-life of 1–2 h; zolpidem (5–10 mg) and triazolam (0.125–0.25 mg), with half-lives of 2–4 h; eszopiclone (1–3 mg), with a half-life of 5–8 h; and temazepam (15–30 mg), with a half-life of 8–20 h. Generally, side effects are minimal when the dose is kept low and the serum concentration is minimized during the waking hours (by using the shortest-acting effective agent). For chronic insomnia, intermittent use is recommended, unless the consequences of untreated insomnia outweigh concerns regarding chronic use. The heterocyclic antidepressants (trazodone, amitriptyline,2 and doxepin) are the most commonly prescribed alternatives to BzRAs due to their lack of abuse potential and lower cost. Trazodone (25–100 mg) is used more commonly than the tricyclic antidepressants, because it has a much shorter half-life (5–9 h) and less anticholinergic activity. The orexin receptor antagonist suvorexant (10–20 mg) can also improve insomnia by blocking the wake-promoting effects of the orexin neuropeptides. It has a long half-life and can produce morning sedation, and as it reduces orexin signaling, it can rarely produce hypnagogic hallucinations and sleep paralysis (see narcolepsy section above). Medications for insomnia are now among the most commonly prescribed medications, but they should be used cautiously. All sedatives increase the risk of injurious falls and confusion in the elderly, and therefore if needed, these medications should be used at the lowest effective dose. Morning sedation can interfere with driving and judgment, and when selecting a medication, one should consider the duration of action. Benzodiazepines carry a risk of addiction and abuse, especially in patients with a history of alcohol or sedative abuse. In patients with depression, all sedatives can worsen the depression. Like alcohol, some sleep-promoting medications can worsen sleep apnea. Sedatives can also produce complex behaviors during sleep, such as sleep walking and sleep eating, although this seems more likely at higher doses. Trazodone and amitriptyline have not been approved by the FDA for treating insomnia.

2

■■RESTLESS LEGS SYNDROME

Patients with restless legs syndrome (RLS) report an irresistible urge to move the legs. Many patients report a creepy-crawly or unpleasant deep ache within the thighs or calves, and those with more severe RLS may have discomfort in the arms as well. For most patients with RLS, these dysesthesias and restlessness are much worse in the evening and first half of the night. The symptoms appear with inactivity and can make sitting still in an airplane or when watching a movie a miserable experience. The sensations are temporarily relieved by movement, stretching, or massage. This nocturnal discomfort usually interferes with sleep, and patients may report daytime sleepiness as a consequence. RLS is very common, affecting 5–10% of adults and is more common in women and older adults. A variety of factors can cause RLS. Iron deficiency is the most common treatable cause, and iron replacement should be considered if the ferritin level is 70, and is about twice as common in men. Most already have or will develop a neurodegenerative disorder. Within 12 years of disease onset, half of RBD patients develop a synucleinopathy such as Parkinson’s disease (Chap. 427) or dementia with Lewy bodies (Chap. 426), or occasionally multiple system atrophy (Chap. 432), and over 90% develop a synucleinopathy by 25 years. RBD can occur in patients taking antidepressants, and in some, these medications may unmask this early indicator of neurodegeneration. Synucleinopathies probably cause neuronal loss in brainstem regions that regulate muscle paralysis during REM sleep, and loss of these neurons permits movements to break through during REM sleep. RBD also occurs in about 30% of patients with narcolepsy, but the underlying cause is probably different, as they seem to be at no increased risk of a neurodegenerative disorder. Many patients with RBD have sustained improvement with clonazepam (0.5–2.0 mg qhs).3 Melatonin at doses up to 9 mg nightly may also prevent attacks. ■■CIRCADIAN RHYTHM SLEEP DISORDERS

A subset of patients presenting with either insomnia or hypersomnia may have a disorder of sleep timing rather than sleep generation. Disorders of sleep timing can be either organic (i.e., due to an abnormality of circadian pacemaker[s]) or environmental/behavioral (i.e., due to a disruption of environmental synchronizers). Effective therapies aim to entrain the circadian rhythm of sleep propensity to an appropriate phase.

Delayed Sleep-Wake Phase Disorder  DSWPD is characterized by: (1) reported sleep onset and wake times persistently later than desired; (2) actual sleep times at nearly the same clock hours daily; and (3) if conducted at the habitual delayed sleep time, essentially normal sleep on polysomnography (except for delayed sleep onset). Patients No medications have been approved by the FDA for the treatment of RBD.

3

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Sleep Disorders

Sleep Bruxism  Bruxism is an involuntary, forceful grinding of

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Sleep Enuresis  Bedwetting, like sleepwalking and night terrors, is another parasomnia that occurs during sleep in the young. Before age 5 or 6 years, nocturnal enuresis should be considered a normal feature of development. The condition usually improves spontaneously by puberty, persists in 1–3% of adolescents, and is rare in adulthood. Treatment consists of bladder training exercises and behavioral therapy. Symptomatic pharmacotherapy is usually accomplished in adults with desmopressin (0.2 mg qhs), oxybutynin chloride (5 mg qhs), or imipramine (10–25 mg qhs). Important causes of nocturnal enuresis in patients who were previously continent for 6–12 months include urinary tract infections or malformations, cauda equina lesions, emotional disturbances, epilepsy, sleep apnea, and certain medications.

with DSWPD exhibit an abnormally delayed endogenous circadian phase, which can be assessed by measuring the onset of secretion of melatonin in either the blood or saliva; this is best done in a dimly lit environment as light suppresses melatonin secretion. Dim-light melatonin onset (DLMO) in DSWPD patients occurs later in the evening than normal, which is about 8:00–9:00 p.m. (i.e., about 1–2 h before habitual bedtime). Patients tend to be young adults. The delayed circadian phase could be due to: (1) an abnormally long, genetically determined intrinsic period of the endogenous circadian pacemaker; (2) reduced phase-advancing capacity of the pacemaker; (3) slower rate of buildup of homeostatic sleep drive during wakefulness; or (4) an irregular prior sleep-wake schedule, characterized by frequent nights when the patient chooses to remain awake while exposed to artificial light well past midnight (for personal, social, school, or work reasons). In most cases, it is difficult to distinguish among these factors, as patients with either a behaviorally induced or biologically driven circadian phase delay may both exhibit a similar circadian phase delay in DLMO, and both factors make it difficult to fall asleep at the desired hour. Late onset of dim-light melatonin secretion can help distinguish DSWD from other forms of sleep-onset insomnia. DSWPD is a chronic condition that can persist for years and may not respond to attempts to reestablish normal bedtime hours. Treatment methods involving phototherapy with blue-enriched light during the morning hours and/or melatonin administration in the evening hours show promise in these patients, although the relapse rate is high.

Advanced Sleep-Wake Phase Disorder  Advanced sleep-wake

phase disorder (ASWPD) is the converse of DSWPD. Most commonly, this syndrome occurs in older people, 15% of whom report that they cannot sleep past 5:00 a.m., with twice that number complaining that they wake up too early at least several times per week. Patients with ASWPD are sleepy during the evening hours, even in social settings. Sleep-wake timing in ASWPD patients can interfere with a normal social life. Patients with this circadian rhythm sleep disorder can be distinguished from those who have early wakening due to insomnia because ASWPD patients show early onset of dim-light melatonin secretion. In addition to age-related ASWPD, an early-onset familial variant of this condition has also been reported. In two families in which ASWPD was inherited in an autosomal dominant pattern, the syndrome was due to missense mutations in a circadian clock component (in the casein kinase binding domain of PER2 in one family, and in casein kinase I delta in the other) that shortens the circadian period. Patients with ASWPD may benefit from bright light and/or blue enriched phototherapy during the evening hours to reset the circadian pacemaker to a later hour.

Non-24-h Sleep-Wake Rhythm Disorder  Non-24-h sleep-

wake rhythm disorder (N24SWRD) most commonly occurs when the primary synchronizing input (i.e., the light-dark cycle) from the environment to the circadian pacemaker is lost (as occurs in many blind people with no light perception), and the maximal phase-advancing capacity of the circadian pacemaker in response to non-photic cues cannot accommodate the difference between the 24-h geophysical day and the intrinsic period of the patient’s circadian pacemaker, resulting in loss of entrainment to the 24-h day. The sleep of most blind patients with N24SWRD is restricted to the nighttime hours due to social or occupational demands. Despite this regular sleep-wake schedule, affected patients with N24SWRD are nonetheless unable to maintain a stable phase relationship between the output of the non-entrained circadian pacemaker and the 24-h day. Therefore, most blind patients present with intermittent bouts of insomnia. When the blind patient’s endogenous circadian rhythms are out of phase with the local environment, nighttime insomnia coexists with excessive daytime sleepiness. Conversely, when the endogenous circadian rhythms of those same patients are in phase with the local environment, symptoms remit. The interval between symptomatic phases may last several weeks to several months in blind patients with N24SWRD, depending on the period of the underlying nonentrained rhythm and the 24-h day. Nightly low-dose (0.5 mg) melatonin administration may improve sleep and,

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in some cases, induce synchronization of the circadian pacemaker. In sighted patients, N24SWRD is usually caused by self-selected exposure to artificial light that inadvertently entrains the circadian pacemaker to a >24-h schedule, and these individuals present with an incremental pattern of successive delays in sleep timing, progressing in and out of phase with local time—a clinical presentation that is seldom seen in blind patients with N24SWRD.

PART 2 Cardinal Manifestations and Presentation of Diseases

Shift-Work Disorder  More than 7 million workers in the United States regularly work at night, either on a permanent or rotating schedule. Many more begin the commute to work or school between 4:00 a.m. and 7:00 a.m., requiring them to commute and then work during a time of day that they would otherwise be asleep. In addition, each week, millions of “day” workers and students elect to remain awake at night or awaken very early in the morning to work or study to meet work or school deadlines, drive long distances, compete in sporting events, or participate in recreational activities. Such schedules can result in both sleep loss and misalignment of circadian rhythms with respect to the sleep-wake cycle. The circadian timing system usually fails to adapt successfully to the inverted schedules required by overnight work or the phase advance required by early morning (4:00 a.m. to 7:00 a.m.) start times. This leads to a misalignment between the desired work-rest schedule and the output of the pacemaker and to disturbed daytime sleep in most such individuals. Excessive work hours (per day or per week), insufficient time off between consecutive days of work or school, and frequent travel across time zones may be contributing factors. Sleep deficiency, increased length of time awake prior to work, and misalignment of circadian phase produce decreased alertness and performance, increased reaction time, and increased risk of performance lapses, thereby resulting in greater safety hazards among night workers and other sleep-deprived individuals. Sleep disturbance nearly doubles the risk of a fatal work accident. In addition, long-term night shift workers have higher rates of breast, colorectal, and prostate cancer and of cardiac, gastrointestinal, metabolic, and reproductive disorders. The World Health Organization has added night-shift work to its list of probable carcinogens. Sleep onset begins in local brain regions before gradually sweeping over the entire brain as sensory thresholds rise and consciousness is lost. A sleepy individual struggling to remain awake may attempt to continue performing routine and familiar motor tasks during the transition state between wakefulness and stage N1 sleep, while unable to adequately process sensory input from the environment. Such sleeprelated attentional failures typically last only seconds but are known on occasion to persist for longer durations. Motor vehicle operators who fail to heed the warning signs of sleepiness are especially vulnerable to sleep-related accidents, as sleep processes can slow reaction times, induce automatic behavior, and intrude involuntarily upon the waking brain, causing catastrophic consequences—including 6400 fatalities and 50,000 debilitating injuries in the United States annually. For this reason, an expert consensus panel has concluded that individuals who have slept 24 consecutive hours increases the risk of percutaneous injuries and more

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than doubles the risk of motor vehicle crashes during the commute home. For these reasons, in 2008, the National Academy of Medicine concluded that the practice of scheduling resident physicians to work for >16 consecutive hours without sleep is hazardous for both resident physicians and their patients. From 5 to 15% of individuals scheduled to work at night or in the early morning hours have much greater-than-average difficulties remaining awake during night work and sleeping during the day; these individuals are diagnosed with chronic and severe shift-work disorder (SWD). Patients with this disorder have a level of excessive sleepiness during work at night or in the early morning and insomnia during day sleep that the physician judges to be clinically significant; the condition is associated with an increased risk of sleep-related accidents and with some of the illnesses associated with night-shift work. Patients with chronic and severe SWD are profoundly sleepy at work. In fact, their sleep latencies during night work average just 2 min, comparable to mean daytime sleep latency durations of patients with narcolepsy or severe sleep apnea.

TREATMENT

Shift-Work Disorder Caffeine is frequently used by night workers to promote wakefulness. However, it cannot forestall sleep indefinitely, and it does not shield users from sleep-related performance lapses. Postural changes, exercise, and strategic placement of nap opportunities can sometimes temporarily reduce the risk of fatigue-related performance lapses. Properly timed exposure to blue-enriched light or bright white light can directly enhance alertness and facilitate more rapid adaptation to night-shift work. Modafinil (200 mg) or armodafinil (150 mg) 30–60 min before the start of an 8-h overnight shift is an effective treatment for the excessive sleepiness during night work in patients with SWD. Although treatment with modafinil or armodafinil significantly improves performance and reduces sleep propensity and the risk of lapses of attention during night work, affected patients remain excessively sleepy. Fatigue risk management programs for night shift workers should promote education about sleep, increase awareness of the hazards associated with sleep deficiency and night work, and screen for common sleep disorders. Work schedules should be designed to minimize: (1) exposure to night work; (2) the frequency of shift rotations; (3) the number of consecutive night shifts; and (4) the duration of night shifts.

Jet Lag Disorder  Each year, >60 million people fly from one

time zone to another, often resulting in excessive daytime sleepiness, sleep-onset insomnia, and frequent arousals from sleep, particularly in the latter half of the night. The syndrome is transient, typically lasting 2–14 d depending on the number of time zones crossed, the direction of travel, and the traveler’s age and phase-shifting capacity. Travelers who spend more time outdoors at their destination reportedly adapt more quickly than those who remain in hotel or seminar rooms, presumably due to brighter (outdoor) light exposure. Avoidance of antecedent sleep loss or napping on the afternoon prior to overnight travel can reduce the difficulties associated with extended wakefulness. Laboratory studies suggest that low doses of melatonin can enhance sleep efficiency, but only if taken when endogenous melatonin concentrations are low (i.e., during the biologic daytime). In addition to jet lag associated with travel across time zones, many patients report a behavioral pattern that has been termed social jet lag, in which bedtimes and wake times on weekends or days off occur 4–8 h later than during the week. Such recurrent displacement of the timing of the sleep-wake cycle is common in adolescents and young adults and is associated with delayed circadian phase, sleep-onset insomnia, excessive daytime sleepiness, poorer academic performance, and increased risk of both obesity and depressive symptoms.

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■■MEDICAL IMPLICATIONS OF CIRCADIAN RHYTHMICITY

■■FURTHER READING

Ding F et al: Changes in the composition of brain interstitial ions control the sleep-wake cycle. Science 352:550, 2016. Ju YE et al: Sleep and Alzheimer disease pathology—A bidirectional relationship. Nat Rev Neurol 10:115, 2014. Lee ML et al: High risk of near-crash driving events following nightshift work. Proc Natl Acad Sci USA 113:176, 2016. Lim AS et al: Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer’s disease. Brain 137:2847, 2014. Liu Y et al: Prevalence of healthy sleep duration among adults— United States, 2014. MMWR Morb Mortal Wkly Rep 65:137, 2016. Riemann D et al: The neurobiology, investigation, and treatment of chronic insomnia. Lancet Neurol 14:547, 2015. Scammell TE: Narcolepsy. N Engl J Med 373:2654, 2015. Scammell TE et al: Neural circuitry of wakefulness and sleep. Neuron 93:747, 2017. Stothard ER et al: Circadian entrainment to the natural light-dark cycle across seasons and the weekend. Curr Biol 27:508, 2017. Xie L et al: Sleep drives metabolite clearance from the adult brain. Science 342:373, 2013.

VIDEO 27-1  A typical episode of severe cataplexy. The patient is joking and then falls to the ground with an abrupt loss of muscle tone. The electromyogram recordings (four lower traces on the right) show reductions in muscle activity during the period of paralysis. The electroencephalogram (top two traces) shows wakefulness throughout the episode. (Video courtesy of Giuseppe Plazzi, University of Bologna.)

VIDEO 27-2  Typical aggressive movements in rapid eye movement (REM) sleep behavior disorder. (Video courtesy of Dr. Carlos Schenck, University of Minnesota Medical School.)

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28

Disorders of the Eye Jonathan C. Horton

THE HUMAN VISUAL SYSTEM

The visual system provides a supremely efficient means for the rapid assimilation of information from the environment to aid in the guidance of behavior. The act of seeing begins with the capture of images focused by the cornea and lens on a light-sensitive membrane in the back of the eye called the retina. The retina is actually part of the brain, banished to the periphery to serve as a transducer for the conversion of patterns of light energy into neuronal signals. Light is absorbed by pigment in two types of photoreceptors: rods and cones. In the human retina there are 100 million rods and 5 million cones. The rods operate in dim (scotopic) illumination. The cones function under daylight (photopic) conditions. The cone system is specialized for color perception and high spatial resolution. The majority of cones are within the macula, the portion of the retina that serves the central 10° of vision. In the middle of the macula a small pit termed the fovea, packed exclusively with cones, provides the best visual acuity. Photoreceptors hyperpolarize in response to light, activating bipolar, amacrine, and horizontal cells in the inner nuclear layer. After processing of photoreceptor responses by this complex retinal circuit, the flow of sensory information ultimately converges on a final common pathway: the ganglion cells. These cells translate the visual image impinging on the retina into a continuously varying barrage of action potentials that propagates along the primary optic pathway to visual centers within the brain. There are a million ganglion cells in each retina and hence a million fibers in each optic nerve. Ganglion cell axons sweep along the inner surface of the retina in the nerve fiber layer, exit the eye at the optic disc, and travel through the optic nerve, optic chiasm, and optic tract to reach targets in the brain. The majority of fibers synapse on cells in the lateral geniculate body, a thalamic relay station. Cells in the lateral geniculate body project in turn to the primary visual cortex. This afferent retinogeniculocortical sensory pathway provides the neural substrate for visual perception. Although the lateral geniculate body is the main target of the retina, separate classes of ganglion cells project to other subcortical visual nuclei involved in different functions. Ganglion cells that mediate pupillary constriction and circadian rhythms are light sensitive owing to a novel visual pigment, melanopsin. Pupil responses are mediated by input to the pretectal olivary nuclei in the midbrain. The pretectal nuclei send their output to the Edinger-Westphal nuclei, which in turn provide parasympathetic innervation to the iris sphincter via an interneuron in the ciliary ganglion. Circadian rhythms are timed by a retinal projection to the suprachiasmatic nucleus. Visual orientation and eye movements are served by retinal input to the superior colliculus. Gaze stabilization and optokinetic reflexes are governed by a group of small retinal targets known collectively as the brainstem accessory optic system. The eyes must be rotated constantly within their orbits to place and maintain targets of visual interest on the fovea. This activity, called foveation, or looking, is governed by an elaborate efferent motor system. Each eye is moved by six extraocular muscles that are supplied by cranial nerves from the oculomotor (III), trochlear (IV), and abducens (VI) nuclei. Activity in these ocular motor nuclei is coordinated by pontine and midbrain mechanisms for smooth pursuit, saccades, and gaze stabilization during head and body movements. Large regions of the frontal and parietooccipital cortex control these brainstem eye movement centers by providing descending supranuclear input.

Disorders of the Eye

Acknowledgment John W. Winkelman, MD, PhD and Gary S. Richardson, MD contributed to this chapter in prior editions, and some material from their work has been retained here.

and Throat

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Prominent circadian variations have been reported in the incidence of acute myocardial infarction, sudden cardiac death, and stroke, the leading causes of death in the United States. Platelet aggregability is increased in the early morning hours, coincident with the peak incidence of these cardiovascular events. Recurrent circadian disruption combined with chronic sleep deficiency, such as occurs during nightshift work, is associated with increased plasma glucose concentrations after a meal due to inadequate pancreatic insulin secretion. Night shift workers with elevated fasting glucose have an increased risk of progressing to diabetes. Blood pressure of night workers with sleep apnea is higher than that of day workers. A better understanding of the possible role of circadian rhythmicity in the acute destabilization of a chronic condition such as atherosclerotic disease could improve the understanding of its pathophysiology. Diagnostic and therapeutic procedures may also be affected by the time of day at which data are collected. Examples include blood pressure, body temperature, the dexamethasone suppression test, and plasma cortisol levels. The timing of chemotherapy administration has been reported to have an effect on the outcome of treatment. In addition, both the toxicity and effectiveness of drugs can vary with time of day. For example, more than a fivefold difference has been observed in mortality rates following administration of toxic agents to experimental animals at different times of day. Anesthetic agents are particularly sensitive to time-of-day effects. Finally, the physician must be aware of the public health risks associated with the ever-increasing demands made by the 24/7 schedules in our round-the-clock society.

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Section 4  Disorders of Eyes, Ears, Nose,

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CLINICAL ASSESSMENT OF VISUAL FUNCTION ■■REFRACTIVE STATE

PART 2 Cardinal Manifestations and Presentation of Diseases

In approaching a patient with reduced vision, the first step is to decide whether refractive error is responsible. In emmetropia, parallel rays from infinity are focused perfectly on the retina. Sadly, this condition is enjoyed by only a minority of the population. In myopia, the globe is too long, and light rays come to a focal point in front of the retina. Near objects can be seen clearly, but distant objects require a diverging lens in front of the eye. In hyperopia, the globe is too short, and hence a converging lens is used to supplement the refractive power of the eye. In astigmatism, the corneal surface is not perfectly spherical, necessitating a cylindrical corrective lens. Most patients elect to wear eyeglasses or contact lenses to neutralize refractive error. An alternative is to permanently alter the refractive properties of the cornea by performing laser in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK). With the onset of middle age, presbyopia develops as the lens within the eye becomes unable to increase its refractive power to accommodate on near objects. To compensate for presbyopia an emmetropic patient must use reading glasses. A patient already wearing glasses for distance correction usually switches to bifocals. The only exception is a myopic patient, who may achieve clear vision at near simply by removing glasses containing the distance prescription. Refractive errors usually develop slowly and remain stable after adolescence, except in unusual circumstances. For example, the acute onset of diabetes mellitus can produce sudden myopia because of lens edema induced by hyperglycemia. Testing vision through a pinhole aperture is a useful way to screen quickly for refractive error. If visual acuity is better through a pinhole than it is with the unaided eye, the patient needs refraction to obtain best corrected visual acuity.

■■VISUAL ACUITY

The Snellen chart is used to test acuity at a distance of 6 m (20 ft). For convenience, a scale version of the Snellen chart called the Rosenbaum card is held at 36 cm (14 in.) from the patient (Fig. 28-1). All subjects should be able to read the 6/6 m (20/20 ft) line with each eye using their refractive correction, if any. Patients who need reading glasses because of presbyopia must wear them for accurate testing with the Rosenbaum card. If 6/6 (20/20) acuity is not present in each eye, the deficiency in vision must be explained. If it is worse than 6/240 (20/800), acuity should be recorded in terms of counting fingers, hand motions, light perception, or no light perception. Legal blindness is defined by the Internal Revenue Service as a best corrected acuity of 6/60 (20/200) or less in the better eye or a binocular visual field subtending 20° or less. Loss of vision in one eye only does not constitute legal blindness. For driving the laws vary by state, but most require a corrected acuity of 6/12 (20/40) in at least one eye for unrestricted privileges. Patients who develop a homonymous hemianopia should not drive.

■■PUPILS

The pupils should be tested individually in dim light with the patient fixating on a distant target. There is no need to check the near response if the pupils respond briskly to light, because isolated loss of constriction (miosis) to accommodation does not occur. For this reason, the ubiquitous abbreviation PERRLA (pupils equal, round, and reactive to light and accommodation) implies a wasted effort with the last step. However, it is important to test the near response if the light response is poor or absent. Light-near dissociation occurs with neurosyphilis (Argyll Robertson pupil), with lesions of the dorsal midbrain (Parinaud’s syndrome), and after aberrant regeneration (oculomotor nerve palsy, Adie’s tonic pupil). An eye with no light perception has no pupillary response to direct light stimulation. If the retina or optic nerve is only partially injured, the direct pupillary response will be weaker than the consensual pupillary response evoked by shining a light into the healthy fellow eye. A relative afferent pupillary defect (Marcus Gunn pupil) is elicited with the swinging flashlight test (Fig. 28-2). It is an extremely useful sign in retrobulbar optic neuritis and other optic nerve diseases, in which

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FIGURE 28-1  The Rosenbaum card is a miniature, scale version of the Snellen chart for testing visual acuity at near. When the visual acuity is recorded, the Snellen distance equivalent should bear a notation indicating that vision was tested at near, not at 6 m (20 ft), or else the Jaeger number system should be used to report the acuity.

it may be the sole objective evidence for disease. In bilateral optic neuropathy, no afferent pupil defect is present if the optic nerves are affected equally. Subtle inequality in pupil size, up to 0.5 mm, is a fairly common finding in normal persons. The diagnosis of essential or physiologic anisocoria is secure as long as the relative pupil asymmetry remains constant as ambient lighting varies. Anisocoria that increases in dim light indicates a sympathetic paresis of the iris dilator muscle. The triad of miosis with ipsilateral ptosis and anhidrosis constitutes Horner’s syndrome, although anhidrosis is an inconstant feature. Brainstem stroke, carotid dissection, and neoplasm impinging on the sympathetic chain occasionally are identified as the cause of Horner’s syndrome, but most cases are idiopathic. Anisocoria that increases in bright light suggests a parasympathetic palsy. The first concern is an oculomotor nerve paresis. This possibility is excluded if the eye movements are full and the patient has no ptosis or diplopia. Acute pupillary dilation (mydriasis) can result from damage to the ciliary ganglion in the orbit. Common mechanisms are infection (herpes zoster, influenza), trauma (blunt, penetrating, surgical), and ischemia (diabetes, temporal arteritis). After denervation of the iris sphincter the pupil does not respond well to light, but the response to near is often relatively intact. When the near stimulus is removed, the pupil redilates very slowly compared with the normal pupil, hence the term tonic pupil. In Adie’s syndrome a tonic pupil is present, sometimes in conjunction with weak or absent tendon reflexes in the lower extremities. This benign disorder, which occurs predominantly in healthy

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pupillary abnormality, a slit-lamp examination is helpful to exclude surgical trauma to the iris, an occult foreign body, perforating injury, intraocular inflammation, adhesions (synechia), angle-closure glaucoma, and iris sphincter rupture from blunt trauma.

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■■EYE MOVEMENTS AND ALIGNMENT

Disorders of the Eye

B

CHAPTER 28

A

Eye movements are tested by asking the patient, with both eyes open, to pursue a small target such as a pen tip into the cardinal fields of gaze. Normal ocular versions are smooth, symmetric, full, and maintained in all directions without nystagmus. Saccades, or quick refixation eye movements, are assessed by having the patient look back and forth between two stationary targets. The eyes should move rapidly and accurately in a single jump to their target. Ocular alignment can be judged by holding a penlight directly in front of the patient at about 1 m. If the eyes are straight, the corneal light reflex will be centered in the middle of each pupil. To test eye alignment more precisely, the cover test is useful. The patient is instructed to look at a small fixation target in the distance. One eye is occluded with a paddle or hand, while the other eye is observed. If the viewing eye shifts position to take up fixation on the target, it was misaligned. If it remains motionless, the first eye is uncovered and the test is repeated on the second eye. If neither eye moves the eyes are aligned orthotropically. If the eyes are orthotropic in primary gaze but the patient complains of diplopia, the cover test should be performed with the head tilted or turned in whatever direction elicits diplopia. With practice, the examiner can detect an ocular deviation (heterotropia) as small as 1–2° with the cover test. In a patient with vertical diplopia, a small deviation can be difficult to detect and easy to dismiss. The magnitude of the deviation can be measured by placing a prism in front of the misaligned eye to determine the power required to neutralize the fixation shift evoked by covering the other eye. Temporary press-on plastic Fresnel prisms, prism eyeglasses, or eye muscle surgery can be used to restore binocular alignment.

■■STEREOPSIS

C FIGURE 28-2  Demonstration of a relative afferent pupil defect (Marcus Gunn pupil) in the left eye, done with the patient fixating on a distant target. A. With dim background lighting, the pupils are equal and relatively large. B. Shining a flashlight into the right eye evokes equal, strong constriction of both pupils. C. Swinging the flashlight over to the damaged left eye causes dilation of both pupils, although they remain smaller than in A. Swinging the flashlight back over to the healthy right eye would result in symmetric constriction back to the appearance shown in B. Note that the pupils always remain equal; the damage to the left retina/optic nerve is revealed by weaker bilateral pupil constriction to a flashlight in the left eye compared with the right eye. (From P Levatin: Arch Ophthalmol 62:768, 1959. Copyright © 1959 American Medical Association. All rights reserved.)

young women, is assumed to represent a mild dysautonomia. Tonic pupils are also associated with multiple system atrophy, segmental hypohidrosis, diabetes, and amyloidosis. Occasionally, a tonic pupil is discovered incidentally in an otherwise completely normal, asymptomatic individual. The diagnosis is confirmed by placing a drop of dilute (0.125%) pilocarpine into each eye. Denervation hypersensitivity produces pupillary constriction in a tonic pupil, whereas the normal pupil shows no response. Pharmacologic dilatation from accidental or deliberate instillation of anticholinergic (atropine, scopolamine) drops can produce pupillary mydriasis. Gardener’s pupil refers to mydriasis induced by exposure to tropane alkaloids, contained in plants such as deadly nightshade, jimsonweed, or angel’s trumpet. When an anticholinergic agent is responsible for pupil dilation, 1% pilocarpine causes no constriction. Both pupils are affected equally by systemic medications. They are small with narcotic use (morphine, oxycodone) and large with anticholinergics (scopolamine). Parasympathetic agents (pilocarpine) used to treat glaucoma produce miosis. In any patient with an unexplained

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Stereoacuity is determined by presenting targets with retinal disparity separately to each eye by using polarized images. The most popular office tests measure a range of thresholds from 800 to 40 s of arc. Normal stereoacuity is 40 s of arc. If a patient achieves this level of stereoacuity, one is assured that the eyes are aligned orthotropically and that vision is intact in each eye. Random dot stereograms have no monocular depth cues and provide an excellent screening test for strabismus.

■■COLOR VISION

The retina contains three classes of cones, with visual pigments of differing peak spectral sensitivity: red (560 nm), green (530 nm), and blue (430 nm). The red and green cone pigments are encoded on the X chromosome, and the blue cone pigment on chromosome 7. Mutations of the blue cone pigment are exceedingly rare. Mutations of the red and green pigments cause congenital X-linked color blindness in 8% of males. Affected individuals are not truly color blind; rather, they differ from normal subjects in the way they perceive color and how they combine primary monochromatic lights to match a particular color. Anomalous trichromats have three cone types, but a mutation in one cone pigment (usually red or green) causes a shift in peak spectral sensitivity, altering the proportion of primary colors required to achieve a color match. Dichromats have only two cone types and therefore will accept a color match based on only two primary colors. Anomalous trichromats and dichromats have 6/6 (20/20) visual acuity, but their hue discrimination is impaired. Ishihara color plates can be used to detect red-green color blindness. The test plates contain a hidden number that is visible only to subjects with color confusion from red-green color blindness. Because color blindness is almost exclusively X-linked, it is worth screening only male children. The Ishihara plates often are used to detect acquired defects in color vision, although they are intended as a screening test for congenital color blindness. Acquired defects in color vision frequently result from disease of the macula or optic nerve. For example, patients with a history of optic neuritis often complain of color desaturation long after their visual acuity has returned to normal. Color blindness also

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can result from bilateral strokes involving the ventral portion of the occipital lobe (cerebral achromatopsia). Such patients can perceive only shades of gray and also may have difficulty recognizing faces (prosopagnosia). Infarcts of the dominant occipital lobe sometimes give rise to color anomia. Affected patients can discriminate colors but cannot name them.

by finger confrontation and then correlating it with the topographic anatomy of the visual pathway (Fig. 28-3). Quantitative visual field mapping is performed by computer-driven perimeters that present a target of variable intensity at fixed positions in the visual field (Fig. 28-3A). By generating an automated printout of light thresholds, these static perimeters provide a sensitive means of detecting scotomas in the visual field. They are exceedingly useful for serial assessment of visual function in chronic diseases such as glaucoma and pseudotumor cerebri. The crux of visual field analysis is to decide whether a lesion is before, at, or behind the optic chiasm. If a scotoma is confined to one

■■VISUAL FIELDS

Vision can be impaired by damage to the visual system anywhere from the eyes to the occipital lobes. One can localize the site of the lesion with considerable accuracy by mapping the visual field deficit

PART 2

Monocular prechiasmal field defects: A

C

B

Cardinal Manifestations and Presentation of Diseases

30°

30°

Blind Normal field spot Central scotoma right eye

D

E

30°

F

30°

Nerve-fiber bundle (arcuate) scotoma

Altitudinal scotoma

30°

Cecocentral scotoma

30°

Enlarged blind-spot with peripheral constriction

Binocular chiasmal or postchiasmal field defects: (Left eye)

(Right eye) G 100°

30°

60°

Junctional scotoma H 30°

Right

Bitemporal hemianopia

Left

I 30°

Optic nerve

Homonymous hemianopia G

J 30°

Optic chiasm H Optic tract

Superior quadrantanopia

J

K 30°

Lateral geniculate body K Optic radiations

Inferior quadrantanopia

L

I

L 30°

Primary visual cortex

Homonymous hemianopia with macular sparing FIGURE 28-3  Ventral view of the brain, correlating patterns of visual field loss with the sites of lesions in the visual pathway. The visual fields overlap partially, creating 120° of central binocular field flanked by a 40° monocular crescent on either side. The visual field maps in this figure were done with a computer-driven perimeter (Humphrey Instruments, Carl Zeiss, Inc.). It plots the retinal sensitivity to light in the central 30° by using a gray scale format. Areas of visual field loss are shown in black. The examples of common monocular, prechiasmal field defects are all shown for the right eye. By convention, the visual fields are always recorded with the left eye’s field on the left and the right eye’s field on the right, just as the patient sees the world.

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DISORDERS ■■RED OR PAINFUL EYE Corneal Abrasions  Corneal abrasions are seen best by placing

a drop of fluorescein in the eye and looking with the slit lamp, using a cobalt-blue light. A penlight with a blue filter will suffice if a slit lamp is not available. Damage to the corneal epithelium is revealed by yellow fluorescence of the exposed basement membrane underlying the epithelium. It is important to check for foreign bodies. To search the conjunctival fornices, the lower lid should be pulled down and the upper lid everted. A foreign body can be removed with a moistened cotton-tipped applicator after a drop of a topical anesthetic such as proparacaine has been placed in the eye. Alternatively, it may be possible to flush the foreign body from the eye by irrigating copiously with saline or artificial tears. If the corneal epithelium has been abraded, antibiotic ointment and a patch should be applied to the eye. A drop of an intermediate-acting cycloplegic such as cyclopentolate hydrochloride 1% helps reduce pain by relaxing the ciliary body. The eye should be reexamined the next day. Minor abrasions may not require patching, antibiotics, or cycloplegia.

Disorders of the Eye

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sessions, patients fixate a central target while visual stimuli are presented within the blind region. The premise of vision restoration programs is that extra stimulation can promote recovery of partially damaged tissue located at the fringe of a cortical lesion. When fixation is controlled rigorously, however, no real improvement of the visual fields can be demonstrated. No effective treatment has been devised for homonymous hemianopia caused by loss of visual cortex.

CHAPTER 28

eye, it must be due to a lesion anterior to the chiasm, involving either the optic nerve or the retina. Retinal lesions produce scotomas that correspond optically to their location in the fundus. For example, a superior-nasal retinal detachment results in an inferior-temporal field cut. Damage to the macula causes a central scotoma (Fig. 28-3B). Optic nerve disease produces characteristic patterns of visual field loss. Glaucoma selectively destroys axons that enter the superotemporal or inferotemporal poles of the optic disc, resulting in arcuate scotomas shaped like a Turkish scimitar, which emanate from the blind spot and curve around fixation to end flat against the horizontal meridian (Fig. 28-3C). This type of field defect mirrors the arrangement of the nerve fiber layer in the temporal retina. Arcuate or nerve fiber layer scotomas also result from optic neuritis, ischemic optic neuropathy, optic disc drusen, and branch retinal artery or vein occlusion. Damage to the entire upper or lower pole of the optic disc causes an altitudinal field cut that follows the horizontal meridian (Fig. 28-3D). This pattern of visual field loss is typical of ischemic optic neuropathy but also results from retinal vascular occlusion, advanced glaucoma, and optic neuritis. About half the fibers in the optic nerve originate from ganglion cells serving the macula. Damage to papillomacular fibers causes a cecocentral scotoma that encompasses the blind spot and macula (Fig. 28-3E). If the damage is irreversible, pallor eventually appears in the temporal portion of the optic disc. Temporal pallor from a cecocentral scotoma may develop in optic neuritis, nutritional optic neuropathy, toxic optic neuropathy, Leber’s hereditary optic neuropathy, Kjer’s dominant optic atrophy, and compressive optic neuropathy. It is worth mentioning that the temporal side of the optic disc is slightly paler than the nasal side in most normal individuals. Therefore, it sometimes can be difficult to decide whether the temporal pallor visible on fundus examination represents a pathologic change. Pallor of the nasal rim of the optic disc is a less equivocal sign of optic atrophy. At the optic chiasm, fibers from nasal ganglion cells decussate into the contralateral optic tract. Crossed fibers are damaged more by compression than are uncrossed fibers. As a result, mass lesions of the sellar region cause a temporal hemianopia in each eye. Tumors anterior to the optic chiasm, such as meningiomas of the tuberculum sella, produce a junctional scotoma characterized by an optic neuropathy in one eye and a superior-temporal field cut in the other eye (Fig. 28-3G). More symmetric compression of the optic chiasm by a pituitary adenoma (see Fig. 373-1), meningioma, craniopharyngioma, glioma, or aneurysm results in a bitemporal hemianopia (Fig. 28-3H). The insidious development of a bitemporal hemianopia often goes unnoticed by the patient and will escape detection by the physician unless each eye is tested separately. It is difficult to localize a postchiasmal lesion accurately, because injury anywhere in the optic tract, lateral geniculate body, optic radiations, or visual cortex can produce a homonymous hemianopia (i.e., a temporal hemifield defect in the contralateral eye and a matching nasal hemifield defect in the ipsilateral eye) (Fig. 28-3I). A unilateral postchiasmal lesion leaves the visual acuity in each eye unaffected, although the patient may read the letters on only the left or right half of the eye chart. Lesions of the optic radiations tend to cause poorly matched or incongruous field defects in each eye. Damage to the optic radiations in the temporal lobe (Meyer’s loop) produces a superior quadrantic homonymous hemianopia (Fig. 28-3J), whereas injury to the optic radiations in the parietal lobe results in an inferior quadrantic homonymous hemianopia (Fig. 28-3K). Lesions of the primary visual cortex give rise to dense, congruous hemianopic field defects. Occlusion of the posterior cerebral artery supplying the occipital lobe is a common cause of total homonymous hemianopia. Some patients with hemianopia after occipital stroke have macular sparing, because the macular representation at the tip of the occipital lobe is supplied by collaterals from the middle cerebral artery (Fig. 28-3L). Destruction of both occipital lobes produces cortical blindness. This condition can be distinguished from bilateral prechiasmal visual loss by noting that the pupil responses and optic fundi remain normal. Partial recovery of homonymous hemianopia has been reported through computer-based rehabilitation therapy. During daily training

Subconjunctival Hemorrhage  This results from rupture of

small vessels bridging the potential space between the episclera and the conjunctiva. Blood dissecting into this space can produce a spectacular red eye, but vision is not affected and the hemorrhage resolves without treatment. Subconjunctival hemorrhage is usually spontaneous but can result from blunt trauma, eye rubbing, or vigorous coughing. Occasionally it is a clue to an underlying bleeding disorder.

Pinguecula  Pinguecula is a small, raised conjunctival nodule, usu-

ally at the nasal limbus. In adults such lesions are extremely common and have little significance unless they become inflamed (pingueculitis). They are more apt to occur in workers with frequent outdoor exposure. A pterygium resembles a pinguecula but has crossed the limbus to encroach on the corneal surface. Removal is justified when symptoms of irritation or blurring develop, but recurrence is a common problem.

Blepharitis  This refers to inflammation of the eyelids. The most

common form occurs in association with acne rosacea or seborrheic dermatitis. The eyelid margins usually are colonized heavily by staphylococci. Upon close inspection, they appear greasy, ulcerated, and crusted with scaling debris that clings to the lashes. Treatment consists of strict eyelid hygiene, using warm compresses and eyelash scrubs with baby shampoo. An external hordeolum (sty) is caused by staphylococcal infection of the superficial accessory glands of Zeis or Moll located in the eyelid margins. An internal hordeolum occurs after suppurative infection of the oil-secreting meibomian glands within the tarsal plate of the eyelid. Topical antibiotics such as bacitracin/ polymyxin B ophthalmic ointment can be applied. Systemic antibiotics, usually tetracyclines or azithromycin, sometimes are necessary for treatment of meibomian gland inflammation (meibomitis) or chronic, severe blepharitis. A chalazion is a painless, chronic granulomatous inflammation of a meibomian gland that produces a pealike nodule within the eyelid. It can be incised and drained, but injection with glucocorticoids is equally effective. Basal cell, squamous cell, or meibomian gland carcinoma should be suspected with any nonhealing ulcerative lesion of the eyelids.

Dacryocystitis  An inflammation of the lacrimal drainage sys-

tem, dacryocystitis can produce epiphora (tearing) and ocular injection. Gentle pressure over the lacrimal sac evokes pain and reflux of mucus or pus from the tear puncta. Dacryocystitis usually occurs

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after obstruction of the lacrimal system. It is treated with topical and systemic antibiotics, followed by probing, silicone stent intubation, or surgery to reestablish patency. Entropion (inversion of the eyelid) or ectropion (sagging or eversion of the eyelid) can also lead to epiphora and ocular irritation.

Conjunctivitis  Conjunctivitis is the most common cause of a red,

PART 2 Cardinal Manifestations and Presentation of Diseases

irritated eye. Pain is minimal, and visual acuity is reduced only slightly. The most common viral etiology is adenovirus infection. It causes a watery discharge, a mild foreign-body sensation, and photophobia. Bacterial infection tends to produce a more mucopurulent exudate. Mild cases of infectious conjunctivitis usually are treated empirically with broad-spectrum topical ocular antibiotics such as sulfacetamide 10%, polymyxin-bacitracin, or a trimethoprim-polymyxin combination. Smears and cultures usually are reserved for severe, resistant, or recurrent cases of conjunctivitis. To prevent contagion, patients should be admonished to wash their hands frequently, not to touch their eyes, and to avoid direct contact with others.

Allergic Conjunctivitis  This condition is extremely common

and often is mistaken for infectious conjunctivitis. Itching, redness, and epiphora are typical. The palpebral conjunctiva may become hypertropic with giant excrescences called cobblestone papillae. Irritation from contact lenses or any chronic foreign body also can induce formation of cobblestone papillae. Atopic conjunctivitis occurs in subjects with atopic dermatitis or asthma. Symptoms caused by allergic conjunctivitis can be alleviated with cold compresses, topical vasoconstrictors, antihistamines (olopatadine), and mast cell stabilizers (cromolyn). Topical glucocorticoid solutions provide dramatic relief of immune-mediated forms of conjunctivitis, but their long-term use is ill advised because of the complications of glaucoma, cataract, and secondary infection. Topical nonsteroidal anti-inflammatory drugs (ketorolac) are better alternatives.

Keratoconjunctivitis Sicca  Also known as dry eye, this pro-

duces a burning foreign-body sensation, injection, and photophobia. In mild cases the eye appears surprisingly normal, but tear production measured by wetting of a filter paper (Schirmer strip) is deficient. A variety of systemic drugs, including antihistaminic, anticholinergic, and psychotropic medications, result in dry eye by reducing lacrimal secretion. Disorders that involve the lacrimal gland directly, such as sarcoidosis and Sjögren’s syndrome, also cause dry eye. Patients may develop dry eye after radiation therapy if the treatment field includes the orbits. Problems with ocular drying are also common after lesions affecting cranial nerve V or VII. Corneal anesthesia is particularly dangerous, because the absence of a normal blink reflex exposes the cornea to injury without pain to warn the patient. Dry eye is managed by frequent and liberal application of artificial tears and ocular lubricants. In severe cases the tear puncta can be plugged or cauterized to reduce lacrimal outflow.

Keratitis  Keratitis is a threat to vision because of the risk of corneal clouding, scarring, and perforation. Worldwide, the two leading causes of blindness from keratitis are trachoma from chlamydial infection and vitamin A deficiency related to malnutrition. In the United States, contact lenses play a major role in corneal infection and ulceration. They should not be worn by anyone with an active eye infection. In evaluating the cornea, it is important to differentiate between a superficial infection (keratoconjunctivitis) and a deeper, more serious ulcerative process. The latter is accompanied by greater visual loss, pain, photophobia, redness, and discharge. Slit-lamp examination shows disruption of the corneal epithelium, a cloudy infiltrate or abscess in the stroma, and an inflammatory cellular reaction in the anterior chamber. In severe cases, pus settles at the bottom of the anterior chamber, giving rise to a hypopyon. Immediate empirical antibiotic therapy should be initiated after corneal scrapings are obtained for Gram’s stain, Giemsa stain, and cultures. Fortified topical antibiotics are most effective, supplemented with subconjunctival antibiotics as required. A fungal etiology should always be considered in a patient with keratitis. Fungal infection is common in warm humid climates, especially after

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penetration of the cornea by plant or vegetable material. Acanthamoeba keratitis is associated with improper disinfection of contact lenses.

Herpes Simplex  The herpesviruses are a major cause of blindness

from keratitis. Most adults in the United States have serum antibodies to herpes simplex, indicating prior viral infection (Chap. 187). Primary ocular infection generally is caused by herpes simplex type 1 rather than type 2. It manifests as a unilateral follicular blepharoconjunctivitis that is easily confused with adenoviral conjunctivitis, unless telltale vesicles are present on the eyelids or conjunctiva. A dendritic pattern of corneal epithelial ulceration revealed by fluorescein staining is pathognomonic for herpes infection but is seen in only a minority of primary infections. Recurrent ocular infection arises from reactivation of the latent herpesvirus. Viral eruption in the corneal epithelium may result in the characteristic herpes dendrite. Involvement of the corneal stroma produces edema, vascularization, and iridocyclitis. Herpes keratitis is treated with cycloplegia, and either a topical antiviral (trifluridine, ganciclovir) or an oral antiviral (acyclovir, ganciclovir) agent. Topical glucocorticoids are effective in mitigating corneal scarring but are generally reserved for cases involving stromal damage, because of the danger of corneal melting and perforation. Topical glucocorticoids also carry the risk of prolonging infection and inducing glaucoma.

Herpes Zoster  Herpes zoster from reactivation of latent varicella (chickenpox) virus causes a dermatomal pattern of painful vesicular dermatitis (Chap. 188). Ocular symptoms can occur after zoster eruption in any branch of the trigeminal nerve but are particularly common when vesicles form on the nose, reflecting nasociliary (V1) nerve involvement (Hutchinson’s sign). Herpes zoster ophthalmicus produces corneal dendrites, which can be difficult to distinguish from those seen in herpes simplex. Stromal keratitis, anterior uveitis, raised intraocular pressure, ocular motor nerve palsies, acute retinal necrosis, and postherpetic scarring and neuralgia are other common sequelae. Herpes zoster ophthalmicus is treated with antiviral agents and cycloplegics. In severe cases, glucocorticoids may be added to prevent permanent visual loss from corneal scarring. Episcleritis  This is an inflammation of the episclera, a thin layer of connective tissue between the conjunctiva and the sclera. Episcleritis resembles conjunctivitis, but it is a more localized process and discharge is absent. Most cases of episcleritis are idiopathic, but some occur in the setting of an autoimmune disease. Scleritis refers to a deeper, more severe inflammatory process that frequently is associated with a connective tissue disease such as rheumatoid arthritis, lupus erythematosus, polyarteritis nodosa, granulomatosis with polyangiitis, or relapsing polychondritis. The inflammation and thickening of the sclera can be diffuse or nodular. In anterior forms of scleritis, the globe assumes a violet hue and the patient complains of severe ocular tenderness and pain. With posterior scleritis, the pain and redness may be less marked, but there is often proptosis, choroidal effusion, reduced motility, and visual loss. Episcleritis and scleritis should be treated with NSAIDs. If these agents fail, topical or even systemic glucocorticoid therapy may be necessary, especially if an underlying autoimmune process is active. Uveitis  Involving the anterior structures of the eye, uveitis also is

called iritis or iridocyclitis. The diagnosis requires slit-lamp examination to identify inflammatory cells floating in the aqueous humor or deposited on the corneal endothelium (keratic precipitates). Anterior uveitis develops in sarcoidosis, ankylosing spondylitis, juvenile rheumatoid arthritis, inflammatory bowel disease, psoriasis, reactive arthritis, and Behçet’s disease. It also is associated with herpes infections, syphilis, Lyme disease, onchocerciasis, tuberculosis, and leprosy. Although anterior uveitis can occur in conjunction with many diseases, no cause is found to explain the majority of cases. For this reason, laboratory evaluation usually is reserved for patients with recurrent or severe anterior uveitis. Treatment is aimed at reducing inflammation and scarring by judicious use of topical glucocorticoids. Dilatation of the pupil reduces pain and prevents the formation of synechiae.

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Posterior Uveitis  This is diagnosed by observing inflammation of

quently misdiagnosed cause of a red, painful eye. Asian populations have a particularly high risk of angle-closure glaucoma. Susceptible eyes have a shallow anterior chamber because the eye has either a short axial length (hyperopia) or a lens enlarged by the gradual development of cataract. When the pupil becomes mid-dilated, the peripheral iris blocks aqueous outflow via the anterior chamber angle and the intraocular pressure rises abruptly, producing pain, injection, corneal edema, obscurations, and blurred vision. In some patients, ocular symptoms are overshadowed by nausea, vomiting, or headache, prompting a fruitless workup for abdominal or neurologic disease. The diagnosis is made by measuring the intraocular pressure during an acute attack or by performing gonioscopy, a procedure that allows one to observe a narrow chamber angle with a mirrored contact lens. Acute angle closure is treated with acetazolamide (PO or IV), topical beta blockers, prostaglandin analogues, α2-adrenergic agonists, and pilocarpine to induce miosis. If these measures fail, a laser can be used to create a hole in the peripheral iris to relieve pupillary block. Many physicians are reluctant to dilate patients routinely for fundus examination because they fear precipitating an angle-closure glaucoma. The risk is actually remote and more than outweighed by the potential benefit to patients of discovering a hidden fundus lesion visible only through a fully dilated pupil. Moreover, a single attack of angle closure after pharmacologic dilatation rarely causes any permanent damage to the eye and serves as an inadvertent provocative test to identify patients with narrow angles who would benefit from prophylactic laser iridectomy.

FIGURE 28-4  Roth’s spot, cotton-wool spot, and retinal hemorrhages in a 48-year-old liver transplant patient with candidemia from immunosuppression.

few seconds results in transient monocular blindness, a term used interchangeably with amaurosis fugax. Patients describe a rapid fading of vision like a curtain descending, sometimes affecting only a portion of the visual field. Amaurosis fugax usually results from an embolus that becomes stuck within a retinal arteriole (Fig. 28-5). If the embolus breaks up or passes, flow is restored and vision returns quickly to normal without permanent damage. With prolonged interruption of blood flow, the inner retina suffers infarction. Ophthalmoscopy reveals zones of whitened, edematous retina following the distribution of branch retinal arterioles. Complete occlusion of the central retinal artery produces arrest of blood flow and a milky retina with a cherry-red fovea (Fig. 28-6). Emboli are composed of cholesterol (Hollenhorst plaque), calcium, or platelet-fibrin debris. The most common source is an atherosclerotic plaque in the carotid artery or aorta, although emboli also can arise from the heart, especially in patients with diseased valves, atrial fibrillation, or wall motion abnormalities. In rare instances, amaurosis fugax results from low central retinal artery perfusion pressure in a patient with a critical stenosis of the ipsilateral carotid artery and poor collateral flow via the circle of Willis. In this situation, amaurosis fugax develops when there is a dip in systemic blood pressure or a slight worsening of the carotid stenosis. Sometimes there is contralateral motor or sensory loss, indicating concomitant hemispheric cerebral ischemia. Retinal arterial occlusion also occurs rarely in association with retinal migraine, lupus erythematosus, anticardiolipin antibodies,

Disorders of the Eye

Acute Angle-Closure Glaucoma  This is an unusual but fre-

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the vitreous, retina, or choroid on fundus examination. It is more likely than anterior uveitis to be associated with an identifiable systemic disease. Some patients have panuveitis, or inflammation of both the anterior and posterior segments of the eye. Posterior uveitis is a manifestation of autoimmune diseases such as sarcoidosis, Behçet’s disease, Vogt-KoyanagiHarada syndrome, and inflammatory bowel disease. It also accompanies diseases such as toxoplasmosis, onchocerciasis, cysticercosis, coccidioidomycosis, toxocariasis, and histoplasmosis; infections caused by organisms such as Candida, Pneumocystis carinii, Cryptococcus, Aspergillus, herpes, and cytomegalovirus (see Fig. 190-1); and other diseases, such as syphilis, Lyme disease, tuberculosis, cat-scratch disease, Whipple’s disease, and brucellosis. In multiple sclerosis, chronic inflammatory changes can develop in the extreme periphery of the retina (pars planitis or intermediate uveitis). Glucocorticoids have been the mainstay of treatment for noninfectious uveitis. Monoclonal antibodies which target proinflammatory cytokines, such as the tumor necrosis factor alpha (TNF-α) inhibitor adalimumab, are effective at preventing vision loss in chronic uveitis.

Endophthalmitis  This results from bacterial, viral, fungal, or parasitic infection of the internal structures of the eye. It usually is acquired by hematogenous seeding from a remote site. Chronically ill, diabetic, or immunosuppressed patients, especially those with a history of indwelling IV catheters or positive blood cultures, are at greatest risk for endogenous endophthalmitis. Although most patients have ocular pain and injection, visual loss is sometimes the only symptom. Septic emboli from a diseased heart valve or a dental abscess that lodge in the retinal circulation can give rise to endophthalmitis. White-centered retinal hemorrhages known as Roth’s spots (Fig. 28-4) are considered pathognomonic for subacute bacterial endocarditis, but they also appear in leukemia, diabetes, and many other conditions. Endophthalmitis also occurs as a complication of ocular surgery, especially glaucoma filtering, occasionally months or even years after the operation. An occult penetrating foreign body or unrecognized trauma to the globe should be considered in any patient with unexplained intraocular infection or inflammation. ■■TRANSIENT OR SUDDEN VISUAL LOSS Amaurosis Fugax  This term refers to a transient ischemic attack

of the retina (Chap. 420). Because neural tissue has a high rate of metabolism, interruption of blood flow to the retina for more than a

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FIGURE 28-5  Hollenhorst plaque lodged at the bifurcation of a retinal arteriole proves that a patient is shedding emboli from the carotid artery, great vessels, or heart.

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FIGURE 28-6  Central retinal artery occlusion in a 78-year-old man reducing acuity to counting fingers in the right eye. Note the splinter hemorrhage on the optic disc and the slightly milky appearance to the macula with a cherry-red fovea.

FIGURE 28-8  Central retinal vein occlusion can produce massive retinal hemorrhage (“blood and thunder”), ischemia, and vision loss.

by insufficient blood flow through the posterior ciliary arteries that

supply the optic disc. It produces painless monocular visual loss that is sudden in onset, followed sometimes by stuttering progression. The optic disc is edematous and usually bordered by nerve fiber layer splinter hemorrhages (Fig. 28-9). AION is divided into two forms: arteritic and nonarteritic. The nonarteritic form is most common. No specific cause is known, although diabetes, renal failure, and hypertension are common risk factors. Case reports have linked erectile dysfunction drugs to AION, but a causal association is doubtful. Evidence is strong that a crowded disc architecture and small optic cup predispose to the development of nonarteritic AION. In patients with a “disc-at-risk,” the advent of AION in one eye increases the likelihood of the same event occurring in the other eye. No treatment is available for nonarteritic AION; glucocorticoids should not be prescribed. About 5% of patients, especially Caucasian females aged >60, develop the arteritic form of AION in conjunction with giant-cell (temporal) arteritis (Chap. 356). It is urgent to recognize arteritic AION so that high doses of glucocorticoids can be instituted immediately to prevent blindness in the second eye. Tocilizumab is an effective alternative to glucocorticoids for sustained suppression of symptoms of giant cell arteritis. Symptoms of polymyalgia rheumatica may be present; the sedimentation rate and C-reactive protein level are usually elevated. In a patient with visual loss from suspected arteritic AION, temporal artery biopsy is mandatory to confirm the diagnosis. Administer glucocorticoids immediately, without waiting for the biopsy to be completed. The biopsy should be obtained as soon as practical, because prolonged glucocorticoid treatment can hide inflammatory changes. It is important to harvest an arterial segment at least 3 cm long and to

FIGURE 28-7  Hypertensive retinopathy with blurred optic disc, scattered hemorrhages, cotton-wool spots (nerve fiber layer infarcts), and foveal exudate in a 62-year-old man with chronic renal failure and a systolic blood pressure of 220.

FIGURE 28-9  Anterior ischemic optic neuropathy from temporal arteritis in a 64-year-old woman with acute disc swelling, splinter hemorrhages, visual loss, and an erythrocyte sedimentation rate of 60 mm/h.

anticoagulant deficiency states (protein S, protein C, and antithrombin deficiency), Susac’s syndrome, pregnancy, IV drug abuse, blood dyscrasias, dysproteinemias, and temporal arteritis. Marked systemic hypertension causes sclerosis of retinal arterioles, splinter hemorrhages, focal infarcts of the nerve fiber layer (cotton-wool spots), and leakage of lipid and fluid (hard exudate) into the macula (Fig. 28-7). In hypertensive crisis, sudden visual loss can result from vasospasm of retinal arterioles and retinal ischemia. In addition, acute hypertension may produce visual loss from ischemic swelling of the optic disc. Patients with acute hypertensive retinopathy should be treated by lowering the blood pressure. However, the blood pressure should not be reduced precipitously, because there is a danger of optic disc infarction from sudden hypoperfusion. Impending branch or central retinal vein occlusion can produce prolonged visual obscurations that resemble those described by patients with amaurosis fugax. The veins appear engorged and phlebitic, with numerous retinal hemorrhages (Fig. 28-8). In some patients, venous blood flow recovers spontaneously, whereas others evolve a frank obstruction with extensive retinal bleeding (“blood and thunder” appearance), infarction, and visual loss. Venous occlusion of the retina is often idiopathic, but hypertension, diabetes, and glaucoma are prominent risk factors. Polycythemia, thrombocythemia, or other factors leading to an underlying hypercoagulable state should be corrected; aspirin treatment may be beneficial.

Anterior Ischemic Optic Neuropathy (AION)  This is caused

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examine a sufficient number of tissue sections. The histological features of granulomatous inflammation are often quite subtle in temporal artery specimens. If the biopsy is declared negative by an experienced pathologist, the diagnosis of arteritic AION is highly unlikely and glucocorticoids should usually be discontinued.

Posterior Ischemic Optic Neuropathy  This is an uncommon

optic nerve. In the Optic Neuritis Treatment Trial (ONTT), the mean age of patients was 32 years, 77% were female, 92% had ocular pain (especially with eye movements), and 35% had optic disc swelling. In most patients, the demyelinating event was retrobulbar and the ocular fundus appeared normal on initial examination (Fig. 28-10), although optic disc pallor slowly developed over subsequent months. Virtually all patients experience a gradual recovery of vision after a single episode of optic neuritis, even without treatment. This rule is so reliable that failure of vision to improve after a first attack of optic neuritis casts doubt on the original diagnosis. Treatment with high-dose IV methylprednisolone (250 mg every 6 h for 3 days) followed by oral prednisone (1 mg/kg per day for 11 days) makes no difference in ultimate acuity 6 months after the attack, but the recovery of visual function occurs more rapidly. Therefore, when visual loss is severe (worse than 20/100), IV followed by PO glucocorticoids are often recommended. For some patients, optic neuritis remains an isolated event. However, the ONTT showed that the 15-year cumulative probability of developing clinically definite multiple sclerosis after optic neuritis is 50%. A brain magnetic resonance (MR) scan is advisable in every patient with a first attack of optic neuritis. If two or more plaques are present on initial imaging, treatment should be considered to prevent the development of additional demyelinating lesions (Chap. 436). A particularly severe form of optic neuritis occurs in neuromyelitis optica (NMO); it is typically longitudinally extensive, and may be bilateral or associated with myelitis. NMO can occur as a primary disorder, in the setting of systemic autoimmune disease or rarely as a paraneoplastic condition. Detection of circulating antibodies directed against aquaporin-4 is diagnostic. Treatment for acute episodes consists of glucocorticoids and, in resistant cases, plasma exchange. Neuromyelitis optica is discussed in detail in Chap. 437.

FIGURE 28-10  Retrobulbar optic neuritis is characterized by a normal fundus examination initially, hence the rubric “the doctor sees nothing, and the patient sees nothing.” Optic atrophy develops after severe or repeated attacks.

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Toxic Optic Neuropathy  This can result in acute visual loss with

bilateral optic disc swelling and cecocentral scotomas. Cases have been reported from exposure to ethambutol, methyl alcohol (moonshine), ethylene glycol (antifreeze), or carbon monoxide. In toxic optic neuropathy, visual loss also can develop gradually and produce optic atrophy (Fig. 28-11) without a phase of acute optic disc edema. Many agents have been implicated in toxic optic neuropathy, but evidence supporting the association is often weak. The following is a partial list of potential offending drugs or toxins: disulfiram, ethchlorvynol, chloramphenicol, amiodarone, monoclonal anti-CD3 antibody, ciprofloxacin, digitalis, streptomycin, lead, arsenic, thallium, d-penicillamine, isoniazid, emetine, and sulfonamides. Metallosis (chromium, cobalt, nickel) from hip implant failure is a rare cause of toxic optic neuropathy. Deficiency states induced by starvation, malabsorption, or alcoholism can lead to insidious visual loss. Thiamine, vitamin B12, and folate levels should be checked in any patient with unexplained bilateral central scotomas and optic pallor.

Disorders of the Eye

Optic Neuritis  This is a common inflammatory disease of the

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This disease usually affects young men, causing gradual, painless, severe central visual loss in one eye, followed weeks to years later by the same process in the other eye. Acutely, the optic disc appears mildly plethoric with surface capillary telangiectasias but no vascular leakage on fluorescein angiography. Eventually optic atrophy ensues. Leber’s optic neuropathy is caused by a point mutation at codon 11778 in the mitochondrial gene encoding nicotinamide adenine dinucleotide dehydrogenase (NADH) subunit 4. Additional mutations responsible for the disease have been identified, most in mitochondrial genes that encode proteins involved in electron transport. Mitochondrial mutations that cause Leber’s neuropathy are inherited from the mother by all her children, but for unknown reasons, daughters are rarely affected. Early stage clinical trials of gene therapy for this condition are in progress.

CHAPTER 28

cause of acute visual loss, induced by the combination of severe anemia and hypotension. Cases have been reported after major blood loss during surgery (especially in patients undergoing cardiac or lumbar spine operations), shock, gastrointestinal bleeding, and renal dialysis. The fundus usually appears normal, although optic disc swelling develops if the process extends anteriorly far enough to reach the globe. Vision can be salvaged in some patients by immediate blood transfusion and reversal of hypotension.

■■LEBER’S HEREDITARY OPTIC NEUROPATHY

Papilledema  This connotes bilateral optic disc swelling from raised intracranial pressure (Fig. 28-12). Headache is a common but not invariable accompaniment. All other forms of optic disc swelling (e.g., from optic neuritis or ischemic optic neuropathy) should be called “optic disc edema.” This convention is arbitrary but serves to avoid confusion. Often it is difficult to differentiate papilledema from other forms of optic disc edema by fundus examination alone. Transient visual obscurations are a classic symptom of papilledema. They can occur in only one eye or simultaneously in both eyes. They usually last seconds but can persist longer. Obscurations follow abrupt shifts in posture or happen spontaneously. When obscurations are prolonged or spontaneous, the papilledema is more threatening. Visual acuity is not affected by papilledema unless the papilledema is severe, longstanding, or accompanied by macular edema and hemorrhage. Visual field testing shows enlarged blind spots and peripheral constriction (Fig. 28-3F). With unremitting papilledema, peripheral visual field loss

FIGURE 28-11  Optic atrophy is not a specific diagnosis but refers to the combination of optic disc pallor, arteriolar narrowing, and nerve fiber layer destruction produced by a host of eye diseases, especially optic neuropathies.

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FIGURE 28-12  Papilledema means optic disc edema from raised intracranial pressure. This young woman developed acute papilledema, with hemorrhages and cotton-wool spots, as a rare side effect of treatment with tetracycline for acne.

progresses in an insidious fashion while the optic nerve develops atrophy. In this setting, reduction of optic disc swelling is an ominous sign of a dying nerve rather than an encouraging indication of resolving papilledema. Evaluation of papilledema requires neuroimaging to exclude an intracranial lesion. MR angiography is appropriate in selected cases to search for a dural venous sinus occlusion or an arteriovenous shunt. If neuroradiologic studies are negative, the subarachnoid opening pressure should be measured in the lateral decubitus position by lumbar puncture. Inaccurate pressure readings are a common pitfall. An elevated pressure, with normal cerebrospinal fluid, points by exclusion to the diagnosis of pseudotumor cerebri (idiopathic intracranial hypertension). Almost all patients are female, and most are obese. Treatment with a carbonic anhydrase inhibitor such as acetazolamide lowers intracranial pressure by reducing the production of cerebrospinal fluid and improves the visual fields. Weight reduction is vital: bariatric surgery should be considered in patients who cannot lose weight by diet control. If vision loss is severe or progressive, a shunt should be performed without delay to prevent blindness. Optic nerve sheath fenestration is less efficacious, and does not address other neurological symptoms. Occasionally, fulminant papilledema produces rapid onset of blindness. In such patients, emergency surgery should be performed to install a shunt without delay.

drusen of the retina, which occur in age-related macular degeneration. Optic disc drusen are most common in people of northern European descent. Their diagnosis is obvious when they are visible as glittering particles on the surface of the optic disc. However, in many patients they are hidden beneath the surface, producing pseudopapilledema. It is important to recognize optic disc drusen to avoid an unnecessary evaluation for papilledema. When optic disc drusen are buried, Bultrasound is the most sensitive way to detect them. They appear hyperechoic because they contain calcium. They are also visible on computed tomography (CT) or optical coherence tomography (OCT), a technique for acquiring cross-section images of the retina. In most patients, optic disc drusen are an incidental, innocuous finding, but they can produce visual obscurations. On perimetry they give rise to enlarged blind spots and arcuate scotomas from damage to the optic disc. With increasing age, drusen tend to become more exposed on the disc surface as optic atrophy develops. Hemorrhage, choroidal neovascular membrane, and AION are more likely to occur in patients with optic disc drusen. No treatment is available.

Vitreous Degeneration  This occurs in all individuals with advancing age, leading to visual symptoms. Opacities develop in the vitreous, casting annoying shadows on the retina. As the eye moves, these distracting “floaters” move synchronously, with a slight lag caused by inertia of the vitreous gel. Vitreous traction on the retina causes mechanical stimulation, resulting in perception of flashing lights. This photopsia is brief and is confined to one eye, in contrast to the bilateral, prolonged scintillations of cortical migraine. Contraction of the vitreous can result in sudden separation from the retina, heralded by an alarming shower of floaters and photopsia. This process, known as vitreous detachment, is a common involutional event in the elderly. It is not harmful unless it damages the retina. A careful examination of the dilated fundus is important in any patient complaining of floaters or photopsia to search for peripheral tears or holes. If such a lesion is found, laser application can forestall a retinal detachment. Occasionally a tear ruptures a retinal blood vessel, causing vitreous hemorrhage and sudden loss of vision. On attempted ophthalmoscopy the fundus is hidden by a dark haze of blood. Ultrasound is required to examine the interior of the eye for a retinal tear or detachment. If the hemorrhage does not resolve spontaneously, the vitreous can be removed surgically. Vitreous hemorrhage also results from the fragile neovascular vessels that proliferate on the surface of the retina in diabetes, sickle cell anemia, and other ischemic ocular diseases. Retinal Detachment  This produces symptoms of floaters, flash-

Optic Disc Drusen  These are refractile deposits within the

ing lights, and a scotoma in the peripheral visual field corresponding to the detachment (Fig. 28-14). If the detachment includes the fovea, there is an afferent pupil defect and the visual acuity is reduced. In most eyes, retinal detachment starts with a hole, flap, or tear in the peripheral

FIGURE 28-13  Optic disc drusen are calcified, mulberry-like deposits of unknown etiology within the optic disc, giving rise to “pseudopapilledema.”

FIGURE 28-14  Retinal detachment appears as an elevated sheet of retinal tissue with folds. In this patient, the fovea was spared, so acuity was normal, but an inferior detachment produced a superior scotoma.

substance of the optic nerve head (Fig. 28-13). They are unrelated to

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retina (rhegmatogenous retinal detachment). Patients with peripheral retinal thinning (lattice degeneration) are particularly vulnerable to this process. Once a break has developed in the retina, liquefied vitreous is free to enter the subretinal space, separating the retina from the pigment epithelium. The combination of vitreous traction on the retinal surface and passage of fluid behind the retina leads inexorably to detachment. Patients with a history of myopia, trauma, or prior cataract extraction are at greatest risk for retinal detachment. The diagnosis is confirmed by ophthalmoscopic examination of the dilated eye.

Transient Ischemic Attacks  Vertebrobasilar insufficiency may

result in acute homonymous visual symptoms. Many patients mistakenly describe symptoms in the left or right eye when in fact the symptoms are occurring in the left or right hemifield of both eyes. Interruption of blood supply to the visual cortex causes a sudden fogging or graying of vision, occasionally with flashing lights or other positive phenomena that mimic migraine. Cortical ischemic attacks are briefer in duration than migraine, occur in older patients, and are not followed by headache. There may be associated signs of brainstem ischemia, such as diplopia, vertigo, numbness, weakness, and dysarthria.

Stroke  Stroke occurs when interruption of blood supply from the posterior cerebral artery to the visual cortex is prolonged. The only finding on examination is a homonymous visual field defect that stops abruptly at the vertical meridian. Occipital lobe stroke usually is due to thrombotic occlusion of the vertebrobasilar system, embolus, or dissection. Lobar hemorrhage, tumor, abscess, and arteriovenous malformation are other common causes of hemianopic cortical visual loss. Factitious (Functional, Nonorganic) Visual Loss  This is

claimed by hysterics or malingerers. The latter account for the vast majority, seeking sympathy, special treatment, or financial gain by feigning loss of sight. The diagnosis is suspected when the history is atypical, physical findings are lacking or contradictory, inconsistencies emerge on testing, and a secondary motive can be identified. In our litigious society, the fraudulent pursuit of recompense has spawned an epidemic of factitious visual loss.

Glaucoma  Glaucoma is a slowly progressive, insidious optic neu-

ropathy that usually is associated with chronic elevation of intraocular pressure. After cataract, it is the most common cause of blindness in the world. It is especially prevalent in people of African descent. The mechanism by which raised intraocular pressure injures the optic nerve is not understood. Axons entering the inferotemporal and superotemporal aspects of the optic disc are damaged first, producing typical nerve fiber bundle or arcuate scotomas on perimetric testing. As fibers are destroyed, the neural rim of the optic disc shrinks and the physiologic cup within the optic disc enlarges (Fig. 28-15). This process is referred to as pathologic “cupping.” The cup-to-disc diameter is expressed as a fraction (e.g., 0.2). The cup-to-disc ratio ranges widely in normal individuals, making it difficult to diagnose glaucoma reliably simply by observing an unusually large or deep optic cup. Careful documentation of serial examinations is helpful. In a patient with physiologic cupping the large cup remains stable, whereas in a patient with glaucoma it expands relentlessly over the years. Observation of progressive cupping and detection of an arcuate scotoma or a nasal step on computerized visual field testing is sufficient to establish the diagnosis of glaucoma. OCT reveals corresponding loss of fibers along the arcuate pathways in the nerve fiber layer. The preponderance of patients with glaucoma have open anterior chamber angles. In most affected individuals the intraocular pressure is elevated. The cause of elevated intraocular pressure is unknown, but it is associated with gene mutations in the heritable forms. Surprisingly, a third of patients with open-angle glaucoma have an intraocular pressure within the normal range of 10–20 mmHg. For this so-called normal or low-tension form of glaucoma, high myopia is a risk factor. Chronic angle-closure glaucoma and chronic open-angle glaucoma are usually asymptomatic. Only acute angle-closure glaucoma causes a red or painful eye, from abrupt elevation of intraocular pressure. In all forms of glaucoma, foveal acuity is spared until end-stage disease is reached. For these reasons, severe and irreversible damage can occur before either the patient or the physician recognizes the diagnosis. Screening of patients for glaucoma by noting the cup-to-disc ratio on ophthalmoscopy and by measuring intraocular pressure is vital. Glaucoma is treated with topical adrenergic agonists, cholinergic agonists, beta blockers, prostaglandin analogues, and carbonic anhydrase inhibitors. Occasionally, systemic absorption of beta blocker from eyedrops

Disorders of the Eye

a visual aura lasting about 20 min. In a typical attack, a small central disturbance in the field of vision marches toward the periphery, leaving a transient scotoma in its wake. The expanding border of migraine scotoma has a scintillating, dancing, or zigzag edge, resembling the bastions of a fortified city, hence the term fortification spectra. Patients’ descriptions of fortification spectra vary widely and can be confused with amaurosis fugax. Migraine patterns usually last longer and are perceived in both eyes, whereas amaurosis fugax is briefer and occurs in only one eye. Migraine phenomena also remain visible in the dark or with the eyes closed. Generally they are confined to either the right or the left visual hemifield, but sometimes both fields are involved simultaneously. Patients often have a long history of stereotypic attacks. After the visual symptoms recede, headache develops in most patients.

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Classic Migraine  (See also Chap. 422) This usually occurs with

outpatient basis. A plastic or silicone intraocular lens is placed within the empty lens capsule in the posterior chamber, substituting for the natural lens and leading to rapid recovery of sight. More than 95% of patients who undergo cataract extraction can expect an improvement in vision. In some patients, the lens capsule remaining in the eye after cataract extraction eventually turns cloudy, causing secondary loss of vision. A small opening, called a posterior capsulotomy, is made in the lens capsule with a laser to restore clarity.

■■CHRONIC VISUAL LOSS Cataract  Cataract is a clouding of the lens sufficient to reduce vision. Most cataracts develop slowly as a result of aging, leading to gradual impairment of vision. The formation of cataract occurs more rapidly in patients with a history of uveitis, diabetes mellitus, ocular trauma or vitrectomy. Cataracts are acquired in a variety of genetic diseases, such as myotonic dystrophy, neurofibromatosis type 2, and galactosemia. Radiation therapy and glucocorticoid treatment can induce cataract as a side effect. The cataracts associated with radiation or glucocorticoids have a typical posterior subcapsular location. Cataract can be detected by noting an impaired red reflex when viewing light reflected from the fundus with an ophthalmoscope or by examining the dilated eye with the slit lamp. The only treatment for cataract is surgical extraction of the opacified lens. Millions of cataract operations are performed each year around the globe. The operation generally is done under local anesthesia on an

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FIGURE 28-15  Glaucoma results in “cupping” as the neural rim is destroyed and the central cup becomes enlarged and excavated. The cup-to-disc ratio is about 0.8 in this patient.

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can be sufficient to cause side effects of bradycardia, hypotension, heart block, bronchospasm, or depression. Laser treatment of the trabecular meshwork in the anterior chamber angle improves aqueous outflow from the eye. If medical or laser treatments fail to halt optic nerve damage from glaucoma, a filter must be constructed surgically (trabeculectomy) or a drainage device placed to release aqueous from the eye in a controlled fashion.

PART 2 Cardinal Manifestations and Presentation of Diseases

Macular Degeneration  This is a major cause of gradual, painless, bilateral central visual loss in the elderly. It occurs in a nonexudative (dry) form and an exudative (wet) form. Inflammation may be important in both forms of macular degeneration; susceptibility is associated with variants in the gene for complement factor H, an inhibitor of the alternative complement pathway. The nonexudative process begins with the accumulation of extracellular deposits called drusen underneath the retinal pigment epithelium. On ophthalmoscopy, they are pleomorphic but generally appear as small discrete yellow lesions clustered in the macula (Fig. 28-16). With time they become larger, more numerous, and confluent. The retinal pigment epithelium becomes focally detached and atrophic, causing visual loss by interfering with photoreceptor function. Treatment with vitamins C and E, beta-carotene, and zinc may retard dry macular degeneration. Exudative macular degeneration, which develops in only a minority of patients, occurs when neovascular vessels from the choroid grow through defects in Bruch’s membrane and proliferate underneath the retinal pigment epithelium or the retina. Leakage from these vessels produces elevation of the retina, with distortion (metamorphopsia) and blurring of vision. Although the onset of these symptoms is usually gradual, bleeding from a subretinal choroidal neovascular membrane sometimes causes acute visual loss. Neovascular membranes can be difficult to see on fundus examination because they are located beneath the retina. Fluorescein angiography and OCT are extremely useful for their detection. Major or repeated hemorrhage under the retina from neovascular membranes results in fibrosis, development of a round (disciform) macular scar, and permanent loss of central vision. A major therapeutic advance has occurred with the discovery that exudative macular degeneration can be treated with intraocular injection of antagonists to vascular endothelial growth factor. Bevacizumab, ranibizumab, or aflibercept is administered by direct injection into the vitreous cavity, beginning on a monthly basis. These antibodies cause the regression of neovascular membranes by blocking the action of vascular endothelial growth factor, thereby improving visual acuity. Central Serous Chorioretinopathy  This primarily affects males between the ages of 20 and 50 years. Leakage of serous fluid from the choroid causes small, localized detachment of the retinal pigment epithelium and the neurosensory retina. These detachments produce acute or chronic symptoms of metamorphopsia and blurred

FIGURE 28-16  Age-related macular degeneration consisting of scattered yellow drusen in the macula (dry form) and a crescent of fresh hemorrhage temporal to the fovea from a subretinal neovascular membrane (wet form).

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vision when the macula is involved. They are difficult to visualize with a direct ophthalmoscope because the detached retina is transparent and only slightly elevated. OCT shows fluid beneath the retina, and fluorescein angiography shows dye streaming into the subretinal space. The cause of central serous chorioretinopathy is unknown. Symptoms may resolve spontaneously if the retina reattaches, but recurrent detachment is common. Laser photocoagulation has benefited some patients with this condition.

Diabetic Retinopathy  A rare disease until 1921, when the discovery of insulin resulted in a dramatic improvement in life expectancy for patients with diabetes mellitus, diabetic retinopathy is now a leading cause of blindness in the United States. The retinopathy takes years to develop but eventually appears in nearly all cases. Regular surveillance of the dilated fundus is crucial for any patient with diabetes. In advanced diabetic retinopathy, the proliferation of neovascular vessels leads to blindness from vitreous hemorrhage, retinal detachment, and glaucoma (Fig. 28-17). These complications can be avoided in most patients by administration of panretinal laser photocoagulation at the appropriate point in the evolution of the disease. Anti-vascular endothelial growth factor antibody treatment is equally effective, but intraocular injections must be given repeatedly. For further discussion of the manifestations and management of diabetic retinopathy, see Chaps. 396–398. Retinitis Pigmentosa  This is a general term for a disparate

group of rod-cone dystrophies characterized by progressive night blindness, visual field constriction with a ring scotoma, loss of acuity, and an abnormal electroretinogram (ERG). It occurs sporadically or in an autosomal recessive, dominant, or X-linked pattern. Irregular black deposits of clumped pigment in the peripheral retina, called bone spicules because of their vague resemblance to the spicules of cancellous bone, give the disease its name (Fig. 28-18). The name is actually a misnomer because retinitis pigmentosa is not an inflammatory process. Most cases are due to a mutation in the gene for rhodopsin, the rod photopigment, or in the gene for peripherin, a glycoprotein located in photoreceptor outer segments. Vitamin A (15,000 IU/d) slightly retards the deterioration of the ERG in patients with retinitis pigmentosa but has no beneficial effect on visual acuity or fields. Leber’s congenital amaurosis, a rare cone dystrophy, has been treated by replacement of the missing RPE65 protein through gene therapy, resulting in slight improvement in visual function. Some forms of retinitis pigmentosa occur in association with rare, hereditary systemic diseases (olivopontocerebellar degeneration, Bassen-Kornzweig disease, Kearns-Sayre syndrome, Refsum’s disease). Chronic treatment with chloroquine, hydroxychloroquine, and phenothiazines (especially thioridazine) can produce visual loss from a toxic retinopathy that

FIGURE 28-17  Proliferative diabetic retinopathy in a 25-year-old man with an 18-year history of diabetes, showing neovascular vessels emanating from the optic disc, retinal and vitreous hemorrhage, cotton-wool spots, and macular exudate. Round spots in the periphery represent recently applied panretinal photocoagulation.

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Epiretinal Membrane  This is a fibrocellular tissue that grows across the inner surface of the retina, causing metamorphopsia and reduced visual acuity from distortion of the macula. A crinkled, cellophane-like membrane is visible on the retinal examination. Epiretinal membrane is most common in patients aged >50 years and is usually unilateral. Most cases are idiopathic, but some occur as a result of hypertensive retinopathy, diabetes, retinal detachment, or trauma. When visual acuity is reduced to the level of about 6/24 (20/80), vitrectomy and surgical peeling of the membrane to relieve macular puckering are recommended. Contraction of an epiretinal membrane sometimes gives rise to a macular hole. Most macular holes, however, are caused by local vitreous traction within the fovea. Vitrectomy can improve acuity in selected cases. Melanoma and Other Tumors  Melanoma is the most common primary tumor of the eye (Fig. 28-19). It causes photopsia, an enlarging scotoma, and loss of vision. A small melanoma is often difficult to differentiate from a benign choroidal nevus. Serial examinations are required to document a malignant pattern of growth. Treatment of

Disorders of the Eye

resembles retinitis pigmentosa. Patients receiving long-term treatment with hydroxychloroquine require regular eye examinations to monitor for potential development of a bull’s eye maculopathy.

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FIGURE 28-18  Retinitis pigmentosa with black clumps of pigment known as “bone spicules.” The patient had peripheral visual field loss with sparing of central (macular) vision.

melanoma is controversial. Options include enucleation, local resection, and irradiation. Metastatic tumors to the eye outnumber primary tumors. Breast and lung carcinomas have a special propensity to spread to the choroid or iris. Leukemia and lymphoma also commonly invade ocular tissues. Sometimes their only sign on eye examination is cellular debris in the vitreous, which can masquerade as a chronic posterior uveitis. In a patient with vision loss, CT or MR scanning should be considered if the cause remains unknown after careful review of the history, visual fields, and thorough examination of the eye. Optic nerve sheath meningioma is a common retrobulbar tumor. It produces the classic triad of opto-ciliary shunt vessels, optic atrophy, and progressive visual loss. Optic disc swelling and proptosis are also frequent signs. Optic nerve glioma in young patients is usually a pilocytic astrocytoma and has a good prognosis for preservation of vision, especially in neurofibromatosis type 1 (Chap. 118). In adults, optic nerve glioma is rare and highly malignant. Chiasmal tumors (pituitary adenoma, meningioma, craniopharyngioma) produce visual loss with few objective findings except for optic disc pallor. Loss of the temporal visual field in each eye is typically described, but in fact, patients complain of vision loss in just one eye. A high degree of vigilance is necessary to avoid missing chiasmal tumors. Although symptoms progress gradually, in rare instances the sudden expansion of a pituitary adenoma from infarction and bleeding (pituitary apoplexy) causes acute retrobulbar visual loss, with headache, nausea, and ocular motor nerve palsies.

■■PROPTOSIS

When the globes appear asymmetric, the clinician must first decide which eye is abnormal. Is one eye recessed within the orbit (enophthalmos), or is the other eye protuberant (exophthalmos, or proptosis)? A small globe or a Horner’s syndrome can give the appearance of enophthalmos. True enophthalmos occurs commonly after trauma, from atrophy of retrobulbar fat, or from fracture of the orbital floor. The position of the eyes within the orbits is measured by using a Hertel exophthalmometer, a handheld instrument that records the position of the anterior corneal surface relative to the lateral orbital rim. If this instrument is not available, relative eye position can be judged by bending the patient’s head forward and looking down upon the orbits. A proptosis of only 2 mm in one eye is detectable from this perspective. The development of proptosis implies a space-occupying lesion in the orbit and usually warrants CT or MR imaging.

Graves’ Ophthalmopathy  This is the leading cause of proptosis in adults (Chap. 375). The proptosis is often asymmetric and can even appear to be unilateral. Orbital inflammation and engorgement of the extraocular muscles, particularly the medial rectus and the inferior rectus, account for the protrusion of the globe. Corneal exposure, lid retraction, lid lag on downgaze, conjunctival injection, restriction of gaze, diplopia, and visual loss from optic nerve compression are cardinal symptoms. Graves’ eye disease is a clinical diagnosis, but laboratory testing can be useful. The serum level of thyroid-stimulating immunoglobulins is often elevated. Orbital imaging usually reveals enlarged extraocular eye muscles, but not always. Graves’ ophthalmopathy can be treated with oral prednisone (60 mg/d) for 1 month, followed by a taper over several months. Worsening of symptoms upon glucocorticoid withdrawal is common. Topical lubricants, taping the eyelids closed at night, moisture chambers, and eyelid surgery are helpful to limit exposure of ocular tissues. Radiation therapy is not effective. Orbital decompression should be performed for severe, symptomatic exophthalmos or if visual function is reduced by optic nerve compression. In patients with diplopia, prisms or eye muscle surgery can be used to restore ocular alignment in primary gaze. Orbital Pseudotumor  This is an idiopathic, inflammatory orbital

FIGURE 28-19  Melanoma of the choroid, appearing as an elevated dark mass in the inferior fundus, with overlying hemorrhage. The black line denotes the plane of the optical coherence tomography scan (below) showing the subretinal tumor.

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syndrome that is distinguished from Graves’ ophthalmopathy by the prominent complaint of pain. Other symptoms include diplopia, ptosis, proptosis, and orbital congestion. Evaluation for sarcoidosis, granulomatosis with polyangiitis, and other types of orbital vasculitis or collagen-vascular disease is negative. Imaging often shows swollen eye muscles (orbital myositis) with enlarged tendons. By contrast, in

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Graves’ ophthalmopathy, the tendons of the eye muscles usually are spared. The Tolosa-Hunt syndrome (Chap. 433) may be regarded as an extension of orbital pseudotumor through the superior orbital fissure into the cavernous sinus. The diagnosis of orbital pseudotumor is difficult. Biopsy of the orbit frequently yields nonspecific evidence of fat infiltration by lymphocytes, plasma cells, and eosinophils. A dramatic response to a therapeutic trial of systemic glucocorticoids indirectly provides the best confirmation of the diagnosis.

PART 2 Cardinal Manifestations and Presentation of Diseases

Orbital Cellulitis  This causes pain, lid erythema, proptosis, conjunctival chemosis, restricted motility, decreased acuity, afferent pupillary defect, fever, and leukocytosis. It often arises from the paranasal sinuses, especially by contiguous spread of infection from the ethmoid sinus through the lamina papyracea of the medial orbit. A history of recent upper respiratory tract infection, chronic sinusitis, thick mucus secretions, or dental disease is significant in any patient with suspected orbital cellulitis. Blood cultures should be obtained, but they are usually negative. Most patients respond to empirical therapy with broad-spectrum IV antibiotics. Occasionally, orbital cellulitis follows an overwhelming course, with massive proptosis, blindness, septic cavernous sinus thrombosis, and meningitis. To avert this disaster, orbital cellulitis should be managed aggressively in the early stages, with immediate imaging of the orbits and antibiotic therapy that includes coverage of methicillin-resistant Staphylococcus aureus (MRSA). Prompt surgical drainage of an orbital abscess or paranasal sinusitis is indicated if optic nerve function deteriorates despite antibiotics. Tumors  Tumors of the orbit cause painless, progressive proptosis. The most common primary tumors are cavernous hemangioma, lymphangioma, neurofibroma, schwannoma, dermoid cyst, adenoid cystic carcinoma, optic nerve glioma, optic nerve meningioma, and benign mixed tumor of the lacrimal gland. Metastatic tumor to the orbit occurs frequently in breast carcinoma, lung carcinoma, and lymphoma. Diagnosis by fine-needle aspiration followed by urgent radiation therapy sometimes can preserve vision. Carotid Cavernous Fistulas  With anterior drainage through

the orbit, these fistulas produce proptosis, diplopia, glaucoma, and corkscrew, arterialized conjunctival vessels. Direct fistulas usually result from trauma. They are easily diagnosed because of the prominent signs produced by high-flow, high-pressure shunting. Indirect fistulas, or dural arteriovenous malformations, are more likely to occur spontaneously, especially in older women. The signs are more subtle, and the diagnosis frequently is missed. The combination of slight proptosis, diplopia, enlarged muscles, and an injected eye often is mistaken for thyroid ophthalmopathy. A bruit heard upon auscultation of the head or reported by the patient is a valuable diagnostic clue. Imaging shows an enlarged superior ophthalmic vein in the orbits. Carotid cavernous shunts can be eliminated by intravascular embolization.

■■PTOSIS Blepharoptosis  This is an abnormal drooping of the eyelid. Uni-

lateral or bilateral ptosis can be congenital, from dysgenesis of the levator palpebrae superioris, or from abnormal insertion of its aponeurosis into the eyelid. Acquired ptosis can develop so gradually that the patient is unaware of the problem. Inspection of old photographs is helpful in dating the onset. A history of prior trauma, eye surgery, contact lens use, diplopia, systemic symptoms (e.g., dysphagia or peripheral muscle weakness), or a family history of ptosis should be sought. Fluctuating ptosis that worsens late in the day is typical of myasthenia gravis. Ptosis evaluation should focus on evidence for proptosis, eyelid masses or deformities, inflammation, pupil inequality, or limitation of motility. The width of the palpebral fissures is measured in primary gaze to determine the degree of ptosis. The ptosis will be underestimated if the patient compensates by lifting the brow with the frontalis muscle.

Mechanical Ptosis  This occurs in many elderly patients from stretching and redundancy of eyelid skin and subcutaneous fat (dermatochalasis). The extra weight of these sagging tissues causes the lid to

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droop. Enlargement or deformation of the eyelid from infection, tumor, trauma, or inflammation also results in ptosis on a purely mechanical basis.

Aponeurotic Ptosis  This is an acquired dehiscence or stretching of the aponeurotic tendon, which connects the levator muscle to the tarsal plate of the eyelid. It occurs commonly in older patients, presumably from loss of connective tissue elasticity. Aponeurotic ptosis is also a common sequela of eyelid swelling from infection or blunt trauma to the orbit, cataract surgery, or contact lens use. Myogenic Ptosis  The causes of myogenic ptosis include myasthe-

nia gravis (Chap. 440) and a number of rare myopathies that manifest with ptosis. The term chronic progressive external ophthalmoplegia refers to a spectrum of systemic diseases caused by mutations of mitochondrial DNA. As the name implies, the most prominent findings are symmetric, slowly progressive ptosis and limitation of eye movements. In general, diplopia is a late symptom because all eye movements are reduced equally. In the Kearns-Sayre variant, retinal pigmentary changes and abnormalities of cardiac conduction develop. Peripheral muscle biopsy shows characteristic “ragged-red fibers.” Oculopharyngeal dystrophy is a distinct autosomal dominant disease with onset in middle age, characterized by ptosis, limited eye movements, and trouble swallowing. Myotonic dystrophy, another autosomal dominant disorder, causes ptosis, ophthalmoparesis, cataract, and pigmentary retinopathy. Patients have muscle wasting, myotonia, frontal balding, and cardiac abnormalities.

Neurogenic Ptosis  This results from a lesion affecting the inner-

vation to either of the two muscles that open the eyelid: Müller’s muscle or the levator palpebrae superioris. Examination of the pupil helps distinguish between these two possibilities. In Horner’s syndrome, the eye with ptosis has a smaller pupil and the eye movements are full. In an oculomotor nerve palsy, the eye with the ptosis has a larger or a normal pupil. If the pupil is normal but there is limitation of adduction, elevation, and depression, a pupil-sparing oculomotor nerve palsy is likely (see next section). Rarely, a lesion affecting the small, central subnucleus of the oculomotor complex will cause bilateral ptosis with normal eye movements and pupils.

■■DOUBLE VISION (DIPLOPIA)

The first point to clarify is whether diplopia persists in either eye after the opposite eye is covered. If it does, the diagnosis is monocular diplopia. The cause is usually intrinsic to the eye and therefore has no dire implications for the patient. Corneal aberrations (e.g., keratoconus, pterygium), uncorrected refractive error, cataract, or foveal traction may give rise to monocular diplopia. Occasionally it is a symptom of malingering or psychiatric disease. Diplopia alleviated by covering one eye is binocular diplopia and is caused by disruption of ocular alignment. Inquiry should be made into the nature of the double vision (purely side-by-side versus partial vertical displacement of images), mode of onset, duration, intermittency, diurnal variation, and associated neurologic or systemic symptoms. If the patient has diplopia while being examined, motility testing should reveal a deficiency corresponding to the patient’s symptoms. However, subtle limitation of ocular excursions is often difficult to detect. For example, a patient with a slight left abducens nerve paresis may appear to have full eye movements despite a complaint of horizontal diplopia upon looking to the left. In this situation, the cover test provides a more sensitive method for demonstrating the ocular misalignment. It should be conducted in primary gaze and then with the head turned and tilted in each direction. In the above example, a cover test with the head turned to the right will maximize the fixation shift evoked by the cover test. Occasionally, a cover test performed in an asymptomatic patient during a routine examination will reveal an ocular deviation. If the eye movements are full and the ocular misalignment is equal in all directions of gaze (comitant deviation), the diagnosis is strabismus. In this condition, which affects about 1% of the population, fusion is disrupted in infancy or early childhood. To avoid diplopia, retinal input from the

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Oculomotor Nerve  The third cranial nerve innervates the medial,

inferior, and superior recti; inferior oblique; levator palpebrae superioris; and the iris sphincter. Total palsy of the oculomotor nerve causes ptosis, a dilated pupil, and leaves the eye “down and out” because of the unopposed action of the lateral rectus and superior oblique. This combination of findings is obvious. More challenging is the diagnosis of early or partial oculomotor nerve palsy. In this setting any combination of ptosis, pupil dilation, and weakness of the eye muscles supplied by the oculomotor nerve may be encountered. Frequent serial examinations during the rapidly evolving phase of the palsy help ensure that the diagnosis is not missed. The advent of an oculomotor nerve palsy with a pupil involvement, especially when accompanied by pain, suggests a compressive lesion, such as a tumor or circle of Willis aneurysm. Urgent neuroimaging should be obtained, along with a CT or MR angiogram. With improvement in the resolution of these non-invasive techniques, catheter angiography is rarely necessary to exclude an aneurysm. A lesion of the oculomotor nucleus in the rostral midbrain produces signs that differ from those caused by a lesion of the nerve itself. There is bilateral ptosis because the levator muscle is innervated by a single central subnucleus. There is also weakness of the contralateral superior rectus, because it is supplied by the oculomotor nucleus on the other side. Occasionally both superior recti are weak. Isolated nuclear oculomotor palsy is rare. Usually neurologic examination reveals additional signs that suggest brainstem damage from infarction, hemorrhage, tumor, or infection. Injury to structures surrounding fascicles of the oculomotor nerve descending through the midbrain has given rise to a number of classic eponymic designations. In Nothnagel’s syndrome, injury to the superior cerebellar peduncle causes ipsilateral oculomotor palsy and contralateral cerebellar ataxia. In Benedikt’s syndrome, injury to the red nucleus results in ipsilateral oculomotor palsy and contralateral tremor, chorea, and athetosis. Claude’s syndrome incorporates features of both of these syndromes, by injury to both the red nucleus and the superior cerebellar peduncle. Finally, in Weber’s syndrome, injury to the cerebral peduncle causes ipsilateral oculomotor palsy with contralateral hemiparesis. In the subarachnoid space the oculomotor nerve is vulnerable to aneurysm, meningitis, tumor, infarction, and compression. In cerebral herniation, the nerve becomes trapped between the edge of the

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Myasthenia Gravis  (See also Chap. 440) This is a major cause of painless diplopia. The diplopia is often intermittent, variable, and not confined to any single ocular motor nerve distribution. The pupils are always normal. Serial measurements of a variable, fatigable ptosis, often accompanied by diplopia, are helpful to establish the diagnosis. Many patients have a purely ocular form of the disease, with no evidence of systemic muscular weakness. The diagnosis can be confirmed by an IV edrophonium injection, which produces a transient reversal of eyelid or eye muscle weakness. Blood tests for antibodies against the acetylcholine receptor or the MuSK protein are frequently negative in the purely ocular form of myasthenia gravis. Botulism from food or wound poisoning can mimic ocular myasthenia. If restrictive orbital disease and myasthenia gravis are excluded, a lesion of a cranial nerve supplying innervation to the extraocular muscles is the most likely cause of binocular diplopia.

tentorium and the uncus of the temporal lobe. Oculomotor palsy also can result from midbrain torsion and hemorrhage during herniation. In the cavernous sinus, oculomotor palsy arises from carotid aneurysm, carotid cavernous fistula, cavernous sinus thrombosis, tumor (pituitary adenoma, meningioma, metastasis), herpes zoster infection, and the Tolosa-Hunt syndrome. The etiology of an isolated, pupil-sparing oculomotor palsy often remains an enigma even after neuroimaging and extensive laboratory testing. Most cases are thought to result from microvascular infarction of the nerve somewhere along its course from the brainstem to the orbit. Usually the patient complains of pain. Diabetes, hypertension, and vascular disease are major risk factors. Spontaneous recovery over a period of months is the rule. If this fails to occur or if new findings develop, the diagnosis of microvascular oculomotor nerve palsy should be reconsidered. Aberrant regeneration is common when the oculomotor nerve is injured by trauma or compression (tumor, aneurysm). Miswiring of sprouting fibers to the levator muscle and the rectus muscles results in elevation of the eyelid upon downgaze or adduction. The pupil also constricts upon attempted adduction, elevation, or depression of the globe. Aberrant regeneration is not seen after oculomotor palsy from microvascular infarct and hence vitiates that diagnosis.

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nonfixating eye may be partially suppressed. In some children, this leads to impaired vision (amblyopia, or “lazy” eye) in the deviated eye. Binocular diplopia results from a wide range of processes: infectious, neoplastic, metabolic, degenerative, inflammatory, and vascular. One must decide whether the diplopia is neurogenic in origin or is due to restriction of globe rotation by local disease in the orbit. Orbital pseudotumor, myositis, infection, tumor, thyroid disease, and muscle entrapment (e.g., from a blowout fracture) cause restrictive diplopia. The diagnosis of restriction is usually made by recognizing other associated signs and symptoms of local orbital disease. Dedicated, high-resolution orbital imaging is helpful when the cause of diplopia is not evident.

Trochlear Nerve  The fourth cranial nerve originates in the mid-

brain, just caudal to the oculomotor nerve complex. Fibers exit the brainstem dorsally and cross to innervate the contralateral superior oblique. The principal actions of this muscle are to depress and intort the globe. A palsy therefore results in hypertropia and excyclotorsion. The cyclotorsion seldom is noticed by patients. Instead, they complain of vertical diplopia, especially upon reading or looking down. The vertical diplopia also is exacerbated by tilting the head toward the side with the muscle palsy and alleviated by tilting it away. This “head tilt test” is a cardinal diagnostic feature. Isolated trochlear nerve palsy results from all the causes listed above for the oculomotor nerve except aneurysm. The trochlear nerve is particularly apt to suffer injury after closed head trauma. The free edge of the tentorium is thought to impinge on the nerve during a concussive blow. Most isolated trochlear nerve palsies are idiopathic and hence are diagnosed by exclusion as “microvascular.” Spontaneous improvement occurs over a period of months in most patients. A base-down prism (conveniently applied to the patient’s glasses as a stick-on Fresnel lens) may serve as a temporary measure to alleviate diplopia. If the palsy does not resolve, the eyes can be realigned by weakening the inferior oblique muscle.

Abducens Nerve  The sixth cranial nerve innervates the lateral

rectus muscle. A palsy produces horizontal diplopia, worse on gaze to the side of the lesion. A nuclear lesion has different consequences, because the abducens nucleus contains interneurons that project via the medial longitudinal fasciculus to the medial rectus subnucleus of the contralateral oculomotor complex. Therefore, an abducens nuclear lesion produces a complete lateral gaze palsy from weakness of both the ipsilateral lateral rectus and the contralateral medial rectus. Foville’s syndrome after dorsal pontine injury includes lateral gaze palsy, ipsilateral facial palsy, and contralateral hemiparesis incurred by damage to descending corticospinal fibers. Millard-Gubler syndrome from ventral pontine injury is similar except for the eye findings. There is lateral rectus weakness only, instead of gaze palsy, because the abducens fascicle is injured rather than the nucleus. Infarct, tumor, hemorrhage, vascular malformation, and multiple sclerosis are the most common etiologies of brainstem abducens palsy. After leaving the ventral pons, the abducens nerve runs forward along the clivus to pierce the dura at the petrous apex, where it enters the cavernous sinus. Along its subarachnoid course it is susceptible to meningitis, tumor (meningioma, chordoma, carcinomatous meningitis), subarachnoid hemorrhage, trauma, and compression by aneurysm or dolichoectatic vessels. At the petrous apex, mastoiditis can produce deafness, pain, and ipsilateral abducens palsy (Gradenigo’s

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syndrome). In the cavernous sinus, the nerve can be affected by carotid aneurysm, carotid cavernous fistula, tumor (pituitary adenoma, meningioma, nasopharyngeal carcinoma), herpes infection, and Tolosa-Hunt syndrome. Unilateral or bilateral abducens palsy is a classic sign of raised intracranial pressure. The diagnosis can be confirmed if papilledema is observed on fundus examination. The mechanism is still debated but probably is related to rostral-caudal displacement of the brainstem. The same phenomenon accounts for abducens palsy from Chiari malformation or low intracranial pressure (e.g., after lumbar puncture, spinal anesthesia, or spontaneous dural cerebrospinal fluid leak). Treatment of abducens palsy is aimed at prompt correction of the underlying cause. However, the cause remains obscure in many instances despite diligent evaluation. As was mentioned above for isolated trochlear or oculomotor palsy, most cases are assumed to represent microvascular infarcts because they often occur in the setting of diabetes or other vascular risk factors. Some cases may develop as a postinfectious mononeuritis (e.g., after a viral flu). Patching one eye, occluding one eyeglass lens with tape, or applying a temporary prism will provide relief of diplopia until the palsy resolves. If recovery is incomplete, eye muscle surgery nearly always can realign the eyes, at least in primary position. A patient with an abducens palsy that fails to improve should be reevaluated for an occult etiology (e.g., chordoma, carcinomatous meningitis, carotid cavernous fistula, myasthenia gravis). Skull base tumors are easily missed even on contrast-enhanced neuroimaging studies.

Multiple Ocular Motor Nerve Palsies  These should not be

attributed to spontaneous microvascular events affecting more than one cranial nerve at a time. This remarkable coincidence does occur, especially in diabetic patients, but the diagnosis is made only in retrospect after all other diagnostic alternatives have been exhausted. Neuroimaging should focus on the cavernous sinus, superior orbital fissure, and orbital apex, where all three ocular motor nerves are in close proximity. In a diabetic or immunocompromised host, fungal infection (Aspergillus, Mucorales, Cryptococcus) is a common cause of multiple nerve palsies. In a patient with systemic malignancy, carcinomatous meningitis is a likely diagnosis. Cytologic examination may be negative despite repeated sampling of the cerebrospinal fluid. The cancer-associated Lambert-Eaton myasthenic syndrome also can produce ophthalmoplegia. Giant cell (temporal) arteritis occasionally manifests as diplopia from ischemic palsies of extraocular muscles. Fisher’s syndrome, an ocular variant of Guillain-Barré, produces ophthalmoplegia with areflexia and ataxia. Often the ataxia is mild, and the reflexes are normal. Antiganglioside antibodies (GQ1b) can be detected in about 50% of cases.

Supranuclear Disorders of Gaze  These are often mistaken for

multiple ocular motor nerve palsies. For example, Wernicke’s encephalopathy can produce nystagmus and a partial deficit of horizontal and vertical gaze that mimics a combined abducens and oculomotor nerve palsy. The disorder occurs in patients who are malnourished, alcoholic, or following bariatric surgery, and can be reversed by thiamine. Infarct, hemorrhage, tumor, multiple sclerosis, encephalitis, vasculitis, and Whipple’s disease are other important causes of supranuclear gaze palsy. Disorders of vertical gaze, especially downward saccades, are an early feature of progressive supranuclear palsy. Smooth pursuit is affected later in the course of the disease. Parkinson’s disease, Huntington’s disease, and olivopontocerebellar degeneration also can affect vertical gaze. The frontal eye field of the cerebral cortex is involved in generation of saccades to the contralateral side. After hemispheric stroke, the eyes usually deviate toward the lesioned side because of the unopposed action of the frontal eye field in the normal hemisphere. With time, this deficit resolves. Seizures generally have the opposite effect: the eyes deviate conjugately away from the irritative focus. Parietal lesions disrupt smooth pursuit of targets moving toward the side of the lesion. Bilateral parietal lesions produce Bálint’s syndrome, which is characterized by impaired eye-hand coordination (optic ataxia), difficulty

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initiating voluntary eye movements (ocular apraxia), and visuospatial disorientation (simultanagnosia).

Horizontal Gaze  Descending cortical inputs mediating horizon-

tal gaze ultimately converge at the level of the pons. Neurons in the paramedian pontine reticular formation are responsible for controlling conjugate gaze toward the same side. They project directly to the ipsilateral abducens nucleus. A lesion of either the paramedian pontine reticular formation or the abducens nucleus causes an ipsilateral conjugate gaze palsy. Lesions at either locus produce nearly identical clinical syndromes, with the following exception: vestibular stimulation (oculocephalic maneuver or caloric irrigation) will succeed in driving the eyes conjugately to the side in a patient with a lesion of the paramedian pontine reticular formation but not in a patient with a lesion of the abducens nucleus.

INTERNUCLEAR OPHTHALMOPLEGIA  This results from damage to the medial longitudinal fasciculus ascending from the abducens nucleus in the pons to the oculomotor nucleus in the midbrain (hence, “internuclear”). Damage to fibers carrying the conjugate signal from abducens interneurons to the contralateral medial rectus motoneurons results in a failure of adduction on attempted lateral gaze. For example, a patient with a left internuclear ophthalmoplegia (INO) will have slowed or absent adducting movements of the left eye (Fig. 28-20). A patient with bilateral injury to the medial longitudinal fasciculus will have bilateral INO. Multiple sclerosis is the most common cause, although tumor, stroke, trauma, or any brainstem process may be responsible. One-and-a-half syndrome is due to a lesion of the medial longitudinal fasciculus combined with a lesion of either the abducens nucleus or the paramedian pontine reticular formation on the same side. The patient’s only horizontal eye movement is abduction of the eye on the other side.

Vertical Gaze  This is controlled at the level of the midbrain. The neuronal circuits affected in disorders of vertical gaze are not fully elucidated, but lesions of the rostral interstitial nucleus of the medial longitudinal fasciculus and the interstitial nucleus of Cajal cause supranuclear paresis of upgaze, downgaze, or all vertical eye movements. Distal basilar artery ischemia is the most common etiology. Skew deviation refers to a vertical misalignment of the eyes, usually constant in all positions of gaze. The finding has poor localizing value because skew deviation has been reported after lesions in widespread regions of the brainstem and cerebellum. Also known as dorsal midbrain syndrome, this is a distinct supranuclear vertical gaze disorder caused by damage to the posterior commissure. It is a classic sign of hydrocephalus from aqueductal stenosis. Pineal region or midbrain tumors, cysticercosis, and stroke also cause Parinaud’s syndrome. Features include loss of upgaze (and sometimes downgaze), convergence-retraction nystagmus on attempted upgaze, downward ocular deviation (“setting sun” sign), lid retraction (Collier’s sign), skew deviation, pseudoabducens palsy, and light-near dissociation of the pupils.

PARINAUD’S SYNDROME 

Nystagmus  This is a rhythmic oscillation of the eyes, occurring

physiologically from vestibular and optokinetic stimulation or pathologically in a wide variety of diseases (Chap. 19). Abnormalities of the eyes or optic nerves, present at birth or acquired in childhood, can produce a complex, searching nystagmus with irregular pendular (sinusoidal) and jerk features. Examples are albinism, Leber’s congenital amaurosis, and bilateral cataract. This nystagmus is commonly referred to as congenital sensory nystagmus. This is a poor term because even in children with congenital lesions, the nystagmus does not appear until weeks after birth. Congenital motor nystagmus, which looks similar to congenital sensory nystagmus, develops in the absence of any abnormality of the sensory visual system. Visual acuity also is reduced in congenital motor nystagmus, probably by the nystagmus itself, but seldom below a level of 20/200.

JERK NYSTAGMUS  This is characterized by a slow drift off the target, followed by a fast corrective saccade. By convention, the nystagmus

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This is the most common form of jerk nystagmus. When the eyes are held eccentrically in the orbits, they have a natural tendency to drift back to primary position. The subject compensates by making a corrective saccade to maintain the deviated eye position. Many normal patients have mild gaze-evoked nystagmus. Exaggerated gaze-evoked nystagmus can be induced by drugs (sedatives, anticonvulsants, alcohol); muscle paresis; myasthenia gravis; demyelinating disease; and cerebellopontine angle, brainstem, and cerebellar lesions.

CHAPTER 28

GAZE-EVOKED NYSTAGMUS 

A

B

VESTIBULAR NYSTAGMUS  Vestibular nystagmus results from dysfunction of the labyrinth (Ménière’s disease), vestibular nerve, or vestibular nucleus in the brainstem. Peripheral vestibular nystagmus often occurs in discrete attacks, with symptoms of nausea and vertigo. There may be associated tinnitus and hearing loss. Sudden shifts in head position may provoke or exacerbate symptoms.

Disorders of the Eye

is named after the quick phase. Jerk nystagmus can be downbeat, upbeat, horizontal (left or right), and torsional. The pattern of nystagmus may vary with gaze position. Some patients will be oblivious to their nystagmus. Others will complain of blurred vision or a subjective to-and-fro movement of the environment (oscillopsia) corresponding to the nystagmus. Fine nystagmus may be difficult to see on gross examination of the eyes. Observation of nystagmoid movements of the optic disc on ophthalmoscopy is a sensitive way to detect subtle nystagmus.

Downbeat nystagmus results from lesions near the craniocervical junction (Chiari malformation, basilar invagination). It also has been reported in brainstem or cerebellar stroke, lithium or anticonvulsant intoxication, alcoholism, and multiple sclerosis. Upbeat nystagmus is associated with damage to the pontine tegmentum from stroke, demyelination, or tumor.

DOWNBEAT NYSTAGMUS 

Opsoclonus  This rare, dramatic disorder of eye movements con-

C

sists of bursts of consecutive saccades (saccadomania). When the saccades are confined to the horizontal plane, the term ocular flutter is preferred. It can result from viral encephalitis, trauma, or a paraneoplastic effect of neuroblastoma, breast carcinoma, and other malignancies. It has also been reported as a benign, transient phenomenon in otherwise healthy patients.

■■FURTHER READING

D FIGURE 28-20  Left internuclear ophthalmoplegia (INO). A. In primary position of gaze, the eyes appear normal. B. Horizontal gaze to the left is intact. C. On attempted horizontal gaze to the right, the left eye fails to adduct. In mildly affected patients, the eye may adduct partially or more slowly than normal. Nystagmus is usually present in the abducted eye. D. T2-weighted axial magnetic resonance image through the pons showing a demyelinating plaque in the left medial longitudinal fasciculus (arrow).

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Bainbridge JW et al: Long-term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med 372:1887, 2015. Buttgerei TF et al: Polymyalgia rheumatica and giant cell arteritis. JAMA 315:2442, 2016. Campochiaro PA et al: Anti-vascular endothelial growth factor agents in the treatment of retinal disease. Ophthalmology 123:S78, 2016. Gross JG et al: Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy. JAMA 314:2137, 2015 Jaffe GJ et al: Adalimumbab in patients with active noninfectious uveitis. N Engl J Med 375:932, 2016 Pearson RA et al: Donor and host photoreceptors engage in material transfer following transplantation of post-mitotic photoreceptor precursors. Nat Commun 7:13029, 2016. Stone JH et al: Trial of tocilizumab in giant-cell arteritis. N Engl J Med 377:317, 2017. Wall M et al: Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: The idiopathic intracranial hypertension treatment trial. JAMA 311:1641, 2014. Williams PA et al: Vitamin B3 modulates mitochrondrial vulnerability and prevents glaucoma in aged mice. Science 355:756, 2017. Yanoff M, Duker J: Ophthalmology, 4th ed. Atlanta, Georgia, Saunders, 2014.

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Disorders of Smell and Taste

Granule cell

Mitral/tufted cell Lateral olfactory tract Granule cell layer

Richard L. Doty, Steven M. Bromley

PART 2 Cardinal Manifestations and Presentation of Diseases

All environmental chemicals necessary for life enter the body by the nose and mouth. The senses of smell (olfaction) and taste (gustation) monitor such chemicals, determine the flavor and palatability of foods and beverages, and warn of dangerous environmental conditions, including fire, air pollution, leaking natural gas, and bacteria-laden foodstuffs. These senses contribute significantly to quality of life and, when dysfunctional, can have untoward physical and psychological consequences. Indeed, a recent longitudinal study of 1162 non-demented elderly persons found, even after controlling for confounders, that those with the lowest baseline olfactory test scores had a 45% mortality rate over a 4-year period, compared to an 18% mortality rate for those with the highest olfactory test scores. A basic understanding of these senses in health and disease is critical for the physician, because thousands of patients present to doctors’ offices each year with complaints of chemosensory dysfunction. Among the more important recent developments in neurology is the discovery that decreased smell function is among the first signs, if not the first sign, of such neurodegenerative diseases as Parkinson’s disease (PD) and Alzheimer’s disease (AD), signifying their “presymptomatic” phase.

■■ANATOMY AND PHYSIOLOGY Olfactory System  Odorous chemicals enter the front of nose

during inhalation and active sniffing, as well as the back of the nose (nasopharynx) during deglutition. After reaching the highest recesses of the nasal cavity, they dissolve in the olfactory mucus and diffuse or are actively transported by specialized proteins to receptors located on the cilia of olfactory receptor cells. The cilia, dendrites, cell bodies, and proximal axonal segments of these bipolar cells are located within a unique neuroepithelium covering the cribriform plate, the superior nasal septum, superior turbinate, and sectors of the middle turbinate (Fig. 29-1). Nearly 400 types of G-protein-coupled odor receptors (GPCRs) are expressed on the cilia of the receptor cells, with only one type of GPCR receptor being expressed on a given cell. Other receptors, including trace amine-associated receptors and members of the non-GPCR membrane-spanning 4-domain family, subfamily A (MS4A) protein family, are also present on some receptor cells. Such a plethora of receptor cell types does not exist in any other sensory system. Importantly, when damaged, the receptor cells can be replaced by stem

Internal plexiform layer Mitral cell layer

Glomerulus

Periglomerular cell

External plexiform layer

Glomerular layer

Nerve fiber layer Olfactory neurons Olfactory receptor cells Olfactory cilia Sensory neuron

FIGURE 29-2  Schematic of the layers and wiring of the olfactory bulb. Each receptor type (red, green, blue) projects to a common glomerulus. The neural activity within each glomerulus is modulated by periglomerular cells. The activity of the primary projection cells, the mitral and tufted cells, is modulated by granule cells, periglomerular cells, and secondary dendrites from adjacent mitral and tufted cells. (From www.med.yale.edu/neurosurg/treloar/index.html.)

cells near the basement membrane, although such replacement is often incomplete. After coalescing into bundles surrounded by glia-like ensheathing cells (termed fila), the receptor cell axons pass through the cribriform plate to the olfactory bulbs, where they synapse with dendrites of other cell types within the glomeruli (Fig. 29-2). These spherical structures, which make up a distinct layer of the olfactory bulb, are a site of convergence of information, because many more fibers enter than leave them. Receptor cells that express the same type of receptor project to the same glomeruli, effectively making each glomerulus a functional unit. The major projection neurons of the olfactory system—the mitral and tufted cells—send primary dendrites into the glomeruli, connecting not only with the incoming receptor cell axons, but with dendrites of periglomerular cells. The activity of the mitral/tufted cells is modulated by the periglomerular cells, secondary dendrites from other mitral/tufted cells, and granule cells, the most numerous cells of the bulb. The latter cells, which are largely GABAergic, receive inputs from central brain structures and modulate the output of the mitral/

FIGURE 29-1  Anatomy of the nose, showing the distribution of olfactory receptors in the roof of the nasal cavity. (Copyright David Klemm, Faculty and Curriculum Support [FACS], Georgetown University Medical Center; used with permission.)

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Olfactory bulb Olfactory tract Medial olfactory stria Lateral olfactory stria Amygdala

that its initial afferent projections bypass the thalamus, persons with damage to the thalamus can exhibit olfactory deficits, particularly ones of odor identification. Such deficits likely reflect the involvement of thalamic connections between the POC and the orbitofrontal cortex (OFC), where odor identification largely occurs. The close anatomic ties between the olfactory system and the amygdala, hippocampus, and hypothalamus help to explain the intimate associations between odor perception and cognitive functions such as memory, motivation, arousal, autonomic activity, digestion, and sex.

Pyriform area Entorhinal area

Spinal cord Cerebellar vermis Cerebellum

FIGURE 29-3  Anatomy of the base of the brain showing the primary olfactory cortex.

tufted cells. Interestingly, like the olfactory receptor cells, some cells within the bulb undergo replacement. Thus, neuroblasts formed within the anterior subventricular zone of the brain migrate along the rostral migratory stream, ultimately becoming granule and periglomerular cells. The axons of the mitral and tufted cells synapse within secondary olfactory structures which largely comprise the primary olfactory cortex (POC) (Fig. 29-3). The POC is defined as those cortical structures that receive direct projections from the olfactory bulb, most notably the piriform and entorhinal cortices. Although olfaction is unique in

Disorders of Smell and Taste

Vagus nerve

present within taste buds—small grapefruit-like segmented structures located on the lateral margins and dorsum of the tongue, roof of the mouth, pharynx, larynx, and superior esophagus (Fig. 29-4). Lingual taste buds are embedded in well-defined protuberances, termed fungiform, foliate, and circumvallate papillae. After dissolving in a liquid, tastants enter the opening of the taste bud—the taste pore—and bind to receptors on microvilli, small extensions of receptor cells within each taste bud. Such binding changes the electrical potential across the taste cell, resulting in neurotransmitter release onto the firstorder taste neurons. Although humans have ~7500 taste buds, not all harbor taste-sensitive cells; some contain only one class of receptor (e.g., cells responsive only to sugars), whereas others contain cells sensitive to more than one class. The number of taste receptor cells per taste bud ranges from zero to well over 100. A small family of three G-protein-coupled receptors (GPCRs), namely T1R1, T1R2, and T1R3, mediate sweet and umami taste sensations. Bitter sensations, on the other hand, depend on T2R receptors, a family of ~30 GPCRs expressed on cells different from those that express the sweet and umami receptors. T2Rs sense a wide range of bitter substances but do not distinguish among them. Sour tastants are sensed by the PKD2L1 receptor, a member of the transient receptor potential protein (TRP) family. Perception of salty sensations, such as induced by sodium chloride, arises from the entry of Na+ ions into the cells via specialized membrane channels, such as the amiloride-sensitive Na+ channel. It is now well established that both bitter and sweet taste-related receptors are also present elsewhere in the body, most notably in the alimentary and respiratory tracts. This important discovery generalizes the concept of taste-related chemoreception to areas of the body

CHAPTER 29

Taste System  Tastants are sensed by specialized receptor cells

195

Taste pore Taste bud Circumvallate

Taste bud TRC Foliate

Taste bud

Fungiform FIGURE 29-4  Schematic of the taste bud and its opening (pore), as well as the location of buds on the three major types of papillae: Fungiform (anterior), foliate (lateral), and circumvallate (posterior).

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carries parasympathetic fibers to the submandibular and sublingual glands, whereas the greater petrosal nerve supplies the palatine glands, thereby influencing saliva production. The axons of the projection cells, which synapse with taste buds, enter the rostral portion of the nucleus of the solitary tract (NTS) within the medulla of the brainstem (Fig. 29-5). From the NTS, neurons then project to a division of the ventroposteromedial thalamic nucleus (VPM) via the medial lemniscus. From here, projections are made to the rostral part of the frontal operculum and adjoining insula, a brain region considered the primary taste cortex (PTC). Projections from the PTC then go to the secondary taste cortex, namely the caudolateral OFC. This brain region is involved in the conscious recognition of taste qualities. Moreover, because it contains cells that are activated by several sensory modalities, it is likely a center for establishing “flavor.”

■■DISORDERS OF OLFACTION

The ability to smell is influenced, in everyday life, by such factors as age, gender, general health, nutrition, smoking, and reproductive state. Women typically outperform men on tests of olfactory function and retain normal smell function to a later age than do men. Estimates of the prevalence of olfactory dysfunction in the general population vary; a recent cross-sectional analysis from the National Health and Nutrition Examination Survey (NHANES 2013–2014) found an overall prevalence of 13.5%. However, it is apparent that significant decrements in the ability to smell are present in >50% of the population between 65 and 80 years of age and in 75% of those aged ≥80 years (Fig. 29-6). Such presbyosmia helps to explain why many elderly report that food has little flavor, a problem that can result in nutritional disturbances. This also helps to explain why a disproportionate number of elderly die in accidental gas poisonings. A relatively complete listing of conditions and disorders that have been associated with olfactory dysfunction is presented in Table 29-1. Aside from aging, the three most common identifiable causes of long-lasting or permanent smell loss seen in the clinic are, in order of frequency, severe upper respiratory infections, head trauma, and chronic rhinosinusitis. The physiologic basis for most head trauma– related losses is the shearing and subsequent scarring of the olfactory fila as they pass from the nasal cavity into the brain cavity. The cribriform plate does not have to be fractured or show pathology for smell loss to be present. Severity of trauma, as indexed by a poor Glasgow Coma Scale score on presentation and the length of posttraumatic amnesia, is associated with higher risk of olfactory impairment. Less than 10% of posttraumatic anosmic patients will recover age-related normal function over time. This increases to nearly 25% of those with less-than-total loss. Upper respiratory infections, such as those Median UPSIT value (with interquartile range)

Cardinal Manifestations and Presentation of Diseases

beyond the mouth and throat, with α-gustducin, the taste-specific G-protein α-subunit, expressed in so-called brush cells found specifically within the human trachea, lung, pancreas, and gallbladder. These brush cells are rich in nitric oxide (NO) synthase, known to defend against xenobiotic organisms, protect the mucosa from acid-induced lesions, and, in the case of the gastrointestinal tract, stimulate vagal and splanchnic afferent neurons. NO further acts on nearby cells, including enteroendocrine cells, absorptive or secretory epithelial cells, mucosal blood vessels, and cells of the immune system. Members of the T2R family of bitter receptors and the sweet receptors of the T1R family have been identified within the gastrointestinal tract and in enteroendocrine cell lines. In some cases, these receptors are important for metabolism, with the T1R3 receptors and gustducin playing decisive roles in the sensing and transport of dietary sugars from the intestinal lumen into absorptive enterocytes via a sodium-dependent glucose transporter and in regulation of hormone release from gut enteroendocrine cells. In other cases, these receptors may be important for airway protection, with a number of T2R bitter receptors in the motile cilia of the human airway that responded to bitter compounds by increasing their beat frequency. One specific T2R38 taste receptor is expressed in human upper respiratory epithelia and responds to acyl-monoserine lactone quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram-negative bacteria. Differences in T2R38 functionality, as related to TAS2R38 genotype, correlate with susceptibility to upper respiratory infections in humans. Taste information is sent to the brain via three cranial nerves (CNs): CN VII (the facial nerve, which involves the intermediate nerve with its branches, the greater petrosal and chorda tympani nerves), CN IX (the glossopharyngeal nerve), and CN X (the vagus nerve) (Fig. 29-5). CN VII innervates the anterior tongue and all of the soft palate, CN IX innervates the posterior tongue, and CN X innervates the laryngeal surface of the epiglottis, larynx, and proximal portion of the esophagus. The mandibular branch of CN V (V3) conveys somatosensory information (e.g., touch, burning, cooling, irritation) to the brain. Although not technically a gustatory nerve, CN V shares primary nerve routes with many of the gustatory nerve fibers and adds temperature, texture, pungency, and spiciness to the taste experience. The chorda tympani nerve is famous for taking a recurrent course through the facial canal in the petrosal portion of the temporal bone, passing through the middle ear, and then exiting the skull via the petrotympanic fissure, where it joins the lingual nerve (a division of CN V) near the tongue. This nerve also

40

219 46

35

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129

161 71

90

109

58

116

68

84

30 25

40

52 58

20 15

20–29

40–49 Age group

21

36

Females (n = 1158) Males (n = 797) Total group (N = 1955)

5–9

FIGURE 29-5  Schematic of the cranial nerves (CNs) that mediate taste function, including the chorda tympani nerve (CN VII), the glossopharyngeal nerve (CN IX), and the vagus nerve (CN X). (Copyright David Klemm, Faculty and Curriculum Support [FACS], Georgetown University Medical Center; used with permission.)

180 155

254

8

60–69

80–89

FIGURE 29-6  Scores on the University of Pennsylvania Smell Identification Test (UPSIT) as a function of subject age and sex. Numbers by each data point indicate sample sizes. Note that women identify odorants better than men at all ages. (From RL Doty et al: Science 226:1421, 1984. Copyright © 1984 American Association for the Advancement of Science.)

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TABLE 29-1  Disorders and Conditions Associated with Compromised Olfactory Function, as Measured by Olfactory Testing

associated with the common cold, influenza, pneumonia, or HIV, can directly and permanently harm the olfactory epithelium by decreasing receptor cell number, damaging cilia on remaining receptor cells, and inducing the replacement of sensory epithelium with respiratory epithelium. The smell loss associated with chronic rhinosinusitis is related to disease severity, with most loss occurring in cases where rhinosinusitis and polyposis are both present. Although systemic glucocorticoid therapy can usually induce short-term functional improvement, it does not, on average, return smell test scores to normal, implying that chronic permanent neural loss is present and/or that short-term administration of systemic glucocorticoids does not completely mitigate the inflammation. It is well established that microinflammation in an otherwise seemingly normal epithelium can influence smell function. A number of neurodegenerative diseases are accompanied by olfactory impairment, including PD, AD, Huntington’s disease, parkinsonism-dementia complex of Guam, dementia with Lewy bodies (DLB), multiple system atrophy, corticobasal degeneration, frontotemporal

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Korsakoff’s psychosis Laryngopharyngeal reflux disease Legionnaires’ disease Leprosy Liver disease Lubag disease Medications Migraine Multiple sclerosis Multi-infarct dementia Myasthenia gravis Narcolepsy with cataplexy Neoplasms, cranial/nasal Nutritional deficiencies Obstructive pulmonary disease Obesity Obsessive compulsive disorder Orthostatic tremor Panic disorder Parkinson’s disease (PD) Pick’s disease Posttraumatic stress disorder Pregnancy Pseudohypoparathyroidism Psychopathy Radiation (therapeutic, cranial) REM behavior disorder Refsum’s disease Renal failure/end-stage kidney disease Restless leg syndrome Rhinosinusitis/polyposis Schizophrenia Seasonal affective disorder Sjögren’s syndrome Stroke Systemic sclerosis Tobacco smoking Toxic chemical exposure Upper respiratory infections Usher syndrome Vitamin B12 deficiency

CHAPTER 29

22q11 deletion syndrome AIDS/HIV infection Adenoid hypertrophy Adrenal cortical insufficiency Age Alcoholism Allergies Alzheimer’s disease Amyotrophic lateral sclerosis (ALS) Anorexia nervosa Asperger’s syndrome Ataxias Attention deficit/hyperactivity disorder Behcet’s disease Bardet-Biedl syndrome Chagas’ disease Chemical exposure Chronic obstructive pulmonary disease Congenital Cushing’s syndrome Cystic fibrosis Degenerative ataxias Depression Diabetes Down’s syndrome Epilepsy Facial paralysis Fibromyalgia Frontotemporal lobe degeneration Gonadal dysgenesis (Turner’s syndrome) Granulomatosis with Polyangiitis (Wegener’s) Guamanian ALS/PD/dementia syndrome Head trauma Herpes simplex encephalitis Hypothyroidism Huntington’s disease Iatrogenesis Idiopathic inflammatory myopathies Kallmann’s syndrome

dementia, and Down’s syndrome; smell loss can also occur in idio- 197 pathic rapid eye movement (REM) behavioral sleep disorder (iRBD), as well as in multiple sclerosis (MS) related to lesions within olfaction-related structures. Olfactory impairment in PD often predates the clinical diagnosis by a number of years. In staged cases, studies of the sequence of formation of abnormal α-synuclein aggregates and Lewy bodies suggest that the olfactory bulbs may be, along with the dorsomotor nucleus of the vagus, the first site of neural damage in PD. In postmortem studies of patients with very mild “presymptomatic” signs of AD, poorer smell function has been associated with higher levels of AD-related pathology. Smell loss is more marked in patients with early clinical manifestations of DLB than in those with mild AD. Interestingly, smell loss is minimal or nonexistent in progressive supranuclear palsy and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. The relative contributions of disease-specific pathology or differential damage to forebrain neuromodulator/neurotransmitter systems in explaining different degrees of olfactory dysfunction among the various neurodegenerative diseases are presently unknown. The smell loss seen in iRBD is of the same magnitude as that found in PD. This is of particular interest because patients with iRBD frequently develop PD and hyposmia. REM behavior disorder is not only seen in its idiopathic form, but can also be associated with narcolepsy (Chap. 27). A study of narcoleptic patients with and without REM behavior disorder demonstrated that narcolepsy, independent of REM behavior disorder, was associated with impairments in olfactory function. Loss of hypothalamic neurons expressing orexin (also known as hypocretin) neuropeptides is believed to be responsible for narcolepsy and cataplexy. Orexin-containing neurons project throughout the entire olfactory system (from the olfactory epithelium to the olfactory cortex), and damage to these projections may be one underlying mechanism for impaired olfactory performance in narcoleptic patients. Administration of intranasal orexin A (hypocretin-1) improved olfactory function, supporting the notion that mild olfactory impairment is not only a primary feature of narcolepsy with cataplexy, but that orexin deficiency may be directly responsible for the loss of smell in this condition.

■■DISORDERS OF TASTE

The majority of patients who present with taste dysfunction exhibit olfactory, not taste, loss. This is because most flavors attributed to taste actually depend on retronasal stimulation of the olfactory receptors during deglutition. As noted earlier, taste buds only mediate basic tastes such as sweet, sour, bitter, salty, and umami. Significant impairment of whole-mouth gustatory function is rare outside of generalized metabolic disturbances or systemic use of some medications, because taste bud regeneration occurs and peripheral damage alone would require the involvement of multiple CN pathways. Taste function can be influenced by age, diet, smoking behavior, use of medications, and other subject-related factors including (1) the release of foul-tasting materials from the oral cavity from oral medical conditions (e.g., gingivitis, purulent sialadenitis) or appliances; (2) transport problems of tastants to the taste buds (e.g., drying, infections, or inflammatory conditions of the orolingual mucosa), (3) damage to the taste buds themselves (e.g., local trauma, invasive carcinomas), (4) damage to the neural pathways innervating the taste buds (e.g., middle ear infections), (5) damage to central structures (e.g., multiple sclerosis, tumor, epilepsy, stroke), and (6) systemic disturbances of metabolism (e.g., diabetes, thyroid disease, medications). Unlike CN VII, CN IX is relatively protected along its path, although iatrogenic interventions such as tonsillectomy, bronchoscopy, laryngoscopy, endotracheal intubation, and radiation therapy can result in selective injury. CN VII damage commonly results from mastoidectomy, tympanoplasty, and stapedectomy, in some cases inducing persistent metallic sensations. Bell’s palsy (Chap. 433) is one of the most common causes of CN VII injury that results in taste disturbance. On rare occasions, migraine (Chap. 422) is associated with a gustatory prodrome or aura, and in some cases tastants can trigger a migraine attack. Interestingly, dysgeusia occurs in some cases of burning mouth syndrome (also termed glossodynia or glossalgia), as does dry mouth and thirst. Burning mouth syndrome is likely associated with dysfunction of the trigeminal nerve (CN V).

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Some of the etiologies suggested for this poorly understood syndrome are amenable to treatment, including (1) nutritional deficiencies (e.g., iron, folic acid, B vitamins, zinc), (2) diabetes mellitus (possibly predisposing to oral candidiasis), (3) denture allergy, (4) mechanical irritation from dentures or oral devices, (5) repetitive movements of the mouth (e.g., tongue thrusting, teeth grinding, jaw clenching), (6) tongue ischemia as a result of temporal arteritis, (7) periodontal disease, (8) reflux esophagitis, and (9) geographic tongue. Although both taste and smell can be adversely influenced by drugs, taste alterations are more common. Indeed, over 250 medications have been reported to alter the ability to taste. Major offenders include antineoplastic agents, antirheumatic drugs, antibiotics, and blood pressure medications. Terbinafine, a commonly used antifungal, has been linked to taste disturbance lasting up to 3 years. In a recent controlled trial, nearly two-thirds of individuals taking eszopiclone (Lunesta) experienced a bitter dysgeusia that was stronger in women, systematically related to the time since drug administration, and positively correlated with both blood and saliva levels of the drug. Intranasal use of nasal gels and sprays containing zinc, which are common over-the-counter prophylactics for upper respiratory viral infections, has been implicated in loss of smell function. Whether their efficacy in preventing such infections, which are the most common cause of anosmia and hyposmia, outweighs their potential detriment to smell function requires study. Dysgeusia occurs commonly in the context of drugs used to treat or minimize symptoms of cancer, with a weighted prevalence from 56 to 76% depending on the type of cancer treatment. Attempts to prevent taste problems from such drugs using prophylactic zinc sulfate or amifostine have proven to be minimally beneficial. Although antiepileptic medications are occasionally used to treat smell or taste disturbances, the use of topiramate has been reported to result in a reversible loss of an ability to detect and recognize tastes and odors during treatment. As with olfaction, a number of systemic disorders can affect taste. These include, but are not limited to, chronic renal failure, end-stage liver disease, vitamin and mineral deficiencies, diabetes mellitus, and hypothyroidism. In diabetes, there appears to be a progressive loss of taste beginning with glucose and then extending to other sweeteners, salty stimuli, and then all stimuli. Psychiatric conditions can be associated with chemosensory alterations (e.g., depression, schizophrenia, bulimia). A recent review of tactile, gustatory, and olfactory hallucinations demonstrated that no one type of hallucinatory experience is pathognomonic to any given diagnosis. Pregnancy is a unique condition with regard to taste function. There appears to be an increase in dislike and intensity of bitter tastes during the first trimester that may help to ensure that pregnant women avoid poisons during a critical phase of fetal development. Similarly, a relative increase in the preference for salt and bitter in the second and third trimesters may support the ingestion of much needed electrolytes to expand fluid volume and support a varied diet.

■■CLINICAL EVALUATION

In most cases, a careful clinical history will establish the probable etiology of a chemosensory problem, including questions about its nature, onset, duration, and pattern of fluctuations. Sudden loss suggests the possibility of head trauma, ischemia, infection, or a psychiatric condition. Gradual loss can reflect the development of a progressive obstructive lesion, although gradual loss can also follow head trauma. Intermittent loss suggests the likelihood of an inflammatory process. The patient should be asked about potential precipitating events, such as cold or flu infections prior to symptom onset, because these often go underappreciated. Information regarding head trauma, smoking habits, drug and alcohol abuse (e.g., intranasal cocaine, chronic alcoholism), exposures to pesticides and other toxic agents, and medical interventions is also informative. A determination of all the medications that the patient was taking before and at the time of symptom onset is important, because many can cause chemosensory disturbances. Comorbid medical conditions associated with smell impairment, such as renal failure, liver disease, hypothyroidism, diabetes, or dementia, should be assessed. Delayed puberty in association with anosmia (with

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or without midline craniofacial abnormalities, deafness, and renal anomalies) suggests the possibility of Kallmann’s syndrome. Recollection of epistaxis, discharge (clear, purulent, or bloody), nasal obstruction, allergies, and somatic symptoms, including headache or irritation, may have localizing value. Questions related to memory, parkinsonian symptoms, and seizure activity (e.g., automatisms, blackouts, auras, déjà vu) should be posed. Pending litigation and the possibility of malingering should be considered. Modern forced-choice olfactory tests can detect malingering from improbable responses. Neurologic and otorhinolaryngologic (ORL) examinations, along with appropriate brain and nasosinus imaging, aid in the evaluation of patients with olfactory or gustatory complaints. The neural evaluation should focus on CN function, with particular attention to possible skull base and intracranial lesions. Visual acuity, field, and optic disc examinations aid in the detection of intracranial mass lesions that produce raised intracranial pressure (papilledema) and optic atrophy. Foster Kennedy syndrome refers to raised intracranial pressure plus a compressive optic neuropathy; typical causes are olfactory groove meningiomas or other frontal lobe tumors. The ORL examination should thoroughly assess the intranasal architecture and mucosal surfaces. Polyps, masses, and adhesions of the turbinates to the septum may compromise the flow of air to the olfactory receptors, because less than a fifth of the inspired air traverses the olfactory cleft in the unobstructed state. Blood tests may be helpful to identify such conditions as diabetes, infection, heavy metal exposure, nutritional deficiency (e.g., vitamin B6 or B12), allergy, and thyroid, liver, and kidney disease. As with other sensory disorders, quantitative sensory testing is advised. Self-reports of patients can be misleading, and a number of patients who complain of chemosensory dysfunction have normal function for their age and gender. Quantitative smell and taste testing provides objective information for worker’s compensation and other legal claims, as well as a way to accurately assess the effects of treatment interventions. A number of standardized olfactory and taste tests are commercially available. The most widely used of these tests, the 40-item University of Pennsylvania Smell Identification Test (UPSIT), uses norms based on nearly 4000 normal subjects. A determination is made of both absolute dysfunction (i.e., mild loss, moderate loss, severe loss, total loss, probable malingering) and relative dysfunction (percentile rank for age and gender). Although electrophysiologic testing is available at some smell and taste centers (e.g., odor event-related potentials), they require complex stimulus presentation and recording equipment and rarely provide additional diagnostic information. With the exception of electrogustometers, commercially available taste tests have only recently become available. Most use filter paper strips impregnated with tastants, so no stimulus preparation is required.

■■TREATMENT AND MANAGEMENT

Given the various mechanisms by which olfactory and gustatory disturbance can occur, management of patients tends to be conditionspecific. For example, patients with hypothyroidism, diabetes, or infections often benefit from specific treatments to correct the underlying disease process that is adversely influencing chemoreception. For most patients who present primarily with obstructive/transport loss affecting the nasal and paranasal regions (e.g., allergic rhinitis, polyposis, intranasal neoplasms, nasal deviations), medical and/or surgical intervention is often beneficial. Antifungal and antibiotic treatments may reverse taste problems secondary to candidiasis or other oral infections. Chlorhexidine mouthwash mitigates some salty or bitter dysgeusias, conceivably as a result of its strong positive charge. Excessive dryness of the oral mucosa is a problem with many medications and conditions, and artificial saliva (e.g., Xerolube) or oral pilocarpine treatments may prove beneficial. Other methods to improve salivary flow include the use of mints, lozenges, or sugarless gum. Flavor enhancers may make food more palatable (e.g., monosodium glutamate), but caution is advised to avoid overusing ingredients containing sodium or sugar, particularly in circumstances when a patient also has underlying hypertension or diabetes. Medications that induce distortions of taste can often be discontinued and replaced with other types of medications or modes of therapy. As mentioned earlier, pharmacologic agents result

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Disorders of Smell and Taste

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percentage of responders was about the same (~50%) as that noted by others to show spontaneous improvement over a similar time period. Antiepileptics and some antidepressants (e.g., amitriptyline) have been used to treat dysosmias and smell distortions, particularly following head trauma. Ironically, amitriptyline is also frequently on the list of medications that can ultimately distort smell and taste function, possibly from its anticholinergic effects. One study suggested that the centrally acting acetylcholinesterase inhibitor donepezil in AD resulted in improvements on smell identification measures that correlated with overall clinician-based impressions of change in dementia severity scores. Alternative therapies, such as acupuncture, meditation, cognitivebehavioral therapy, and yoga, can help patients manage uncomfortable experiences associated with chemosensory disturbance and oral pain syndromes and to cope with the psychosocial stressors surrounding the impairment. Additionally, modification of diet and eating habits is also important. By accentuating the other sensory experiences of a meal, such as food texture, aroma, temperature, and color, one can optimize the overall eating experience for a patient. In some cases, a flavor enhancer like monosodium glutamate (MSG) can be added to foods to increase palatability and encourage intake. Proper oral and nasal hygiene and routine dental care are extremely important ways for patients to protect themselves from disorders of the mouth and nose that can ultimately result in chemosensory disturbance. Patients should be warned not to overcompensate for their taste loss by adding excessive amounts of sugar or salt. Smoking cessation and the discontinuance of oral tobacco use are essential in the management of any patient with smell and/or taste disturbance and should be repeatedly emphasized. A major and often overlooked element of therapy comes from chemosensory testing itself. Confirmation or lack of conformation of loss is beneficial to patients who come to believe, in light of unsupportive family members and medical providers, that they may be “crazy.” In cases where the loss is minor, patients can be informed of the likelihood of a more positive prognosis. Importantly, quantitative testing places the patient’s problem into overall perspective. Thus, it is often therapeutic for an older person to know that, while his or her smell function is not what it used to be, it still falls above the average of his or her peer group. Without testing, many such patients are simply told that they are getting old and nothing can be done for them, leading in some cases to depression and decreased self-esteem.

CHAPTER 29

in taste disturbances much more frequently than smell disturbances. It is important to note, however, that many drug-related effects are long lasting and not reversed by short-term drug discontinuance. A recent study of endoscopic sinus surgery in patients with chronic rhinosinusitis and hyposmia revealed that patients with severe olfactory dysfunction prior to the surgery had a more dramatic and sustained improvement over time compared to patients with more mild olfactory dysfunction prior to intervention. In the case of intranasal and sinus-related inflammatory conditions, such as seen with allergy, viruses, and traumas, the use of intranasal or systemic glucocorticoids may also be helpful. One common approach is to use a tapering course of oral prednisone. Topical intranasal administration of glucocorticoids was found to be less effective in general than systemic administration, however the effects of different nasal administration techniques were not analyzed; for example, intranasal glucocorticoids are more effective if administered in the Moffett’s position (head in the inverted position such as over the edge of the bed with the bridge of the nose perpendicular to the floor). After head trauma, an initial trial of glucocorticoids may help to reduce local edema and the potential deleterious deposition of scar tissue around olfactory fila at the level of the cribriform plate. Treatments are limited for patients with chemosensory loss or primary injury to neural pathways. Nonetheless, spontaneous recovery can occur. In a follow-up study of 542 patients presenting to our center with smell loss from a variety of causes, modest improvement occurred over an average time period of 4 years in about half of the participants. However, only 11% of the anosmic and 23% of the hyposmic patients regained normal age-related function. Interestingly, the amount of dysfunction present at the time of presentation, not etiology, was the best predictor of prognosis. Other predictors were age and the duration of dysfunction prior to initial testing. Several studies have reported that patients with hyposmia may benefit from repeated smelling of odors over the course of weeks or months. The usual paradigm is to smell odors such as eucalyptol, citronella, eugenol, and phyenyl ethyl alcohol before going to bed and immediately upon awakening each day. The rationale for such an approach comes from animal studies demonstrating that prolonged exposure to odorants can induce increased neural activity within the olfactory bulb. There is also limited evidence that α-lipoic acid (400 mg/d), an essential cofactor for many enzyme complexes with possible antioxidant effects, may be beneficial in mitigating smell loss following viral infection of the upper respiratory tract. However, double-blind studies are needed to confirm this observation. α-lipoic acid has also been suggested to be useful in some cases of hypogeusia and burning mouth syndrome. The use of zinc and vitamin A in treating olfactory disturbances is controversial, and there does not appear to be much benefit beyond replenishing established deficiencies. However, zinc has been shown to improve taste function secondary to hepatic deficiencies, and retinoids (bioactive vitamin A derivatives) are known to play an essential role in the survival of olfactory neurons. One protocol in which zinc was infused with chemotherapy treatments suggested a possible protective effect against developing taste impairment. Diseases of the alimentary tract can not only influence chemoreceptive function, but also occasionally influence vitamin B12 absorption. This can result in a relative deficiency of vitamin B12, theoretically contributing to olfactory nerve disturbance. Vitamin B2 (riboflavin) and magnesium supplements are reported in the alternative literature to aid in the management of migraine that, in turn, may be associated with smell dysfunction. Because vitamin D deficiency is a cofactor of chemotherapy-induced mucocutaneous toxicity and dysgeusia, adding vitamin D3, 1000–2000 units per day, may benefit some patients with smell and taste complaints during or following chemotherapy. A number of medications have reportedly been used with success in ameliorating olfactory symptoms, although strong scientific evidence for efficacy is generally lacking. A report that theophylline improved smell function was uncontrolled and failed to account for the fact that some meaningful improvement occurs without treatment; indeed, the

■■FURTHER READING

Devanand DP et al: Olfactory identification deficits are associated with increased mortality in a multiethnic urban community. Ann Neurol 78:401, 2015. Doty RL: Olfaction in Parkinson’s disease and related disorders. Neurobiol Dis 46:527, 2012. Doty RL: Neurotoxic exposure and alterations in olfaction and gustation. Handbook Clin Neurol 131:299, 2015. Doty RL (ed): Handbook of Olfaction and Gustation, 3rd ed. Hoboken, Wiley-Liss, 2015. Doty RL et al: Influences of hormone replacement therapy on olfactory and cognitive function in the menopause. Neurobiol Aging 36:2053, 2015. Doty RL et al: Taste function in early stage treated and untreated Parkinson’s disease. J Neurol 262:547, 2015. Kohli P et al: The association between olfaction and depression: A systematic review. Chem Senses 41:479, 2016. Liu G et al: Prevalence and risk factors of taste and smell impairment in a nationwide sample of the US population: A cross-sectional study. BMJ Open 6:e013246, 2016. London B et al: Predictors of prognosis in patients with olfactory disturbance. Ann Neurol 63:159, 2008. Pekala K et al: Efficacy of olfactory training in patients with olfactory loss: A systematic review and meta-analysis. Int Forum Allergy Rhinol 6:299, 2016. Perricone C et al: Smell and autoimmunity: A comprehensive review. Clin Rev Allergy Immunol 45:87, 2013.

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30

Disorders of Hearing Anil K. Lalwani

Hearing loss can present at any age and is one of the most common sensory disorders in humans. Nearly 10% of the adult population has some hearing loss, and one-third of individuals age >65 years have a hearing loss of sufficient magnitude to require a hearing aid.

PART 2

PHYSIOLOGY OF HEARING

Cardinal Manifestations and Presentation of Diseases

The function of the external and middle ear is to amplify sound to facilitate conversion of the mechanical energy of the sound wave into an electrical signal by the inner ear hair cells, a process called mechanotransduction (Fig. 30-1). Sound waves enter the external auditory canal and set the tympanic membrane (eardrum) in motion, which in turn moves the malleus, incus, and stapes of the middle ear. Movement of the footplate of the stapes causes pressure changes in the fluid-filled inner ear, eliciting a traveling wave in the basilar membrane of the cochlea. The tympanic membrane and the ossicular chain in the middle ear serve as an impedance-matching mechanism, improving the efficiency of energy transfer from air to the fluid-filled inner ear. In its absence, nearly 99.9% of the acoustical energy would be reflected and thus not heard. Instead, the ear drum and the ossicles boost the sound energy nearly 200-fold by the time it reaches the inner ear. Within the cochlea of the inner ear, there are two types of hair cells that aid in hearing: inner and outer. The inner and outer hair cells of the organ of Corti have different innervation patterns, but both are mechanoreceptors; they detect the mechanical energy of the acoustical signal and aid its conversion to an electrical signal that travels by the auditory nerve. The afferent innervation relates principally to the inner hair cells while the efferent innervation relates principally to the outer hair cells. The outer hair cells outnumber the inner hair cells by nearly 6:1 (20,000 vs 3500). The motility of the outer hair cells alters the micromechanics of the inner hair cells, creating a cochlear amplifier, which explains the exquisite sensitivity and frequency selectivity of the cochlea. Stereocilia of the hair cells of the organ of Corti, which rests on the basilar membrane, are in contact with the tectorial membrane and are deformed by the traveling wave. The deformation stretches tiny filamentous connections (tip links) between stereocilia, leading to opening of ion channels, influx of potassium, and hair cell depolarization and subsequent neurotransmission. A point of maximal displacement of the basilar membrane is determined by the frequency of the stimulating tone. High-frequency tones cause maximal displacement of the basilar membrane near the base of the cochlea, whereas for low-frequency External acoustic meatus

sounds, the point of maximal displacement is toward the apex of the cochlea. Beginning in the cochlea, the frequency specificity is maintained at each point of the central auditory pathway: dorsal and ventral cochlear nuclei, trapezoid body, superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate body, and auditory cortex. At low frequencies, individual auditory nerve fibers can respond more or less synchronously with the stimulating tone. At higher frequencies, phase-locking occurs so that neurons alternate in response to particular phases of the cycle of the sound wave. Intensity is encoded by the amount of neural activity in individual neurons, the number of neurons that are active, and the specific neurons that are activated. There is evidence that the right and left ears as well as the central nervous system may process speech asymmetrically. Generally, a sound is processed symmetrically from the peripheral to the central auditory system. However, a “right ear advantage” exists for dichotic listening tasks, in which subjects are asked to report on competing sounds presented to each ear. In most individuals, a perceptual right ear advantage for consonant-vowel syllables, stop consonants, and words also exists. Similarly, whereas central auditory processing for sounds is symmetric with minimal lateral specialization for the most part, speech processing is lateralized. There is specialization of the left auditory cortex for speech recognition and production, and of the right hemisphere for emotional and tonal aspects of speech. Left hemisphere dominance for speech is found in 95–98% of right-handed persons and 70–80% of left-handed persons.

■■DISORDERS OF THE SENSE OF HEARING

Hearing loss can result from disorders of the auricle, external auditory canal, middle ear, inner ear, or central auditory pathways (Fig. 30-2). In general, lesions in the auricle, external auditory canal, or middle ear that impede the transmission of sound from the external environment to the inner ear cause conductive hearing loss, whereas lesions that impair mechanotransduction in the inner ear or transmission of the electrical signal along the eighth nerve to the brain cause sensorineural hearing loss.

Conductive Hearing Loss  The external ear, the external auditory

canal, and the middle ear apparatus are designed to collect and amplify sound and efficiently transfer the mechanical energy of the sound wave to the fluid-filled cochlea. Factors that obstruct the transmission of sound or dampen the acoustical energy result in conductive hearing loss. Conductive hearing loss can occur from obstruction of the external auditory canal by cerumen, debris, and foreign bodies; swelling of the lining of the canal; atresia or neoplasms of the canal; perforations of the tympanic membrane; disruption of the ossicular chain, as occurs with necrosis of the long process of the incus in trauma or infection; otosclerosis; or fluid, scarring, or neoplasms in the middle ear. Rarely, inner

Semicircular canals

Middle ear Stapes

Semicircular canals

Incus Malleus

Cochlea Vestibulocochlear nerve

Anterior

Membranous labyrinth (contains endolymph)

Posterior

Inner ear

Bony labyrinth (contains perilymph)

Ampulla of semicircular canal

Lateral

Utricle Saccule

Auricle or pinna

Cochlea

External acoustic canal

Tympanic membrane

Vestibule Eustachian tube

Round window

Lobe

A

External ear

Oval window

B

Cochlear duct

FIGURE 30-1  Ear anatomy. A. Drawing of modified coronal section through external ear and temporal bone, with structures of the middle and inner ear demonstrated. B. High-resolution view of inner ear.

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201 Hearing loss Cerumen impaction TM perforation Cholesteatoma SOM AOM External auditory canal atresia/ stenosis Eustachian tube dysfunction Tympanosclerosis

History abnormal

normal Otologic examination

Mixed HL

Impedance audiometry

Impedance audiometry

Otosclerosis Cerumen impaction Ossicular fixation Cholesteatoma* Temporal bone trauma* Inner ear dehiscence or “third window”

abnormal

normal

AOM SOM TM perforation* Eustachian tube dysfunction Cerumen impaction Cholesteatoma* Temporal bone trauma* Ossicular discontinuity* Middle ear tumor*

Stapes gusher syndrome* Inner ear malformation* Otosclerosis Temporal bone trauma* Inner ear dehiscence or “third window”

SNHL

abnormal AOM TM perforation* Cholesteatoma* Temporal bone trauma* Middle ear tumors* glomus tympanicum glomus jugulare

Chronic

Acute asymmetric/symmetric CNS infection† Tumors† Cerebellopontine angle CNS Stroke† Trauma*

Asymmetric

Symmetric

Inner ear malformation* Presbycusis Noise exposure Radiation therapy

MRI/BAER normal Endolymphatic hydrops Labyrinthitis* Perilymphatic fistula* Radiation therapy

Disorders of Hearing

normal

CHAPTER 30

Conductive HL

Pure tone and speech audiometry

abnormal Labyrinthitis* Inner ear malformations* Cerebellopontine angle tumors Arachnoid cyst; facial nerve tumor; lipoma; meningioma; vestibular schwannoma Multiple sclerosis†

*Computed tomography (CT) scan of temporal bone. † Magnetic resonance imaging (MRI) scan.

FIGURE 30-2  An algorithm for the approach to hearing loss. AOM, acute otitis media; BAER, brainstem auditory-evoked response; CNS, central nervous system; HL, hearing loss; SNHL, sensorineural hearing loss; SOM, serous otitis media; TM, tympanic membrane.

ear malformations or pathologies, such as superior semicircular canal dehiscence, lateral semicircular canal dysplasia, incomplete partition of the inner ear, and large vestibular aqueduct, are also associated with conductive hearing loss. Eustachian tube dysfunction is extremely common in adults and may predispose to acute otitis media (AOM) or serous otitis media (SOM). Trauma, AOM, and chronic otitis media are the usual factors responsible for tympanic membrane perforation. While small perforations often heal spontaneously, larger defects usually require surgical intervention. Tympanoplasty is highly effective (>90%) in the repair of tympanic membrane perforations. Otoscopy is usually sufficient to diagnose AOM, SOM, chronic otitis media, cerumen impaction, tympanic membrane perforation, and eustachian tube dysfunction; tympanometry can be useful to confirm the clinical suspicion of these conditions. Cholesteatoma, a benign tumor composed of stratified squamous epithelium in the middle ear or mastoid, occurs frequently in adults. This is a slowly growing lesion that destroys bone and normal ear tissue. Theories of pathogenesis include traumatic immigration and invasion of squamous epithelium through a retraction pocket of the tympanic membrane, implantation of squamous epithelia in the middle ear through a perforation or surgery, and metaplasia following chronic infection and irritation. A chronically draining ear that fails to respond to appropriate antibiotic therapy should raise suspicion of a cholesteatoma. On examination, there is often a perforation of the tympanic membrane filled with cheesy white squamous debris. The presence of an aural polyp obscuring the tympanic membrane is also highly suggestive of an underlying cholesteatoma. Conductive hearing loss secondary to ossicular erosion is common. Bony destruction visualized on computerized tomography (CT) of the temporal bone is

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highly suggestive of cholesteatoma. Surgery is required to remove this destructive process and reconstruct the ossicles. Conductive hearing loss with a normal ear canal and intact tympanic membrane suggests either ossicular pathology or the presence of “third window” in the inner ear (see below). Fixation of the stapes from otosclerosis is a common cause of low-frequency conductive hearing loss. It occurs equally in men and women and is inherited as an autosomal dominant trait with incomplete penetrance; in some cases, it may be a manifestation of osteogenesis imperfecta. Hearing impairment usually presents between the late teens and the forties. In women, the otosclerotic process is accelerated during pregnancy, and the hearing loss is often first noticeable at this time. A hearing aid or a simple outpatient surgical procedure (stapedectomy) can provide excellent auditory rehabilitation. Extension of otosclerosis beyond the stapes footplate to involve the cochlea (cochlear otosclerosis) can lead to mixed or sensorineural hearing loss. Fluoride therapy to prevent hearing loss from cochlear otosclerosis is of uncertain value. Disorders that lead to the formation of a pathologic “third window” in the inner ear can be associated with conductive hearing loss. There are normally two major openings, or windows, that connect the inner ear with the middle ear and serve as conduits for transmission of sound; these are, respectively, the oval and round windows. A third window is formed where the normally hard otic bone surrounding the inner ear is eroded; dissipation of the acoustic energy at the third window is responsible for the “inner ear conductive hearing loss.” The superior semicircular canal dehiscence syndrome resulting from erosion of the otic bone over the superior circular canal can present with conductive hearing loss that mimics otosclerosis. A common symptom is vertigo evoked by loud sounds (Tullio phenomenon), by Valsalva maneuvers that change middle ear pressure, or by applying positive

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pressure on the tragus (the cartilage anterior to the external opening of the ear canal). Patients with this syndrome also complain of fullness of the ear, pulsatile tinnitus, and being able to hear the movement of their eyes and neck. A large jugular bulb or jugular bulb diverticulum can create a “third window” by eroding into the vestibular aqueduct or posterior semicircular canal; the symptoms are similar to those of the superior semicircular canal dehiscence syndrome. Low activation threshold on the vestibular-evoked myogenic potential test (VEMP test, see below) and inner ear erosion on CT are diagnostic. Recalcitrant vertigo and dizziness may respond to surgical repair of the dehiscence.

PART 2

Sensorineural Hearing Loss  Sensorineural hearing loss results

Cardinal Manifestations and Presentation of Diseases

from either damage to the mechanotransduction apparatus of the cochlea or disruption of the electrical conduction pathway from the inner ear to the brain. Thus, injury to hair cells, supporting cells, auditory neurons, or the central auditory pathway can cause sensorineural hearing loss. Damage to the hair cells of the organ of Corti may be caused by intense noise, viral infections, ototoxic drugs (e.g., salicylates, quinine and its synthetic analogues, aminoglycoside antibiotics, loop diuretics such as furosemide and ethacrynic acid, and cancer chemotherapeutic agents such as cisplatin), fractures of the temporal bone, meningitis, cochlear otosclerosis (see above), Ménière’s disease, and aging. Congenital malformations of the inner ear may be the cause of hearing loss in some adults. Genetic predisposition alone or in concert with environmental exposures may also be responsible (see below). Exposure to loud noise, either a short burst or over a more prolonged period of time, can lead to noise-induced hearing loss. Acute exposure to noise can lead to either temporary or permanent threshold shifts, depending on the intensity and duration of sound, due to hair cell injury and/or death. Typically, with permanent hearing loss there is a “noise notch” with elevated hearing thresholds at 3000–4000 Hz. More recently, loud noise exposure has also been associated with “hidden hearing loss”—hidden, because routine audiometry shows the pure tone hearing to be normal. Patients usually complains of not being able to hear clearly and are more bothered by the presence of background noise. In contrast to hair cell loss, hidden hearing loss is thought to be due to loss of auditory synapses on hair cells following noise exposure. In an increasingly noisy world, avoiding acoustic trauma with ear plugs or earmuffs is highly recommended to prevent noise-induced or hidden hearing loss. Presbycusis (age-associated hearing loss) is the most common cause of sensorineural hearing loss in adults. It is estimated to affect over half of the adults aged >75 in the United States, a population that is expected to double in size over the next 40 years. In the early stages, it is characterized by symmetric, gentle to sharply sloping, highfrequency hearing loss (Fig. 30-3). With progression, the hearing loss involves all frequencies. More importantly, the hearing impairment is associated with significant loss in clarity. There is a loss of discrimination for phonemes, recruitment (abnormal growth of loudness), and particular difficulty in understanding speech in noisy environments such as at restaurants and social events. Poor hearing is also associated with an increased incidence of cognitive impairment and rate of cognitive decline. In the elderly, left untreated, hearing loss leads to diminished quality of life, and has been shown to increase overall morbidity and mortality through falls and accidents. Hearing aids are helpful in enhancing the signal-to-noise ratio by amplifying sounds that are close to the listener. Hearing aid use has been shown to reduce cognitive decline. Although hearing aids are able to amplify sounds, they cannot restore the clarity of hearing. Thus, amplification with hearing aids may provide only limited rehabilitation once the word recognition score deteriorates below 50%. Cochlear implants are the treatment of choice when hearing aids prove inadequate, even when hearing loss is incomplete (see below). Ménière’s disease is characterized by episodic vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. Tinnitus and/or deafness may be absent during the initial attacks of vertigo, but it invariably appears as the disease progresses and increases in severity during acute attacks. The annual incidence of Ménière’s disease is 0.5–7.5 per 1000; onset is most frequently in the fifth decade of life but may also occur in young adults or the elderly. Histologically, there

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0 10 20 Right Left 50 dB SRT 55 dB 64% Disc. 70%

30 40 dB HL

202

50 60 70 80 90

100 250

500

1000

2000

4000

8000

Frequency (Hz) FIGURE 30-3  Presbyacusis or age-related hearing loss. The audiogram shows a moderate to severe downsloping sensorineural hearing loss typical of presbyacusis. The loss of high-frequency hearing is associated with a decreased speech discrimination score; consequently, patients complain of lack of clarity of hearing, especially in a noisy background. HL, hearing threshold level; SRT, speech reception threshold.

is distention of the endolymphatic system (endolymphatic hydrops) leading to degeneration of vestibular and cochlear hair cells. This may result from endolymphatic sac dysfunction secondary to infection, trauma, autoimmune disease, inflammatory causes, or tumor; an idiopathic etiology constitutes the largest category and is most accurately referred to as Ménière’s disease. Although any pattern of hearing loss can be observed, typically, low-frequency, unilateral sensorineural hearing impairment is present. An abnormal VEMP test may be helpful in detecting Ménière’s disease in a clinically unaffected contralateral ear. Magnetic resonance imaging (MRI) should be obtained to exclude retrocochlear pathology such as a cerebellopontine angle tumor or demyelinating disorder. Therapy is directed toward the control of vertigo. A 2-g/d low-salt diet is the mainstay of treatment for control of rotatory vertigo. Diuretics, a short course of oral glucocorticoids, intratympanic glucocorticoids, or intratympanic gentamicin may also be useful adjuncts in recalcitrant cases. Surgical therapy of vertigo is reserved for unresponsive cases and includes endolymphatic sac decompression, labyrinthectomy, and vestibular nerve section. Both labyrinthectomy and vestibular nerve section abolish rotatory vertigo in >90% of cases. Unfortunately, there is no effective therapy for hearing loss, tinnitus, or aural fullness from Ménière’s disease. Sensorineural hearing loss may also result from any neoplastic, vascular, demyelinating, infectious, or degenerative disease or trauma affecting the central auditory pathways. Characteristically, a reduction in clarity of hearing and speech comprehension is much greater than the loss of the ability to hear pure tone. Auditory testing is consistent with an auditory neuropathy; normal otoacoustic emissions (OAEs) and an abnormal auditory brainstem response (ABR) is typical (see below). Hearing loss can accompany hereditary sensorimotor neuropathies and inherited disorders of myelin. Tumors of the cerebellopontine angle such as vestibular schwannoma and meningioma (Chap. 86) usually present with asymmetric sensorineural hearing loss with greater deterioration of speech understanding than pure tone hearing. Multiple sclerosis (Chap. 436) may present with acute unilateral or bilateral hearing loss; typically, pure tone testing remains relatively stable while speech understanding fluctuates. Isolated labyrinthine infarction can present with acute hearing loss and vertigo due to a cerebrovascular accident involving the posterior circulation, usually the anterior inferior cerebellar artery; it may also be the heralding sign of impending catastrophic basilar artery infarction (Chap. 419). HIV (Chap. 197), which can produce both peripheral and central auditory system pathology, is another consideration in the evaluation of sensorineural hearing impairment. A finding of conductive and sensorineural hearing loss in combination is termed mixed hearing loss. Mixed hearing losses can result

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More than half of childhood hearing impairment is thought to be hereditary; hereditary hearing impairment (HHI) can also manifest later in life. HHI may be classified as either nonsyndromic, when hearing loss is the only clinical abnormality, or syndromic, when hearing loss is associated with anomalies in other organ systems. Nearly two-thirds of HHIs are nonsyndromic. Between 70 and 80% of nonsyndromic HHI is inherited in an autosomal recessive manner and designated DFNB; another 15–20% is autosomal dominant (DFNA). Less than 5% is X-linked (DFNX) or maternally inherited via the mitochondria. More than 150 loci harboring genes for nonsyndromic HHI have been mapped, with recessive loci outnumbering dominant ones; numerous genes have now been identified (Table 30-1). The hearing genes fall into the categories of structural proteins (MYH9, MYO7A, MYO15, TECTA, DIAPH1), transcription factors (POU3F4, POU4F3), ion channels (KCNQ4, SLC26A4), and gap junction proteins (GJB2, GJB3, GJB6). Several of these genes, including GJB2, TECTA, and TMC1, cause both autosomal dominant and recessive forms of nonsyndromic HHI. In general, the hearing loss associated with dominant genes has its onset in adolescence or adulthood, varies in severity, and progresses with age, whereas the hearing loss associated with recessive inheritance is congenital and profound. Connexin 26, product of the GJB2 gene, is particularly important because it is responsible for nearly 20% of all cases of childhood deafness; half of genetic deafness in children is GJB2-related. Two frameshift mutations, 35delG and 167delT, account for >50% of the cases; however, screening for these two mutations alone is insufficient, and sequencing of the entire gene is required to fully capture GJB2-related recessive deafness. The 167delT mutation is highly prevalent in Ashkenazi Jews; ~1 in 1765 individuals in this population are homozygous and affected. GJB2 hearing loss can also vary among the members of the same family, suggesting that other genes or factors influence the auditory phenotype. A single mutation in GJB2 in combination with a single mutation in GJB6 (connexin 30) can also lead to hearing loss and is an example of digenic inheritance of hearing loss. In addition to GJB2, several other nonsyndromic genes are associated with hearing loss that progresses with age. The contribution of

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APPROACH TO THE PATIENT

Disorders of the Sense of Hearing The goal in the evaluation of a patient with auditory complaints is to determine (1) the nature of the hearing impairment (conductive vs sensorineural vs mixed), (2) the severity of the impairment (mild, moderate, severe, or profound), (3) the anatomy of the impairment (external ear, middle ear, inner ear, or central auditory pathway), and (4) the etiology. The presence of signs and symptoms associated with hearing loss should be ascertained (Table 30-3). The history should elicit characteristics of the hearing loss, including the duration of deafness, unilateral versus bilateral involvement, nature of onset (sudden vs insidious), and rate of progression (rapid vs slow). Symptoms of tinnitus, vertigo, imbalance, aural fullness, otorrhea, headache, facial nerve dysfunction, and head and neck paresthesias should be noted. Information regarding head trauma, exposure to ototoxins, occupational or recreational noise exposure, and family history of hearing impairment may also be important. A sudden onset of unilateral hearing loss, with or without tinnitus, may represent a viral infection of the inner ear, vestibular schwannoma, or a stroke. Patients with unilateral hearing loss (sensory or conductive) usually complain of reduced hearing, poor sound localization, and difficulty hearing clearly in the presence of background noise. Gradual progression of a hearing deficit is common with otosclerosis, noise-induced hearing loss, vestibular schwannoma, or Ménière’s disease. Small vestibular schwannomas typically present with asymmetric hearing impairment, tinnitus, and imbalance (rarely vertigo); cranial neuropathy, in particular of the trigeminal or facial nerve, may accompany larger tumors. In addition to hearing loss, Ménière’s disease may be associated with episodic vertigo, tinnitus, and aural fullness. Hearing loss with otorrhea is most likely due to chronic otitis media or cholesteatoma. Examination should include the auricle, external ear canal, and tympanic membrane. In the elderly, the external ear canal is often dry and fragile; it is preferable to clean cerumen with wall-mounted suction or cerumen loops and to avoid irrigation. In examining the eardrum, the topography of the tympanic membrane is more important than the presence or absence of the light reflex. In addition to the pars tensa (the lower two-thirds of the tympanic membrane), the pars flaccida (upper one-third of the tympanic membrane) above the short process of the malleus should also be examined for retraction pockets that may be evidence of chronic eustachian tube dysfunction or cholesteatoma. Insufflation of the ear canal is necessary to assess tympanic membrane mobility and compliance. Careful inspection of the nose, nasopharynx, and upper respiratory tract is important. Unilateral serous effusion or unexplained otalgia should prompt a fiberoptic examination of the nasopharynx and larynx to exclude neoplasms. Cranial nerves should be evaluated with special attention to facial and trigeminal nerves, which are commonly affected with tumors involving the cerebellopontine angle. The Rinne and Weber tuning fork tests, with a 512-Hz tuning fork, are used to screen for hearing loss, differentiate conductive from sensorineural hearing losses, and confirm the findings of

Disorders of Hearing

■■GENETIC CAUSES OF HEARING LOSS

genetics to presbycusis is also becoming better understood. Sensitivity 203 to aminoglycoside ototoxicity can be maternally transmitted through a mitochondrial mutation. Susceptibility to noise-induced hearing loss may also be genetically determined. There are >400 syndromic forms of hearing loss. These include Usher’s syndrome (retinitis pigmentosa and hearing loss), Waardenburg’s syndrome (pigmentary abnormality and hearing loss), Pendred’s syndrome (thyroid organification defect and hearing loss), Alport’s syndrome (renal disease and hearing loss), Jervell and Lange-Nielsen syndrome (prolonged QT interval and hearing loss), neurofibromatosis type 2 (bilateral acoustic schwannoma), and mitochondrial disorders (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes [MELAS]; myoclonic epilepsy and ragged red fibers [MERRF]; and progressive external ophthalmoplegia [PEO]) (Table 30-2).

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from pathology of both the middle and inner ear, as can occur in otosclerosis involving the ossicles and the cochlea, head trauma, chronic otitis media, cholesteatoma, middle ear tumors, and some inner ear malformations. Trauma resulting in temporal bone fractures may be associated with conductive, sensorineural, or mixed hearing loss. If the fracture spares the inner ear, there may simply be conductive hearing loss due to rupture of the tympanic membrane or disruption of the ossicular chain. These abnormalities can be surgically corrected. Profound hearing loss and severe vertigo are associated with temporal bone fractures involving the inner ear. A perilymphatic fistula associated with leakage of inner ear fluid into the middle ear can occur and may require surgical repair. An associated facial nerve injury is not uncommon. CT is best suited to assess fracture of the traumatized temporal bone, evaluate the ear canal, and determine the integrity of the ossicular chain and involvement of the inner ear. Cerebrospinal fluid leaks that accompany temporal bone fractures are usually self-limited; the value of prophylactic antibiotics is uncertain. Tinnitus is defined as the perception of a sound when there is no sound in the environment. It can have a buzzing, roaring, or ringing quality and may be pulsatile (synchronous with the heartbeat). Tinnitus is often associated with either a conductive or sensorineural hearing loss. The pathophysiology of tinnitus is not well understood. The cause of the tinnitus can usually be determined by finding the cause of the associated hearing loss. Tinnitus may be the first symptom of a serious condition such as a vestibular schwannoma. Pulsatile tinnitus requires evaluation of the vascular system of the head to exclude vascular tumors such as glomus jugulare tumors, aneurysms, dural arteriovenous fistulas, and stenotic arterial lesions; it may also occur with SOM, superior semicircular dehiscence, and inner ear dehiscence. It is most commonly associated with some abnormality of the jugular bulb such as a large jugular bulb or jugular bulb diverticulum.

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  TABLE 30-1 Hereditary Hearing Impairment Genes DESIGNATION

GENE

FUNCTION

Autosomal Dominant

PART 2 Cardinal Manifestations and Presentation of Diseases

  DFNA1 DFNA2A DFNA2B DFNA3A DFNA3B DFNA4   DFNA5 DFNA6/14/38 DFNA8/12 DFNA9 DFNA10 DFNA11 DFNA13 DFNA15 DFNA17 DFNA20/26 DFNA22 DFNA23 DFNA25 DFNA28 DFNA36 DFNA41 DFNA44

CRYM DIAPH1 KCNQ4 GJB3 (Cx31) GJB2 (Cx26) GJB6 (Cx30) MYH14 CEACAM16 DFNA5 WFS1 TECTA COCH EYA4 MYO7A COL11A2 POU4F3 MYH9 ACTG1 MYO6 SIX1 SLC17A8 GRHL2 TMC1 P2RX2 CCDC50

DFNA50 DFNA51 DFNA56 DFNA64

MIRN96 TJP2 TNC SMAC/DIABLO

DFNA65 DFNA66 DFNA67 DFNA68 DFNA69 DFNA70

TBC1D24 CD164 OSBPL2 HOMER2 KITLG MCM2

DFNA71

DMXL2

Thyroid hormone–binding protein Cytoskeletal protein Potassium channel Gap junction Gap junction Gap junction Class II nonmuscle myosin Cell adhesion molecule Unknown Transmembrane protein Tectorial membrane protein Unknown Developmental gene Cytoskeletal protein Cytoskeletal protein Transcription factor Cytoskeletal protein Cytoskeletal protein Unconventional myosin Developmental gene Vesicular glutamate transporter Transcription factor Transmembrane protein Purinergic receptor Effector of epidermal growth factor–mediated signaling MicroRNA Tight junction protein Extracellular matrix protein Mitochondrial proapoptotic protein ARF6-interacting protein Sialomucin Intracellular lipid receptor Stereociliary scaffolding protein Ligand for KIT receptor Initiation and elongation during DNA replication Regulator of Notch signaling

Autosomal Recessive DFNB1A DFNB1B DFNB2 DFNB3 DFNB4 DFNB6 DFNB7/B11 DFNB9 DFNB8/10 DFNB12 DFNB15/72/95 DFNB16 DFNB18 DFNB18B DFNB21 DFNB22

GJB2 (CX26) GJB6 (CX30) MYO7A MYO15 PDS (SLC26A4) TMIE TMC1 OTOF TMPRSS3 CDH23 GIPC3 STRC USH1C OTOG TECTA OTOA

DFNB23 DFNB24

PCDH15 RDX

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Gap junction Gap junction Cytoskeletal protein Cytoskeletal protein Chloride/iodide transporter Transmembrane protein Transmembrane protein Trafficking of membrane vesicles Transmembrane serine protease Intercellular adherence protein PDZ domain–containing protein Stereocilia protein Unknown Tectorial membrane protein Tectorial membrane protein Gel attachment to nonsensory cell Morphogenesis and cohesion Cytoskeletal protein

DESIGNATION

GENE

FUNCTION

DFNB25

GRXCR1

DFNB28 DFNB29 DFNB30 DFNB31 DFNB35

TRIOBP CLDN14 MYO3A WHRN ESRRB

DFNB36

ESPN

DFNB37 DFNB39 DFNB42

MYO6 HFG ILDR1

DFNB44 DFNB48

ADCY1 CIB2

DFNB49 DFNB49 DFNB53 DFNB59 DFNB60

BDP1 MARVELD2 COL11A2 PJVK SLC22A4

DFNB61 DFNB63 DFNB66 DFNB66/67 DFNB68

SLC26A5 LRTOMT/COMT2 DCDC2 LHFPL5 S1PR2

DFNB70

PNPT1

DFNB73 DFNB74 DFNB76 DFNB77 DFNB79 DFNB82 DFNB84

BSND MSRB3 SYNE4 LOXHD1 TPRN GPSM2 PTPRQ

DFNB84 DFNB86 DFNB88 DFNB89 DFNB91 DFNB93 DFNA97

OTOGL TBC1D24 ELMOD3 KARS SERPINB6 CABP2 MET

DFNB98

TSPEAR

DFNB99 DFNB101 DFNB102 DFNB103 DFNB105

TMEM132E GRXCR2 EPS8 CLIC5 CDC14A

 

FAM65B

 

EPS8L2

 

ROR1

Reversible S-glutathionylation of proteins Cytoskeletal-organizing protein Tight junctions Hybrid motor-signaling myosin PDZ domain–containing protein Estrogen-related receptor beta protein Ca-insensitive actin-bundling protein Unconventional myosin Hepatocyte growth factor Ig-like domain–containing receptor Adenylate cyclase Calcium and integrin binding protein Subunit of RNA polymerase Tight junction protein Collagen protein Zn-binding protein Prestin, motor protein of cochlear outer hair cell Motor protein Putative methyltransferase Ciliary protein Tetraspan protein Tetraspan membrane protein of hair cell stereocilia Mitochondrial–RNA–import protein Beta subunit of chloride channel Methionine sulfoxide reductase Part of LINC  tethering complex Stereociliary protein Unknown G protein signaling modulator Type III receptor-like proteintyrosine phosphatase family Otogelin-like protein GTPase-activating protein GTPase-activating protein Lysyl-tRNA synthetase Protease inhibitor Calcium-binding protein Oncogene/hepatocyte growth factor receptor Epilepsy-associated repeats containing protein Transmembrane protein Maintaining stereocilia bundles Epidermal growth factor receptor Chloride ion transport Protein phosphatase involved in hair cell ciliogenesis Membrane-associated protein in stereocilia Actin remodeling in response to EGF stimulation Receptor tyrosine kinase-like orphan receptor

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TABLE 30-2  Syndromic Hereditary Hearing Impairment Genes FUNCTION Cytoskeletal protein Developmental gene Developmental gene Developmental gene Delayed rectifier K+ channel

KCNE1 NDP SLC26A4 FOXI1 KCNJ10

Delayed rectifier K+ channel Cell–cell interactions Chloride/iodide transporter Transcriptional activator of SLC26A4 Inwardly rectifying K+ channel Nucleolar-cytoplasmic transport Subunit of RNA polymerases I and III Subunit of RNA polymerases I and III Cytoskeletal protein Unknown Intercellular adherence protein Cell adhesion molecule Harmonin-associated protein Calcium- and integrin-binding protein Cell adhesion molecule G protein–coupled receptor PDZ domain–containing protein Cellular synapse protein Histidyl-tRNA synthetase PDZ domain–containing protein Transcription factor Transcription factor Transcription factor Endothelin B receptor Endothelin B receptor ligand Transcription factor

Treacher Collins syndrome TCOF1 POLR1D POLR1C

Usher’s syndrome        

MYO7A USH1C CDH23 PCDH15 SANS CIB2

       

USH2A VLGR1 WHRN CLRN1 HARS PDZD7 PAX3 MITF SNAI2 EDNRB EDN3 SOX10

WS type I, III WS type II   WS type IV    

Abbreviations: BOR, branchio-oto-renal syndrome; WS, Waardenburg’s syndrome.

audiologic evaluation. The Rinne test compares the ability to hear by air conduction with the ability to hear by bone conduction. The tines of a vibrating tuning fork are held near the opening of the external auditory canal, and then the stem is placed on the mastoid process; for direct contact, it may be placed on teeth or dentures. The patient is asked to indicate whether the tone is louder by air conduction or bone conduction. Normally, and in the presence of sensorineural hearing loss, a tone is heard louder by air conduction than by bone conduction; however, with conductive hearing loss of ≥30 dB (see “Audiologic Assessment,” below), the bone-conduction stimulus is perceived as louder than the air-conduction stimulus. For the Weber test, the stem of a vibrating tuning fork is placed on the head in the midline and the patient is asked whether the tone is heard in both

TABLE 30-3  Signs and Symptoms Suggestive of Hearing Loss Saying “huh” a great deal Reduced clarity of hearing Difficulty understanding conversations in background noise Family complaining of hearing loss Tinnitus Turning the volume up on radio or television Sensitivity to noises Fullness in the ear Avoiding social settings

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■■LABORATORY ASSESSMENT OF HEARING Audiologic Assessment  The minimum audiologic assessment for hearing loss should include the measurement of pure tone airconduction and bone-conduction thresholds, speech reception threshold, word recognition score, tympanometry, acoustic reflexes, and acoustic-reflex decay. This test battery provides a screening evaluation of the entire auditory system and allows one to determine whether further differentiation of a sensory (cochlear) from a neural (retrocochlear) hearing loss is indicated. Pure tone audiometry assesses hearing acuity for pure tones. The test is administered by an audiologist and is performed in a soundattenuated chamber. The pure tone stimulus is delivered with an audiometer, an electronic device that allows the presentation of specific frequencies (generally between 250 and 8000 Hz) at specific intensities. Air- and bone-conduction thresholds are established for each ear. Airconduction thresholds are determined by presenting the stimulus in air with the use of headphones. Bone-conduction thresholds are determined by placing the stem of a vibrating tuning fork or an oscillator of an audiometer in contact with the head. In the presence of a hearing loss, broad-spectrum noise is presented to the nontest ear for masking purposes so that responses are based on perception from the ear under test. The responses are measured in decibels (dBs). An audiogram is a plot of intensity in dBs of hearing threshold versus frequency. A dB is equal to 20 times the logarithm of the ratio of the sound pressure required to achieve threshold in the patient to the sound pressure required to achieve threshold in a normal-hearing person. Therefore, a change of 6 dB represents doubling of sound pressure, and a change of 20 dB represents a tenfold change in sound pressure. Loudness, which depends on the frequency, intensity, and duration of a sound, doubles with approximately each 10-dB increase in sound pressure level. Pitch, on the other hand, does not directly correlate with frequency. The perception of pitch changes slowly in the low and high frequencies. In the middle tones, which are important for human speech, pitch varies more rapidly with changes in frequency. Pure tone audiometry establishes the presence and severity of hearing impairment, unilateral versus bilateral involvement, and the type of hearing loss. Conductive hearing losses with a large mass component, as is often seen in middle ear effusions, produce elevation of thresholds that predominate in the higher frequencies. Conductive hearing losses with a large stiffness component, as in fixation of the footplate of the stapes in early otosclerosis, produce threshold elevations in the lower frequencies. Often, the conductive hearing loss involves all frequencies, suggesting involvement of both stiffness and mass. In general, sensorineural hearing losses such as presbycusis affect higher frequencies more than lower frequencies (Fig. 30-3). An exception is Ménière’s disease, which is characteristically associated with low-frequency sensorineural hearing loss (though any frequency can be affected). Noise-induced hearing loss has an unusual pattern of hearing impairment in which the loss at 4000 Hz is greater than at higher frequencies. Vestibular schwannomas characteristically affect the higher frequencies, but any pattern of hearing loss can be observed. Speech recognition requires greater synchronous neural firing than is necessary for appreciation of pure tones. Speech audiometry tests the clarity with which one hears. The speech reception threshold (SRT) is defined as the intensity at which speech is recognized as a meaningful symbol and is obtained by presenting two-syllable words with an equal accent on each syllable. The intensity at which the patient can repeat 50% of the words correctly is the SRT. Once the SRT is determined, discrimination or word recognition ability is tested by presenting onesyllable words at 25–40 dB above the SRT. The words are phonetically balanced in that the phonemes (speech sounds) occur in the list of words at the same frequency that they occur in ordinary conversational

Disorders of Hearing

GENE COL4A3-5 EYA1 SIX5 SIX1 KCNQ1

205

CHAPTER 30

SYNDROME Alport’s syndrome BOR syndrome     Jervell and Lange-Nielsen syndrome   Norrie’s disease Pendred’s syndrome  

ears or better in one ear than in the other. With a unilateral conductive hearing loss, the tone is perceived in the affected ear. With a unilateral sensorineural hearing loss, the tone is perceived in the unaffected ear. A 5-dB difference in hearing between the two ears is required for lateralization.

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PART 2 Cardinal Manifestations and Presentation of Diseases

English. An individual with normal hearing or conductive hearing loss can repeat 88–100% of the phonetically balanced words correctly. Patients with a sensorineural hearing loss have variable loss of discrimination. As a general rule, neural lesions produce greater deficits in discrimination than do cochlear lesions. For example, in a patient with mild asymmetric sensorineural hearing loss, a clue to the diagnosis of vestibular schwannoma is the presence of greater than expected deterioration in discrimination ability. Deterioration in discrimination ability at higher intensities above the SRT also suggests a lesion in the eighth nerve or central auditory pathways. Tympanometry measures the impedance of the middle ear to sound and is useful in diagnosis of middle ear effusions. A tympanogram is the graphic representation of change in impedance or compliance as the pressure in the ear canal is changed. Normally, the middle ear is most compliant at atmospheric pressure, and the compliance decreases as the pressure is increased or decreased (type A); this pattern is seen with normal hearing or in the presence of sensorineural hearing loss. Compliance that does not change with change in pressure suggests middle ear effusion (type B). With a negative pressure in the middle ear, as with eustachian tube obstruction, the point of maximal compliance occurs with negative pressure in the ear canal (type C). A tympanogram in which no point of maximal compliance can be obtained is most commonly seen with discontinuity of the ossicular chain (type Ad). A reduction in the maximal compliance peak can be seen in otosclerosis (type As). During tympanometry, an intense tone elicits contraction of the stapedius muscle. The change in compliance of the middle ear with contraction of the stapedius muscle can be detected. The presence or absence of this acoustic reflex is important in determining the etiology of hearing loss as well as in the anatomic localization of facial nerve paralysis. The acoustic reflex can help differentiate between conductive hearing loss due to otosclerosis and that caused by an inner ear “third window”: it is absent in otosclerosis and present in inner ear conductive hearing loss. Normal or elevated acoustic reflex thresholds in an individual with sensorineural hearing impairment suggest a cochlear hearing loss. An absent acoustic reflex in the setting of sensorineural hearing loss is not helpful in localizing the site of lesion. Assessment of acoustic reflex decay helps differentiate sensory from neural hearing losses. In neural hearing loss, such as with vestibular schwannoma, the reflex adapts or decays with time. OAEs generated by outer hair cells only can be measured with microphones inserted into the external auditory canal. The emissions may be spontaneous or evoked with sound stimulation. The presence of OAEs indicates that the outer hair cells of the organ of Corti are intact and can be used to assess auditory thresholds and to distinguish sensory from neural hearing losses.

Evoked Responses  Electrocochleography measures the earliest

evoked potentials generated in the cochlea and the auditory nerve. Receptor potentials recorded include the cochlear microphonic, generated by the outer hair cells of the organ of Corti, and the summating potential, generated by the inner hair cells in response to sound. The whole nerve action potential representing the composite firing of the first-order neurons can also be recorded during electrocochleography. Clinically, the test is useful in the diagnosis of Ménière’s disease, in which an elevation of the ratio of summating potential to action potential is seen. Brainstem auditory-evoked responses (BAERs), also known as (ABRs), are useful in differentiating the site of sensorineural hearing loss. In response to sound, five distinct electrical potentials arising from different stations along the peripheral and central auditory pathway (eighth nerve, cochlear nucleus, superior olivary complex, lateral lemniscus, and inferior colliculus) can be identified using computer averaging from scalp surface electrodes. BAERs are valuable in situations in which patients cannot or will not give reliable voluntary thresholds. They are also used to assess the integrity of the auditory nerve and brainstem in various clinical situations, including intraoperative monitoring, and in determination of brain death. The VEMP test investigates otolith and vestibular nerve function by presenting a high-level acoustic stimuli and evoking a short-latency electromyographic potential; cVEMP (or cervical VEMP) and oVEMP

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(or ocular VEMP) have been described. The cVEMP elicits a vestibulocollic reflex whose afferent limb arises from acoustically sensitive cells in the saccule, with signals conducted via the inferior vestibular nerve. cVEMP is a biphasic, short-latency response recorded from the tonically contracted sternocleidomastoid muscle in response to loud auditory clicks or tones. cVEMPs may be diminished or absent in patients with early and late Ménière’s disease, vestibular neuritis, benign paroxysmal positional vertigo, and vestibular schwannoma. On the other hand, the threshold for VEMPs may be lower in cases of superior canal dehiscence, other inner ear dehiscence, and perilymphatic fistula. The oVEMP, in contrast, is a response involving the utricle primarily and superior vestibular nerve. The oVEMP excitatory response is recorded from the extraocular muscle. The oVEMP is abnormal in superior vestibular neuritis.

Imaging Studies  The choice of radiologic tests is largely deter-

mined by whether the goal is to evaluate the bony anatomy of the external, middle, and inner ear or to image the auditory nerve and brain. Axial and coronal CT of the temporal bone with fine 0.3-mm cuts is ideal for determining the caliber of the external auditory canal, integrity of the ossicular chain, and presence of middle ear or mastoid disease; it can also detect inner ear malformations. CT is also ideal for the detection of bone erosion with chronic otitis media and cholesteatoma. Pöschl reformatting in the plane of the superior semicircular canal is required for the identification of dehiscence or absence of bone over the superior semicircular canal. MRI is superior to CT for imaging of retrocochlear pathology such as vestibular schwannoma, meningioma, other lesions of the cerebellopontine angle, demyelinating lesions of the brainstem, and brain tumors. Both CT and MRI are equally capable of identifying inner ear malformations and assessing cochlear patency for preoperative evaluation of patients for cochlear implantation.

TREATMENT

Disorders of the Sense of Hearing In general, conductive hearing losses are amenable to surgical correction, whereas sensorineural hearing losses are usually managed medically. Atresia of the ear canal can be surgically repaired, often with significant improvement in hearing. Alternatively, the conductive hearing loss associated with atresia can be addressed with a bone-anchored hearing aid (BAHA). Tympanic membrane perforations due to chronic otitis media or trauma can be repaired with an outpatient tympanoplasty. Likewise, conductive hearing loss associated with otosclerosis can be treated by stapedectomy, which is successful in >95% of cases. Tympanostomy tubes allow the prompt return of normal hearing in individuals with middle ear effusions. Hearing aids are effective and well tolerated in patients with conductive hearing losses. Patients with mild, moderate, and severe sensorineural hearing losses are regularly rehabilitated with hearing aids of varying configuration and strength. Hearing aids have been improved to provide greater fidelity and have been miniaturized. The current generation of hearing aids can be placed entirely within the ear canal, thus reducing any stigma associated with their use. In general, the more severe the hearing impairment, the larger the hearing aid required for auditory rehabilitation. Digital hearing aids lend themselves to individual programming, and multiple and directional microphones at the ear level may be helpful in noisy surroundings. Because all hearing aids amplify noise as well as speech, the only absolute solution to the problem of noise is to place the microphone closer to the speaker than the noise source. This arrangement is not possible with a self-contained, cosmetically acceptable device. A significant limitation of rehabilitation with a hearing aid is that although it is able to enhance detection of sound with amplification, it cannot restore clarity of hearing that is lost with presbycusis. The cost of a single hearing aid (~$2300 US) is a significant obstacle for many hearing-impaired individuals and usually bilateral amplification is recommended. To reduce cost and spur innovation, efforts are underway to create a new category for “basic” hearing

6/1/18 3:15 PM

Magnetic headpiece Back microphone

Implant

Sound processor

Front microphone Electrode array inside cochlea

Hearing nerve

T-MicTM2 microphone

Disorders of Hearing

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Headpiece microphone

CHAPTER 30

aids that could be sold over-the-counter, similar to some eyeglasses and contact lenses. By reducing the cost of hearing aids to consumers, promoting innovation, and increasing competition, this new class of devices could fundamentally change the way hearing rehabilitation is delivered. Patients with unilateral deafness have difficulty with sound localization and reduced clarity of hearing in background noise. They may benefit from a contralateral routing of signal (CROS) hearing aid in which a microphone is placed on the hearing-impaired side, and the sound is transmitted to the receiver placed on the contralateral ear. The same result may be obtained with a BAHA, in which a hearing aid clamps to a screw integrated into the skull on the hearing-impaired side. Like the CROS hearing aid, the BAHA transfers the acoustic signal to the contralateral hearing ear, but it does so by vibrating the skull. Patients with profound deafness on one side and some hearing loss in the better ear are candidates for a BICROS hearing aid; it differs from the CROS hearing aid in that the patient wears a hearing aid, and not simply a receiver, in the better ear. Unfortunately, while CROS and BAHA devices provide benefit, they do not restore hearing in the deaf ear. Only cochlear implants can restore hearing (see below). Increasingly, cochlear implants are being investigated for the treatment of patients with single-sided deafness; early reports show great promise in not only restoring hearing and reducing tinnitus, but also improving sound localization and performance in background noise. In many situations, including lectures and the theater, hearingimpaired persons benefit from assistive devices that are based on the principle of having the speaker closer to the microphone than any source of noise. Assistive devices include infrared and frequencymodulated (FM) transmission as well as an electromagnetic loop around the room for transmission to the individual’s hearing aid. Hearing aids with telecoils can also be used with properly equipped telephones in the same way. In the event that the hearing aid provides inadequate rehabilitation, cochlear implants may be appropriate (Fig. 30-4). Criteria for implantation include severe to profound hearing loss with open-set sentence cognition of ≤40% under best-aided conditions. Worldwide, >600,000 hearing-impaired individuals have received cochlear implants. Cochlear implants are neural prostheses that convert sound energy to electrical energy and can be used to stimulate the auditory division of the eighth nerve directly. In most cases of profound hearing impairment, the auditory hair cells are lost but the ganglionic cells of the auditory division of the eighth nerve are preserved. Cochlear implants consist of electrodes that are inserted into the cochlea through the round window, speech processors that extract acoustical elements of speech for conversion to electrical currents, and a means of transmitting the electrical energy through the skin. Patients with implants experience sound that helps with speech reading, allows open-set word recognition, and helps in modulating the person’s own voice. Usually, within the first 3–6 months after implantation, adult patients can understand speech without visual cues. With the current generation of multichannel cochlear implants, nearly 75% of patients are able to converse on the telephone. Bilateral cochlear implantations are increasingly being performed, especially in children; these patients perform better in background noise, have better sound localization, and are less fatigued by the “work” compared to monaural hearing. The first hybrid cochlear implant for the treatment of highfrequency hearing loss has now been approved by the U.S. Food and Drug Administration. Patients with presbyacusis typically have normal low-frequency hearing, while suffering from high-frequency hearing loss associated with loss of clarity that cannot always be adequately rehabilitated with a hearing aid. However, these patients are not candidates for conventional cochlear implants because they have too much residual hearing. The hybrid implant has been specifically designed for this patient population; it has a shorter electrode than a conventional cochlear implant and can be introduced into the cochlea atraumatically, thus preserving low-frequency hearing. Individuals with a hybrid implant use their own natural low-frequency

FIGURE 30-4  A cochlear implant is composed of an external microphone and speech processor worn on the ear and a receiver implanted underneath the temporalis muscle. The internal receiver is attached to an electrode that is placed surgically in the cochlea.

“acoustic” hearing and rely on the implant for providing “electrical” high-frequency hearing. Patients who have received the hybrid implant perform better on speech discrimination tests in both quiet and noisy backgrounds. For individuals who have had both eighth nerves destroyed by trauma or bilateral vestibular schwannomas (e.g., neurofibromatosis type 2), brainstem auditory implants placed near the cochlear nucleus may provide auditory rehabilitation. Currently, brainstem implants provide sound awareness but unfortunately speech understanding remains elusive. Tinnitus often accompanies hearing loss. As for background noise, tinnitus can degrade speech comprehension in individuals with hearing impairment. Patients with tinnitus should be advised to minimize caffeine ingestion, avoid high dosage of nonsteroidal anti-inflammatory drugs (NSAIDs), and reduce stress. Therapy for tinnitus is usually directed toward minimizing the appreciation of tinnitus. Relief of the tinnitus may be obtained by masking it with background music. Hearing aids are also helpful in tinnitus suppression, as are tinnitus maskers, devices that present a sound to the affected ear that is more pleasant to listen to than the tinnitus. The use of a tinnitus masker is often followed by several hours of inhibition of the tinnitus. Antidepressants have also been shown to be beneficial in helping patients cope with tinnitus. Hard-of-hearing individuals often benefit from a reduction in unnecessary noise in the environment (e.g., radio or television) to enhance the signal-to-noise ratio. Speech comprehension is aided by lip reading; therefore, the impaired listener should be seated so that the face of the speaker is well illuminated and easily seen. Although speech should be in a loud, clear voice, one should be aware that in sensorineural hearing losses in general and in hard-of-hearing elderly in particular, recruitment (abnormal perception of loud sounds) may be troublesome. Above all, optimal communication cannot take place without both parties giving it their full and undivided attention.

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TABLE 30-4  Decibel (Loudness) Level of Common Environmental Noise

PART 2 Cardinal Manifestations and Presentation of Diseases

SOURCE Weakest sound heard Whisper Normal conversation City traffic inside car OSHA Monitoring Requirement Begins Jackhammer Subway train at 200 ft Power mower Power saw Painful Sound Jet engine at 100 feet 12-gauge shotgun blast Loudest sound that can occur

DECIBEL (dB) 0 30 55–65 85 90 95 95 107 110 125 140 165 194

Abbreviation: OSHA, Occupational Safety and Health Administration.

■■PREVENTION

Conductive hearing losses may be prevented by prompt antibiotic therapy of adequate duration for AOM and by ventilation of the middle ear with tympanostomy tubes in middle ear effusions lasting ≥12 weeks. Loss of vestibular function and deafness due to aminoglycoside antibiotics can largely be prevented by careful monitoring of serum peak and trough levels. Some 10 million Americans have noise-induced hearing loss, and 20 million are exposed to hazardous noise in their employment. Noise-induced hearing loss can be prevented by avoidance of exposure to loud noise or by regular use of ear plugs or fluid-filled ear muffs to attenuate intense sound. Table 30-4 lists loudness levels for a variety of environmental sounds. High-risk activities for noiseinduced hearing loss include use of electrical equipment for wood and metal working and target practice or hunting with small firearms. All internal-combustion and electric engines, including snow and leaf blowers, snowmobiles, outboard motors, and chainsaws, require protection of the user with hearing protectors. Virtually all noiseinduced hearing loss is preventable through education, which should begin before the teenage years. Programs for conservation of hearing in the workplace are required by the Occupational Safety and Health Administration (OSHA) whenever the exposure over an 8-h period averages 85 dB. OSHA mandates that workers in such noisy environments have hearing monitoring and protection programs that include a preemployment screen, an annual audiologic assessment, and the mandatory use of hearing protectors. Exposure to loud sounds above 85 dB in the work environment is restricted by OSHA, with halving of allowed exposure time for each increment of 5 dB above this threshold; for example, exposure to 90 dB is permitted for 8 h; 95 dB for 4 h, and 100 dB for 2 h (Table 30-5).

TABLE 30-5  OSHA Daily Permissible Noise Level Exposure SOUND LEVEL (dB) 90 92 95 97 100 102 105 110 115

DURATION PER DAY (h) 8 6 4 3 2 1.5 1 0.5 ≤0.25

Note: Exposure to impulsive or impact noise should not exceed 140-dB peak sound pressure level. Source: From https://www.osha.gov/pls/oshaweb/owadisp.show_document? p_table=standards&p_id=9735.

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■■FURTHER READING

Espinosa-Sanchez JM, Lopez-Escamez JA: Menière’s disease. Handb Clin Neurol 137:257, 2016. Moser T, Starr A: Auditory neuropathy—neural and synaptic mechanisms. Nat Rev Neurol 12:135, 2016. Patel M et al: Intratympanic methylprednisolone versus gentamicin in patients with unilateral Ménière’s disease: A randomised, double-blind, comparative effectiveness trial. Lancet 388:2753, 2016. Tikka C et al: Interventions to prevent occupational noise-induced hearing loss. Cochrane Database Syst Rev 7:CD006396, 2017. Wilson BS et al: Global hearing health care: New findings and perspectives. Lancet 390:2503, 2017.

31

Sore Throat, Earache, and Upper Respiratory Symptoms Michael A. Rubin, Larry C. Ford, Ralph Gonzales

Infections of the upper respiratory tract (URIs) have a tremendous impact on public health. They are among the most common reasons for visits to primary care providers, and although the illnesses are typically mild, their high incidence and transmission rates place them among the leading causes of time lost from work or school. Even though a minority (~25%) of cases are caused by bacteria, URIs are the leading diagnoses for which antibiotics are prescribed on an outpatient basis in the United States, often inappropriately. Antibiotics are more often misprescribed in adults than in pediatric populations. The enormous consumption of antibiotics for these illnesses has contributed to the rise in antibiotic resistance among common community-acquired pathogens such as Streptococcus pneumoniae—a trend that in itself has an enormous influence on public health and on the individual patient. Although most URIs are caused by viruses, distinguishing patients with primary viral infection from those with primary bacterial infection is difficult. Signs and symptoms of bacterial and viral URIs are typically indistinguishable. Until consistent, inexpensive, and rapid testing becomes available and is used widely, acute infections will be diagnosed largely on clinical grounds. The judicious use and potential for misuse of antibiotics in this setting pose ongoing challenges.

NONSPECIFIC INFECTIONS OF THE UPPER RESPIRATORY TRACT

Nonspecific URIs are a broadly defined group of disorders that collectively constitute the leading cause of ambulatory care visits in the United States. By definition, nonspecific URIs have no prominent localizing features. They are identified by a variety of descriptive names, including acute infective rhinitis, acute rhinopharyngitis/nasopharyngitis, acute coryza, and acute nasal catarrh, as well as by the inclusive label common cold.

■■ETIOLOGY

The large assortment of URI classifications reflects the wide variety of causative infectious agents and the varied manifestations of common pathogens. Nearly all nonspecific URIs are caused by viruses spanning multiple virus families and many antigenic types. For instance, there are at least 100 immunotypes of rhinovirus (Chap. 194), the most common cause of URI (~30–40% of cases); other causes include influenza virus (three immunotypes; Chap. 195) as well as parainfluenza virus (four immunotypes), coronavirus (at least three immunotypes), and adenovirus (47 immunotypes) (Chap. 194). Respiratory syncytial virus (RSV), a well-established pathogen in pediatric populations, is also a recognized cause of significant disease in elderly and immunocompromised individuals. A host of additional viruses, including some viruses not typically associated with URIs (e.g., enteroviruses, rubella virus,

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and varicella-zoster virus), account for a small percentage of cases in adults each year. Although new diagnostic modalities (e.g., nasopharyngeal swab for polymerase chain reaction) can assign a viral etiology, there are few specific treatment options, and no pathogen is identified in a substantial proportion of cases. A specific diagnostic workup beyond a clinical diagnosis is generally unnecessary in an otherwise healthy adult.

susceptible to infection with a variety of pathogens, including viruses, bacteria, and, rarely, fungi. Sinusitis affects a tremendous proportion of the population, accounts for millions of visits to primary care physicians each year, and is the fifth leading diagnosis for which antibiotics are prescribed. It typically is classified by duration of illness (acute vs. chronic); by etiology (infectious vs. noninfectious); and, when infectious, by the offending pathogen type (viral, bacterial, or fungal).

■■CLINICAL MANIFESTATIONS

■■ACUTE RHINOSINUSITIS

Nonspecific Upper Respiratory Infections Antibiotics have no role in the treatment of uncomplicated nonspecific URI, and their misuse facilitates the emergence of antimicrobial resistance; in healthy volunteers, a single course of a commonly prescribed antibiotic like azithromycin can result in macrolide resistance in oral streptococci many months later. In the absence of clinical evidence of bacterial infection, treatment remains entirely symptom based, with use of decongestants and nonsteroidal antiinflammatory drugs. Clinical trials of zinc, vitamin C, echinacea, and other alternative remedies have revealed no consistent benefit in the treatment of nonspecific URI.

INFECTIONS OF THE SINUS

Rhinosinusitis refers to an inflammatory condition involving the nasal sinuses. Although most cases of sinusitis involve more than one sinus, the maxillary sinus is most commonly involved; next, in order of frequency, are the ethmoid, frontal, and sphenoid sinuses. Each sinus is lined with a respiratory epithelium that produces mucus, which is transported out by ciliary action through the sinus ostium and into the nasal cavity. Normally, mucus does not accumulate in the sinuses, which remain mostly sterile despite their adjacency to the bacterium-filled nasal passages. When the sinus ostia are obstructed or when ciliary clearance is impaired or absent, the secretions can be retained, producing the typical signs and symptoms of sinusitis. As these secretions accumulate with obstruction, they become more

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Etiology  The ostial obstruction in rhinosinusitis can arise from both infectious and noninfectious causes. Noninfectious etiologies include allergic rhinitis (with either mucosal edema or polyp obstruction), barotrauma (e.g., from deep-sea diving or air travel), and exposure to chemical irritants. Obstruction can also occur with nasal and sinus tumors (e.g., squamous cell carcinoma) or granulomatous diseases (e.g., granulomatosis with polyangiitis, rhinoscleroma), and conditions leading to altered mucus content (e.g., cystic fibrosis) can cause sinusitis through impaired mucus clearance. In intensive care units, nasotracheal intubation and nasogastric tubes are major risk factors for nosocomial sinusitis. Viral rhinosinusitis is far more common than bacterial sinusitis, although relatively few studies have sampled sinus aspirates for the presence of different viruses. In the studies that have done so, the viruses most commonly isolated—both alone and with bacteria—have been rhinovirus, parainfluenza virus, and influenza virus. Bacterial causes of sinusitis have been better described. Among communityacquired cases, S. pneumoniae and nontypable Haemophilus influenzae are the most common pathogens, accounting for 50–60% of cases. Moraxella catarrhalis causes disease in a significant percentage (20%) of children but a lesser percentage of adults. Other streptococcal species and Staphylococcus aureus cause only a small percentage of cases, although there is increasing concern about methicillin-resistant S. aureus (MRSA) as an emerging cause. It is difficult to assess whether a cultured bacterium represents a true infecting organism, an insufficiently deep sample (which would not be expected to be sterile), or—especially in the case of previous sinus surgeries—a colonizing organism. Anaerobes occasionally are found in association with infections of the roots of premolar teeth that spread to the adjacent maxillary sinuses. The role of atypical organisms like Chlamydia pneumoniae and Mycoplasma pneumoniae in the pathogenesis of acute sinusitis is unclear. Nosocomial cases commonly are associated with bacteria prevalent in the hospital environment, including S. aureus, Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, and Enterobacter species. Often, these infections are polymicrobial and can involve organisms that are highly resistant to numerous antibiotics. Fungi also are established causes of sinusitis, although most acute cases affect immunocompromised patients and represent invasive, life-threatening infections. The best-known example is rhinocerebral mucormycosis caused by fungi of the order Mucorales, which includes Rhizopus, Rhizomucor, Mucor, Lichtheimia (formerly Mycocladus, formerly Absidia), and Cunninghamella (Chap. 213). These infections classically occur in diabetic patients with ketoacidosis but can also develop in transplant recipients, patients with hematologic malignancies, and patients receiving chronic glucocorticoid or deferoxamine therapy. Other hyaline molds, such as Aspergillus and Fusarium species, also are occasional causes of this disease.

Sore Throat, Earache, and Upper Respiratory Symptoms

TREATMENT

Acute rhinosinusitis—defined as sinusitis of 10–14 days in children) accompanied by the three cardinal signs of purulent nasal discharge, nasal obstruction, and facial pain (Table 31-1). The fact that, even among patients who meet these criteria, only 40–50% have true bacterial sinusitis prompts some authorities to favor 14 days of symptoms before considering treatment. The use of CT or sinus radiography is not recommended for acute disease, particularly early in the course of illness (i.e., at 10 d or Severe symptoms of any duration, including unilateral/focal facial swelling or tooth pain

TREATMENT RECOMMENDATIONSa Initial therapy: Amoxicillin/clavulanate, 500/125 mg PO tid or 875/125 mg PO bidb Penicillin allergy: Doxycycline, 100 mg PO bid; or An antipneumococcal fluoroquinolone (e.g., moxifloxacin, 400 mg/d PO daily)c Exposure to antibiotics within 30 d or >30% prevalence of penicillin-resistant Streptococcus pneumoniae: Amoxicillin/clavulanate (extended release), 2000/125 mg PO bid; or Doxycycline, 100 mg PO bid; or An antipneumococcal fluoroquinolone (e.g., moxifloxacin, 400 mg PO daily)c Recent treatment failure: Amoxicillin/clavulanate (extended release), 2000 mg PO bid; or An antipneumococcal fluoroquinolone (e.g., moxifloxacin, 400 mg PO daily)c

a The duration of therapy is 5–7 days if symptoms improve within the first few days of treatment but can be up to 7–10 days, with appropriate follow-up. Severe disease may warrant IV antibiotics and consideration of hospital admission. b In areas where the prevalence of antibiotic resistance is low, amoxicillin can be considered as initial therapy in patients without recent antibiotic exposure. c Fluoroquinolones carry a risk of tendinitis and neuropathy and should be used only if other options are not reasonable, with consideration of risks and benefits.

the sinus microbiome is augmented by molecular techniques, the hope is for an even more tailored treatment regimen.

TREATMENT

Acute Rhinosinusitis Most patients with a clinical diagnosis of acute rhinosinusitis improve without antibiotic therapy. The preferred initial approach in patients with mild to moderate symptoms of short duration is therapy aimed at symptom relief and facilitation of sinus drainage, such as with oral and topical decongestants, nasal saline lavage, and—at least in patients with a history of chronic sinusitis or allergies—nasal glucocorticoids. Newer studies have cast doubt on the role of antibiotics and nasal glucocorticoids in acute rhinosinusitis. In one notable double-blind, randomized, placebo-controlled trial, neither antibiotics nor topical glucocorticoids had a significant impact on cure in the study population of patients, the majority of whom had had symptoms for 12 weeks. This illness is most commonly associated with either bacteria or fungi, and clinical cure in most cases is very difficult. Many patients have undergone treatment with repeated courses of antibacterial agents and multiple sinus surgeries, increasing their risk of colonization with antibiotic-resistant pathogens and of surgical complications. These patients often have high rates of morbidity, sometimes over many years. In chronic bacterial sinusitis, infection is thought to be due to the impairment of mucociliary clearance from repeated infections rather than to persistent bacterial infection. The pathogenesis of this condition, however, is poorly understood. The role of biofilms in such chronic infections continues to be explored, including the contribution that low-virulence pathogens may play in this complex, interacting milieu. Although certain conditions (e.g., cystic fibrosis) can predispose patients to chronic bacterial sinusitis, most patients with chronic rhinosinusitis do not have obvious underlying conditions that result in the obstruction of sinus drainage, the impairment of ciliary action, or immune dysfunction. Patients experience constant nasal congestion and sinus pressure, with intermittent periods of greater severity, which may persist for years. CT can be helpful in determining the extent of disease, detecting an underlying anatomic defect or obstructing process (e.g., a polyp), and assessing the response to therapy. Management should involve an otolaryngologist to conduct endoscopic examinations and obtain tissue samples for histologic examination and culture. An endoscopy-derived culture not only has a higher yield but also allows direct visualization for abnormal anatomy. Chronic fungal sinusitis is a disease of immunocompetent hosts and is usually noninvasive, although slowly progressive invasive disease is sometimes seen. Noninvasive disease, which typically is associated with hyaline molds such as Aspergillus species and dematiaceous molds such as Curvularia or Bipolaris species, can present as a number of different scenarios. In mild, indolent disease, which usually occurs in the setting of repeated failures of antibacterial therapy, only nonspecific mucosal changes may be seen on sinus CT. Although there is some controversy on this point, endoscopic surgery is usually curative in these cases, with no need for antifungal therapy. Another form of disease presents as long-standing, often unilateral symptoms and opacification of a single sinus on imaging studies as a result of a mycetoma (fungus ball) within the sinus. Treatment for this condition also is surgical, although systemic antifungal therapy may be warranted in the rare case in which bony erosion occurs. A third form of disease, known as allergic fungal sinusitis, is seen in patients with a history of nasal polyposis and asthma, who often have had multiple sinus surgeries. Patients with this condition produce a thick, eosinophil-laden mucus with the consistency of peanut butter that contains sparse fungal hyphae on histologic examination. These patients often present with pansinusitis.

intranasal glucocorticoids; and mechanical irrigation of the sinus with sterile saline solution. When this management approach fails, sinus surgery may be indicated and sometimes provides significant, albeit short-term, alleviation. Treatment of chronic fungal sinusitis consists of surgical removal of impacted mucus. Recurrence, unfortunately, is common.

CHAPTER 31

complications such as abscess and orbital involvement. Immunocompromised patients with acute invasive fungal sinusitis usually require extensive surgical debridement and treatment with IV antifungal agents active against fungal hyphal forms, such as amphotericin B. Specific therapy should be individualized according to the fungal species and its susceptibilities as well as the individual patient’s characteristics. Treatment of nosocomial sinusitis should begin with broadspectrum antibiotics to cover common and often resistant pathogens such as S. aureus and gram-negative bacilli. Therapy then should be tailored to the results of culture and susceptibility testing of sinus aspirates.

Perichondritis  Perichondritis, an infection of the perichondrium of the auricular cartilage, typically follows local trauma (e.g., piercings, burns, or lacerations). Occasionally, when the infection spreads down to the cartilage of the pinna itself, patients may develop chondritis. The infection may closely resemble auricular cellulitis, with erythema, swelling, and extreme tenderness of the pinna, although the lobule is less often involved in perichondritis. The most common pathogens are P. aeruginosa and S. aureus, although other gram-negative and gram-positive organisms occasionally are involved. Treatment consists of systemic antibiotics active against both P. aeruginosa and S. aureus. An antipseudomonal penicillin (e.g., piperacillin) or a combination of a penicillinase-resistant penicillin and an antipseudomonal quinolone (e.g., nafcillin plus ciprofloxacin) is typically used. Incision and drainage may be helpful for culture and for resolution of infection, which often takes weeks. When perichondritis fails to respond to adequate antimicrobial therapy, clinicians should consider a noninfectious inflammatory etiology such as relapsing polychondritis. Otitis Externa  The term otitis externa refers to a collection of dis-

eases involving primarily the auditory meatus. Otitis externa usually results from a combination of heat and retained moisture, with desquamation and maceration of the epithelium of the outer ear canal. The disease exists in several forms: localized, diffuse, chronic, and invasive. All forms are predominantly bacterial in origin, with P. aeruginosa and S. aureus the most common pathogens. Acute localized otitis externa (furunculosis) can develop in the outer third of the ear canal, where skin overlies cartilage and hair follicles are numerous. As in furunculosis elsewhere on the body, S. aureus is the usual pathogen, and treatment typically consists of an oral antistaphylococcal penicillin (e.g., dicloxacillin or cephalexin), with incision and drainage in cases of abscess formation.

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PART 2 Cardinal Manifestations and Presentation of Diseases

Acute diffuse otitis externa is also known as swimmer’s ear, although it can develop in patients who have not recently been swimming. Heat, humidity, and the loss of protective cerumen lead to excessive moisture and elevation of the pH in the ear canal, which in turn lead to skin maceration and irritation. Infection may then follow; the predominant pathogen is P. aeruginosa, although other bacteria—and rarely yeasts—have been recovered from patients with this condition. The illness often starts with itching and progresses to severe pain, which is usually elicited by manipulation of the pinna or tragus. The onset of pain is generally accompanied by the development of an erythematous, swollen ear canal, often with scant white, clumpy discharge. Treatment consists of cleansing the canal to remove debris and enhance the activity of topical therapeutic agents—usually hypertonic saline or mixtures of alcohol and acetic acid. Inflammation can also be decreased by adding glucocorticoids to the treatment regimen or by using Burow’s solution (aluminum acetate in water). Antibiotics are most effective when given topically. Otic mixtures provide adequate pathogen coverage; these preparations usually combine neomycin with polymyxin, with or without glucocorticoids. Systemic antimicrobial agents typically are reserved for severe disease or infections in immunocompromised hosts. Chronic otitis externa is caused primarily by repeated local irritation, most commonly arising from persistent drainage from a chronic middle-ear infection. Other causes of repeated irritation, such as insertion of cotton swabs or other foreign objects into the ear canal, can lead to this condition, as can rare chronic infections such as syphilis, tuberculosis, and leprosy. Chronic otitis externa typically presents as erythematous, scaling dermatitis in which the predominant symptom is pruritus rather than pain; this condition must be differentiated from several others that produce a similar clinical picture, such as atopic dermatitis, seborrheic dermatitis, psoriasis, and dermatomycosis. Therapy consists of identifying and treating or removing the offending process, although successful resolution is frequently difficult. Invasive otitis externa, also known as malignant or necrotizing otitis externa, is an aggressive and potentially life-threatening disease that occurs predominantly in elderly diabetic patients and other immunocompromised persons. The disease begins in the external canal as a soft-tissue infection that progresses slowly over weeks to months and often is difficult to distinguish from a severe case of chronic otitis externa because of the presence of purulent otorrhea and an erythematous swollen ear and external canal. Severe, deep-seated otalgia, frequently out of proportion to findings on examination, is often noted and can help differentiate invasive from chronic otitis externa. The characteristic finding on examination is granulation tissue in the posteroinferior wall of the external canal, near the junction of bone and cartilage. If left unchecked, the infection can migrate to the base of the skull (resulting in skull-base osteomyelitis) and onward to the meninges and brain, with a high mortality rate. Cranial nerve involvement is seen occasionally, with the facial nerve usually affected first and most often. Thrombosis of the sigmoid sinus can occur if the infection extends to the area. CT, which can reveal osseous erosion of the temporal bone and skull base, can be used to help determine the extent of disease, as can gallium and technetium-99 scintigraphy studies. P. aeruginosa is by far the most common offender, although S. aureus, Staphylococcus epidermidis, Aspergillus, Actinomyces, and some gram-negative bacteria also have been associated with this disease. In all cases, the external ear canal should be cleansed and a biopsy specimen of the granulation tissue within the canal (or of deeper tissues) obtained for culture of the offending organism. IV antibiotic therapy should be given for a prolonged course (6–8 weeks) and directed specifically toward the recovered pathogen. For P. aeruginosa, the regimen typically includes an antipseudomonal penicillin or cephalosporin (e.g., piperacillin or cefepime), sometimes with an aminoglycoside or a fluoroquinolone, the latter of which can even be administered orally given its excellent bioavailability. In addition, antibiotic drops containing an agent active against Pseudomonas (e.g., ciprofloxacin) are usually prescribed and are combined with glucocorticoids to reduce inflammation. Cases of invasive Pseudomonas otitis externa recognized in the early stages can sometimes be treated with oral and otic

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fluoroquinolones alone, albeit with close follow-up. Extensive surgical debridement, once an important component of the treatment approach, is now rarely indicated. In necrotizing otitis externa, recurrence is documented up to 20% of the time. Aggressive glycemic control in diabetics is important not only for effective treatment but also for prevention of recurrence. The role of hyperbaric oxygen has not been clearly established.

■■INFECTIONS OF MIDDLE-EAR STRUCTURES

Otitis media is an inflammatory condition of the middle ear that results from dysfunction of the eustachian tube in association with a number of illnesses, including URIs and chronic rhinosinusitis. The inflammatory response in these conditions leads to the development of a sterile transudate within the middle-ear and mastoid cavities. Infection may occur if bacteria or viruses from the nasopharynx contaminate this fluid, producing an acute (or sometimes chronic) illness.

Acute Otitis Media  Acute otitis media results when pathogens

from the nasopharynx are introduced into the inflammatory fluid collected in the middle ear (e.g., by nose blowing during a URI). Pathogenic proliferation in this space leads to the development of the typical signs and symptoms of acute middle-ear infection. The diagnosis of acute otitis media requires the demonstration of fluid in the middle ear (with tympanic membrane [TM] immobility) and the accompanying signs or symptoms of local or systemic illness (Table 31-2). Acute otitis media typically follows a viral URI. The causative viruses (most commonly RSV, influenza virus, rhinovirus, and enterovirus) can themselves cause subsequent acute otitis media; more often, they predispose the patient to bacterial otitis media. Studies using tympanocentesis have consistently found S. pneumoniae to be the most important bacterial cause, isolated in up to 35% of cases. H. influenzae (nontypable strains) and M. catarrhalis also are common bacterial causes of acute otitis media, and concern is increasing with MRSA as an emerging etiologic agent. Viruses, such as those mentioned above, have been recovered either alone or with bacteria in 17–40% of cases.

ETIOLOGY 

Fluid in the middle ear is typically demonstrated or confirmed with pneumatic otoscopy. In the absence of fluid, the TM moves visibly with the application of positive and negative pressure, but this movement is dampened when fluid is present. With bacterial infection, the TM can also be erythematous, bulging, or retracted and occasionally can perforate spontaneously. The signs and symptoms accompanying infection can be local or systemic, including otalgia, otorrhea, diminished hearing, and fever. Erythema of the TM is often evident but is nonspecific as it frequently is seen in association with inflammation of the upper respiratory mucosa. Other signs and symptoms occasionally reported include vertigo, nystagmus, and tinnitus.

CLINICAL MANIFESTATIONS 

TREATMENT

Acute Otitis Media There has been considerable debate on the usefulness of antibiotics for the treatment of acute otitis media. A higher proportion of treated than untreated patients are free of illness 3–5 days after diagnosis. The difficulty of predicting which patients will benefit from antibiotic therapy has led to different approaches. In the Netherlands, for instance, physicians typically manage acute otitis media with initial observation, administering anti-inflammatory agents for aggressive pain management and reserving antibiotics for high-risk patients, patients with complicated disease, or patients whose condition does not improve after 48–72 h. In contrast, many experts in the United States continue to recommend antibiotic therapy for children 2 years of age and for mild to moderate disease without middle-ear effusion in children 6 months to 2 years of age. Treatment

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TABLE 31-2  Guidelines for the Diagnosis and Treatment of Acute Otitis Media ILLNESS SEVERITY Mild to moderate  

TREATMENT RECOMMENDATIONS Observation alone (deferring antibiotic therapy for 48–72 h and limiting management to symptom relief) 2 yrs with bilateral disease, TM perforation, high fever, Amoxicillin, 90 mg/kg qd (up to 2 g) PO in divided doses (bid), plus clavulanate, immunocompromise, emesis 6.4 mg/kg qd PO in divided doses (bid); or Ceftriaxone, 50 mg/kg IV/IM qd for 3 d; or Clindamycin, 30–40 mg/kg qd PO in divided doses (tid) As above, with temperature ≥39.0°C (≥102°F); or Initial therapya: Moderate to severe otalgia Amoxicillin, 90 mg/kg qd (up to 2 g) PO in divided doses (bid), plus clavulanate, 6.4 mg/kg qd PO in divided doses (bid); or Ceftriaxone, 50 mg/kg IV/IM qd for 3 d Exposure to antibiotics within 30 d or recent treatment failurea,b: Ceftriaxone, 50 mg/kg IV/IM qd for 3 d; or Clindamycin, 30–40 mg/kg qd PO in divided doses (tid); or Consider tympanocentesis with culture

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Duration (unless otherwise specified): 10 days for patients 2 yrs or 6 mo to 2 yrs without middle-ear effusion

Chronic Otitis Media  Chronic suppurative otitis media is characterized by persistent or recurrent purulent otorrhea in the setting of TM perforation. Usually, there is also some degree of conductive hearing loss. This condition can be categorized as active or inactive. Inactive disease is characterized by a central perforation of the TM, which allows drainage of purulent fluid from the middle ear. When the perforation is more peripheral, squamous epithelium from the auditory canal may invade the middle ear through the perforation, forming a mass of keratinaceous debris (cholesteatoma) at the site of invasion. This mass can enlarge and has the potential to erode bone and promote further infection, which can lead to meningitis, brain abscess, or paralysis of cranial nerve VII. Treatment of chronic active otitis media is surgical; mastoidectomy, myringoplasty, and tympanoplasty can be performed as outpatient surgical procedures, with an overall success rate of ~80%. Chronic inactive otitis media is more difficult to cure, usually requiring repeated courses of topical antibiotic drops during periods of drainage. Systemic antibiotics may offer better cure rates, but their role in the treatment of this condition remains unclear. Mastoiditis  Acute mastoiditis was relatively common among children before the introduction of antibiotics. Because the mastoid air

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for ambulatory care visits by both adults and children. Although sore throat is a symptom in many noninfectious illnesses as well, the overwhelming majority of patients with a new sore throat have acute pharyngitis of viral or bacterial etiology.

■■ACUTE PHARYNGITIS

PART 2

Millions of visits to primary care providers each year are for sore throat; the majority of cases of acute pharyngitis are caused by typical respiratory viruses. The most important source of concern is infection with group A β-hemolytic Streptococcus (S. pyogenes), which is associated with acute glomerulonephritis and acute rheumatic fever. The risk of rheumatic fever can be reduced by timely penicillin therapy.

Cardinal Manifestations and Presentation of Diseases

FIGURE 31-1  Acute mastoiditis. Axial CT image shows an acute fluid collection within the mastoid air cells on the left.

cells connect with the middle ear, the process of fluid collection and infection is usually the same in the mastoid as in the middle ear. Early and frequent treatment of acute otitis media is most likely the reason that the incidence of acute mastoiditis has declined to only 1.2–2.0 cases per 100,000 person-years in countries with high prescribing rates for acute otitis media. In countries such as the Netherlands, where antibiotics are used sparingly for acute otitis media, the incidence rate of acute mastoiditis is roughly twice that in countries like the United States. However, neighboring Denmark has a rate of acute mastoiditis similar to that in the Netherlands but an antibiotic-prescribing rate for acute otitis media more similar to that in the United States. In typical acute mastoiditis, purulent exudate collects in the mastoid air cells (Fig. 31-1), producing pressure that may result in erosion of the surrounding bone and formation of abscess-like cavities that are usually evident on CT. Patients typically present with pain, erythema, and swelling of the mastoid process along with displacement of the pinna, usually in conjunction with the typical signs and symptoms of acute middle-ear infection. Rarely, patients can develop severe complications if the infection tracks under the periosteum of the temporal bone to cause a subperiosteal abscess, erodes through the mastoid tip to cause a deep neck abscess, or extends posteriorly to cause septic thrombosis of the lateral sinus. Purulent fluid should be cultured whenever possible to help guide antimicrobial therapy. Initial empirical therapy usually is directed against the typical organisms associated with acute otitis media, such as S. pneumoniae, H. influenzae, and M. catarrhalis. Patients with more severe or prolonged courses of illness should be treated for infection with S. aureus and gram-negative bacilli (including Pseudomonas). Broad-spectrum empirical therapy should be narrowed once culture results become available. Most patients can be treated conservatively with IV antibiotics; surgery (cortical mastoidectomy) is reserved for complicated cases and those in which conservative treatment has failed.

INFECTIONS OF THE PHARYNX AND ORAL CAVITY

Oropharyngeal infections range from mild, self-limited viral illnesses to serious, life-threatening bacterial infections. The most common presenting symptom is sore throat—one of the most common reasons

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Etiology  A wide variety of organisms cause acute pharyngitis. The relative importance of the different pathogens can only be estimated, since a significant proportion of cases (~30%) have no identified cause. Together, respiratory viruses are the most common identifiable cause of acute pharyngitis, with rhinoviruses and coronaviruses accounting for large proportions of cases (~20% and at least 5%, respectively). Influenza virus, parainfluenza virus, and adenovirus also account for a measurable share of cases, with the former two more seasonal and the latter as part of the more clinically severe syndrome of pharyngoconjunctival fever. Other important but less common viral causes include herpes simplex virus (HSV) types 1 and 2, coxsackievirus A, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Acute HIV infection can present as acute pharyngitis and should always be considered in at-risk populations. Acute bacterial pharyngitis is typically caused by S. pyogenes, which accounts for ~5–15% of all cases of acute pharyngitis in adults; rates vary with the season and with utilization of the health care system. Group A streptococcal pharyngitis is primarily a disease of children aged 5–15 years; it is uncommon among children 90% in controlled settings. Since the sensitivities achieved in routine clinical practice are often lower, several medical and professional societies continue to recommend that all negative rapid antigen-detection tests in children be confirmed by a throat culture to limit transmission and complications of illness caused by group A streptococci. The Centers for Disease Control and Prevention, the Infectious Diseases Society of America, and the American Academy of Family Physicians do not recommend backup culture when adults have negative results from a highly sensitive rapid antigen-detection test, however, because of the lower prevalence and smaller benefit in this age group. Cultures and rapid diagnostic tests for other causes of acute pharyngitis, such as influenza virus, adenovirus, HSV, EBV, CMV, and M. pneumoniae, are available in many locations and can be used when these pathogens are suspected. The diagnosis of acute EBV infection depends primarily on the detection of antibodies to the virus with a heterophile agglutination assay (monospot slide test) or enzyme-linked immunosorbent assay. Testing for HIV, ideally through a combination antigen/antibody method, should be performed when acute primary HIV infection is suspected. If other bacterial causes are suspected (particularly N. gonorrhoeae, C. diphtheriae, or Y. enterocolitica), specific cultures should be requested since these organisms may be missed on routine throat swab culture.

TREATMENT

Pharyngitis Antibiotic treatment of pharyngitis due to S. pyogenes confers numerous benefits, including a decrease in the risk of rheumatic fever—the primary focus of treatment. The magnitude of this benefit is fairly

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Diagnosis  The primary goal of diagnostic testing is to separate

small, since rheumatic fever is now a rare disease, even among untreated patients. Nevertheless, when therapy is started within 48 h of illness onset, symptom duration is decreased modestly. An additional benefit of therapy is the potential to reduce the transmission of streptococcal pharyngitis, particularly in areas of overcrowding or close contact. Antibiotic therapy for acute pharyngitis is therefore recommended in cases in which S. pyogenes is confirmed as the etiologic agent by rapid antigen-detection test or throat swab culture. Otherwise, antibiotics should be given in routine cases only when another bacterial cause has been identified. Effective therapy for streptococcal pharyngitis consists of either a single dose of IM benzathine penicillin or a full 10-day course of oral penicillin (Fig. 31-2). Azithromycin can be used in place of penicillin, although its potential utility is waning and its use in some parts of the world (particularly Europe) is prohibited as a result of resistance among S. pyogenes strains. Broader-spectrum (and often more expensive) antibiotics also are active against streptococci but offer no greater efficacy than the agents mentioned above. Testing for cure is unnecessary and may reveal only chronic colonization. There is no evidence to support antibiotic treatment of group C or G streptococcal pharyngitis or pharyngitis in which mycoplasmas or chlamydiae have been recovered. Cultures can be of benefit because F. necrophorum, an increasingly common cause of bacterial pharyngitis in young adults, is not covered by macrolide therapy. Long-term penicillin prophylaxis (benzathine penicillin G, 1.2 million units IM every 3–4 weeks; or penicillin VK, 250 mg PO twice daily) is indicated for patients at risk of recurrent rheumatic fever in order to prevent what could be catastrophic sequelae of recurrent streptococcal pharyngitis. Antibiotic shortages, sometimes the result of manufacturing difficulties or delays, natural disasters, and regulatory or other issues, can preclude the use of the optimal antibiotic. These shortages can be regional, national, or international. Communication with pharmacists and the use of antibiotic stewardship teams can help mitigate the effects of shortages, yield recommendations for the use of alternative agents, and prevent delays in treatment that can affect patients’ access to antibiotics. Treatment of viral pharyngitis is entirely symptom-based except in infection with influenza virus or HSV. For influenza, the armamentarium includes the adamantanes amantadine and rimantadine and the neuraminidase inhibitors oseltamivir and zanamivir. Administration of all these agents needs to be started within 48 h of symptom onset to reduce illness duration meaningfully. Among these agents, only oseltamivir and zanamivir are active against both influenza A and influenza B and therefore can be used when local patterns of infection and antiviral resistance are unknown. Oropharyngeal HSV infection sometimes responds to treatment with antiviral agents such as acyclovir, although these drugs are often reserved for immunosuppressed patients.

CHAPTER 31

pharyngeal inflammation and exudate, but the presence of vesicles and shallow ulcers on the palate can help differentiate the two diseases. This HSV syndrome is distinct from pharyngitis caused by coxsackievirus (herpangina), which is associated with small vesicles that develop on the soft palate and uvula and then rupture to form shallow white ulcers. Acute pharyngitis coupled with fever, fatigue, generalized lymphadenopathy, and (on occasion) splenomegaly is characteristic of infectious mononucleosis due to EBV or CMV. Acute primary infection with HIV is frequently associated with fever and acute pharyngitis as well as with myalgias, arthralgias, malaise, and occasionally a nonpruritic maculopapular rash, which may be followed by lymphadenopathy and mucosal ulcerations without exudate. The clinical features of acute pharyngitis caused by streptococci of groups A, C, and G are similar, ranging from a relatively mild illness without many accompanying symptoms to clinically severe cases with profound pharyngeal pain, fever, chills, and abdominal pain. A hyperemic pharyngeal membrane with tonsillar hypertrophy and exudate is usually seen, along with tender anterior cervical adenopathy. Coryzal manifestations, including cough, are typically absent; when present, they suggest a viral etiology. Strains of S. pyogenes that generate erythrogenic toxin can also produce scarlet fever characterized by an erythematous rash and strawberry tongue. The other types of acute bacterial pharyngitis (e.g., gonococcal, diphtherial, and yersinial) often present as exudative pharyngitis with or without other clinical features. Their etiologies are often suggested only by the clinical history.

Complications  Although rheumatic fever is the best-known com-

plication of acute streptococcal pharyngitis, the risk of its following acute infection remains quite low. Other complications include acute glomerulonephritis and numerous suppurative conditions, such as peritonsillar abscess (quinsy), otitis media, mastoiditis, sinusitis, bacteremia, and pneumonia—all of which occur at low rates. Although antibiotic treatment of acute streptococcal pharyngitis can prevent the development of rheumatic fever, there is no evidence that it can prevent acute glomerulonephritis. Some evidence supports antibiotic use to prevent the suppurative complications of streptococcal pharyngitis, particularly peritonsillar abscess, which can also involve oral anaerobes such as Fusobacterium. Abscesses usually are accompanied by severe pharyngeal pain, dysphagia, fever, and dehydration; in addition, medial displacement of the tonsil and lateral displacement of the uvula are often evident on examination. Although early use of IV antibiotics (e.g., clindamycin, penicillin G with metronidazole) may eliminate the need for surgical drainage in some cases, treatment typically involves needle aspiration or incision and drainage.

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C. albicans. Thrush occurs predominantly in neonates, immunocompromised Acute pharyngitis patients (especially those with AIDS), and in adults recipients of prolonged antibiotic or glucocorticoid therapy. In addition to sore throat, patients often report a burning tongue or abnormal taste, and physical examination reveals friable white or Yes Symptoms No streptococcal gray plaques on the gingiva, tongue, and consistent with viral testing oral mucosa, often with underlying eryURI? thema. Treatment, which usually consists of a topical antifungal (nystatin or clotrimazole) or oral fluconazole, is typically No No successful. In the uncommon cases of fluconazole-refractory thrush that are seen in some patients with HIV/AIDS or in Yes Risk factors for HIV, patients with resistant organisms that can Test accordingly gonorrhea? sometimes complicate the treatment of recurrent oral candidiasis, other therapeutic options include oral voriconazole, an IV echinocandin (caspofungin, micafunNo gin, or anidulafungin), or amphotericin B deoxycholate, if needed. In these cases, therapy based on culture and susceptibilNegative* Group A Strep Symptomatic ity test results is ideal. RADT or throat management Vincent angina, also known as acute culture necrotizing ulcerative gingivitis or trench mouth, is a unique and dramatic form of gingivitis characterized by painful, Positive inflamed gingiva with ulcerations of the interdental papillae that bleed easily. Since oral anaerobes are the cause, Yes patients typically have halitosis and frePenicillin allergy? quently present with fever, malaise, and lymphadenopathy. Treatment consists of debridement and oral administration of penicillin plus metronidazole, with No clindamycin or doxycycline alone as an • Penicillin G 1.2 million • Cephalexin 500 mg orally alternative. units IM × 1, or BID or TID (only if nonLudwig angina is a rapidly progressive, anaphylactic penicillin potentially fulminant form of cellulitis allergy), or • Penicillin VK 250 mg that involves the bilateral sublingual and orally QID, or 500 mg submandibular spaces and that typically † 500 mg • Azithromycin orally BID, or originates from an infected or recently orally QD × 5 days, or extracted tooth, most commonly a lower • Amoxicillin 500 mg second or third molar. Improved dental • Clindamycin 300 mg orally BID care has reduced the incidence of this orally TID disorder substantially. Infection in these areas leads to dysphagia, odynophagia, NOTE: All treatment durations are for 10 days with appropriate follow-up, and “woody” edema in the sublingual unless otherwise specified. region, forcing the tongue up and back with the potential for airway obstruc*Confirmation of a negative rapid antigen-detection test by a throat culture is not required in adults. tion. Fever, dysarthria, and drooling also †Macrolides do not treat F. necrophorum, a cause of pharyngitis in young adults (see text). may occur, and patients may speak in Abbreviations: URI, upper respiratory infection; RADT, rapid antigen detection test a “hot potato” voice. Intubation or tracheostomy may be necessary to secure FIGURE 31-2  Algorithm for the diagnosis and treatment of acute pharyngitis. the airway, as asphyxiation is the most common cause of death. Patients should be admitted to the hospital and closely monitored during treatment ■■ORAL INFECTIONS Aside from periodontal diseases such as gingivitis, infections of the with IV antibiotics directed against streptococci and oral anaerobes. oral cavity most commonly involve HSV or Candida species. In addition Recommended agents include ampicillin/sulbactam, clindamycin, or to causing painful cold sores on the lips, HSV can infect the tongue and high-dose penicillin plus metronidazole. Septic thrombophlebitis of the internal jugular vein (Lemierre disease) buccal mucosa, causing the formation of irritating vesicles. Although topical antiviral agents (e.g., acyclovir and penciclovir) can be used is a rare anaerobic oropharyngeal infection caused predominantly by externally for cold sores, with possible benefit, oral or IV acyclovir F. necrophorum. The illness typically starts as a sore throat (most comis often needed for primary infections, extensive oral infections, and monly in adolescents and young adults), which may present as exudainfections in immunocompromised patients. Oropharyngeal candid- tive tonsillitis or peritonsillar abscess. Infection of the deep pharyngeal iasis (thrush) is caused by a variety of Candida species, most often tissue allows organisms to drain into the lateral pharyngeal space,

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■■LARYNGITIS

Laryngitis is defined as any inflammatory process involving the larynx and can be caused by a variety of infectious and noninfectious processes. The vast majority of laryngitis cases seen in clinical practice in developed countries are acute. Acute laryngitis is a common syndrome caused predominantly by the same viruses responsible for many other URIs. In fact, most cases of acute laryngitis occur in the setting of a viral URI.

Etiology  Nearly all major respiratory viruses have been implicated in acute viral laryngitis, including rhinovirus, influenza virus, parainfluenza virus, adenovirus, coxsackievirus, coronavirus, and RSV. Acute laryngitis can also be associated with acute bacterial respiratory infections such as those caused by group A Streptococcus or C. diphtheriae (although diphtheria has been virtually eliminated in the United States). Another bacterial pathogen thought to play a role (albeit unclear) in the pathogenesis of acute laryngitis is M. catarrhalis, which has been recovered from nasopharyngeal cultures in a significant percentage of cases. Chronic laryngitis of infectious etiology is much less common in developed than in developing countries. Laryngitis due to Mycobacterium tuberculosis is often difficult to distinguish from laryngeal cancer, in part because of the frequent absence of signs, symptoms, and radiographic findings typical of pulmonary disease. Histoplasma and Blastomyces may cause laryngitis, often as a complication of systemic infection. Candida species can cause laryngitis as well, often in association with thrush or esophagitis and particularly in immunosuppressed patients. Rare cases of chronic laryngitis are due to Coccidioides and Cryptococcus. Clinical Manifestations  Laryngitis is characterized by hoarseness and also can be associated with reduced vocal pitch or aphonia. As acute laryngitis is caused primarily by respiratory viruses, these symptoms usually occur in association with other symptoms and signs of URI, including rhinorrhea, nasal congestion, cough, and sore throat. Direct laryngoscopy often reveals diffuse laryngeal erythema and edema, along with vascular engorgement of the vocal folds. In addition, chronic disease (e.g., tuberculous laryngitis) often includes mucosal nodules and ulcerations visible on laryngoscopy; these lesions are sometimes mistaken for laryngeal cancer.

TREATMENT

Laryngitis Acute laryngitis is usually treated with humidification and voice rest alone. Antibiotics are not recommended except when group A Streptococcus is cultured, in which case penicillin is the drug of choice. The choice of therapy for chronic laryngitis depends on the pathogen, whose identification usually requires biopsy with culture.

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217

■■CROUP

The term croup actually denotes a group of diseases collectively referred to as “croup syndrome,” all of which are acute and predominantly viral respiratory illnesses characterized by marked swelling of the subglottic region of the larynx. Croup primarily affects children 90%; in contrast, the annual incidence in adults has changed little since the introduction of Hib vaccine. Because of the danger of airway obstruction, acute epiglottitis constitutes a medical emergency, particularly in children, and prompt diagnosis and airway protection are of the utmost importance.

Etiology  After the introduction of the Hib vaccine in the mid-1980s, disease incidence among children in the United States declined dramatically. Nevertheless, lack of vaccination or vaccine failure has meant that many pediatric cases seen today are still due to Hib. In adults and (more recently) in children, a variety of other bacterial pathogens have been associated with epiglottitis, the most common being group A Streptococcus. Other pathogens—seen less frequently— include S. pneumoniae, Haemophilus parainfluenzae, and S. aureus (including MRSA). Viruses have not been established as causes of acute epiglottitis.

Sore Throat, Earache, and Upper Respiratory Symptoms

INFECTIONS OF THE LARYNX AND EPIGLOTTIS

Patients with laryngeal tuberculosis are highly contagious because of the large number of organisms that are easily aerosolized. These patients should be managed in the same way as patients with active pulmonary disease.

CHAPTER 31

which contains the carotid artery and internal jugular vein. Septic thrombophlebitis of the internal jugular vein can result, with associated pain, dysphagia, and unilateral neck swelling and stiffness. Sepsis usually occurs 3–10 days after the onset of sore throat and is often coupled with metastatic infection to the lung and other distant sites, with pulmonary abscess or empyema. Occasionally, the infection can extend along the carotid sheath and into the posterior mediastinum, resulting in mediastinitis, or it can erode into the carotid artery, with the early sign of repeated small bleeds into the mouth. The mortality rate from these invasive infections can be as high as 50%. Treatment consists of IV antibiotics (clindamycin or ampicillin/sulbactam) and surgical drainage of any purulent collections. The concomitant use of anticoagulants to prevent embolization remains controversial and is not typically advised; both the risks and the benefits of their use must be carefully considered.

Clinical Manifestations and Diagnosis  Epiglottitis typically

presents more acutely in young children than in adolescents or adults. On presentation, most children have had symptoms for 10 mmHg, the presence of COPD, acute asthma, or pericardial disease should be considered. During the general examination, signs of anemia (pale conjunctivae), cyanosis, and cirrhosis (spider angiomata, gynecomastia) should be sought. Examination of the chest should focus on symmetry of movement; percussion (dullness is indicative of pleural effusion; hyperresonance is a sign of

TABLE 33-2  Differential Diagnosis of Disease Processes Underlying Dyspnea POSSIBLE PRESENTING DYSPNEA SYMPTOMS Chest tightness, tachypnea, increased WOB, air hunger, inability to get a deep breath Air hunger, inability to get a deep breath

TYPE OF PROCESS Airways disease

EXAMPLE OF DISEASE PROCESS Asthma, COPD

 

Parenchymal disease

Interstitial lung diseasea

 

Chest wall disease

Kyphoscoliosis, Neuromuscular (NM) weakness

Pulmonary and cardiac

Pulmonary vasculature

Pulmonary Hypertension

Tachypnea

Cardiac

Left heart failure ---------------Pericardial disease

Chest tightness, air hunger

Other

Variable

Coronary artery disease, cardio-myopathyc _____________ Restrictive pericarditis; Cardiac tamponade Anemia Deconditioning Psychological

SYSTEM Pulmonary

POSSIBLE PHYSICAL FINDINGS Wheezing, accessory muscle use, exertional hypoxemia (especially with COPD) Dry end-inspiratory crackles, clubbing, exertional hypoxemia

POSSIBLE MECHANISMS UNDERLYING DYSPNEA Increased WOB, hypoxemia, hypercapnia, stimulation of pulmonary receptors

Elevated R heart pressures, exertional hypoxemia Elevated L heart pressures; wet crackles on lung examination; pulsus paradoxus (pericardial disease)

Increased respiratory drive, hypoxemia, stimulation of vascular receptors Increased WOB and drive, hypoxemia, stimulation of vascular and pulmonary receptors^

Variable

Metabo-receptors (anemia, poor fitness); chemoreceptors (anaerobic metabolism from poor fitness); some subjects may have increased sensitivity to hypercapnia

Increased WOB, increased respiratory drive, hypoxemia, hypercapnia, stimulation of pulmonary receptors Increased WOB, Decreased Increased WOB; stimulation inability to get a deep diaphragm excursion; ofpulmonary receptors (if breath atelectasis atelectasis is present)

Exertional breathlessness Poor fitness Anxiety

INITIAL DIAGNOSTIC STUDIES (AND POSSIBLE FINDINGS) Peak flow (reduced); Spirometry (OVD); CXR (hyper-inflation; loss of lung parenchyma in COPD) Spirometry and lung volumes (RVD); CXR and chest CT (interstitial lung disease) Spirometry and lung volumes (RVD); MIP and MEPs (reduced in NM weakness) Diffusion capacity (reduced); ECG; ECHO (to evaluate PA pressures)b Consider BNP testing in the acute setting; ECG, ECHO, may need stress testing and/or LHC

Hematocrit for anemia; exclude other causes

a Differential diagnosis of interstitial lung disease includes idiopathic pulmonary fibrosis, collagen vascular disease, drug or occupation-induced pneumonitis, lymphangitic spread of malignancy; processes that are more alveolar rather than interstitial in nature can also less commonly contribute to parenchymal lung disease underlying chronic dyspnea and include entities such as hypersensitivity pneumonitis, bronchiolitis obliterans organizing pneumonia, etc. bWould additionally consider these patients for CT angiography to evaluate for presence of thromboemboli, ventilation/perfusion scanning to evaluate for the presence of chronic thromboembolic disease, and right heart catheterization (RHC) to further evaluate pulmonary hypertension. cDiastolic dysfunction in the setting of a stiff left ventricle is often seen and contributes significantly to insidious dyspnea that can be difficult to treat. ^May stimulate metaboreceptors if cardiac output is sufficiently reduced to a result in a lactic acidosis.

Abbreviations: BNP, brain natriuretic peptide; COPD, chronic obstructive pulmonary disease; CT, computed tomography; CT angio, CT angiography; CXR, chest x-ray; ECHO, echocardiogram; ECG, electrocardiogram; LHC, left heart catheterization; MIP/MEP, maximal inspiratory and maximal expiratory pressures (obtained in the PFT laboratory); OVD, obstructive ventilatory defect; RVD, restrictive ventilatory defect; WOB, work of breathing.

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History and Physical Examination, plus: Walking oximetry Peak flow assessment

Diagnosis obtained?

Yes

Treat

No

Yes

Treat

No Further testing (“Phase 2”): Chest CT (consider angiography for thromboembolic disease) Lung Volumes, DLCO, tests of neuromuscular function Echocardiogram, Cardiac stress testing

Diagnosis obtained?

Yes

Treat

No Further testing (“Phase 3”): Consider Cardiopulmonary Exercise Testing (and subspecialty referral) FIGURE 33-2  Possible algorithm for the evaluation of the patient with dyspnea. As described in the text, the approach should begin with a detailed history and physical examination, followed by progressive testing and ultimately more invasive testing and subspecialty referral as is indicated to determine the underlying cause of dyspnea. (Adapted from NG Karnani et al: Am Fam Physician 71:1529, 2005.)

emphysema); and auscultation (wheezes, rhonchi, prolonged expiratory phase, and diminished breath sounds are clues to disorders of the airways; rales suggest interstitial edema or fibrosis). The cardiac examination should focus on signs of elevated right heart pressures (jugular venous distention, edema, accentuated pulmonic component to the second heart sound); left ventricular dysfunction (S3 and S4 gallops); and valvular disease (murmurs). When examining the abdomen with the patient in the supine position, the physician should note whether there is paradoxical movement of the abdomen as well as the presence of increased respiratory distress in the supine position: inward motion during inspiration is a sign of diaphragmatic weakness, and rounding of the abdomen during exhalation is suggestive of pulmonary edema. Clubbing of the digits may be an indication of interstitial pulmonary fibrosis or bronchiectasis, and joint swelling or deformation as well as changes consistent with Raynaud’s disease may be indicative of a collagen-vascular process that can be associated with pulmonary disease. Patients should be asked to walk under observation with oximetry in order to reproduce the symptoms. The patient should be examined during and at the end of exercise for new findings that were not present at rest (e.g., presence of wheezing), and for changes in oxygen saturation. CHEST IMAGING After the history elicitation and the physical examination, a chest radiograph should be obtained if the diagnosis remains elusive. The

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LABORATORY STUDIES Initial laboratory testing should include a hematocrit to exclude occult anemia as an underlying cause of reduced oxygen-carrying capacity contributing to dyspnea, and a basic metabolic panel may be helpful to exclude a significant underlying metabolic acidosis (and conversely, an elevated bicarbonate might point toward the possibility of carbon dioxide retention that might be seen in chronic respiratory failure—in such a setting, an arterial blood gas may provide useful additional information). Additional laboratory studies should include electrocardiography to seek evidence of ventricular hypertrophy and prior myocardial infarction and spirometry that can be diagnostic of the presence of an obstructive ventilatory defect, and suggest the possibility of a restrictive ventilatory defect (that then might prompt additional pulmonary function laboratory testing, including lung volumes, diffusion capacity, and possible tests of neuromuscular function). Echocardiography is indicated when systolic dysfunction, pulmonary hypertension, or valvular heart disease is suspected. Bronchoprovocation testing and/or home peak-flow monitoring may be useful in patients with intermittent symptoms suggestive of asthma who have a normal physical examination and spirometry; up to one-third of patients with the clinical diagnosis of asthma do not have reactive airways disease when formally tested. Measurement of brain natriuretic peptide levels in serum is increasingly used to assess for CHF in patients presenting with acute dyspnea but may be elevated in the presence of right ventricular strain as well.

Dyspnea

Diagnosis obtained?

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CHAPTER 33

Further testing (“Phase 1”): Chest X-ray Spirometry ECG CBC, Basic Metabolic Panel

lung volumes should be assessed: hyperinflation is consistent with obstructive lung disease, whereas low lung volumes suggest interstitial edema or fibrosis, diaphragmatic dysfunction, or impaired chest wall motion. The pulmonary parenchyma should be examined for evidence of interstitial disease, infiltrates, and emphysema. Prominent pulmonary vasculature in the upper zones indicates pulmonary venous hypertension, while enlarged central pulmonary arteries may suggest pulmonary arterial hypertension. An enlarged cardiac silhouette can point toward dilated cardiomyopathy or valvular disease. Bilateral pleural effusions are typical of CHF and some forms of collagen-vascular disease. Unilateral effusions raise the specter of carcinoma and pulmonary embolism but may also occur in heart failure or in the case of a parapneumonic effusion. CT of the chest is generally reserved for further evaluation of the lung parenchyma (interstitial lung disease) and possible pulmonary embolism if there remains diagnostic uncertainty.

DISTINGUISHING CARDIOVASCULAR FROM RESPIRATORY SYSTEM DYSPNEA If a patient has evidence of both pulmonary and cardiac disease that is either not responsive to treatment, or it remains unclear what factors are primarily driving dyspnea, a cardiopulmonary exercise test (CPET) can be carried out to determine which system is responsible for the exercise limitation. CPET includes incremental symptomlimited exercise (cycling or treadmill) with measurements of ventilation and pulmonary gas exchange, and in some cases includes non-invasive and invasive measures of pulmonary vascular pressures and cardiac output. If, at peak exercise, the patient achieves predicted maximal ventilation, demonstrates an increase in dead space or hypoxemia, or develops bronchospasm, the respiratory system may be the cause of the problem. Alternatively, if the heart rate is >85% of the predicted maximum, if the anaerobic threshold occurs early, if the blood pressure becomes excessively high or decreases during exercise, if the O2 pulse (O2 consumption/heart rate, an indicator of stroke volume) falls, or if there are ischemic changes on the electrocardiogram, an abnormality of the cardiovascular system is likely the explanation for the breathing discomfort. Additionally, a CPET may also help point toward a peripheral extraction deficit, or metabolic/neuromuscular disease as potential underlying processes driving dyspnea.

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TREATMENT

12

Dyspnea

10

PART 2 Cardinal Manifestations and Presentation of Diseases

The first goal is to correct the underlying condition(s) driving dyspnea and address potentially reversible causes with appropriate treatment for the particular condition. Multiple different interventions may be necessary, given that dyspnea often arises from multifactorial causes. If relief of dyspnea with treatment of the underlying condition(s) is not fully possible, an effort is made to lessen the intensity of the symptom and its effect on the patient’s quality of life. Despite an increased understanding of the mechanisms underlying dyspnea, there has been limited progress in treatment strategies for dyspnea. Supplemental O2 should be administered if the resting O2 saturation is ≤88% or if the patient’s saturation drops to these levels with activity or sleep. In particular, for patients with COPD, supplemental oxygen for those with hypoxemia has been shown to improve mortality, and pulmonary rehabilitation programs have demonstrated positive effects on dyspnea, exercise capacity, and rates of hospitalization. Opioids have been shown to reduce symptoms of dyspnea, largely through reducing air hunger, thus, likely suppressing respiratory drive and influencing cortical activity. However, opioids should be considered for each patient individually based upon the risk-benefit profile as regards the effects of respiratory depression. Studies of anxiolytics for dyspnea have not demonstrated consistent benefit. Additional approaches are under study for dyspnea, including inhaled furosemide that might alter afferent sensory information. Acknowledgment With prior contributions from Richard M. Schwartzstein.

■■FURTHER READING

Banzett RB et al: Multidimensional dyspnea profile: An instrument for clinical and laboratory research. Eur Respir J 45:1681, 2015. Laviolette L, Laveneziana P on behalf of the ERS Research Seminar Faculty: Dyspnoea: A multidimensional and multidisciplinary approach. Eur Respir J 43:1750, 2014. Parshall MB et al: An Official American Thoracic Society Statement: Update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 185:435, 2012. Wahls SA: Causes and evaluation of chronic dyspnea. Am Fam Physician 86:173, 2012.

34

Cough

Christopher H. Fanta

COUGH

Cough performs an essential protective function for human airways and lungs. Without an effective cough reflex, we are at risk for retained airway secretions and aspirated material predisposing to infection, atelectasis, and respiratory compromise. At the other extreme, excessive coughing can be exhausting; can be complicated by emesis, syncope, muscular pain, or rib fractures; can aggravate low back pain, abdominal or inguinal hernias, and urinary incontinence; and can be a major impediment to social interactions. Cough is often a clue to the presence of respiratory disease. In many instances, cough is an expected and accepted manifestation of disease, as in acute respiratory tract infection. However, persistent cough in the absence of other respiratory symptoms commonly causes patients to seek medical attention.

■■COUGH MECHANISM

Spontaneous cough is triggered by stimulation of sensory nerve endings that are thought to be primarily rapidly adapting receptors and

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Patient’s Predicted

8 6 Flow (L/sec)

230

4

Coughs

2 0 –2

1

2

3

4

5

6

7

8

9 10 11

–4 –6 –8 –10

Volume (L)

FIGURE 34-1  Flow-volume curve shows spikes of high expiratory flow achieved with cough.

C fibers. Both chemical (e.g., capsaicin) and mechanical (e.g., particulates in air pollution) stimuli may initiate the cough reflex. A cationic ion channel—the transient receptor potential vanilloid 1 (TRPV1)—found on rapidly adapting receptors and C fibers is the receptor for capsaicin, and its expression is increased in patients with chronic cough. Afferent nerve endings richly innervate the pharynx, larynx, and airways to the level of the terminal bronchioles and extend into the lung parenchyma. They may also be located in the external auditory meatus (the auricular branch of the vagus nerve, or Arnold’s nerve) and in the esophagus. Sensory signals travel via the vagus and superior laryngeal nerves to a region of the brainstem in the nucleus tractus solitarius vaguely identified as the “cough center.” The cough reflex involves a highly orchestrated series of involuntary muscular actions, with the potential for input from cortical pathways as well. The vocal cords adduct, leading to transient upper-airway occlusion. Expiratory muscles contract, generating positive intrathoracic pressures as high as 300 mmHg. With sudden release of the laryngeal contraction, rapid expiratory flows are generated, exceeding the normal “envelope” of maximal expiratory flow seen on the flow-volume curve (Fig. 34-1). Bronchial smoothmuscle contraction together with dynamic compression of airways narrows airway lumens and maximizes the velocity of exhalation. The kinetic energy available to dislodge mucus from the inside of airway walls is directly proportional to the square of the velocity of expiratory airflow. A deep breath preceding a cough optimizes the function of the expiratory muscles; a series of repetitive coughs at successively lower lung volumes sweeps the point of maximal expiratory velocity progressively further into the lung periphery.

■■IMPAIRED COUGH

Weak or ineffective cough compromises the ability to clear lower respiratory tract secretions, predisposing to more serious infections and their sequelae. Weakness or paralysis of the expiratory (abdominal and intercostal) muscles and pain in the chest wall or abdomen are foremost on the list of causes of impaired cough (Table 34-1). Cough strength is generally assessed qualitatively; peak expiratory flow or maximal expiratory pressure at the mouth can be used as a surrogate marker for cough strength. A variety of assistive devices and techniques have been developed to improve cough strength, running the gamut from TABLE 34-1  Causes of Impaired Cough Decreased respiratory muscle strength Chest wall or abdominal pain Chest wall deformity (e.g., severe kyphoscoliosis) Impaired glottic closure or tracheostomy Tracheobronchomalacia Abnormal airway secretions Central respiratory depression (e.g., anesthesia, sedation, or coma)

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simple (splinting of the abdominal muscles with a tightly held pillow to reduce postoperative pain while coughing) to complex (a mechanical cough-assist device supplied via face mask or tracheal tube that applies a cycle of positive pressure followed rapidly by negative pressure). Cough may fail to clear secretions despite a preserved ability to generate normal expiratory velocities; such failure may be due to either abnormal airway secretions (e.g., bronchiectasis due to cystic fibrosis) or structural abnormalities of the airways (e.g., tracheomalacia with excessive expiratory collapse of the trachea during cough).

■■ASSESSMENT OF CHRONIC COUGH

Except for our ability to detect the sound of excess airway secretions, details as to the resonance of the cough, its time of occurrence during the day, and the pattern of coughing (e.g., occurring in paroxysms) infrequently provide useful etiologic clues. Regardless of cause, cough often worsens upon first lying down at night, with talking, or with the hyperpnea of exercise; it frequently improves with sleep. An exception may involve the cough that occurs only with certain allergic exposures or exercise in cold air, as in asthma. Useful historical questions include what circumstances surrounded the onset of cough, what makes the cough better or worse, and does the cough produce sputum. The physical examination seeks clues suggesting the presence of cardiopulmonary disease, including findings such as wheezing or crackles on chest examination. Examination of the auditory canals and tympanic membranes (for irritation of the latter resulting in stimulation of Arnold’s nerve), the nasal passageways (for rhinitis or polyps), and the nails (for clubbing) may also provide etiologic clues. Because cough can be a manifestation of a systemic disease such as sarcoidosis or vasculitis, a thorough general examination is likewise important. In virtually all instances, evaluation of chronic cough merits a chest radiograph. The list of diseases that can cause persistent cough without other symptoms and without detectable abnormalities on physical examination is long. It includes serious illnesses such as sarcoidosis or Hodgkin’s disease in young adults, lung cancer in older patients, and (worldwide) pulmonary tuberculosis. An abnormal chest film prompts an evaluation aimed at explaining the radiographic abnormality. In a patient with chronic productive cough, examination of expectorated sputum is warranted, because determining the cause of mucus hypersecretion is critically important. Purulent-appearing sputum should be sent for routine bacterial culture and, in certain circumstances, mycobacterial culture as well. Cytologic examination of mucoid sputum may be useful to assess for malignancy and oropharyngeal aspiration and to distinguish neutrophilic from eosinophilic bronchitis. Expectoration of blood— whether streaks of blood, blood mixed with airway secretions, or pure blood—deserves a special approach to assessment and management.

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It is commonly held that (alone or in combination) the use of an ACE inhibitor; postnasal drainage; gastroesophageal reflux; and asthma account for >90% of cases of chronic cough with a normal or noncontributory chest radiograph. However, clinical experience does not support this contention, and strict adherence to this concept discourages the search for alternative explanations by both clinicians and researchers. In recent years, the concept of a distinct “cough hypersensitivity syndrome” has emerged, emphasizing the putative role of sensitized sensory nerve endings and afferent neural pathways in causing chronic refractory cough, akin to chronic neuropathic pain. It presents with a dry or minimally productive cough and a tickle or sensitivity in the throat, made worse with talking, laughing, or exertion. It is more common in women than men and can last for years. Specific diagnostic criteria are lacking; the diagnosis is suspected when alternative etiologies are excluded by diagnostic testing or failed therapeutic trials. It is uncertain whether persistent daily coughing elicits an inflammatory response and is thereby self-perpetuating. ACE inhibitor–induced cough occurs in 5–30% of patients taking these agents and is not dose-dependent. ACE metabolizes bradykinin and other tachykinins, such as substance P. The mechanism of ACE inhibitor–associated cough may involve sensitization of sensory nerve endings due to accumulation of bradykinin. Any patient with chronic unexplained cough who is taking an ACE inhibitor should have a trial period off the medication, regardless of the timing of the onset of cough relative to the initiation of ACE inhibitor therapy. In most instances, a safe alternative is available; angiotensin-receptor blockers do not cause cough. Failure to observe a decrease in cough after 1 month off medication argues strongly against this etiology. Postnasal drainage of any etiology can cause cough as a response to stimulation of sensory receptors of the cough-reflex pathway in the hypopharynx or aspiration of draining secretions into the trachea. Clues suggesting this etiology include postnasal drip, frequent throat clearing, and sneezing and rhinorrhea. On speculum examination of the nose, excess mucoid or purulent secretions, inflamed and edematous nasal mucosa, and/or polyps may be seen; in addition, secretions or a cobblestoned appearance of the mucosa along the posterior pharyngeal wall may be noted. Unfortunately, there is no means by which to quantitate postnasal drainage. In many instances, this diagnosis must rely on subjective information provided by the patient. This assessment must also be counterbalanced by the fact that many people who have chronic postnasal drainage do not experience cough. Linking gastroesophageal reflux to chronic cough poses similar challenges. It is thought that reflux of gastric contents into the lower esophagus may trigger cough via reflex pathways initiated in the esophageal mucosa. Reflux to the level of the pharynx (laryngopharyngeal reflux), with consequent aspiration of gastric contents, causes a chemical bronchitis and possibly pneumonitis that can elicit cough for days afterward, but it is a rare finding among persons with chronic cough. Retrosternal burning after meals or on recumbency, frequent eructation, hoarseness, and throat pain may be indicative of gastroesophageal reflux. Nevertheless, reflux may also elicit minimal or no symptoms. Glottic inflammation detected on laryngoscopy may be a manifestation of recurrent reflux to the level of the throat, but it is a nonspecific finding. Quantification of the frequency and level of reflux requires a somewhat invasive procedure to measure esophageal pH (either nasopharyngeal placement of a catheter with a pH probe into the esophagus for 24 h or endoscopic placement of a radiotransmitter capsule into the esophagus) and, with newer techniques, non-acid reflux. The precise interpretation of test results that permits an etiologic linking of reflux events and cough remains debated. Again, assigning the cause of cough to gastroesophageal reflux must be weighed against the observation that many people with symptomatic reflux do not experience chronic cough. Cough alone as a manifestation of asthma is common among children but not among adults. Cough due to asthma in the absence of wheezing, shortness of breath, and chest tightness is referred to as “cough-variant asthma.” A history suggestive of cough-variant asthma

Cough

Cough may occur in the context of other respiratory symptoms that together point to a diagnosis; for example, cough accompanied by wheezing, shortness of breath, and chest tightness after exposure to a cat or other sources of allergens suggests asthma. At times, however, cough is the dominant or sole symptom of disease, and it may be of sufficient duration and severity that relief is sought. The duration of cough is a clue to its etiology, at least retrospectively. Acute cough (8 weeks) may be caused by a wide variety of cardiopulmonary diseases, including those of inflammatory, infectious, neoplastic, and cardiovascular etiologies. When initial assessment with chest examination and radiography is normal, cough-variant asthma, gastroesophageal reflux, nasopharyngeal drainage, and medications (angiotensin-converting enzyme [ACE] inhibitors) are the most common identifiable causes of chronic cough. In a long-time cigarette smoker, an early-morning, productive cough suggests chronic bronchitis. A dry, irritative cough that lingers for >2 months following one or more respiratory tract infections (“post-bronchitic cough”) is a very common cause of chronic cough, especially in the winter months.

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CHAPTER 34

■■SYMPTOMATIC COUGH

■■CHRONIC COUGH WITH A NORMAL CHEST RADIOGRAPH

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PART 2 Cardinal Manifestations and Presentation of Diseases

ties the onset of cough to exposure to typical triggers for asthma and the resolution of cough to discontinuation of exposure. Objective testing can establish the diagnosis of asthma (airflow obstruction on spirometry that varies over time or reverses in response to a bronchodilator) or exclude it with certainty (a negative response to a bronchoprovocation challenge—e.g., with methacholine). In a patient capable of taking reliable measurements, home expiratory peak flow monitoring can be a cost-effective method to support or discount a diagnosis of asthma. Chronic eosinophilic bronchitis causes chronic cough with a normal chest radiograph. This condition is characterized by sputum eosinophilia in excess of 3% without airflow obstruction or bronchial hyperresponsiveness and is successfully treated with inhaled glucocorticoids. Treatment of chronic cough in a patient with a normal chest radiograph is often empirical and is targeted at the most likely cause(s) of cough as determined by history, physical examination, and possibly pulmonary-function testing. Therapy for postnasal drainage depends on the presumed etiology (infection, allergy, or vasomotor rhinitis) and may include systemic antihistamines; decongestants; antibiotics; nasal saline irrigation; and nasal pump sprays with glucocorticoids, antihistamines, or anticholinergics. Antacids, histamine type 2 (H2) receptor antagonists, and proton-pump inhibitors are used to neutralize or decrease the production of gastric acid in gastroesophageal reflux disease; dietary changes, elevation of the head and torso during sleep, and medications to improve gastric emptying are additional therapeutic measures. Cough-variant asthma typically responds well to inhaled glucocorticoids and intermittent use of inhaled β-agonist bronchodilators. Patients who fail to respond to treatment targeting the common causes of chronic cough or who have had these causes excluded by appropriate diagnostic testing should undergo chest CT. Diseases causing cough that may be missed on chest x-ray include tumors, early interstitial lung disease, bronchiectasis, and atypical mycobacterial pulmonary infection. On the other hand, patients with chronic cough who have normal findings on chest examination, lung function testing, oxygenation assessment, and chest CT can be reassured as to the absence of serious pulmonary pathology.

■■GLOBAL CONSIDERATIONS

Regular exposure to air pollution can cause chronic cough and throat clearing, as well as lower respiratory tract disease. Smoke from cooking and heating fuels in poorly ventilated homes; toxic exposures in work settings lacking implementation of occupational safety standards; and ambient chemicals and particulates in highly polluted outdoor air are all forms of air pollution causing cough. Limited therapeutic options are available; treatment focuses on improving environmental air quality (e.g., use of a stove chimney in the home), removal from the exposure, and use of an appropriate face mask.

■■SYMPTOM-BASED TREATMENT OF COUGH

Empiric treatment of chronic idiopathic cough with inhaled corticosteroids, inhaled anticholinergic bronchodilators, and macrolide antibiotics has been tried without consistent success. Currently available cough suppressants are only modestly effective. Most potent are narcotic cough suppressants, such as codeine or hydrocodone, which are thought to act in the “cough center” in the brainstem. The tendency of narcotic cough suppressants to cause drowsiness and constipation and their potential for addictive dependence limit their appeal for long-term use. Dextromethorphan is an over-the-counter, centrally acting cough suppressant with fewer side effects and less efficacy than the narcotic cough suppressants. Dextromethorphan is thought to have a different site of action than narcotic cough suppressants and can be used in combination with them if necessary. Benzonatate is thought to inhibit neural activity of sensory nerves in the cough-reflex pathway. It is generally free of side effects; however, its effectiveness in suppressing cough is variable and unpredictable. Attempts to treat cough hypersensitivity syndrome have focused on inhibition of neural pathways. Small case series and randomized clinical trials have indicated benefit from

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off-label use of gabapentin, pregabalin, or amitriptyline. Recent studies suggest a role for behavioral modification using specialized speech therapy techniques, but widespread application of this modality is currently not practical. Novel cough suppressants without the limitations of currently available agents are greatly needed. Approaches that are being explored include the development of neurokinin receptor antagonists, TRPV1 ion channel antagonists, and novel opioid and opioid-like receptor agonists.

■■FURTHER READING

Brightling CE et al: Eosinophilic bronchitis as an important cause of chronic cough. Am J Respir Crit Care Med 160:406, 1999. Gibson PG, Vertigan AE: Management of chronic refractory cough. BMJ 351:h5590, 2015. Kahrilas PJ et al: Chronic cough due to gastroesophageal reflux in adults: CHEST Guideline and Expert Panel Report. Chest 150:1341, 2016. Ramsay LE et al: Double-blind comparison of losartan, lisinopril and hydrochlorothiazide in hypertensive patients with previous angiotensin converting enzyme inhibitor-associated cough. J Hypertens Suppl 13:S73, 1995. Ryan NM et al: Gabapentin for refractory chronic cough: a randomized, double-blind, placebo-controlled trial. Lancet 380:1583, 2012. Smith JA, Woodcock A: Chronic cough. N Engl J Med 375:1544, 2016.

35

Hemoptysis

Anna K. Brady, Patricia A. Kritek

Hemoptysis is the expectoration of blood from the respiratory tract. The first step in evaluation is to ascertain whether the bleeding is coming from the respiratory tree or instead originating from the nasal cavities (i.e., epistaxis) or the gastrointestinal tract (i.e., hematemesis) as the therapies for these etiologies will be significantly different. Once established as hemoptysis, the exact nature of the expectoration is important as the term can be applied to blood-tinged phlegm, the pink frothy sputum of pulmonary edema, or frank blood. Next steps include identifying the source and etiology of bleeding.

ANATOMY AND PHYSIOLOGY OF HEMOPTYSIS

Hemoptysis can arise from anywhere in the respiratory tract; from the glottis to the alveolus. Most commonly, bleeding arises from the bronchi or medium sized airways, but a thorough evaluation of the entire respiratory tree is often necessary. A unique feature of the lung that predisposes to hemoptysis of varied severity is its dual blood supply—the pulmonary and bronchial circulations. The former is a low-pressure system that is essential to gas exchange at the alveolar level; in contrast, the bronchial arteries originate from the aorta and are under systemic pressure. The bronchial arteries supply the airways and have the ability to neovascularize tumors, dilate airways of bronchiectasis, and cavitary lesions. Most hemoptysis is due to vessels in the bronchial circulation and is, therefore, under systemic pressure, making it more challenging to arrest the bleeding.

ETIOLOGY 

Hemoptysis commonly results from infection, malignancy, or vascular disease; however, the differential for bleeding from the respiratory tree is varied and broad.

Infections  Most blood-tinged sputum and small-volume hemoptysis is due to viral bronchitis. Patients with chronic bronchitis are at risk for bacterial superinfection with organisms such as Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis, increasing airway inflammation and potential for bleeding. Similarly, patients

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adenocarcinomas of the breast and colon) can also cause bleeding. Kaposi’s sarcoma, seen in advanced acquired immunodeficiency syndrome, is very vascular and can develop anywhere along the respiratory tract, from the bronchi to the oral cavity.

■■EVALUATION AND MANAGEMENT History  The first step in evaluating hemoptysis is to determine the amount or severity of bleeding. A patient’s description of the sputum (e.g., flecks of blood, pink-tinged, or frank blood or clot) is helpful if you cannot examine it. An approach to management of hemoptysis is outlined in Fig. 35-1. It is crucial to determine whether the amount of blood expectorated is massive; while there is no agreed-upon volume, blood loss of 400 mL in 24 hours or 100–150 mL expectorated at one time are considered massive hemoptysis. These numbers derive from the volume of the tracheobronchial tree (generally 100–200 mL). This determination is clinically important as patients rarely die of exsanguination and, instead, are at risk of death due to asphyxiation from blood filling the airways and airspaces. Most patients cannot describe the volume of their hemoptysis in mL, so using referents like cups (one U.S. cup is 236 mL) can be helpful. Fortunately, massive hemoptysis only accounts for 5–15% of cases of hemoptysis. Careful history may point to the cause of hemoptysis. Fever, chills, or antecedent cough may suggest infection. A history of smoking or unintentional weight loss makes malignancy more likely. Patients should be asked about inhalational exposures. A thorough medical history with careful attention to chronic pulmonary disease should

Hemoptysis

Mechanical and Other Causes  In addition to infection, vascular disease, and malignancy, other insults to the pulmonary system can cause hemoptysis. Pulmonary endometriosis causes cyclical bleeding known as catamenial hemoptysis. Foreign body aspiration can lead to airway irritation and bleeding. Diagnostic and therapeutic procedures are also potential offenders: pulmonary vein stenosis can result from left atrial procedures, such as pulmonary vein isolation, and pulmonary artery catheters can lead to rupture of the pulmonary artery if the distal balloon is kept inflated. Finally, in the setting of thrombocytopenia, coagulopathy, anticoagulation, or antiplatelet therapy, even minor insults can cause hemoptysis.

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CHAPTER 35

with bronchiectasis are prone to hemoptysis with exacerbations of disease. Due to recurrent bacterial infection, bronchiectatic airways are dilated, inflamed, and highly vascular, supplied by the bronchial circulation. In several case series, bronchiectasis is the leading cause of massive hemoptysis and subsequent death. Tuberculosis had long been the most common cause of hemoptysis worldwide, but it is now surpassed in industrialized countries by bronchitis and bronchiectasis. In patients with tuberculosis, development of cavitary disease is frequently the source of bleeding but rarer complications such as the erosion of a pulmonary artery aneurysm into a preexisting cavity (i.e., Rasmussen’s aneurysm) can also be the source. Other infectious agents such as endemic fungi, Nocardia, and nontuberculous mycobacteria can present as cavitary lung disease complicated by hemoptysis. In addition, Aspergillus species can develop into mycetomas within preexisting cavities, with neovascularization to these inflamed spaces leading to bleeding. Pulmonary abscesses and necrotizing pneumonia can cause bleeding by devitalizing lung parenchyma. Common responsible organisms include Staphylococcus aureus, Klebsiella pneumoniae, and oral anaerobes. Paragonimiasis can mimic tuberculosis and is another significant cause of hemoptysis seen globally; it is common in Southeast Asia and China, although cases have been reported in North America from raw crayfish ingestion. It should be considered as a cause of hemoptysis in recent immigrants from endemic areas.

Vascular  Hemoptysis commonly results from pulmonary edema due to elevated left ventricular end-diastolic pressure. While the classic description of the sputum expectorated in pulmonary edema is “pink and frothy,” a spectrum of hemoptysis including frank blood can be seen. A pulmonary embolism with parenchymal infarction can present with hemoptysis, although most pulmonary emboli do not cause hemoptysis and will present with other signs and symptoms. An ectatic vessel in an airway or a pulmonary arteriovenous malformation can be a source of bleeding. While rare, rupture of an aortobronchial fistula can result in massive bleeding and sudden death; these fistulae arise in the setting of aortic pathology such as aneurysm or pseudoaneurysm and can cause small bleeding episodes that herald massive hemoptysis. Diffuse alveolar hemorrhage (DAH), despite causing significant bleeding into the lung parenchyma, uncommonly results in hemoptysis. A range of insults cause DAH, including immune-mediated capillaritis from diseases such as systemic lupus erythePatient with hemoptysis matosus, toxicity from cocaine and other inhalants, and stem cell transplantation. Rule out other sources: History and physical -Oropharynx The so-called “pulmonary-renal” synexamination -Gastrointestinal tract dromes, including granulomatosis with Quantify amount of bleeding polyangiitis and anti-glomerular basement membrane disease, may lead to both hemoptysis and hematuria (though one Non-massive Massive manifestation may be present without the other). DAH more commonly presents with diffuse ground glass opacities on imaging No risk factors Risk factors Protect airway and anemia, so the absence of hemoptysis should not exclude the diagnosis. Malignancy  Bronchogenic carcinoma

of any histology is a common cause of hemoptysis (both massive and non-massive) in modern published series. Hemoptysis often indicates airway involvement of the tumor and can be a presenting symptom of carcinoid tumors, vascular lesions that frequently arise in the proximal airways. Small cell and squamous cell carcinomas are frequently central in nature and more likely to erode into major pulmonary vessels, resulting in massive hemoptysis. Pulmonary metastases from distant tumors (e.g., melanoma, sarcoma,

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Treat underlying disease (usually infection) Persistent bleeding

CXR, CBC, UA, creatinine, coagulation studies

Bleeding stops

Bleeding contimues Embolization or resection

CT scan Bronchoscopy Treat underlying disease

Persistent bleeding

FIGURE 35-1  Approach to the management of hemoptysis. CBC, complete blood count; CT, computed tomography; CXR, chest x-ray; UA, urinalysis.

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234

be obtained, and the clinician should determine risk factors for malignancy and bronchiectatic lung disease (e.g., cystic fibrosis, sarcoidosis).

PART 2

Physical Examination  Reviewing the vital signs is an important first step. The presence of hypoxemia, tachypnea, and tachycardia should raise concern. Clinicians should examine the nasal and oral cavities; observe the patient’s breathing pattern, with careful attention to any respiratory distress; and auscultate the lungs. Clubbing can suggest underlying lung disease such as lung cancer or cystic fibrosis. Signs of bleeding diathesis (e.g., skin or mucosal ecchymoses and petechiae) or teleangectasias may suggest other predispositions to hemoptysis. Diagnostic Studies  Initial studies should include measurement

Cardinal Manifestations and Presentation of Diseases

of a complete blood count to assess for infection, anemia, or thrombocytopenia, coagulation parameters, measurement of electrolytes and renal function, as well as urinalysis to exclude pulmonary-renal disease. In patients with small, non-massive hemoptysis, outpatient evaluation can be pursued. All patients with hemoptysis need chest imaging. A chest radiograph is usually obtained first, though it frequently does not localize bleeding and can appear normal. In patients without risk factors for malignancy and with a normal chest radiograph, treating for bronchitis and ensuring close follow-up is a reasonable strategy, with further diagnostic workup if bleeding persists. In contrast, patients with risk factors for malignancy (i.e., age >40 or a smoking history) should undergo additional testing. First, chest computed tomography (CT) should be obtained to better identify masses, bronchiectasis, and parenchymal lesions. Following CT, a flexible bronchoscopy should be performed to exclude bronchogenic carcinoma unless imaging reveals a lesion that can be sampled without bronchoscopy. Small case series show that patients with hemoptysis and unrevealing bronchoscopies have good outcomes.

Interventions  When the amount of hemoptysis is massive, there

are three simultaneous goals: first, protect the non-bleeding lung; second, locate the site of bleeding; and third, control the bleeding. Protecting the airway and non-bleeding lung is paramount in the management of massive hemoptysis, since asphyxiation can happen quickly. If the side of bleeding is known, the patient should be positioned with the bleeding side down, to use gravitational advantage to keep blood out of the non-bleeding lung. Endotracheal intubation should be avoided unless truly necessary, since suctioning through an endotracheal tube is a less effective means of removing blood and clot than the cough reflex. If intubation is required, take steps to protect the non-bleeding lung either by selective intubation of one lung (i.e., the non-bleeding lung) or insertion of a double-lumen endotracheal tube. Locating the bleeding site is sometimes obvious, but frequently it can be difficult to determine the source of hemoptysis. A chest radiograph, if it shows new opacities, can be helpful in localizing the side or site of bleeding, though this test is not adequate by itself. CT angiography helps by localizing active extravasation. Flexible bronchoscopy may be useful to identify the side of bleeding (although it has only a 50% chance of locating the site). Experts do not agree on the timing of bronchoscopy, though in some cases—cystic fibrosis, for instance— bronchoscopy is not recommended because it may delay definitive management. Finally, proceeding directly to angiography is also a reasonable strategy given that it has both diagnostic and therapeutic capabilities. Controlling the bleeding during an episode of massive hemoptysis can be accomplished in one of three ways: from the airway lumen, from the involved blood vessel, or by surgical resection of both airway and vessel involved. Bronchoscopic measures are generally only temporizing: a flexible bronchoscope can be used to suction clot and insert a balloon catheter that occludes the involved airway. Rigid bronchoscopy, done by an interventional pulmonologist or thoracic surgeon, may allow therapeutic interventions of bleeding airway lesions such as photocoagulation and cautery. Because most massive hemoptysis arises from the bronchial circulation, bronchial artery embolization is the procedure of choice for control of massive hemoptysis. It is not

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without risk—embolization of the anterior spinal artery is a known complication—but is generally successful in the short term, with >80% success rate at controlling bleeding immediately, though bleeding can recur if the underlying disease (e.g., a mycetoma) is not treated. Surgical resection has a high mortality rate (up to 15–40%) and should not be pursued unless initial measures have failed and bleeding is ongoing. Ideal candidates for surgery have localized disease but otherwise normal lung parenchyma.

■■FURTHER READING

Adelman M et al: Cryptogenic hemoptysis: Clinical features, bronchoscopic findings, and natural history in 67 patients. Ann Int Med 102:829, 1985. Flume PA et al: CF pulmonary guidelines. Pulmonary complications: Hemoptysis and pneumothorax. AJRCCM 182:298, 2010. Hirshberg B et al: Hemoptysis: Etiology, evaluation, and outcome in a tertiary care hospital. Chest 112:440, 1997. Johnson JL: Manifestations of hemoptysis: How to manage minor, moderate, and massive bleeding. Postgrad Med 112:4:101, 2002. Lordan JL et al: The pulmonary physician in critical care: Illustrative case 7. Assessment and management of massive hemoptysis. Thorax 58:814, 2003. Sopko DR, Smith TP: Bronchial artery embolization for massive hemoptysis. Semin Intervent Radiol 28:48, 2011.

36

Hypoxia and Cyanosis Joseph Loscalzo

HYPOXIA

The fundamental purpose of the cardiorespiratory system is to deliver O2 and nutrients to cells and to remove CO2 and other metabolic products from them. Proper maintenance of this function depends not only on intact cardiovascular and respiratory systems, but also on an adequate number of red blood cells and hemoglobin, and a supply of inspired gas containing adequate O2.

■■RESPONSES TO HYPOXIA

Decreased O2 availability to cells results in an inhibition of oxidative phosphorylation and increased anaerobic glycolysis. This switch from aerobic to anaerobic metabolism, the Pasteur effect, reduces the rate of adenosine 5′-triphosphate (ATP) production. In severe hypoxia, when ATP production is inadequate to meet the energy requirements of ionic and osmotic equilibrium, cell membrane depolarization leads to uncontrolled Ca2+ influx and activation of Ca2+-dependent phospholipases and proteases. These events, in turn, cause cell swelling, activation of apoptotic pathways, and, ultimately, cell death. The adaptations to hypoxia are mediated, in part, by the upregulation of genes encoding a variety of proteins, including glycolytic enzymes, such as phosphoglycerate kinase and phosphofructokinase, as well as the glucose transporters Glut-1 and Glut-2; and by growth factors, such as vascular endothelial growth factor (VEGF) and erythropoietin, which enhance erythrocyte production. The hypoxia-induced increase in expression of these key proteins is governed by the hypoxiasensitive transcription factor, hypoxia-inducible factor-1 (HIF-1). During hypoxia, systemic arterioles dilate, at least in part, by opening of KATP channels in vascular smooth-muscle cells due to the hypoxia-induced reduction in ATP concentration. By contrast, in pulmonary vascular smooth-muscle cells, inhibition of K+ channels causes depolarization which, in turn, activates voltage-gated Ca2+ channels raising the cytosolic [Ca2+] and causing smooth-muscle cell contraction. Hypoxia-induced pulmonary arterial constriction shunts blood away from poorly ventilated portions toward better ventilated portions of

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the lung; however, it also increases pulmonary vascular resistance and right ventricular afterload.

usual quantity of O2 is removed from it, the Po2 and saturation in the venous blood decline to a greater extent than normal.

Effects on the Central Nervous System  Changes in the central nervous system (CNS), particularly the higher centers, are especially important consequences of hypoxia. Acute hypoxia causes impaired judgment, motor incoordination, and a clinical picture resembling acute alcohol intoxication. High-altitude illness is characterized by headache secondary to cerebral vasodilation, gastrointestinal symptoms, dizziness, insomnia, fatigue, or somnolence. Pulmonary arterial and sometimes venous constriction causes capillary leakage and high-altitude pulmonary edema (HAPE) (Chap. 33), which intensifies hypoxia, further promoting vasoconstriction. Rarely, high-altitude cerebral edema (HACE) develops, which is manifest by severe headache and papilledema and can cause coma. As hypoxia becomes more severe, the regulatory centers of the brainstem are affected, and death usually results from respiratory failure.

Carbon Monoxide (CO) Intoxication  (See also Chap. S11)

■■CAUSES OF HYPOXIA Respiratory Hypoxia  When hypoxia occurs from respiratory failure, Pao2 declines, and when respiratory failure is persistent, the hemoglobin-oxygen (Hb-O2) dissociation curve (see Fig. 94-2) is displaced to the right, with greater quantities of O2 released at any level of tissue Po2. Arterial hypoxemia, that is, a reduction of O2 saturation of arterial blood (Sao2), and consequent cyanosis are likely to be more marked when such depression of Pao2 results from pulmonary disease than when the depression occurs as the result of a decline in the fraction of oxygen in inspired air (Fio2). In this latter situation, Paco2 falls secondary to anoxia-induced hyperventilation and the Hb-O2 dissociation curve is displaced to the left, limiting the decline in Sao2 at any level of Pao2. The most common cause of respiratory hypoxia is ventilation-perfusion mismatch resulting from perfusion of poorly ventilated alveoli. Respiratory hypoxemia may also be caused by hypoventilation, in which case it is associated with an elevation of Paco2 (Chap. 279). These two forms of respiratory hypoxia are usually correctable by inspiring 100% O2 for several minutes. A third cause of respiratory hypoxia is shunting of blood across the lung from the pulmonary arterial to the venous bed (intrapulmonary right-to-left shunting) by perfusion of nonventilated portions of the lung, as in pulmonary atelectasis or through pulmonary arteriovenous connections. The low Pao2 in this situation is only partially corrected by an Fio2 of 100%. Hypoxia Secondary to High Altitude  As one ascends rapidly

to 3000 m (~10,000 ft), the reduction of the O2 content of inspired air (Fio2) leads to a decrease in alveolar Po2 to ∼60 mmHg, and a condition termed high-altitude illness develops (see above). At higher altitudes, arterial saturation declines rapidly and symptoms become more serious; and at 5000 m, unacclimated individuals usually cease to be able to function normally owing to the changes in CNS function described above.

Hypoxia Secondary to Right-to-Left Extrapulmonary Shunting  From a physiologic viewpoint, this cause of hypoxia

resembles intrapulmonary right-to-left shunting but is caused by congenital cardiac malformations, such as tetralogy of Fallot, transposition of the great arteries, and Eisenmenger’s syndrome (Chap. 264). As in pulmonary right-to-left shunting, the Pao2 cannot be restored to normal with inspiration of 100% O2.

Anemic Hypoxia  A reduction in hemoglobin concentration of the blood is accompanied by a corresponding decline in the O2-carrying capacity of the blood. Although the Pao2 is normal in anemic hypoxia, the absolute quantity of O2 transported per unit volume of blood is diminished. As the anemic blood passes through the capillaries and the

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Circulatory Hypoxia  As in anemic hypoxia, the Pao2 is usually

normal, but venous and tissue Po2 values are reduced as a consequence of reduced tissue perfusion and greater tissue O2 extraction. This pathophysiology leads to an increased arterial-mixed venous O2 difference (a-v-O2 difference), or gradient. Generalized circulatory hypoxia occurs in heart failure (Chap. 252) and in most forms of shock (Chap. 296).

Specific Organ Hypoxia  Localized circulatory hypoxia may

occur as a result of decreased perfusion secondary to arterial obstruction, as in localized atherosclerosis in any vascular bed, or as a consequence of vasoconstriction, as observed in Raynaud’s phenomenon (Chap. 275). Localized hypoxia may also result from venous obstruction and the resultant expansion of interstitial fluid causing arteriolar compression and, thereby, reduction of arterial inflow. Edema, which increases the distance through which O2 must diffuse before it reaches cells, can also cause localized hypoxia. In an attempt to maintain adequate perfusion to more vital organs in patients with reduced cardiac output secondary to heart failure or hypovolemic shock, vasoconstriction may reduce perfusion in the limbs and skin, causing hypoxia of these regions.

Hypoxia and Cyanosis

ulates the chemoreceptor reflex arc to induce venoconstriction and systemic arterial vasodilation. These acute changes are accompanied by transiently increased myocardial contractility, which is followed by depressed myocardial contractility with prolonged hypoxia.

Hemoglobin that binds with CO (carboxy-hemoglobin, COHb) is unavailable for O2 transport. In addition, the presence of COHb shifts the Hb-O2 dissociation curve to the left (see Fig. 94-2) so that O2 is unloaded only at lower tensions, further contributing to tissue hypoxia.

CHAPTER 36

Effects on the Cardiovascular System  Acute hypoxia stim-

235

Increased O2 Requirements  If the O2 consumption of tissues is

elevated without a corresponding increase in perfusion, tissue hypoxia ensues and the Po2 in venous blood declines. Ordinarily, the clinical picture of patients with hypoxia due to an elevated metabolic rate, as in fever or thyrotoxicosis, is quite different from that in other types of hypoxia: the skin is warm and flushed owing to increased cutaneous blood flow that dissipates the excessive heat produced, and cyanosis is usually absent. Exercise is a classic example of increased tissue O2 requirements. These increased demands are normally met by several mechanisms operating simultaneously: (1) increase in the cardiac output and ventilation and, thus, O2 delivery to the tissues; (2) a preferential shift in blood flow to the exercising muscles by changing vascular resistances in the circulatory beds of exercising tissues, directly and/or reflexly; (3) an increase in O2 extraction from the delivered blood and a widening of the arteriovenous O2 difference; and (4) a reduction in the pH of the tissues and capillary blood, shifting the Hb-O2 curve to the right (see Fig. 94-2), and unloading more O2 from hemoglobin. If the capacity of these mechanisms is exceeded, then hypoxia, especially of the exercising muscles, will result.

Improper Oxygen Utilization  Cyanide (Chap. 450) and several

other similarly acting poisons cause cellular hypoxia. The tissues are unable to use O2, and, as a consequence, the venous blood tends to have a high O2 tension. This condition has been termed histotoxic hypoxia.

■■ADAPTATION TO HYPOXIA

An important component of the respiratory response to hypoxia originates in special chemosensitive cells in the carotid and aortic bodies and in the respiratory center in the brainstem. The stimulation of these cells by hypoxia increases ventilation, with a loss of CO2, and can lead to respiratory alkalosis. When combined with the metabolic acidosis resulting from the production of lactic acid, the serum bicarbonate level declines (Chap. 51). With the reduction of Pao2, cerebrovascular resistance decreases and cerebral blood flow increases in an attempt to maintain O2 delivery to the brain. However, when the reduction of Pao2 is accompanied by hyperventilation and a reduction of Paco2, cerebrovascular resistance rises, cerebral blood flow falls, and tissue hypoxia intensifies. The diffuse, systemic vasodilation that occurs in generalized hypoxia increases the cardiac output. In patients with underlying heart disease,

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236

PART 2

the requirements of peripheral tissues for an increase of cardiac output with hypoxia may precipitate congestive heart failure. In patients with ischemic heart disease, a reduced Pao2 may intensify myocardial ischemia and further impair left ventricular function. One of the important compensatory mechanisms for chronic hypoxia is an increase in the hemoglobin concentration and in the number of red blood cells in the circulating blood, that is, the development of polycythemia secondary to erythropoietin production (Chap. 99). In persons with chronic hypoxemia secondary to prolonged residence at a high altitude (>13,000 ft, 4200 m), a condition termed chronic mountain sickness develops. This disorder is characterized by a blunted respiratory drive, reduced ventilation, erythrocytosis, cyanosis, weakness, right ventricular enlargement secondary to pulmonary hypertension, and even stupor.

Cardinal Manifestations and Presentation of Diseases

CYANOSIS

Cyanosis refers to a bluish color of the skin and mucous membranes resulting from an increased quantity of reduced hemoglobin (i.e., deoxygenated hemoglobin) or of hemoglobin derivatives (e.g., methemoglobin or sulfhemoglobin) in the small blood vessels of those tissues. It is usually most marked in the lips, nail beds, ears, and malar eminences. Cyanosis, especially if developed recently, is more commonly detected by a family member than the patient. The florid skin characteristic of polycythemia vera (Chap. 99) must be distinguished from the true cyanosis discussed here. A cherry-colored flush, rather than cyanosis, is caused by COHb (Chap. 450). The degree of cyanosis is modified by the color of the cutaneous pigment and the thickness of the skin, as well as by the state of the cutaneous capillaries. The accurate clinical detection of the presence and degree of cyanosis is difficult, as proved by oximetric studies. In some instances, central cyanosis can be detected reliably when the Sao2 has fallen to 85%; in others, particularly in dark-skinned persons, it may not be detected until it has declined to 75%. In the latter case, examination of the mucous membranes in the oral cavity and the conjunctivae rather than examination of the skin is more helpful in the detection of cyanosis. The increase in the quantity of reduced hemoglobin in the mucocutaneous vessels that produces cyanosis may be brought about either by an increase in the quantity of venous blood as a result of dilation of the venules (including precapillary venules) or by a reduction in the Sao2 in the capillary blood. In general, cyanosis becomes apparent when the concentration of reduced hemoglobin in capillary blood exceeds 40 g/L (4 g/dL). It is the absolute, rather than the relative, quantity of reduced hemoglobin that is important in producing cyanosis. Thus, in a patient with severe anemia, the relative quantity of reduced hemoglobin in the venous blood may be very large when considered in relation to the total quantity of hemoglobin in the blood. However, since the concentration of the latter is markedly reduced, the absolute quantity of reduced hemoglobin may still be low, and, therefore, patients with severe anemia and even marked arterial desaturation may not display cyanosis. Conversely, the higher the total hemoglobin content, the greater the tendency toward cyanosis; thus, patients with marked polycythemia tend to be cyanotic at higher levels of Sao2 than patients with normal hematocrit values. Likewise, local passive congestion, which causes an increase in the total quantity of reduced hemoglobin in the vessels in a given area, may cause cyanosis. Cyanosis is also observed when nonfunctional hemoglobin, such as methemoglobin (consequential or acquired) or sulfhemoglobin (Chap. 94), is present in blood. Cyanosis may be subdivided into central and peripheral types. In central cyanosis, the Sao2 is reduced or an abnormal hemoglobin derivative is present, and the mucous membranes and skin are both affected. Peripheral cyanosis is due to a slowing of blood flow and abnormally great extraction of O2 from normally saturated arterial blood; it results from vasoconstriction and diminished peripheral blood flow, such as occurs in cold exposure, shock, congestive failure, and peripheral vascular disease. Often in these conditions, the mucous membranes of the oral cavity or those beneath the tongue may be spared. Clinical differentiation between central and peripheral cyanosis may not always

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be straightforward, and in conditions such as cardiogenic shock with pulmonary edema, there may be a mixture of both types.

■■DIFFERENTIAL DIAGNOSIS Central Cyanosis  (Table 36-1) Decreased Sao2 results from a marked reduction in the Pao2. This reduction may be brought about by a decline in the Fio2 without sufficient compensatory alveolar hyperventilation to maintain alveolar Po2. Cyanosis usually becomes manifest in an ascent to an altitude of 4000 m (13,000 ft). Seriously impaired pulmonary function, through perfusion of unventilated or poorly ventilated areas of the lung or alveolar hypoventilation, is a common cause of central cyanosis (Chap. 279). This condition may occur acutely, as in extensive pneumonia or pulmonary edema, or chronically, with chronic pulmonary diseases (e.g., emphysema). In the latter situation, secondary polycythemia is generally present and clubbing of the fingers (see below) may occur. Another cause of reduced Sao2 is shunting of systemic venous blood into the arterial circuit. Certain forms of congenital heart disease are associated with cyanosis on this basis (see above and Chap. 264). Pulmonary arteriovenous fistulae may be congenital or acquired, solitary or multiple, microscopic or massive. The severity of cyanosis produced by these fistulae depends on their size and number. They occur with some frequency in hereditary hemorrhagic telangiectasia. Sao2 reduction and cyanosis may also occur in some patients with cirrhosis, presumably as a consequence of pulmonary arteriovenous fistulae or portal vein–pulmonary vein anastomoses. In patients with cardiac or pulmonary right-to-left shunts, the presence and severity of cyanosis depend on the size of the shunt relative to the systemic flow and on the Hb-O2 saturation of the venous blood. With increased extraction of O2 from the blood by the exercising muscles, the venous blood returning to the right side of the heart is more unsaturated than at rest, and shunting of this blood intensifies the cyanosis. Secondary polycythemia occurs frequently in patients in this setting and contributes to the cyanosis. Cyanosis can be caused by small quantities of circulating methemoglobin (Hb Fe3+) and by even smaller quantities of sulfhemoglobin (Chap. 94); both of these hemoglobin derivatives impair oxygen delivery to the tissues. Although they are uncommon causes of cyanosis, these abnormal hemoglobin species should be sought by spectroscopy when cyanosis is not readily explained by malfunction of the TABLE 36-1  Causes of Cyanosis Central Cyanosis Decreased arterial oxygen saturation   Decreased atmospheric pressure—high altitude   Impaired pulmonary function   Alveolar hypoventilation   Inhomogeneity in pulmonary ventilation and perfusion (perfusion of hypoventilated alveoli)    Impaired oxygen diffusion   Anatomic shunts    Certain types of congenital heart disease    Pulmonary arteriovenous fistulas    Multiple small intrapulmonary shunts   Hemoglobin with low affinity for oxygen Hemoglobin abnormalities   Methemoglobinemia—hereditary, acquired  Sulfhemoglobinemia—acquired   Carboxyhemoglobinemia (not true cyanosis) Peripheral Cyanosis Reduced cardiac output Cold exposure Redistribution of blood flow from extremities Arterial obstruction Venous obstruction

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circulatory or respiratory systems. Generally, digital clubbing does not occur with them.

Peripheral Cyanosis  Probably the most common cause of

Cyanosis Certain features are important in arriving at the cause of cyanosis: 1. It is important to ascertain the time of onset of cyanosis. Cyanosis present since birth or infancy is usually due to congenital heart disease. 2. Central and peripheral cyanosis must be differentiated. Evidence of disorders of the respiratory or cardiovascular systems is helpful. Massage or gentle warming of a cyanotic extremity will increase peripheral blood flow and abolish peripheral, but not central, cyanosis. 3. The presence or absence of clubbing of the digits (see below) should be ascertained. The combination of cyanosis and clubbing is frequent in patients with congenital heart disease and right-toleft shunting and is seen occasionally in patients with pulmonary disease, such as lung abscess or pulmonary arteriovenous fistulae. In contrast, peripheral cyanosis or acutely developing central cyanosis is not associated with clubbed digits. 4. Pao2 and Sao2 should be determined, and, in patients with cyanosis in whom the mechanism is obscure, spectroscopic examination of the blood should be performed to look for abnormal types of hemoglobin (critical in the differential diagnosis of cyanosis).

37

Edema

Eugene Braunwald, Joseph Loscalzo

Edema

APPROACH TO THE PATIENT

237

Callemeyn J et al: Clubbing and hypertrophic osteoarthropathy: Insights into diagnosis, pathophysiology, and clinical significance. Acta Clin Belg 22:1, 2016. MacIntyre NR: Tissue hypoxia: Implications for the respiratory clinician. Respir Care 59:1590, 2014.

CHAPTER 37

peripheral cyanosis is the normal vasoconstriction resulting from exposure to cold air or water. When cardiac output is reduced, cutaneous vasoconstriction occurs as a compensatory mechanism so that blood is diverted from the skin to more vital areas such as the CNS and heart, and cyanosis of the extremities may result even though the arterial blood is normally saturated. Arterial obstruction to an extremity, as with an embolus, or arteriolar constriction, as in cold-induced vasospasm (Raynaud’s phenomenon) (Chap. 275), generally results in pallor and coldness, and there may be associated cyanosis. Venous obstruction, as in thrombophlebitis or deep venous thrombosis, dilates the subpapillary venous plexuses and thereby intensifies cyanosis.

■■FURTHER READING

PLASMA AND INTERSTITIAL FLUID EXCHANGE

About two-thirds of total body water is intracellular and one-third is extracellular. Approximately one-fourth of the latter is in the plasma and the remainder comprises the interstitial fluid. Edema represents an excess of interstitial fluid that has become evident clinically. There is constant interchange of fluid between the two compartments of the extracellular fluid. The hydrostatic pressure within the capillaries and the colloid oncotic pressure in the interstitial fluid promote the movement of water and diffusible solutes from plasma to the interstitium. This movement is most prominent at the arterial origin of the capillary and falls progressively with the decline in intracapillary pressure and the rise in oncotic pressure toward the venular end. Fluid is returned from the interstitial space into the vascular system largely through the lymphatic system. These interchanges of fluids are normally balanced so that the volumes of the intravascular and interstitial compartments remain constant. However, a net movement of fluid from the intravascular to the interstitial spaces takes place and may be responsible for the development of edema under the following conditions: (1) an increase in intracapillary hydrostatic pressure; (2) inadequate lymphatic drainage; (3) reductions in the oncotic pressure in the plasma; (4) damage to the capillary endothelial barrier; and (5) increases in the oncotic pressure in the interstitial space.

■■REDUCTION OF EFFECTIVE ARTERIAL VOLUME

CLUBBING

The selective bulbous enlargement of the distal segments of the fingers and toes due to proliferation of connective tissue, particularly on the dorsal surface, is termed clubbing; there is also increased sponginess of the soft tissue at the base of the clubbed nail. Clubbing may be hereditary, idiopathic, or acquired and associated with a variety of disorders, including cyanotic congenital heart disease (see above), infective endocarditis, and a variety of pulmonary conditions (among them primary and metastatic lung cancer, bronchiectasis, asbestosis, sarcoidosis, lung abscess, cystic fibrosis, tuberculosis, and mesothelioma), as well as with some gastrointestinal diseases (including inflammatory bowel disease and hepatic cirrhosis). In some instances, it is occupational, for example, in jackhammer operators. Clubbing in patients with primary and metastatic lung cancer, mesothelioma, bronchiectasis, or hepatic cirrhosis may be associated with hypertrophic osteoarthropathy. In this condition, the subperiosteal formation of new bone in the distal diaphyses of the long bones of the extremities causes pain and symmetric arthritis-like changes in the shoulders, knees, ankles, wrists, and elbows. The diagnosis of hypertrophic osteoarthropathy may be confirmed by bone radiograph or magnetic resonance imaging (MRI). Although the mechanism of clubbing is unclear, it appears to be secondary to humoral substances that cause dilation of the vessels of the distal digits as well as growth factors released from platelet precursors in the digital circulation. In certain circumstances, clubbing is reversible, such as following lung transplantation for cystic fibrosis.

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In many forms of edema, the effective arterial blood volume, a parameter that represents the filling of the arterial tree and that effectively perfuses the tissues, is reduced. Underfilling of the arterial tree may be caused by a reduction of cardiac output and/or systemic vascular resistance, by the pooling of blood in the splanchnic veins (as in cirrhosis), and by hypoalbuminemia (Fig. 37-1A). As a consequence of this underfilling, a series of physiologic responses designed to restore the effective arterial volume to normal are set into motion. A key element of these responses is the renal retention of sodium and, therefore, water, thereby restoring effective arterial volume, but sometimes also leading to the development or intensification of edema.

■■RENAL FACTORS AND THE RENIN-ANGIOTENSINALDOSTERONE SYSTEM

The diminished renal blood flow characteristic of states in which the effective arterial blood volume is reduced is translated by the renal juxtaglomerular cells (specialized myoepithelial cells surrounding the afferent arteriole) into a signal for increased renin release. Renin is an enzyme with a molecular mass of about 40,000 Da that acts on its substrate, angiotensinogen, an α2-globulin synthesized by the liver, to release angiotensin I, a decapeptide, which in turn is converted to angiotensin II (AII), an octapeptide. AII has generalized vasoconstrictor properties, particularly on the renal efferent arterioles. This action reduces the hydrostatic pressure in the peritubular capillaries, whereas the increased filtration fraction raises the colloid osmotic pressure in these vessels, thereby enhancing salt and water reabsorption in the proximal tubule as well as in the ascending limb of the loop of Henle.

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238 ↓Extracellular fluid volume

Low output heart failure, Pericardial tamponade Constrictive pericarditis

↓Oncotic pressure and/or ↑capillary permeability

↓Cardiac output Effective arterial volume

Activation of ventricular and arterial receptors

PART 2

Nonosmotic vasopressin stimulation

Activation of RAAS

SNS stimulation

Cardinal Manifestations and Presentation of Diseases

↑Systemic and renal arterial vascular resistance

Renal H2O retention

Renal Na+ retention

Restoration of effective arterial volume A

■■ARGININE VASOPRESSIN

(See also Chap. 374) The secretion of arginine vasopressin (AVP) by the posterior pituitary gland occurs in response to increased intracellular osmolar concentration; by stimulating V2 receptors, AVP increases the reabsorption of free water in the distal tubules and collecting ducts of the kidneys, thereby increasing total-body water. Circulating AVP is elevated in many patients with heart failure secondary to a nonosmotic stimulus associated with decreased effective arterial volume and reduced compliance of the left atrium. Such patients fail to show the normal reduction of AVP with a reduction of osmolality, contributing to edema formation and hyponatremia.

■■ENDOTHELIN-1

This potent peptide vasoconstrictor is released by endothelial cells. Its concentration in the plasma is elevated in patients with severe heart failure and contributes to renal vasoconstriction, sodium retention, and edema.

■■NATRIURETIC PEPTIDES

High-output cardiac failure

Sepsis

Cirrhosis

Arteriovenous fistula

Pregnancy

Arterial vasodilators

↓Systemic vascular resistance Effective arterial volume

Activation of arterial baroreceptors Nonosmotic AVP stimulation ↑Cardiac output

Renal H2O retention

SNS stimulation

Activation of RAAS

↑Systemic arterial, vascular, and renal resistance

Renal Na+ retention

Maintenance of arterial circulatory integrity B FIGURE 37-1  Clinical conditions in which a decrease in cardiac output (A) and systemic vascular resistance (B) cause arterial underfilling with resulting neurohumoral activation and renal sodium and water retention. In addition to activating the neurohumoral axis, adrenergic stimulation causes renal vasoconstriction and enhances sodium and fluid transport by the proximal tubule epithelium. RAAS, renin-angiotensin aldosterone system; SNS, sympathetic nervous system. (Modified from RW Schrier: Ann Intern Med 113:155, 1990.)

The renin-angiotensin-aldosterone system (RAAS) operates as both a hormonal and paracrine system. Its activation causes sodium and water retention and thereby contributes to edema formation. Blockade of the conversion of angiotensin I to AII and blockade of the AII receptors enhance sodium and water excretion and reduce many forms of edema. AII that enters the systemic circulation stimulates the production of aldosterone by the zona glomerulosa of the adrenal cortex. Aldosterone in turn enhances sodium reabsorption (and potassium excretion) by the collecting tubule, further favoring edema formation. Blockade of the action of aldosterone by spironolactone or eplerenone (aldosterone antagonists) or by amiloride (a blocker of epithelial sodium channels) often induces a moderate diuresis in edematous states.

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Atrial distention causes release into the circulation of atrial natriuretic peptide (ANP), a polypeptide. A high-molecular-weight precursor of ANP is stored in secretory granules within atrial myocytes. A closely related natriuretic peptide (pre-prohormone brain natriuretic peptide) is stored primarily in ventricular myocytes and is released when ventricular diastolic pressure rises. Released ANP and BNP (which is derived from its precursor) bind to the natriuretic receptor-A, which causes: (1) excretion of sodium and water by augmenting glomerular filtration rate, inhibiting sodium reabsorption in the proximal tubule, and inhibiting release of renin and aldosterone; and (2) dilation of arterioles and venules by antagonizing the vasoconstrictor actions of AII, AVP, and sympathetic stimulation. Thus, elevated levels of natriuretic peptides have the capacity to oppose sodium retention in hypervolemic and edematous states. Although circulating levels of ANP and BNP are elevated in heart failure and in cirrhosis with ascites, these natriuretic peptides are not sufficiently potent to prevent edema formation. Indeed, in edematous states, resistance to the actions of natriuretic peptides may be increased, further reducing their effectiveness. Further discussion of the control of sodium and water balance is found in Chap. S1.

■■CLINICAL CAUSES OF EDEMA

A weight gain of several kilograms usually precedes overt manifestations of generalized edema. Anasarca refers to gross, generalized edema. Ascites (Chap. 46) and hydrothorax refer to accumulation of excess fluid in the peritoneal and pleural cavities, respectively, and are considered special forms of edema. Edema is recognized by the persistence of an indentation of the skin after pressure known as “pitting” edema. In its more subtle form, edema may be detected by noting that after the stethoscope is removed from the chest wall, the rim of the bell leaves an indentation on the skin of the chest for a few minutes. Edema may be present when the ring on a finger fits more snugly than in the past or when a patient complains

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of difficulty putting on shoes, particularly in the evening. Edema may also be recognized by puffiness of the face, which is most readily apparent in the periorbital areas.

■■GENERALIZED EDEMA

The differences among the major causes of generalized edema are shown in Table 37-1. Cardiac, renal, hepatic, or nutritional disorders are responsible for a large majority of patients with generalized edema. Consequently, the differential diagnosis of generalized edema should be directed toward identifying or excluding these several conditions.

Edema of Renal Disease  (See also Chap. 308) The edema that

occurs during the acute phase of glomerulonephritis is characteristically associated with hematuria, proteinuria, and hypertension. In most instances, the edema results from primary retention of sodium and water by the kidneys owing to renal dysfunction. This state differs from most forms of heart failure in that it is characterized by a normal (or sometimes even increased) cardiac output. Patients with chronic renal failure may also develop edema due to primary renal retention of sodium and water.

Nephrotic Syndrome and Other Hypoalbuminemic States  The primary alteration in the nephrotic syndrome is a

Hepatic Cirrhosis  (See also Chap. 337) This condition is charac-

terized in part by hepatic venous outflow obstruction, which in turn expands the splanchnic blood volume, and hepatic lymph formation. Intrahepatic hypertension acts as a stimulus for renal sodium retention and causes a reduction of effective arterial blood volume. These alterations are frequently complicated by hypoalbuminemia secondary to reduced hepatic synthesis of albumin, as well as peripheral arterial vasodilation. These effects reduce the effective arterial blood volume, leading to activation of the sodium- and water-retaining mechanisms described above (Fig. 37-1B). The concentration of circulating aldosterone often is elevated by the failure of the liver to metabolize this hormone. Initially, the excess interstitial fluid is localized preferentially proximal (upstream) to the congested portal venous system, causing ascites (Chap. 46). In later stages, particularly when there is severe hypoalbuminemia, peripheral edema may develop. A sizable accumulation of ascitic fluid may increase intraabdominal pressure and impede venous return from the lower extremities and contribute to the accumulation of the edema.

Edema

systolic emptying of the ventricle(s) and/or the impairment of ventricular relaxation promotes an accumulation of blood in the venous circulation at the expense of the effective arterial volume. In addition, the activation of the sympathetic nervous system and the RAAS (see above) acts in concert to cause renal vasoconstriction and reduction of glomerular filtration and salt and water retention. Sodium and water retention continue, and the increment in blood volume accumulates in the venous circulation, raising venous and intracapillary pressure resulting in edema (Fig. 37-1). The presence of overt cardiac disease, as manifested by cardiac enlargement and/or ventricular hypertrophy, together with clinical evidence of cardiac failure, such as dyspnea, basilar rales, venous distention, and hepatomegaly, usually indicates that edema results from heart failure. Noninvasive tests such as electrocardiography, echocardiography, and measurements of BNP (or NTproBNP) are helpful in establishing the diagnosis of heart disease. The edema of heart failure typically occurs in the dependent portions of the body.

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CHAPTER 37

Heart Failure  (See also Chap. 252) In heart failure, the impaired

diminished colloid oncotic pressure due to losses of large quantities (≥3.5 g/d) of protein into the urine, and hypoalbuminemia (50 years old, endoscopy is advocated to screen for Barrett’s metaplasia. Endoscopy is not needed in low risk patients who exhibit a therapeutic response to acid suppressants. Ambulatory esophageal pH testing using a catheter method or a wireless capsule endoscopically attached to the esophageal wall is considered for drug-refractory symptoms and atypical symptoms like unexplained chest pain. High-resolution esophageal manometry is ordered when surgical treatment of GERD is considered. A low LES pressure predicts failure of drug therapy and provides a rationale to proceed to surgery. Poor esophageal body peristalsis raises concern about postoperative dysphagia and directs the choice of surgical technique. Nonacidic reflux may be detected by combined esophageal impedance-pH testing in medicationunresponsive patients. Upper endoscopy is recommended as the initial test in patients with unexplained dyspepsia who are >55 years old or who have TABLE 41-3  Alarm Symptoms in Gastroesophageal Reflux Disease Odynophagia or dysphagia Unexplained weight loss Recurrent vomiting Occult or gross gastrointestinal bleeding Jaundice Palpable mass or adenopathy Family history of gastroesophageal malignancy

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258

PART 2 Cardinal Manifestations and Presentation of Diseases

alarm factors because of the purported elevated risks of malignancy and ulcer in these groups. However, findings of endoscopy performed for uninvestigated dyspepsia include erosive esophagitis in 13%, peptic ulcer in 8%, and gastric or esophageal malignancy in only 0.3%. Management of patients 1 billion individuals suffer one or more episodes of acute diarrhea each year. Among the 100 million persons affected annually by acute diarrhea in the United States, nearly half must restrict activities, 10% consult physicians, ~250,000 require hospitalization, and ~5000 die (primarily the elderly). The annual economic burden to society may exceed $20 billion. Acute infectious diarrhea remains one of the most common causes of mortality in developing countries, particularly among impoverished infants, accounting for 1.8 million deaths per year. Recurrent, acute diarrhea in children in tropical countries results in environmental enteropathy with long-term impacts on physical and intellectual development. Constipation, by contrast, is rarely associated with mortality and is exceedingly common in developed countries, leading to frequent self-medication and, in a third of those, to medical consultation. Population statistics on chronic diarrhea and constipation are more uncertain, perhaps due to variable definitions and reporting, but the frequency of these conditions is also high. U.S. population surveys put prevalence rates for chronic diarrhea at 2–7% and for chronic constipation at 12–19%, with women being affected twice as often as men. Diarrhea

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NORMAL PHYSIOLOGY

While the primary function of the small intestine is the digestion and assimilation of nutrients from food, the small intestine and colon together perform important functions that regulate the secretion and absorption of water and electrolytes, the storage and subsequent transport of intraluminal contents aborally, and the salvage of some nutrients that are not absorbed in the small intestine after bacterial metabolism of carbohydrate allows salvage of short-chain fatty acids. The main motor functions are summarized in Table 42-1. Alterations in fluid and electrolyte handling contribute significantly to diarrhea. Alterations in motor and sensory functions of the colon result in highly prevalent syndromes such as irritable bowel syndrome (IBS), chronic diarrhea, and chronic constipation.

259

Diarrhea and Constipation

■■FURTHER READING

and constipation are among the most common patient complaints presenting to internists and primary care physicians, and they account for nearly 50% of referrals to gastroenterologists. Although diarrhea and constipation may present as mere nuisance symptoms at one extreme, they can be severe or life threatening at the other. Even mild symptoms may signal a serious underlying gastrointestinal (GI) lesion, such as colorectal cancer, or systemic disorder, such as thyroid disease. Given the heterogeneous causes and potential severity of these common complaints, it is imperative for clinicians to appreciate the pathophysiology, etiologic classification, diagnostic strategies, and principles of management of diarrhea and constipation, so that rational and cost-effective care can be delivered.

CHAPTER 42

PPIs, and show acid reflux on pH monitoring. Surgery also is effective for some cases of nonacidic reflux. Individuals who respond less well to fundoplication include those with atypical symptoms or who have esophageal body motor disturbances. Dysphagia, gas-bloat syndrome, and gastroparesis are long-term complications of fundoplication; ~60% develop recurrent GERD symptoms over time. Studies assessing the utility and safety of gastroesophageal junction endoscopic therapies (radiofrequency therapy, transoral fundoplication, endoscopic stapling, antireflux mucosectomy) and laparoscopic magnetic sphincter augmentation to enhance gastroesophageal barrier function in GERD are ongoing. Gas and bloating can be troubling symptoms in some patients with indigestion that are difficult to treat. Dietary exclusion of gas-producing foods such as legumes and use of simethicone or activated charcoal provide benefits in some cases. Low FODMAP (fermentable oligosaccharide, disaccharide, monosaccharide, and polyol) diets and therapies to modify gut flora (nonabsorbable antibiotics, probiotics) reduce gaseous symptoms in some IBS patients. The utility of low-FODMAP diets, antibiotics, and probiotics in functional dyspepsia is unproven. Herbal remedies such as STW 5 (Iberogast, a mixture of nine herbal agents) are useful in some dyspeptic patients. Psychological treatments (e.g., behavioral therapy, psychotherapy, hypnotherapy) may be offered for refractory functional dyspepsia, but no convincing data confirm their efficacy.

■■NEURAL CONTROL

The small intestine and colon have intrinsic and extrinsic innervation. The intrinsic innervation, also called the enteric nervous system, comprises myenteric, submucosal, and mucosal neuronal layers. The function of these layers is modulated by interneurons through the actions of neurotransmitter amines or peptides, including acetylcholine, vasoactive intestinal peptide (VIP), opioids, norepinephrine, serotonin, adenosine triphosphate (ATP), and nitric oxide (NO). The myenteric plexus regulates smooth-muscle function through intermediary pacemaker-like cells called the interstitial cells of Cajal, and the submucosal plexus affects secretion, absorption, and mucosal blood flow. The enteric nervous system receives input from the extrinsic nerves, but it is capable of independent control of these functions. The extrinsic innervations of the small intestine and colon are part of the autonomic nervous system and also modulate motor and secretory functions. The parasympathetic nerves convey visceral sensory pathways from and excitatory pathways to the small intestine and colon. Parasympathetic fibers via the vagus nerve reach the small intestine and proximal colon along the branches of the superior mesenteric artery. The distal colon is supplied by sacral parasympathetic nerves (S2–4) via the pelvic plexus; these fibers course through the wall of the colon as ascending intracolonic fibers as far as, and in some instances including, the proximal colon. The chief excitatory neurotransmitters controlling motor function are acetylcholine and the tachykinins, such as substance P. The sympathetic nerve supply modulates motor functions and reaches the small intestine and colon alongside their TABLE 42-1  Normal Gastrointestinal Motility: Functions at Different Anatomic Levels Stomach and Small Bowel Synchronized MMC in fasting Accommodation, trituration, mixing, transit   Stomach ~3 h   Small bowel ~3 h Ileal reservoir empties boluses Colon: Irregular Mixing, Fermentation, Absorption, Transit Ascending, transverse: reservoirs Descending: conduit Sigmoid/rectum: volitional reservoir Abbreviation: MMC, migrating motor complex.

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260

arterial vessels. Sympathetic input to the gut is generally excitatory to sphincters and inhibitory to non-sphincteric muscle. Visceral afferents convey sensation from the gut to the central nervous system (CNS). Some afferent fibers synapse in the prevertebral ganglia and reflexly modulate intestinal motility, blood flow, and secretion.

■■INTESTINAL FLUID ABSORPTION AND SECRETION

PART 2 Cardinal Manifestations and Presentation of Diseases

On an average day, 9 L of fluid enter the GI tract, ~1 L of residual fluid reaches the colon, and the stool excretion of fluid constitutes about 0.2 L/d. The colon has a large capacitance and functional reserve and may recover up to four times its usual volume of 0.8 L/d, provided the rate of flow permits reabsorption to occur. Thus, the colon can partially compensate for excess fluid delivery to the colon that may result from intestinal absorptive or secretory disorders. In the small intestine and colon, sodium absorption is predominantly electrogenic (i.e., it can be measured as an ionic current across the membrane because there is not an equivalent loss of a cation from the cell), and uptake takes place at the apical membrane; it is compensated for by the export functions of the basolateral sodium pump. There are several active transport proteins at the apical membrane, especially in the small intestine, whereby sodium ion entry is coupled to monosaccharides (e.g., glucose through the transporter SGLT1, or fructose through GLUT-5). Glucose then exits the basal membrane through a specific transport protein, GLUT-5, creating a glucose concentration and osmotic gradient between the lumen and the intercellular space, drawing water and electrolytes passively from the lumen. A variety of neural and nonneural mediators regulate colonic fluid and electrolyte balance, including cholinergic, adrenergic, and serotonergic mediators. Angiotensin and aldosterone also influence colonic absorption, reflecting the common embryologic development of the distal colonic epithelium and the renal tubules.

■■SMALL-INTESTINAL MOTILITY

During the fasting period, the motility of the small intestine is characterized by a cyclical event called the migrating motor complex (MMC), which serves to clear nondigestible residue from the small intestine (the intestinal “housekeeper”). This organized, propagated series of contractions lasts, on average, 4 min, occurs every 60–90 min, and usually involves the entire small intestine. After food ingestion, the small intestine produces irregular, mixing contractions of relatively low amplitude, except in the distal ileum where more powerful contractions occur intermittently and empty the ileum by bolus transfers.

■■ILEOCOLONIC STORAGE AND SALVAGE

colon acts as a conduit (average transit time, 3 h). The colon is efficient at conserving sodium and water, a function that is particularly important in sodium-depleted patients in whom the small intestine alone is unable to maintain sodium balance. Diarrhea or constipation may result from alteration in the reservoir function of the proximal colon or the propulsive function of the left colon. Constipation may also result from disturbances of the rectal or sigmoid reservoir, typically as a result of dysfunction of the pelvic floor, the anal sphincters, the coordination of defecation, or dehydration.

■■COLONIC MOTILITY AND TONE

The small-intestinal MMC only rarely continues into the colon. However, short duration or phasic contractions mix colonic contents and high-amplitude (>75 mmHg) propagated contractions (HAPCs) are sometimes associated with mass movements through the colon and normally occur approximately five times per day, usually on awakening in the morning and postprandially. Increased frequency of HAPCs may result in diarrhea or urgency. The predominant phasic contractions in the colon are irregular and nonpropagated and serve a “mixing” function. Colonic tone refers to the background contractility upon which phasic contractile activity (typically contractions lasting 15°. Voluntary relaxation of the external anal sphincter (striated muscle innervated by the pudendal nerve) in response to the sensation produced by distention permits the evacuation of feces. Defecation can also be delayed voluntarily by contraction of the external anal sphincter.

The distal ileum acts as a reservoir, emptying intermittently by bolus movements. This action allows time for salvage of fluids, electrolytes, and nutrients. Segmentation by haustra compartmentalizes the colon and facilitates mixing, retention of residue, At rest During straining and formation of solid stools. There is increased appreciation of the intimate Pubis interaction between the colonic function and the luminal ecology. The resident microorganisms, predominantly anaerobic bacteria, in the colon are necessary for the digestion of unabsorbed carbohydrates that reach the Puborectalis Coccyx colon even in health, thereby providing a vital source of nutrients to the mucosa. Normal intestinal flora also Anorectal Anorectal keeps pathogens at bay by a variety of External anal angle angle sphincter mechanisms including a crucial role in Internal anal the development and maintenance of sphincter A B Descent of the pelvic floor a potent but well-regulated immune FIGURE 42-1  Sagittal view of the anorectum (A) at rest and (B) during straining to defecate. Continence is response capacity to pathogens and tolerance to normal ingesta. In health, maintained by normal rectal sensation and tonic contraction of the internal anal sphincter and the puborectalis muscle, which wraps around the anorectum, maintaining an anorectal angle between 80° and 110°. During defecation, the ascending and transverse regions the pelvic floor muscles (including the puborectalis) relax, allowing the anorectal angle to straighten by at least 15°, of colon function as reservoirs (average and the perineum descends by 1–3.5 cm. The external anal sphincter also relaxes and reduces pressure on the anal transit time, 15 h), and the descending canal. (Reproduced with permission from A Lembo, M Camilleri: N Engl J Med 349:1360, 2003.)

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DIARRHEA ■■DEFINITION

More than 90% of cases of acute diarrhea are caused by infectious agents; these cases are often accompanied by vomiting, fever, and abdominal pain. The remaining 10% or so are caused by medications, toxic ingestions, ischemia, food indiscretions, and other conditions.

Infectious Agents  Most infectious diarrheas are acquired by

fecal-oral transmission or, more commonly, via ingestion of food or water contaminated with pathogens from human or animal feces. In the immunocompetent person, the resident fecal microflora, containing >500 taxonomically distinct species, are rarely the source of diarrhea and may actually play a role in suppressing the growth of ingested pathogens. Disturbances of flora by antibiotics can lead to diarrhea by reducing the digestive function or by allowing the overgrowth of pathogens, such as Clostridium difficile (Chap. 129). Acute infection or injury occurs when the ingested agent overwhelms or bypasses the host’s mucosal immune and nonimmune (gastric acid, digestive enzymes, mucus secretion, peristalsis, and suppressive resident flora) defenses. Established clinical associations with specific enteropathogens may offer diagnostic clues. In the United States, five high-risk groups are recognized:

1. Travelers. Nearly 40% of tourists to endemic regions of Latin America, Africa, and Asia develop so-called traveler’s diarrhea, most commonly due to enterotoxigenic or enteroaggregative Escherichia coli as well as to Campylobacter, Shigella, Aeromonas, norovirus, Coronavirus, and Salmonella. Visitors to Russia (especially St. Petersburg) may have increased risk of Giardia-associated diarrhea; visitors to Nepal may acquire Cyclospora. Campers, backpackers, and swimmers in wilderness areas may become infected with Giardia. Cruise ships may be affected by outbreaks of gastroenteritis caused by agents such as norovirus. 2. Consumers of certain foods. Diarrhea closely following food consumption at a picnic, banquet, or restaurant may suggest infection with Salmonella, Campylobacter, or Shigella from chicken; enterohemorrhagic E. coli (O157:H7) from undercooked hamburger; Bacillus cereus from fried rice or other reheated food; Staphylococcus aureus or Salmonella from mayonnaise or creams; Salmonella from eggs; Listeria from fresh or frozen uncooked foods or soft cheeses; and Vibrio species, Salmonella, or acute hepatitis A from seafood, especially if raw. State departments of public health issue communications regarding food-related illnesses, which may have originated domestically or been imported, but ultimately cause epidemics in the United States (e.g., the Cyclospora epidemic of 2013 in midwestern states that resulted from bagged salads).

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Diarrhea and Constipation

■■ACUTE DIARRHEA

261

CHAPTER 42

Diarrhea is loosely defined as passage of abnormally liquid or unformed stools at an increased frequency. For adults on a typical Western diet, stool weight >200 g/d can generally be considered diarrheal. Diarrhea may be further defined as acute if 4 weeks in duration. Two common conditions, usually associated with the passage of stool totaling 50 years; often presents as acute lower abdominal pain preceding watery, then bloody diarrhea; and generally results in acute inflammatory changes in the sigmoid or left colon while sparing the rectum. Acute diarrhea may accompany colonic diverticulitis and graft-versus-host disease. Acute diarrhea, often associated with systemic compromise, can follow ingestion of toxins including organophosphate insecticides, amanita and other

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262

TABLE 42-2  Association Between Pathobiology of Causative Agents and Clinical Features in Acute Infectious Diarrhea

PART 2 Cardinal Manifestations and Presentation of Diseases

PATHOBIOLOGY/AGENTS INCUBATION PERIOD Toxin producers   Preformed toxin    Bacillus cereus, Staphylococcus 1–8 h aureus, Clostridium perfringens 8–24 h Enterotoxin   Vibrio cholerae, enterotoxigenic 8–72 h Escherichia coli, Klebsiella pneumoniae, Aeromonas species Enteroadherent  Enteropathogenic and 1–8 d enteroadherent E. coli, Giardia organisms, cryptosporidiosis, helminths Cytotoxin producers   Clostridium difficile 1–3 d  Hemorrhagic E. coli 12–72 h Invasive organisms   Minimal inflammation   Rotavirus and norovirus 1–3 d Variable inflammation   Salmonella, Campylobacter, 12 h–11 d and Aeromonas species, Vibrio parahaemolyticus, Yersinia Severe inflammation   Shigella species, enteroinvasive 12 h–8 d E. coli, Entamoeba histolytica

VOMITING

ABDOMINAL PAIN

FEVER

DIARRHEA

3–4+

1–2+

0–1+

3–4+, watery

2–4+

1–2+

0–1+

3–4+, watery

0–1+

1–3+

0–2+

1–2+, watery, mushy

0–1+ 0–1+

3–4+ 3–4+

1–2+ 1–2+

1–3+, usually watery, occasionally bloody 1–3+, initially watery, quickly bloody

1–3+

2–3+

3–4+

1–3+, watery

0–3+

2–4+

3–4+

1–4+, watery or bloody

0–1+

3–4+

3–4+

1–2+, bloody

Source: Adapted from DW Powell, in T Yamada (ed): Textbook of Gastroenterology and Hepatology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2003.

mushrooms, arsenic, and preformed toxins in seafood such as ciguatera (from algae that the fish eat) and scombroid (an excess of histamine due to inadequate refrigeration). Acute anaphylaxis to food ingestion can have a similar presentation. Conditions causing chronic diarrhea can also be confused with acute diarrhea early in their course. This confusion may occur with inflammatory bowel disease (IBD) and some of the other inflammatory chronic diarrheas that may have an abrupt rather than insidious onset and exhibit features that mimic infection.

Acute Diarrhea

History and physical exam

Likely noninfectious

Likely infectious

Evaluate and treat accordingly

APPROACH TO THE PATIENT

Acute Diarrhea The decision to evaluate acute diarrhea depends on its severity and duration and on various host factors (Fig. 42-2). Most episodes of acute diarrhea are mild and self-limited and do not justify the cost and potential morbidity rate of diagnostic or pharmacologic interventions. Indications for evaluation include profuse diarrhea with dehydration, grossly bloody stools, fever ≥38.5°C (≥101°F), duration >48 h without improvement, recent antibiotic use, new community outbreaks, associated severe abdominal pain in patients aged >50 years, and elderly (≥70 years) or immunocompromised patients. In some cases of moderately severe febrile diarrhea associated with fecal leukocytes (or increased fecal levels of the leukocyte proteins, such as calprotectin) or with gross blood, a diagnostic evaluation might be avoided in favor of an empirical antibiotic trial (see below). The cornerstone of diagnosis in those suspected of severe acute infectious diarrhea is microbiologic analysis of the stool. Workup includes cultures for bacterial and viral pathogens; direct inspection for ova and parasites; and immunoassays for certain bacterial toxins (C. difficile), viral antigens (rotavirus), and protozoal antigens (Giardia, E. histolytica). The aforementioned clinical and epidemiologic associations may assist in focusing the evaluation. If a particular pathogen or set of possible pathogens is so implicated, either the whole panel of routine studies may not be necessary or, in some instances, special cultures may be appropriate as for enterohemorrhagic and other types of E. coli, Vibrio species, and Yersinia. Molecular diagnosis of

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Mild (unrestricted)

Moderate (activities altered)

Severe (incapacitated)

Institute fluid and electrolyte replacement

Observe

Resolves

Fever ≥38.5°C, bloody stools, fecal WBCs, immunocompromised or elderly host Persists*

Stool microbiology studies

Yes†

No

Antidiarrheal agents Pathogen found Resolves

Persists* No

Empirical treatment + further evaluation

Yes†

Select specific treatment

FIGURE 42-2  Algorithm for the management of acute diarrhea. Consider empirical treatment before evaluation with (*) metronidazole and with (†) quinolone. WBCs, white blood cells.

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Acute Diarrhea Fluid and electrolyte replacement are of central importance to all forms of acute diarrhea. Fluid replacement alone may suffice for mild cases. Oral sugar-electrolyte solutions (iso-osmolar sport drinks or designed formulations) should be instituted promptly with severe diarrhea to limit dehydration, which is the major cause of death. Profoundly dehydrated patients, especially infants and the elderly, require IV rehydration. In moderately severe nonfebrile and nonbloody diarrhea, antimotility and antisecretory agents such as loperamide can be useful adjuncts to control symptoms. Such agents should be avoided with febrile dysentery, which may be exacerbated or prolonged by them. Bismuth subsalicylate may reduce symptoms of vomiting and diarrhea but should not be used to treat immunocompromised patients or those with renal impairment because of the risk of bismuth encephalopathy. Judicious use of antibiotics is appropriate in selected instances of acute diarrhea and may reduce its severity and duration (Fig. 42-2). Many physicians treat moderately to severely ill patients with febrile dysentery empirically without diagnostic evaluation using a quinolone, such as ciprofloxacin (500 mg bid for 3–5 d). Empirical treatment can also be considered for suspected giardiasis with metronidazole (250 mg qid for 7 d). Selection of antibiotics and dosage regimens are otherwise dictated by specific pathogens, geographic patterns of resistance, and conditions found (Chaps. 128, 156, and 160–166). Because of resistance to first-line treatments, newer agents such as nitazoxanide may be required for Giardia and Cryptosporidium infections. Antibiotic coverage is indicated, whether or not a causative organism is discovered, in patients who are immunocompromised, have mechanical heart valves or recent vascular grafts, or are elderly. Bismuth subsalicylate may reduce the frequency of traveler’s diarrhea. Antibiotic prophylaxis is only indicated for certain patients traveling to high-risk countries in whom the likelihood or seriousness of acquired diarrhea would be especially high, including those with immunocompromise, IBD, hemochromatosis, or gastric achlorhydria. Use of ciprofloxacin, azithromycin, or rifaximin may reduce bacterial diarrhea in such travelers by 90%, though rifaximin is not suitable for invasive disease but rather as treatment for uncomplicated traveler’s diarrhea. There is little role for endoscopic evaluation in most circumstances except in immunocompromised patients. Finally, physicians should be vigilant to identify if an outbreak of diarrheal illness is occurring and to alert the public health authorities promptly. This may reduce the ultimate size of the affected population.

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263

Diarrhea lasting >4 weeks warrants evaluation to exclude serious underlying pathology. In contrast to acute diarrhea, most of the causes of chronic diarrhea are noninfectious. The classification of chronic diarrhea by pathophysiologic mechanism facilitates a rational approach to management, although many diseases cause diarrhea by more than one mechanism (Table 42-3).

Secretory Causes  Secretory diarrheas are due to derangements in fluid and electrolyte transport across the enterocolonic mucosa. They are characterized clinically by watery, large-volume fecal outputs that are typically painless and persist with fasting. Because there is TABLE 42-3  Major Causes of Chronic Diarrhea According to Predominant Pathophysiologic Mechanism Secretory Causes            

Exogenous stimulant laxatives Chronic ethanol ingestion Other drugs and toxins Endogenous laxatives (dihydroxy bile acids) Idiopathic secretory diarrhea or bile acid diarrhea Certain bacterial infections

  Bowel resection, disease, or fistula (↓ absorption)   Partial bowel obstruction or fecal impaction  Hormone-producing tumors (carcinoid, VIPoma, medullary cancer of thyroid, mastocytosis, gastrinoma, colorectal villous adenoma)   Addison’s disease   Congenital electrolyte absorption defects

Diarrhea and Constipation

TREATMENT

■■CHRONIC DIARRHEA

CHAPTER 42

pathogens in stool can be made by identification of unique DNA sequences, and evolving microarray technologies have led to more rapid, sensitive, specific, and cost-effective diagnosis. Persistent diarrhea is commonly due to Giardia (Chap. 218), but additional causative organisms that should be considered include C. difficile (especially if antibiotics had been administered), E. histolytica, Cryptosporidium, Campylobacter, and others. If stool studies are unrevealing, flexible sigmoidoscopy with biopsies and upper endoscopy with duodenal aspirates and biopsies may be indicated. Brainerd diarrhea is an increasingly recognized entity characterized by an abrupt-onset diarrhea that persists for at least 4 weeks, but may last 1–3 years, and is thought to be of infectious origin. It may be associated with subtle inflammation of the distal small intestine or proximal colon. Structural examination by sigmoidoscopy, colonoscopy, or abdominal computed tomography (CT) scanning (or other imaging approaches) may be appropriate in patients with uncharacterized persistent diarrhea to exclude IBD or as an initial approach in patients with suspected noninfectious acute diarrhea such as might be caused by ischemic colitis, diverticulitis, or partial bowel obstruction.

Osmotic Causes        

Osmotic laxatives (Mg2+, PO4−3, SO4−2) Lactase and other disaccharide deficiencies Nonabsorbable carbohydrates (sorbitol, lactulose, polyethylene glycol) Gluten and FODMAP intolerance

Steatorrheal Causes  Intraluminal maldigestion (pancreatic exocrine insufficiency, bacterial overgrowth, bariatric surgery, liver disease)  Mucosal malabsorption (celiac sprue, Whipple’s disease, infections, abetalipoproteinemia, ischemia, drug-induced enteropathy)   Postmucosal obstruction (1° or 2° lymphatic obstruction) Inflammatory Causes   Idiopathic inflammatory bowel disease (Crohn’s, chronic ulcerative colitis)   Lymphocytic and collagenous colitis  Immune-related mucosal disease (1° or 2° immunodeficiencies, food allergy, eosinophilic gastroenteritis, graft-versus-host disease)   Infections (invasive bacteria, viruses, and parasites, Brainerd diarrhea)   Radiation injury   Gastrointestinal malignancies Dysmotile Causes   Irritable bowel syndrome (including postinfectious IBS)   Visceral neuromyopathies  Hyperthyroidism   Drugs (prokinetic agents)  Postvagotomy Factitial Causes  Munchausen   Eating disorders Iatrogenic Causes  Cholecystectomy   Ileal resection   Bariatric surgery   Vagotomy, fundoplication Abbreviation: FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols.

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264

no malabsorbed solute, stool osmolality is accounted for by normal endogenous electrolytes with no fecal osmotic gap. Side effects from regular ingestion of drugs and toxins are the most common secretory causes of chronic diarrhea. Hundreds of prescription and over-the-counter medications (see earlier section, “Acute Diarrhea, Other Causes”) may produce diarrhea. Surreptitious or habitual use of stimulant laxatives (e.g., senna, cascara, bisacodyl, ricinoleic acid [castor oil]) must also be considered. Chronic ethanol consumption may cause a secretory-type diarrhea due to enterocyte injury with impaired sodium and water absorption as well as rapid transit and other alterations. Inadvertent ingestion of certain environmental toxins (e.g., arsenic) may lead to chronic rather than acute forms of diarrhea. Certain bacterial infections may occasionally persist and be associated with a secretory-type diarrhea. The oral angiotensin-receptor blocker, olmesartan, is associated with diarrhea due to sprue-like enteropathy. BOWEL RESECTION, MUCOSAL DISEASE, OR ENTEROCOLIC FISTULA  These conditions may result in a secretory-type diarrhea because of inadequate surface for reabsorption of secreted fluids and electrolytes. Unlike other secretory diarrheas, this subset of conditions tends to worsen with eating. With disease (e.g., Crohn’s ileitis) or resection of 3 L/d; daily volumes as high as 20 L have been reported. Life-threatening dehydration; neuromuscular dysfunction from associated hypokalemia, hypomagnesemia, or hypercalcemia; flushing; and hyperglycemia may accompany a VIPoma. Medullary carcinoma of the thyroid may present with watery diarrhea caused by calcitonin, other secretory peptides, or prostaglandins. Prominent diarrhea is often associated with metastatic disease and poor prognosis. Systemic mastocytosis, which may be associated with the skin lesion

HORMONES 

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urticaria pigmentosa, may cause diarrhea that is either secretory and mediated by histamine or inflammatory due to intestinal infiltration by mast cells. Large colorectal villous adenomas may rarely be associated with a secretory diarrhea that may cause hypokalemia, can be inhibited by NSAIDs, and are apparently mediated by prostaglandins. CONGENITAL DEFECTS IN ION ABSORPTION  Rarely, defects in specific carriers associated with ion absorption cause watery diarrhea from birth. These disorders include defective Cl−/HCO3− exchange (congenital chloridorrhea) with alkalosis (which results from a mutated DRA [down-regulated in adenoma] gene) and defective Na+/H+ exchange (congenital sodium diarrhea), which results from a mutation in the NHE3 (sodium-hydrogen exchanger) gene and results in acidosis. Some hormone deficiencies may be associated with watery diarrhea, such as occurs with adrenocortical insufficiency (Addison’s disease) that may be accompanied by skin hyperpigmentation.

Osmotic Causes  Osmotic diarrhea occurs when ingested, poorly absorbable, osmotically active solutes draw enough fluid into the lumen to exceed the reabsorptive capacity of the colon. Fecal water output increases in proportion to such a solute load. Osmotic diarrhea characteristically ceases with fasting or with discontinuation of the causative agent. Ingestion of magnesium-containing antacids, health supplements, or laxatives may induce osmotic diarrhea typified by a stool osmotic gap (>50 mosmol/L): serum osmolarity (typically 290 mosmol/kg) − (2 × [fecal sodium + potassium concentration]). Measurement of fecal osmolarity is no longer recommended because, even when measured immediately after evacuation, it may be erroneous because carbohydrates are metabolized by colonic bacteria, causing an increase in osmolarity.

OSMOTIC LAXATIVES 

Carbohydrate malabsorption due to acquired or congenital defects in brush-border disaccharidases and other enzymes leads to osmotic diarrhea with a low pH. One of the most common causes of chronic diarrhea in adults is lactase deficiency, which affects three-fourths of nonwhites worldwide and 5–30% of persons in the United States; the total lactose load at any one time influences the symptoms experienced. Most patients learn to avoid milk products without requiring treatment with enzyme supplements. Some sugars, such as sorbitol, lactulose, or fructose, are frequently malabsorbed, and diarrhea ensues with ingestion of medications, gum, or candies sweetened with these poorly or incompletely absorbed sugars.

CARBOHYDRATE MALABSORPTION 

Chronic diarrhea, bloating, and abdominal pain are recognized as symptoms of non-celiac gluten intolerance (which is associated with impaired intestinal or colonic barrier function) and intolerance of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). The latter’s effects represent the interaction between the GI microbiome and the nutrients.

WHEAT AND FODMAP INTOLERANCE 

Steatorrheal Causes  Fat malabsorption may lead to greasy, foul-smelling, difficult-to-flush diarrhea often associated with weight loss and nutritional deficiencies due to concomitant malabsorption of amino acids and vitamins. Increased fecal output is caused by the osmotic effects of fatty acids, especially after bacterial hydroxylation, and, to a lesser extent, by the neutral fat. Quantitatively, steatorrhea is defined as stool fat exceeding the normal 7 g/d; rapid-transit diarrhea may result in fecal fat up to 14 g/d; daily fecal fat averages 15–25 g with small-intestinal diseases and is often >32 g with pancreatic exocrine insufficiency. Intraluminal maldigestion, mucosal malabsorption, or lymphatic obstruction may produce steatorrhea. This condition most commonly results from pancreatic exocrine insufficiency, which occurs when >90% of pancreatic secretory function is lost. Chronic pancreatitis, usually a sequel of ethanol abuse, most frequently causes pancreatic insufficiency. Other causes include cystic fibrosis, pancreatic duct obstruction, and, rarely, somatostatinoma. Bacterial overgrowth in the small intestine may deconjugate bile acids and alter micelle formation, impairing fat digestion; it occurs with stasis from a blind-loop, small-bowel diverticulum or dysmotility and is especially likely in the elderly. Finally,

INTRALUMINAL MALDIGESTION 

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cirrhosis or biliary obstruction may lead to mild steatorrhea due to deficient intraluminal bile acid concentration.

Inflammatory Causes  Inflammatory diarrheas are generally accompanied by pain, fever, bleeding, or other manifestations of inflammation. The mechanism of diarrhea may not only be exudation but, depending on lesion site, may include fat malabsorption, disrupted fluid/electrolyte absorption, and hypersecretion or hypermotility from release of cytokines and other inflammatory mediators. The unifying feature on stool analysis is the presence of leukocytes or leukocyte-derived proteins such as calprotectin. With severe inflammation, exudative protein loss can lead to anasarca (generalized edema). Any middle-aged or older person with chronic inflammatory-type diarrhea, especially with blood, should be carefully evaluated to exclude a colorectal tumor.

The illnesses in this category, which include Crohn’s disease and chronic ulcerative colitis, are among the most common organic causes of chronic diarrhea in adults and range in severity from mild to fulminant and life-threatening. They may be associated with uveitis, polyarthralgias, cholestatic liver disease (primary sclerosing cholangitis), and skin lesions (erythema nodosum, pyoderma gangrenosum). Microscopic colitis, including both lymphocytic and collagenous colitis, is an increasingly recognized cause of chronic watery diarrhea, especially in middle-aged women and those on NSAIDs, statins, proton pump inhibitors (PPIs), and selective serotonin reuptake inhibitors (SSRIs); biopsy of a normal-appearing colon is required for histologic diagnosis. It may coexist with symptoms suggesting IBS or with celiac sprue or drug-induced enteropathy. It typically responds well to anti-inflammatory drugs (e.g., bismuth), the opioid agonist loperamide, or to budesonide. IDIOPATHIC INFLAMMATORY BOWEL DISEASE 

Immunodeficiency may lead to prolonged infectious diarrhea. With selective IgA deficiency or common variable hypogammaglobulinemia, diarrhea is particularly prevalent and often the result of giardiasis, bacterial overgrowth, or sprue.

PRIMARY OR SECONDARY FORMS OF IMMUNODEFICIENCY 

EOSINOPHILIC GASTROENTERITIS  Eosinophil infiltration of the mucosa, muscularis, or serosa at any level of the GI tract may cause diarrhea,

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Chronic inflammatory diarrhea may be caused by radiation enterocolitis, chronic graft-versus-host disease, Behçet’s syndrome, and Cronkhite-Canada syndrome, among others.

OTHER CAUSES 

Dysmotility Causes  Rapid transit may accompany many diar-

rheas as a secondary or contributing phenomenon, but primary dysmotility is an unusual etiology of true diarrhea. Stool features often suggest a secretory diarrhea, but mild steatorrhea of up to 14 g of fat per day can be produced by maldigestion from rapid transit alone. Hyperthyroidism, carcinoid syndrome, and certain drugs (e.g., prostaglandins, prokinetic agents) may produce hypermotility with resultant diarrhea. Primary visceral neuromyopathies or idiopathic acquired intestinal pseudoobstruction may lead to stasis with secondary bacterial overgrowth causing diarrhea. Diabetic diarrhea, often accompanied by peripheral and generalized autonomic neuropathies, may occur in part because of intestinal dysmotility. The exceedingly common IBS (10% point prevalence, 1–2% per year incidence) is characterized by disturbed intestinal and colonic motor and sensory responses to various stimuli. Symptoms of stool frequency typically cease at night, alternate with periods of constipation, are accompanied by abdominal pain relieved with defecation, and rarely result in weight loss.

Diarrhea and Constipation

POSTMUCOSAL LYMPHATIC OBSTRUCTION  The pathophysiology of this condition, which is due to the rare congenital intestinal lymphangiectasia or to acquired lymphatic obstruction secondary to trauma, tumor, cardiac disease or infection, leads to the unique constellation of fat malabsorption with enteric losses of protein (often causing edema) and lymphocytopenia. Carbohydrate and amino acid absorption are preserved.

265

CHAPTER 42

MUCOSAL MALABSORPTION  Mucosal malabsorption occurs from a variety of enteropathies, but it most commonly occurs from celiac disease. This gluten-sensitive enteropathy affects all ages and is characterized by villous atrophy and crypt hyperplasia in the proximal small bowel and can present with fatty diarrhea associated with multiple nutritional deficiencies of varying severity. Celiac disease is much more frequent than previously thought; it affects ~1% of the population, frequently presents without steatorrhea, can mimic IBS, and has many other GI and extraintestinal manifestations. Tropical sprue may produce a similar histologic and clinical syndrome but occurs in residents of or travelers to tropical climates; abrupt onset and response to antibiotics suggest an infectious etiology. Whipple’s disease, due to the bacillus Tropheryma whipplei and histiocytic infiltration of the small-bowel mucosa, is a less common cause of steatorrhea that most typically occurs in young or middle-aged men; it is frequently associated with arthralgias, fever, lymphadenopathy, and extreme fatigue, and it may affect the CNS and endocardium. A similar clinical and histologic picture results from Mycobacterium avium-intracellulare infection in patients with AIDS. Abetalipoproteinemia is a rare defect of chylomicron formation and fat malabsorption in children, associated with acanthocytic erythrocytes, ataxia, and retinitis pigmentosa. Several other conditions may cause mucosal malabsorption including infections, especially with protozoa such as Giardia, numerous medications (e.g., olmesartan, mycophenolate mofetil, colchicine, cholestyramine, neomycin), amyloidosis, and chronic ischemia.

pain, vomiting, or ascites. Affected patients often have an atopic history, Charcot-Leyden crystals due to extruded eosinophil contents may be seen on microscopic inspection of stool, and peripheral eosinophilia is present in 50–75% of patients. While hypersensitivity to certain foods occurs in adults, true food allergy causing chronic diarrhea is rare.

Factitial Causes  Factitial diarrhea accounts for up to 15% of unexplained diarrheas referred to tertiary care centers. Either as a form of Munchausen syndrome (deception or self-injury for secondary gain) or eating disorders, some patients covertly self-administer laxatives alone or in combination with other medications (e.g., diuretics) or surreptitiously add water or urine to stool sent for analysis. Such patients are typically women, often with histories of psychiatric illness, and disproportionately from careers in health care. Hypotension and hypokalemia are common co-presenting features. The evaluation of such patients may be difficult: contamination of the stool with water or urine is suggested by very low or high stool osmolarity, respectively. Such patients often deny this possibility when confronted, but they do benefit from psychiatric counseling when they acknowledge their behavior.

APPROACH TO THE PATIENT

Chronic Diarrhea The laboratory tools available to evaluate the very common problem of chronic diarrhea are extensive, and many are costly and invasive. As such, the diagnostic evaluation must be rationally directed by a careful history, including medications, and physical examination (Fig. 42-3). When this strategy is unrevealing, simple triage tests are often warranted to direct the choice of more complex investigations (Fig. 42-3). The history, physical examination (Table 42-4), and routine blood studies should attempt to characterize the mechanism of diarrhea, identify diagnostically helpful associations, and assess the patient’s fluid/electrolyte and nutritional status. Patients should be questioned about the onset, duration, pattern, aggravating (especially diet) and relieving factors, and stool characteristics of their diarrhea. The presence or absence of fecal incontinence, fever, weight loss, pain, certain exposures (travel, medications, contacts with diarrhea), and common extraintestinal manifestations (skin changes, arthralgias, oral aphthous ulcers) should be noted. A family history of inflammatory bowel disease (IBD) or sprue may indicate those possibilities. Physical findings may offer clues such as a thyroid mass, wheezing, heart murmurs, edema, hepatomegaly, abdominal masses, lymphadenopathy, mucocutaneous abnormalities, perianal fistulas, or anal sphincter laxity. Peripheral blood leukocytosis, elevated sedimentation rate, or C-reactive protein suggests inflammation; anemia reflects blood loss or nutritional deficiencies; or eosinophilia may

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266 Chronic diarrhea Exclude iatrogenic problem: medication, surgery

Blood p.r.

PART 2

Colonoscopy + biopsy

No blood, features of malabsorption

Pain aggravated before BM, relieved with BM, sense incomplete evacuation

Fatty diarrhea

Small bowel: imaging, biopsy, aspirate

Consider functional diarrhea

Suspect IBS

Cardinal Manifestations and Presentation of Diseases

Dietary exclusion, e.g., lactose, sorbitol Limited screen for organic disease: hematology, chemistry, CRP, ESR, Fe, folate, B12, TTG-igA, C4, stool for excess fat, calprotectin

Low serum K+

Screening tests all normal

Stool vol, osm, pH; laxative screen; hormonal screen

Opioid Rx + follow-up

Low Hb, Alb; abnormal MCV, MCH; excess fat in stool

Colonoscopy + biopsy

Small bowel: x-ray, biopsy, aspirate; stool 48h fat

Persistent chronic diarrhea

Stool fat >20g/day: pancreatic function

Stool fat 14–20g/day: search for small bowel cause

Normal and stool fat 200 g/d, additional stool analyses should be performed that might include electrolyte concentration, pH, occult blood testing, leukocyte inspection (or leukocyte protein assay), fat quantitation, and laxative screens. For secretory diarrheas (watery, normal osmotic gap), possible medication-related side effects or surreptitious laxative use should be reconsidered. Microbiologic studies should be done including fecal bacterial cultures (including media for Aeromonas and Plesiomonas), inspection for ova and parasites, and Giardia antigen assay (the most sensitive test for giardiasis). Small-bowel bacterial overgrowth can be excluded by intestinal aspirates with quantitative cultures or with glucose or lactulose breath tests involving measurement of breath hydrogen, methane, or other metabolite. However, interpretation of these breath tests may be confounded by disturbances of intestinal transit. Upper endoscopy and colonoscopy with biopsies and small-bowel x-rays (formerly barium, but increasingly CT with enterography or magnetic resonance with enteroclysis) are helpful to rule out structural or occult inflammatory disease. When suggested by history or other findings, screens for peptide hormones should be pursued (e.g., serum gastrin, VIP, calcitonin, and thyroid hormone/thyroid-stimulating hormone, urinary 5-hydroxyindolacetic acid, histamine). Further evaluation of osmotic diarrhea should include tests for lactose intolerance and magnesium ingestion, the two most common causes. Low fecal pH suggests carbohydrate malabsorption; lactose malabsorption can be confirmed by lactose breath testing or by a therapeutic trial with lactose exclusion and observation of the effect of lactose challenge (e.g., a liter of milk). Lactase determination on small-bowel biopsy is not generally available. If fecal magnesium or laxative levels are elevated, inadvertent or surreptitious ingestion should be considered and psychiatric help should be sought. For those with proven fatty diarrhea, endoscopy with small-bowel biopsy (including aspiration for Giardia and quantitative cultures) should be performed; if this procedure is unrevealing, a smallbowel radiograph is often an appropriate next step. If small-bowel studies are negative or if pancreatic disease is suspected, pancreatic exocrine insufficiency should be excluded with direct tests, such as the secretin-cholecystokinin stimulation test or a variation that could be performed endoscopically. In general, indirect tests such as assay of fecal elastase or chymotrypsin activity or a bentiromide test have fallen out of favor because of low sensitivity and specificity. Chronic inflammatory-type diarrheas should be suspected by the presence of blood or leukocytes in the stool. Such findings warrant

CONSTIPATION ■■DEFINITION

Constipation is a common complaint in clinical practice and usually refers to persistent, difficult, infrequent, or seemingly incomplete defecation. Because of the wide range of normal bowel habits, constipation is difficult to define precisely. Most persons have at least three bowel movements per week; however, low stool frequency alone is not the sole criterion for the diagnosis of constipation. Many constipated patients have a normal frequency of defecation but complain of excessive straining, hard stools, lower abdominal fullness, or a sense of incomplete evacuation. The individual patient’s symptoms must be analyzed in detail to ascertain what is meant by “constipation” or “difficulty” with defecation. Stool form and consistency are well correlated with the time elapsed from the preceding defecation. Hard, pellety stools occur with slow transit, whereas loose, watery stools are associated with rapid transit. Both small pellety or very large stools are more difficult to expel than normal stools. The perception of hard stools or excessive straining is more difficult to assess objectively, and the need for enemas or digital disimpaction is a clinically useful way to corroborate the patient’s perceptions of difficult defecation. Psychosocial or cultural factors may also be important. A person whose parents attached great importance to daily defecation will

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268

TABLE 42-5  Causes of Constipation in Adults TYPES OF CONSTIPATION AND CAUSES

EXAMPLES

Recent Onset Colonic obstruction Anal sphincter spasm Medications

Chronic Constipation

Neoplasm; stricture: ischemic, diverticular, inflammatory Anal fissure, painful hemorrhoids

Clinical and basic laboratory tests Bloods, chest and abd x-ray Exclude mechanical obstruction, e.g., colonoscopy

Chronic

PART 2

Irritable bowel syndrome Medications Colonic pseudoobstruction Disorders of rectal evacuation

Cardinal Manifestations and Presentation of Diseases

Endocrinopathies Psychiatric disorders Neurologic disease Generalized muscle disease

Constipation-predominant, alternating Ca2+ blockers, antidepressants Slow-transit constipation, megacolon (rare Hirschsprung’s, Chagas’ diseases) Pelvic floor dysfunction; anismus; descending perineum syndrome; rectal mucosal prolapse; rectocele Hypothyroidism, hypercalcemia, pregnancy Depression, eating disorders, drugs Parkinsonism, multiple sclerosis, spinal cord injury Progressive systemic sclerosis

■■CAUSES

Pathophysiologically, chronic constipation generally results from inadequate fiber or fluid intake or from disordered colonic transit or anorectal function. These result from neurogastroenterologic disturbance, certain drugs, advancing age, or in association with a large number of systemic diseases that affect the GI tract (Table 42-5). Constipation of recent onset may be a symptom of significant organic disease such as tumor, anorectal irritation, or stricture. In idiopathic constipation, a subset of patients exhibits delayed emptying of the ascending and transverse colon with prolongation of transit (often in the proximal colon) and a reduced frequency of propulsive HAPCs. Outlet obstruction to defecation (also called evacuation disorders) accounts for about a quarter of cases presenting with constipation in tertiary care and may cause delayed colonic transit, which is usually corrected by biofeedback retraining of the disordered defecation. Constipation of any cause may be exacerbated by hospitalization or chronic illnesses that lead to physical or mental impairment and result in inactivity or physical immobility.

APPROACH TO THE PATIENT

Constipation A careful history should explore the patient’s symptoms and confirm whether he or she is indeed constipated based on frequency (e.g., fewer than three bowel movements per week), consistency (lumpy/hard), excessive straining, prolonged defecation time, or need to support the perineum or digitate the anorectum to facilitate stool evacuation. In the vast majority of cases (probably >90%), there is no underlying cause (e.g., cancer, depression, or hypothyroidism), and constipation responds to ample hydration, exercise, and supplementation of dietary fiber (15–25 g/d). A good diet and medication history and attention to psychosocial issues are key. Physical examination and, particularly, a rectal examination should exclude fecal impaction and most of the important diseases that present with constipation and possibly indicate features suggesting an evacuation disorder (e.g., high anal sphincter tone, failure of perineal descent, or paradoxical puborectalis contraction during straining to simulate stool evacuation). The presence of weight loss, rectal bleeding, or anemia with constipation mandates either flexible sigmoidoscopy plus barium

Consider functional bowel disease

Abnormal Slow colonic transit

No known underlying disorder

Known disorder

Anorectal manometry and balloon expulsion

Normal

Rx

become greatly concerned when he or she misses a daily bowel movement; some children withhold stool to gain attention or because of fear of pain from anal irritation; and some adults habitually ignore or delay the call to have a bowel movement.

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Normal

Colonic transit

Rectoanal angle measurement, defecation proctography?

Appropriate Rx: Rehabilitation program, surgery, or other

FIGURE 42-4  Algorithm for the management of constipation. abd, abdominal.

enema or colonoscopy alone, particularly in patients aged >40 years, to exclude structural diseases such as cancer or strictures. Colonoscopy alone is most cost-effective in this setting because it provides an opportunity to biopsy mucosal lesions, perform polypectomy, or dilate strictures. Barium enema has advantages over colonoscopy in the patient with isolated constipation because it is less costly and identifies colonic dilation and all significant mucosal lesions or strictures that are likely to present with constipation. Melanosis coli, or pigmentation of the colon mucosa, indicates the use of anthraquinone laxatives such as cascara or senna; however, this is usually apparent from a careful history. An unexpected disorder such as megacolon or cathartic colon may also be detected by colonic radiographs. Measurement of serum calcium, potassium, and thyroid-stimulating hormone levels will identify rare patients with metabolic disorders. Patients with more troublesome constipation may not respond to fiber alone and may be helped by a bowel-training regimen, which involves taking an osmotic laxative (e.g., magnesium salts, lactulose, sorbitol, polyethylene glycol) and evacuating with enema or suppository (e.g., glycerin or bisacodyl) as needed. After breakfast, a distraction-free 15–20 min on the toilet without straining is encouraged. Excessive straining may lead to development of hemorrhoids and, if there is weakness of the pelvic floor or injury to the pudendal nerve, may result in obstructed defecation from descending perineum syndrome several years later. Those few who do not benefit from the simple measures delineated above or require long-term treatment or fail to respond to potent laxatives should undergo further investigation (Fig. 42-4). Novel agents that induce secretion (e.g., lubiprostone, a chloride channel activator, or linaclotide, a guanylate cyclase C agonist that activates chloride secretion) are also available.

■■INVESTIGATION OF SEVERE CONSTIPATION

A small minority (probably 90% of those with other organic diseases have at least one laboratory abnormality. In patients presenting with substantial UWL, major organic and malignant diseases are unlikely when a baseline evaluation is completely normal. Careful follow-up rather than undirected testing is advised since the prognosis of weight loss of undetermined cause is generally favorable.

Unintentional Weight Loss

Medications  Sedatives  Antibiotics  Nonsteroidal anti-inflammatory drugs   Serotonin reuptake inhibitors  Metformin  Levodopa  Angiotensin-converting enzyme inhibitors   Other drugs Disorders of the mouth and teeth  Caries  Dysgeusia Age-related factors   Physiologic changes   Visual impairment   Decreased taste and smell   Functional disabilities Neurologic  Stroke   Parkinson’s disease   Neuromuscular disorders  Dementia Social  Isolation   Economic hardship Psychiatric and behavioral  Depression  Anxiety  Paranoia  Bereavement  Alcoholism   Eating disorders   Increased activity or exercise Idiopathic

CHAPTER 43

Cancer  Colon  Hepatobiliary  Hematologic  Lung  Breast  Genitourinary  Ovarian  Prostate Gastrointestinal disorders  Malabsorption   Peptic ulcer   Inflammatory bowel disease  Pancreatitis  Obstruction/constipation   Pernicious anemia Endocrine and metabolic  Hyperthyroidism   Diabetes mellitus  Pheochromocytoma   Adrenal insufficiency Cardiac disorders   Chronic ischemia   Chronic congestive heart failure Respiratory disorders  Emphysema  Chronic obstructive pulmonary disease Renal insufficiency Rheumatologic disease Infections  HIV  Tuberculosis   Parasitic infection   Subacute bacterial endocarditis

TREATMENT

Unintentional Weight Loss The first priority in managing weight loss is to identify and treat the underlying causes. Treatment of underlying metabolic, psychiatric, infectious, or other systemic disorders may be sufficient to restore weight and functional status gradually. Medications that cause nausea or anorexia should be withdrawn or changed, if possible. TABLE 43-2  Assessment and Testing for Involuntary Weight Loss

features and may present as “apathetic hyperthyroidism” or T3 toxicosis (Chap. 375). Neurologic injuries such as stroke, quadriplegia, and multiple sclerosis may lead to visceral and autonomic dysfunction that can impair caloric intake. Dysphagia from these neurologic insults is a common mechanism. Functional disability that compromises activities of daily living (ADLs) is a common cause of undernutrition in the elderly. Visual impairment from ophthalmic or central nervous system disorders such as a tremor can limit the ability of people to prepare and eat meals. UWL may be one of the earliest manifestations of Alzheimer’s dementia. Isolation and depression are significant causes of UWL that may manifest as an inability to care for oneself, including nutritional needs. A cytokine-mediated inflammatory metabolic cascade can be both a cause of and a manifestation of depression. Bereavement can be a cause of UWL and, when present, is often more pronounced in men. More intense forms of mental illness such as paranoid disorders may lead to delusions about food and cause weight loss. Alcoholism can be a significant source of weight loss and malnutrition. Elderly persons living in poverty may have to choose whether to purchase food or use the money for other expenses, including medications. Institutionalization is an independent risk factor, as up to 30–50% of nursing home patients have inadequate food intake. Medications can cause anorexia, nausea, vomiting, gastrointestinal distress, diarrhea, dry mouth, and changes in taste. This is particularly an issue in the elderly, many of whom take five or more medications.

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Indications

Laboratory

5% weight loss in 30 d 10% weight loss in 180 d

Complete blood count Comprehensive electrolyte and metabolic panel, including liver and renal function tests Thyroid function tests Erythrocyte sedimentation rate C-reactive protein Ferritin HIV testing, if indicated

Body mass index 3 L/d and the urine is dilute (3 L/d and urine osmolality is >300 mosmol/L, a solute diuresis is clearly present and a search for the responsible solute(s) is mandatory. Excessive filtration of a poorly reabsorbed solute such as glucose or mannitol can depress reabsorption of NaCl and water in the proximal tubule and lead to enhanced excretion in the urine. Poorly controlled diabetes mellitus with glucosuria is the most common cause of a solute diuresis, leading to volume depletion and serum hypertonicity. Since the urine sodium concentration is less than that of blood, more water than sodium is lost, causing hypernatremia and hypertonicity. Common iatrogenic solute diuresis occurs in association with mannitol administration, radiocontrast media, and high-protein feedings (enteral or parenteral), leading to increased urea production and excretion. Less commonly, excessive sodium loss may result from cystic renal diseases or Bartter’s syndrome or may develop during a tubulointerstitial process (such as resolving ATN). In these so-called salt-wasting disorders, the tubule damage results in direct impairment of sodium reabsorption and indirectly reduces the responsiveness of the tubule to aldosterone. Usually, the sodium losses are mild, and the obligatory urine output is 15–20 beats/min upon standing), and orthostatic hypotension (a >10–20 mmHg drop in blood pressure on standing). More severe fluid loss leads to hypovolemic shock, with hypotension, tachycardia, peripheral vasoconstriction, and peripheral hypoperfusion; these patients may exhibit peripheral cyanosis, cold extremities, oliguria, and altered mental status.

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298

PART 2 Cardinal Manifestations and Presentation of Diseases

Routine chemistries may reveal an increase in blood urea nitrogen (BUN) and creatinine, reflective of a decrease in GFR. Creatinine is the more dependable measure of GFR, because BUN levels may be influenced by an increase in tubular reabsorption (“prerenal azotemia”), an increase in urea generation in catabolic states, hyperalimentation, or gastrointestinal bleeding, and/or a decreased urea generation in decreased protein intake. In hypovolemic shock, liver function tests and cardiac biomarkers may show evidence of hepatic and cardiac ischemia, respectively. Routine chemistries and/or blood gases may reveal evidence of acid-base disorders. For example, bicarbonate loss due to diarrheal illness is a very common cause of metabolic acidosis; alternatively, patients with severe hypovolemic shock may develop lactic acidosis with an elevated anion gap. The neurohumoral response to hypovolemia stimulates an increase in renal tubular Na+ and water reabsorption. Therefore, the urine Na+ concentration is typically 450 mOsm/kg. The reduction in both GFR and distal tubular Na+ delivery may cause a defect in renal potassium excretion, with an increase in plasma K+ concentration. Of note, patients with hypovolemia and a hypochloremic alkalosis due to vomiting, diarrhea, or diuretics will typically have a urine Na+ concentration >20 mM and urine pH of >7.0, due to the increase in filtered HCO3–; the urine Cl– concentration in this setting is a more accurate indicator of volume status, with a level 20 mM in patients with renal causes of hypovolemia, such as acute tubular necrosis; similarly, patients with DI will have an inappropriately dilute urine.

TREATMENT

Hypovolemia The therapeutic goals in hypovolemia are to restore normovolemia and replace ongoing fluid losses. Mild hypovolemia can usually be treated with oral hydration and resumption of a normal maintenance diet. More severe hypovolemia requires intravenous hydration, tailoring the choice of solution to the underlying pathophysiology. Isotonic, “normal” saline (0.9% NaCl, 154 mM Na+) is the most appropriate resuscitation fluid for normonatremic or hyponatremic patients with severe hypovolemia; colloid solutions such as intravenous albumin are not demonstrably superior for this purpose. Hypernatremic patients should receive a hypotonic solution, 5% dextrose if there has only been water loss (as in DI), or hypotonic

saline (1/2 or 1/4 normal saline) if there has been water and Na+-Cl– loss; changes in free water administration should be made if necessary, based on frequent measuring of serum chemistries. Patients with bicarbonate loss and metabolic acidosis, as occur frequently in diarrhea, should receive intravenous bicarbonate, either an isotonic solution (150 meq of Na+-HCO3– in 5% dextrose) or a more hypotonic bicarbonate solution in dextrose or dilute saline. Patients with severe hemorrhage or anemia should receive red cell transfusions, without increasing the hematocrit beyond 35%.

SODIUM DISORDERS

Disorders of serum Na+ concentration are caused by abnormalities in water homeostasis, leading to changes in the relative ratio of Na+ to body water. Water intake and circulating AVP constitute the two key effectors in the defense of serum osmolality; defects in one or both of these two defense mechanisms cause most cases of hyponatremia and hypernatremia. In contrast, abnormalities in sodium homeostasis per se lead to a deficit or surplus of whole-body Na+-Cl– content, a key determinant of the ECFV and circulatory integrity. Notably, volume status also modulates the release of AVP by the posterior pituitary, such that hypovolemia is associated with higher circulating levels of the hormone at each level of serum osmolality. Similarly, in “hypervolemic” causes of arterial underfilling, e.g., heart failure and cirrhosis, the associated neurohumoral activation encompasses an increase in circulating AVP, leading to water retention and hyponatremia. Therefore, a key concept in sodium disorders is that the absolute plasma Na+ concentration tells one nothing about the volume status of a given patient, which furthermore must be taken into account in the diagnostic and therapeutic approach.

■■HYPONATREMIA

Hyponatremia, which is defined as a plasma Na+ concentration 20

UNa 20

Renal losses Diuretic excess Mineral corticoid deficiency Salt-losing deficiency Bicarbonaturia with renal tubal acidosis and metabolic alkalosis Ketonuria Osmotic diuresis Cerebral salt wasting syndrome

Extrarenal losses Vomiting Diarrhea Third spacing of fluids Burns Pancreatitis Trauma

Glucocorticoid deficiency Hypothyroidism Stress Drugs Syndrome of inappropriate antidiuretic hormone secretion

Hypervolemia • Total body water ↑↑ • Total body sodium ↑

UNa >20

Acute or chronic renal failure

UNa 6 mm, and a history of change (e.g., an increase in size or development of associated symptoms such as pruritus or pain).

CHAPTER 52

Lichenification: A distinctive thickening of the skin that is characterized by accentuated skin-fold markings. Scale: Excessive accumulation of stratum corneum. Crust: Dried exudate of body fluids that may be either yellow (i.e., serous crust) or red (i.e., hemorrhagic crust). Erosion: Loss of epidermis without an associated loss of dermis. Ulcer: Loss of epidermis and at least a portion of the underlying dermis. Excoriation: Linear, angular erosions that may be covered by crust and are caused by scratching. Atrophy: An acquired loss of substance. In the skin, this may appear as a depression with intact epidermis (i.e., loss of dermal or subcutaneous tissue) or as sites of shiny, delicate, wrinkled lesions (i.e., epidermal atrophy). Scar: A change in the skin secondary to trauma or inflammation. Sites may be erythematous, hypopigmented, or hyperpigmented depending on their age or character. Sites on hair-bearing areas may be characterized by destruction of hair follicles.

Papule c Red

Plaque

a

Vesicle

b

Bulla

FIGURE 52-3  A schematic representation of several common primary skin lesions (see Table 52-1).

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326

TABLE 52-4  Selected Common Dermatologic Conditions DIAGNOSIS Acne vulgaris

COMMON DISTRIBUTION Face, upper back, chest

PART 2

Rosacea

Blush area of cheeks, nose, forehead, chin

Seborrheic dermatitis Atopic dermatitis

Scalp, eyebrows, perinasal areas Antecubital and popliteal fossae; may be widespread Ankles, lower legs over medial malleoli

Stasis dermatitis

USUAL MORPHOLOGY Open and closed comedones, erythematous papules, pustules, cysts Erythema, telangiectases, papules, pustules

Cardinal Manifestations and Presentation of Diseases

Erythema with greasy yellow-brown scale Patches and plaques of erythema, scaling, and lichenification; pruritus Patches of erythema and scaling on background of hyperpigmentation associated with signs of venous insufficiency Deep vesicles

Dyshidrotic eczema

Palms, soles, sides of fingers and toes

Allergic contact dermatitis

Anywhere

Psoriasis

Elbows, knees, scalp, lower back, fingernails (may be generalized)

Lichen planus

Wrists, ankles, mouth (may be widespread) Extensor surfaces of arms and thighs, buttocks Forehead, cheeks, temples, upper lip Periorificial, trunk, extensor surfaces of extremities, flexor wrists, axillae

Violaceous flat-topped papules and plaques Keratotic follicular papules with surrounding erythema

Actinic keratosis

Sun-exposed areas

Basal cell carcinoma

Face

Squamous cell carcinoma

Face, especially lower lip, ears

Skin-colored or red-brown macule or papule with dry, rough, adherent scale Papule with pearly, telangiectatic border on sundamaged skin Indurated and possibly hyperkeratotic lesions often showing ulceration and/or crusting

Keratosis pilaris

Melasma Vitiligo

Localized erythema, vesicles, scale, and pruritus (e.g., fingers, earlobes—nickel; dorsal aspect of foot—shoe; exposed surfaces— poison ivy) Papules and plaques covered with silvery scale; nails have pits

DIAGNOSIS Seborrheic keratosis Folliculitis Impetigo Herpes simplex Herpes zoster

Varicella

Pityriasis rosea

Tinea versicolor

Trunk (Christmas tree pattern); herald patch followed by multiple smaller lesions Chest, back, abdomen, proximal extremities

Candidiasis

Groin, beneath breasts, vagina, oral cavity

Dermatophytosis

Feet, groin, beard, or scalp Groin, axillae, between fingers and toes, beneath breasts Anywhere

Scabies

Tan to brown patches

Insect bites

Chalk-white macules

Cherry angioma Keloid Dermatofibroma

Trunk Anywhere (site of previous injury) Anywhere

Symmetric erythematous papules and plaques with a collarette of scale Scaly hyper- or hypopigmented macules

Erythematous macerated areas with satellite pustules; white, friable patches on mucous membranes Varies with site (e.g., tinea corporis—scaly annular plaque) Excoriated papules, burrows, pruritus Erythematous papules with central puncta Red, blood-filled papules Firm tumor, pink, purple, or brown Firm red to brown nodule that shows dimpling of overlying skin with lateral compression Fleshy papules

Acrochordons (skin tags)

Groin, axilla, neck

Urticaria

Anywhere

Wheals, sometimes with surrounding flare; pruritus

Transient acantholytic dermatosis Xerosis

Trunk, especially anterior chest

Erythematous papules

Extensor extremities, especially legs

Dry, erythematous, scaling patches; pruritus

the formulation of a differential diagnosis (Table 52-4). For example, the finding of scaling papules, which are present in psoriasis or atopic dermatitis, places the patient in a different diagnostic category than would hemorrhagic papules, which may indicate vasculitis or sepsis (Figs. 52-4 and 52-5, respectively). It is also important to differentiate primary from secondary skin lesions. If the examiner focuses on linear erosions overlying an area of erythema and scaling, he or she may incorrectly assume that the erosion is the primary lesion and that the redness and scale are secondary, whereas the correct interpretation would be that the patient has a pruritic eczematous dermatitis with erosions caused by scratching.

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COMMON DISTRIBUTION USUAL MORPHOLOGY Trunk, face, extremities Brown plaques with adherent, greasy scale; “stuck on” appearance Any hair-bearing area Follicular pustules Anywhere Papules, vesicles, pustules, often with honey-colored crusts Lips, genitalia Grouped vesicles progressing to crusted erosions Dermatomal, usually Vesicles limited to a dermatome trunk but may be (often painful) anywhere Face, trunk, relative Lesions arise in crops and quickly sparing of extremities progress from erythematous macules, to papules, to vesicles, to pustules, to crusted sites.

APPROACH TO THE PATIENT

Skin Disorder In examining the skin it is usually advisable to assess the patient before taking an extensive history. This approach ensures that the entire cutaneous surface will be evaluated, and objective findings can be integrated with relevant historical data. Four basic features of a skin lesion must be noted and considered during a physical examination: the distribution of the eruption, the types of primary and secondary lesions, the shape of individual lesions, and the arrangement of the lesions. An ideal skin examination includes evaluation

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of the skin, hair, and nails as well as the mucous membranes of the mouth, eyes, nose, nasopharynx, and anogenital region. In the initial examination, it is important that the patient be disrobed as completely as possible to minimize chances of missing important individual skin lesions and permit accurate assessment of the distribution of the eruption. The patient should first be viewed from a distance of about 1.5–2 m (4–6 ft) so that the general character of the skin and the distribution of lesions can be evaluated. Indeed, the distribution of lesions often correlates highly with diagnosis (Fig. 52-6). For example, a hospitalized patient with a generalized erythematous exanthem is more likely to have a drug eruption than is a patient with a similar rash limited to the sun-exposed portions of the face. Once the distribution of the lesions has been established, the nature of the primary lesion must be determined. Thus, when lesions are distributed on elbows, knees, and scalp, the most likely possibility based solely on distribution is psoriasis or dermatitis herpetiformis (Figs. 52-7 and 52-8, respectively). The primary lesion in psoriasis is a scaly papule that soon forms erythematous plaques covered with a white scale, whereas that of dermatitis herpetiformis is an urticarial papule that quickly becomes a small vesicle. In this manner, identification of the primary lesion directs the examiner toward the proper diagnosis. Secondary changes in skin can also be quite helpful. For example, scale represents excessive epidermis, while

Approach to the Patient with a Skin Disorder

FIGURE 52-4  Necrotizing vasculitis. Palpable purpuric papules on the lower legs are seen in this patient with cutaneous small-vessel vasculitis. (Courtesy of Robert Swerlick, MD; with permission.)

1.  Evolution of lesions a.  Site of onset b.  Manner in which the eruption progressed or spread c. Duration d.  Periods of resolution or improvement in chronic eruptions 2.  Symptoms associated with the eruption a.  Itching, burning, pain, numbness b.  What, if anything, has relieved symptoms c.  Time of day when symptoms are most severe 3.  Current or recent medications (prescribed as well as over-the-counter) 4.  Associated systemic symptoms (e.g., malaise, fever, arthralgias) 5.  Ongoing or previous illnesses 6.  History of allergies 7.  Presence of photosensitivity 8.  Review of systems 9. Family history (particularly relevant for patients with melanoma, atopy, psoriasis, or acne) 10.  Social, sexual, or travel history

327

CHAPTER 52

crust is the result of a discontinuous epithelial cell layer. Palpation of skin lesions can yield insight into the character of an eruption. Thus, red papules on the lower extremities that blanch with pressure can be a manifestation of many different diseases, but hemorrhagic red papules that do not blanch with pressure indicate palpable purpura characteristic of necrotizing vasculitis (Fig. 52-4). The shape of lesions is also an important feature. Flat, round, erythematous papules and plaques are common in many cutaneous diseases. However, target-shaped lesions that consist in part of erythematous plaques are specific for erythema multiforme (Fig. 52-9). Likewise, the arrangement of individual lesions is important. Erythematous papules and vesicles can occur in many conditions, but their arrangement in a specific linear array suggests an external etiology such as allergic contact dermatitis (Fig. 52-10) or primary irritant dermatitis. In contrast, lesions with a generalized arrangement are common and suggest a systemic etiology. As in other branches of medicine, a complete history should be obtained to emphasize the following features:

■■DIAGNOSTIC TECHNIQUES

Many skin diseases can be diagnosed on the basis of gross clinical appearance, but sometimes relatively simple diagnostic procedures can yield valuable information. In most instances, they can be performed at the bedside with a minimum of equipment.

Skin Biopsy  A skin biopsy is a straightforward minor surgical pro-

cedure; however, it is important to biopsy a lesion that is most likely to yield diagnostic findings. This decision may require expertise in skin diseases and knowledge of superficial anatomic structures in selected areas of the body. In this procedure, a small area of skin is anesthetized with 1% lidocaine with or without epinephrine. The skin lesion in question can be excised or saucerized with a scalpel or removed by punch biopsy. In the latter technique, a punch is pressed against the surface of the skin and rotated with downward pressure until it penetrates to the subcutaneous tissue. The circular biopsy is then lifted with forceps, and the bottom is cut with iris scissors. Biopsy sites may or may not need suture closure, depending on size and location.

KOH Preparation  A potassium hydroxide (KOH) preparation is

FIGURE 52-5  Meningococcemia. An example of fulminant meningococcemia with extensive angular purpuric patches. (Courtesy of Stephen E. Gellis, MD; with permission.)

Harrisons_20e_Part2_p0065-p0418.indd 327

performed on scaling skin lesions where a fungal infection is suspected. The edge of such a lesion is scraped gently with a no. 15 scalpel blade. The removed scale is collected on a glass microscope slide and then treated with 1 or 2 drops of a solution of 10–20% KOH. KOH dissolves keratin and allows easier visualization of fungal elements. Brief heating of the slide accelerates dissolution of keratin. When the preparation is viewed under the microscope, the refractile hyphae are seen more easily when the light intensity is reduced and the condenser is lowered. This technique can be used to identify hyphae in dermatophyte infections, pseudohyphae and budding yeasts in Candida infections,

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328 Psoriasis Skin tags Epidermal inclusion cyst

Acne vulgaris

Herpes zoster

Pityriasis rosea

Seborrheic keratoses Keratosis pilaris

Cherry angioma Atopic dermatitis

Psoriasis Psoriasis

Lichen planus

PART 2

Tinea or Candida cruris Actinic keratoses

Folliculitis Dyshidrotic eczema Hand eczema

Cardinal Manifestations and Presentation of Diseases

Perianal lesions Hemorrhoids Condyloma acuminata Herpes simplex Dermatitis Vitiligo

A

Verruca vulgaris

Atopic dermatitis

Contact dermatitis Skin tags C

Stasis dermatitis

Verruca plantaris Tinea pedis

Lichen planus

Xanthelasma

Aphthous stomatitis

Acne rosacea

Geographic tongue

Perleche Acne vulgaris

Tinea pedis

Herpes labialis

Seborrheic dermatitis

Seborrheic dermatitis

Stasis ulcer

Lichen simplex chronicus B

Melasma

Basal cell carcinoma

Dermatofibroma

Asteatotic eczema

Seborrheic dermatitis

Actinic keratoses

Psoriasis

Leukoplakia Squamous cell carcinoma Oral hairy leukoplakia

D

FIGURE 52-6  Distribution of some common dermatologic diseases and lesions.

and “spaghetti and meatballs” yeast forms in tinea versicolor. The same sampling technique can be used to obtain scale for culture of selected pathogenic organisms.

Tzanck Smear  A Tzanck smear is a cytologic technique most often

Diascopy  Diascopy is designed to assess whether a skin lesion will

blanch with pressure as, for example, in determining whether a red lesion is hemorrhagic or simply blood-filled. Urticaria (Fig. 52-11) will blanch with pressure, whereas a purpuric lesion caused by necrotizing vasculitis (Fig. 52-4) will not. Diascopy is performed by pressing a microscope slide or magnifying lens against a lesion and noting the amount of blanching that occurs. Granulomas often have an opaque to transparent, brown-pink “apple jelly” appearance on diascopy.

used in the diagnosis of herpesvirus infections (herpes simplex virus [HSV] or varicella zoster virus [VZV]) (see Figs. 188-1 and 188-3). An early vesicle, not a pustule or crusted lesion, is unroofed, and the base of the lesion is scraped gently with a scalpel blade. The material is placed on a glass slide, air-dried, and stained with Giemsa or Wright’s stain. Multinucleated epithelial giant cells suggest the presence of HSV or VZV; culture, immunofluorescence microscopy, or genetic testing must be performed to identify the specific virus.

Wood’s Light  A Wood’s lamp generates 360-nm ultraviolet (“black”) light that can be used to aid the evaluation of certain skin disorders. For example, a Wood’s lamp will cause erythrasma (a superficial, intertriginous infection caused by Corynebacterium minutissimum)

FIGURE 52-7  Psoriasis. This papulosquamous skin disease is characterized by small and large erythematous papules and plaques with overlying adherent silvery scale.

FIGURE 52-8  Dermatitis herpetiformis. This disorder typically displays pruritic, grouped papulovesicles on elbows, knees, buttocks, and posterior scalp. Vesicles are often excoriated due to associated pruritus.

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CHAPTER 53 FIGURE 52-12  Vitiligo. Characteristic lesions display an acral distribution and striking depigmentation as a result of loss of melanocytes.

to show a characteristic coral pink color, and wounds colonized by Pseudomonas will appear pale blue. Tinea capitis caused by certain dermatophytes (e.g., Microsporum canis or M. audouinii) exhibits a yellow fluorescence. Pigmented lesions of the epidermis such as freckles are accentuated, while dermal pigment such as postinflammatory hyperpigmentation fades under a Wood’s light. Vitiligo (Fig. 52-12) appears totally white under a Wood’s lamp, and previously unsuspected areas of involvement often become apparent. A Wood’s lamp may also aid in the demonstration of tinea versicolor, sites of depigmentation within and/or surrounding melanomas, and in recognition of ash leaf spots in patients with tuberous sclerosis.

Patch Tests  Patch testing is designed to document sensitivity to a specific antigen. In this procedure, a battery of suspected allergens is applied to the patient’s back under occlusive dressings and allowed to remain in contact with the skin for 48 h. The dressings are removed, and the area is examined for evidence of delayed hypersensitivity reactions (e.g., erythema, edema, or papulovesicles). This test is best performed by physicians with special expertise in patch testing and is often helpful in the evaluation of patients with chronic dermatitis. ■■FURTHER READING

Bolognia JL et al (eds): Dermatology, 4th ed. Philadelphia, Elsevier, 2018. Goldsmith LA et al (eds): Fitzpatrick’s Dermatology in General Medicine, 8th ed. New York, McGraw-Hill, 2012. James WD: Andrews’ Diseases of the Skin: Clinical Dermatology, 12th ed. Philadelphia, Elsevier, 2016. FIGURE 52-10  Allergic contact dermatitis (ACD). A. An example of ACD in its acute phase, with sharply demarcated, weeping, eczematous plaques in a perioral distribution. B. ACD in its chronic phase, with an erythematous, lichenified, weeping plaque on skin chronically exposed to nickel in a metal snap. (B, Courtesy of Robert Swerlick, MD; with permission.)

53

Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders

FIGURE 52-9  Erythema multiforme. This eruption is characterized by multiple erythematous plaques with a target or iris morphology. It usually represents a hypersensitivity reaction to drugs (e.g., sulfonamides) or infections (e.g., HSV). (Courtesy of the Yale Resident’s Slide Collection; with permission.)

Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders Leslie P. Lawley, Calvin O. McCall, Thomas J. Lawley

ECZEMA AND DERMATITIS

FIGURE 52-11  Urticaria. Discrete and confluent, edematous, erythematous papules and plaques are characteristic of this whealing eruption.

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Eczema is a type of dermatitis, and these terms are often used synonymously (e.g., atopic eczema or atopic dermatitis [AD]). Eczema is a reaction pattern that presents with variable clinical findings and the common histologic finding of spongiosis (intercellular edema of the epidermis). Eczema is the final common expression for a number of disorders, including those discussed in the following sections.

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TABLE 53-1  Clinical Features of Atopic Dermatitis 1.  Pruritus and scratching 2.  Course marked by exacerbations and remissions 3.  Lesions typical of eczematous dermatitis 4. Personal or family history of atopy (asthma, allergic rhinitis, food allergies, or eczema) 5.  Clinical course lasting >6 weeks 6.  Lichenification of skin 7.  Presence of dry skin

PART 2 Cardinal Manifestations and Presentation of Diseases

Primary lesions may include erythematous macules, papules, and vesicles, which can coalesce to form patches and plaques. In severe eczema, secondary lesions from infection or excoriation, marked by weeping and crusting, may predominate. In chronic eczematous conditions, lichenification (cutaneous hypertrophy and accentuation of normal skin markings) may alter the characteristic appearance of eczema.

■■ATOPIC DERMATITIS

AD is the cutaneous expression of the atopic state, characterized by a family history of asthma, allergic rhinitis, or eczema. The prevalence of AD is increasing worldwide. Some of its features are shown in Table 53-1. The etiology of AD is only partially defined, but there is a clear genetic predisposition. When both parents are affected by AD, >80% of their children manifest the disease. When only one parent is affected, the prevalence drops to slightly >50%. A characteristic defect in AD that contributes to the pathophysiology is an impaired epidermal barrier. In many patients, a mutation in the gene encoding filaggrin, a structural protein in the stratum corneum, is responsible. Patients with AD may display a variety of immunoregulatory abnormalities, including increased IgE synthesis; increased serum IgE levels; and impaired, delayed-type hypersensitivity reactions. The clinical presentation often varies with age. Half of patients with AD present within the first year of life, and 80% present by 5 years of age. About 80% ultimately coexpress allergic rhinitis or asthma. The infantile pattern is characterized by weeping inflammatory patches and crusted plaques on the face, neck, and extensor surfaces. The childhood and adolescent pattern is typified by dermatitis of flexural skin, particularly in the antecubital and popliteal fossae (Fig. 53-1). AD may resolve spontaneously, but approximately 40% of all individuals affected as children will have dermatitis in adult life. The distribution of lesions in adults may be similar to those seen in childhood; however, adults frequently have localized disease manifesting as lichen simplex chronicus or hand eczema (see below). In patients with localized disease, AD may be suspected because of a typical personal or family history or the presence of cutaneous stigmata of AD such as perioral pallor, an extra fold of skin beneath the lower eyelid (Dennie-Morgan folds), increased palmar skin markings, and an increased incidence of

FIGURE 53-1  Atopic dermatitis. Hyperpigmentation, lichenification, and scaling in the antecubital fossae are seen in this patient with atopic dermatitis. (Courtesy of Robert Swerlick, MD; with permission.)

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cutaneous infections, particularly with Staphylococcus aureus. Regardless of other manifestations, pruritus is a prominent characteristic of AD in all age groups and is exacerbated by dry skin. Many of the cutaneous findings in affected patients, such as lichenification, are secondary to rubbing and scratching.

TREATMENT

Atopic Dermatitis Therapy for AD should include avoidance of cutaneous irritants, adequate moisturizing through the application of emollients, judicious use of topical anti-inflammatory agents, and prompt treatment of secondary infection. Patients should be instructed to bathe no more often than daily, using warm or cool water, and to use only mild bath soap. Immediately after bathing, while the skin is still moist, a topical anti-inflammatory agent in a cream or ointment base should be applied to areas of dermatitis, and all other skin areas should be lubricated with a moisturizer. Approximately 30 g of a topical agent is required to cover the entire body surface of an average adult. Low- to mid-potency topical glucocorticoids are employed in most treatment regimens for AD. Skin atrophy and the potential for systemic absorption are constant concerns, especially with more potent agents. Low-potency topical glucocorticoids or nonglucocorticoid anti-inflammatory agents should be selected for use on the face and in intertriginous areas to minimize the risk of skin atrophy. Two nonglucocorticoid anti-inflammatory agents are available: tacrolimus ointment and pimecrolimus cream. These agents are macrolide immunosuppressants that are approved by the U.S. Food and Drug Administration (FDA) for topical use in AD. Reports of broader effectiveness appear in the literature. These agents do not cause skin atrophy, nor do they suppress the hypothalamic-pituitary-adrenal axis. However, concerns have emerged regarding the potential for lymphomas in patients treated with these agents. Thus, caution should be exercised when these agents are considered. Currently, they are also more costly than topical glucocorticoids. Barrier-repair products that attempt to restore the impaired epidermal barrier are also nonglucocorticoid agents and are gaining popularity in the treatment of AD. Secondary infection of eczematous skin may lead to exacerbation of AD. Crusted and weeping skin lesions may be infected with S. aureus. When secondary infection is suspected, eczematous lesions should be cultured and patients treated with systemic antibiotics active against S. aureus. The initial use of penicillinase-resistant penicillins or cephalosporins is preferable. Dicloxacillin or cephalexin (250 mg qid for 7–10 days) is generally adequate for adults; however, antibiotic selection must be directed by culture results and clinical response. More than 50% of S. aureus isolates are now methicillin resistant in some communities. Current recommendations for the treatment of infection with these community-acquired methicillin-resistant S. aureus (CA-MRSA) strains in adults include trimethoprim-sulfamethoxazole (one double-strength tablet bid), minocycline (100 mg bid), doxycycline (100 mg bid), or clindamycin (300–450 mg qid). Duration of therapy should be 7–10 days. Inducible resistance may limit clindamycin’s usefulness. Such resistance can be detected by the double-disk diffusion test, which should be ordered if the isolate is erythromycin resistant and clindamycin sensitive. As an adjunct, antibacterial washes or dilute sodium hypochlorite baths (0.005% bleach) and intermittent nasal mupirocin may be useful. Control of pruritus is essential for treatment, because AD often represents “an itch that rashes.” Antihistamines are most often used to control pruritus. Diphenhydramine (25 mg every 4–6 h), hydroxyzine (10–25 mg every 6 h), or doxepin (10–25 mg at bedtime) are useful primarily due to their sedating action. Higher doses of these agents may be required, but sedation can become bothersome. Patients need to be counseled about driving or operating heavy equipment after taking these medications. When used at bedtime, sedating antihistamines may improve the patient’s sleep. Although they are effective in urticaria, nonsedating antihistamines and selective H2 blockers are of little use in controlling the pruritus of AD.

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■■LICHEN SIMPLEX CHRONICUS

■■CONTACT DERMATITIS

Contact dermatitis is an inflammatory skin process caused by an exogenous agent or agents that directly or indirectly injure the skin. In irritant contact dermatitis (ICD), this injury is caused by an inherent characteristic of a compound—for example, a concentrated acid or base. Agents that cause allergic contact dermatitis (ACD) induce an antigen-specific immune response (e.g., poison ivy dermatitis). The clinical lesions of contact dermatitis may be acute (wet and edematous) or chronic (dry, thickened, and scaly), depending on the persistence of the insult (see Chap. 52, Fig. 52-10).

Irritant Contact Dermatitis  ICD is generally well demarcated and often localized to areas of thin skin (eyelids, intertriginous areas) or areas where the irritant was occluded. Lesions may range from minimal skin erythema to areas of marked edema, vesicles, and ulcers. Prior exposure to the offending agent is not necessary, and the reaction develops in minutes to a few hours. Chronic low-grade irritant dermatitis is the most common type of ICD, and the most common area of involvement is the hands (see below). The most common irritants encountered are chronic wet work, soaps, and detergents. Treatment should be directed toward the avoidance of irritants and the use of protective gloves or clothing. Allergic Contact Dermatitis  ACD is a manifestation of

■■HAND ECZEMA

Hand eczema is a very common, chronic skin disorder in which both exogenous and endogenous factors play important roles. It may be associated with other cutaneous disorders such as AD, and contact with various agents may be involved. Hand eczema represents a large proportion of cases of occupation-associated skin disease. Chronic, excessive exposure to water and detergents, harsh chemicals, or allergens may initiate or aggravate this disorder. It may present with dryness and cracking of the skin of the hands as well as with variable amounts of erythema and edema. Often, the dermatitis will begin under rings, where water and irritants are trapped. Dyshidrotic eczema, a variant of hand eczema, presents with multiple, intensely pruritic, small papules and vesicles on the thenar and hypothenar eminences and the sides of the fingers (Fig. 53-2). Lesions tend to occur in crops that slowly form crusts and then heal. The evaluation of a patient with hand eczema should include an assessment of potential occupation-associated exposures. The history should be directed to identifying possible irritant or allergen exposures.

TREATMENT

Hand Eczema Therapy for hand eczema is directed toward avoidance of irritants, identification of possible contact allergens, treatment of coexistent infection, and application of topical glucocorticoids. Whenever possible, the hands should be protected by gloves, preferably vinyl.

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Lichen simplex chronicus may represent the end stage of a variety of pruritic and eczematous disorders, including AD. It consists of a circumscribed plaque or plaques of lichenified skin due to chronic scratching or rubbing. Common areas involved include the posterior nuchal region, dorsum of the feet, and ankles. Treatment of lichen simplex chronicus centers on breaking the cycle of chronic itching and scratching. High-potency topical glucocorticoids are helpful in most cases, but, in recalcitrant cases, application of topical glucocorticoids under occlusion or intralesional injection of glucocorticoids may be required.

while the dermatitis runs its course. For those patients who require systemic therapy, daily oral prednisone—beginning at 1 mg/kg, but usually ≤60 mg/d—is sufficient. The dose should be tapered over 2–3 weeks, and each daily dose should be taken in the morning with food. Identification of a contact allergen can be a difficult and timeconsuming task. Allergic contact dermatitis should be suspected in patients with dermatitis unresponsive to conventional therapy or with an unusual and patterned distribution. Patients should be questioned carefully regarding occupational exposures and topical medications. Common sensitizers include preservatives in topical preparations, nickel sulfate, potassium dichromate, thimerosal, neomycin sulfate, fragrances, formaldehyde, and rubber-curing agents. Patch testing is helpful in identifying these agents but should not be attempted when patients have widespread active dermatitis or are taking systemic glucocorticoids.

CHAPTER 53

Treatment with systemic glucocorticoids should be limited to severe exacerbations unresponsive to topical therapy. In the patient with chronic AD, therapy with systemic glucocorticoids will generally clear the skin only briefly, and cessation of the systemic therapy will invariably be accompanied by a return, if not a worsening, of the dermatitis. Patients who do not respond to conventional therapies should be considered for patch testing to rule out allergic contact dermatitis (ACD). The role of dietary allergens in AD is controversial, and there is little evidence that they play any role outside of infancy, during which a small percentage of patients with AD may be affected by food allergens.

delayed-type hypersensitivity mediated by memory T lymphocytes in the skin. Prior exposure to the offending agent is necessary to develop the hypersensitivity reaction, which may take as little as 12 h or as much as 72 h to develop. The most common cause of ACD is exposure to plants, especially to members of the family Anacardiaceae, including the genus Toxicodendron. Poison ivy, poison oak, and poison sumac are members of this genus and cause an allergic reaction marked by erythema, vesiculation, and severe pruritus. The eruption is often linear or angular, corresponding to areas where plants have touched the skin. The sensitizing antigen common to these plants is urushiol, an oleoresin containing the active ingredient pentadecylcatechol. The oleoresin may adhere to skin, clothing, tools, and pets, and contaminated articles may cause dermatitis even after prolonged storage. Blister fluid does not contain urushiol and is not capable of inducing skin eruption in exposed subjects.

TREATMENT

Contact Dermatitis If contact dermatitis is suspected and an offending agent is identified and removed, the eruption will resolve. Usually, treatment with high-potency topical glucocorticoids is enough to relieve symptoms

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FIGURE 53-2  Dyshidrotic eczema. This example is characterized by deep-seated vesicles and scaling on palms and lateral fingers, and the disease is often associated with an atopic diathesis.

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PART 2

The use of rubber gloves (latex) to protect dermatitic skin is sometimes associated with the development of hypersensitivity reactions to components of the gloves, which could be a type I hypersensitivity reaction to the latex manifested by the development of hives, itching, angioedema, and possibly anaphylaxis within minutes to hours of exposure or a type IV hypersensitivity reaction to rubber accelerators with worsening of eczematous eruptions days after exposure. Patients can be treated with cool moist compresses followed by application of a mid- to high-potency topical glucocorticoid in a cream or ointment base. As in AD, treatment of secondary infection is essential for good control. In addition, patients with hand eczema should be examined for dermatophyte infection by potassium hydroxide (KOH) preparation and culture (see below).

Cardinal Manifestations and Presentation of Diseases

■■NUMMULAR ECZEMA

Nummular eczema is characterized by circular or oval “coinlike” lesions, beginning as small edematous papules that become crusted and scaly. The etiology of nummular eczema is unknown, but dry skin is a contributing factor. Common locations are the trunk or the extensor surfaces of the extremities, particularly on the pretibial areas or dorsum of the hands. Nummular eczema occurs more frequently in men and is most common in middle age. The treatment of nummular eczema is similar to that for AD.

■■ASTEATOTIC ECZEMA

Asteatotic eczema, also known as xerotic eczema or “winter itch,” is a mildly inflammatory dermatitis that develops in areas of extremely dry skin, especially during the dry winter months. Clinically, there may be considerable overlap with nummular eczema. This form of eczema accounts for a large number of physician visits because of the associated pruritus. Fine cracks and scale, with or without erythema, characteristically develop in areas of dry skin, especially on the anterior surfaces of the lower extremities in elderly patients. Asteatotic eczema responds well to topical moisturizers and the avoidance of cutaneous irritants. Overbathing and the use of harsh soaps exacerbate asteatotic eczema.

■■STASIS DERMATITIS AND STASIS ULCERATION

Stasis dermatitis develops on the lower extremities secondary to venous incompetence and chronic edema. Patients may give a history of deep venous thrombosis and may have evidence of vein removal or varicose veins. Early findings in stasis dermatitis consist of mild erythema and scaling associated with pruritus. The typical initial site of involvement is the medial aspect of the ankle, often over a distended vein (Fig. 53-3).

Stasis dermatitis may become acutely inflamed, with crusting and exudate. In this state, it is easily confused with cellulitis. Of note, symmetrical and bilateral involvement is more likely stasis dermatitis whereas unilateral involvement may represent cellulitis. Chronic stasis dermatitis is often associated with dermal fibrosis that is recognized clinically as brawny edema of the skin. As the disorder progresses, the dermatitis becomes progressively pigmented due to chronic erythrocyte extravasation leading to cutaneous hemosiderin deposition. Stasis dermatitis may be complicated by secondary infection and contact dermatitis. Severe stasis dermatitis may precede the development of stasis ulcers.

TREATMENT

Stasis Dermatitis and Stasis Ulceration Patients with stasis dermatitis and stasis ulceration benefit greatly from leg elevation and the routine use of compression stockings with a gradient of at least 30–40 mmHg. Stockings providing less compression, such as antiembolism hose, are poor substitutes. Use of emollients and/or mid-potency topical glucocorticoids and avoidance of irritants are also helpful in treating stasis dermatitis. Protection of the legs from injury, including scratching, and control of chronic edema are essential to prevent ulcers. Diuretics may be required to adequately control chronic edema. Stasis ulcers are difficult to treat, and resolution is slow. It is extremely important to elevate the affected limb as much as possible. The ulcer should be kept clear of necrotic material by gentle debridement and covered with a semipermeable dressing and a compression dressing or compression stocking. Glucocorticoids should not be applied to ulcers, because they may retard healing; however, they may be applied to the surrounding skin to control itching, scratching, and additional trauma. Secondarily infected lesions should be treated with appropriate oral antibiotics, but it should be noted that all ulcers will become colonized with bacteria, and the purpose of antibiotic therapy should not be to clear all bacterial growth. Care must be taken to exclude treatable causes of leg ulcers (hypercoagulation, vasculitis) before beginning the chronic management outlined above.

■■SEBORRHEIC DERMATITIS

Seborrheic dermatitis is a common, chronic disorder characterized by greasy scales overlying erythematous patches or plaques. Induration and scale are generally less prominent than in psoriasis, but clinical overlap exists between these diseases (“sebopsoriasis”). The most common location is in the scalp, where it may be recognized as severe dandruff. On the face, seborrheic dermatitis affects the eyebrows, eyelids, glabella, and nasolabial folds (Fig. 53-4). Scaling of the external auditory canal is common in seborrheic dermatitis. In addition, the postauricular areas often become macerated and tender. Seborrheic dermatitis may also develop in the central chest, axilla, groin, submammary folds, and gluteal cleft. Rarely, it may cause widespread generalized dermatitis. Pruritus is variable. Seborrheic dermatitis may be evident within the first few weeks of life, and within this context it typically occurs in the scalp (“cradle cap”), face, or groin. It is rarely seen in children beyond infancy but becomes evident again during adolescent and adult life. Although it is frequently seen in patients with Parkinson’s disease, in those who have had cerebrovascular accidents, and in those with HIV infection, the overwhelming majority of individuals with seborrheic dermatitis have no underlying disorder.

TREATMENT

Seborrheic Dermatitis FIGURE 53-3  Stasis dermatitis. An example of stasis dermatitis showing erythematous, scaly, and oozing patches over the lower leg. Several stasis ulcers are also seen in this patient.

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Treatment with low-potency topical glucocorticoids in conjunction with a topical antifungal agent, such as ketoconazole cream or ciclopirox cream, is often effective. The scalp and beard areas

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PAPULOSQUAMOUS DISORDERS (TABLE 53-2) ■■PSORIASIS

Psoriasis is one of the most common dermatologic diseases, affecting up to 2% of the world’s population. It is an immune-mediated disease clinically characterized by erythematous, sharply demarcated papules and rounded plaques covered by silvery micaceous scale. The skin lesions of psoriasis are variably pruritic. Traumatized areas often develop lesions of psoriasis (the Koebner or isomorphic phenomenon). In addition, other external factors may exacerbate psoriasis, including infections, stress, and medications (lithium, beta blockers, and antimalarial drugs). The most common variety of psoriasis is called plaque-type. Patients with plaque-type psoriasis have stable, slowly enlarging plaques, which remain basically unchanged for long periods of time. The most commonly involved areas are the elbows, knees, gluteal cleft, and scalp. Involvement tends to be symmetric. Plaque psoriasis generally develops slowly and runs an indolent course. It rarely remits spontaneously.

Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders

may benefit from antidandruff shampoos, which should be left in place 3–5 min before rinsing. High-potency topical glucocorticoid solutions (betamethasone or clobetasol) are effective for control of severe scalp involvement. High-potency glucocorticoids should not be used on the face because this treatment is often associated with steroid-induced rosacea or atrophy.

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CHAPTER 53

FIGURE 53-4  Seborrheic dermatitis. Central facial erythema with overlying greasy, yellowish scale is seen in this patient. (Courtesy of Jean Bolognia, MD; with permission.)

Inverse psoriasis affects the intertriginous regions, including the axilla, groin, submammary region, and navel; it also tends to affect the scalp, palms, and soles. The individual lesions are sharply demarcated plaques (see Chap. 52, Fig. 52-7), but they may be moist and without scale due to their locations. Guttate psoriasis (eruptive psoriasis) is most common in children and young adults. It develops acutely in individuals without psoriasis or in those with chronic plaque psoriasis. Patients present with many small erythematous, scaling papules, frequently after upper respiratory tract infection with β-hemolytic streptococci. The differential diagnosis should include pityriasis rosea and secondary syphilis. In pustular psoriasis, patients may have disease localized to the palms and soles, or the disease may be generalized. Regardless of the extent of disease, the skin is erythematous, with pustules and variable scale. Localized to the palms and soles, it is easily confused with eczema. When it is generalized, episodes are characterized by fever (39°–40°C [102.2°–104.0°F]) lasting several days, an accompanying generalized eruption of sterile pustules, and a background of intense erythema; patients may become erythrodermic. Episodes of fever and pustules are recurrent. Local irritants, pregnancy, medications, infections, and systemic glucocorticoid withdrawal can precipitate this form of psoriasis. Oral retinoids are the treatment of choice in nonpregnant patients. Fingernail involvement, appearing as punctate pitting, onycholysis, nail thickening, or subungual hyperkeratosis, may be a clue to the diagnosis of psoriasis when the clinical presentation is not classic. According to the National Psoriasis Foundation, up to 30% of patients with psoriasis have psoriatic arthritis (PsA). It develops most commonly between the ages of 30 and 50 years. There are five subtypes of PsA: symmetric PsA, asymmetric PsA, distal PsA, spondylitis, and arthritis mutilans. Approximately 50% of PsA is classified as symmetric, which may resemble rheumatoid arthritis. Asymmetric arthritis comprises about 35% of cases. It can involve any joint and may present as “sausage digits.” Distal PsA is the classic form; however, it occurs in only about 5% of patients with PsA. It can involve fingers and toes; fingernails and toenails are often dystrophic, including nail pitting. Spondylitis also occurs in ~5% of patients with PsA. Arthritis mutilans is severe and deforming, and affects primarily the small joints of the hands and feet. It accounts for fewer than 5% of PsA cases. An increased risk of metabolic syndrome, including increased morbidity and mortality from cardiovascular events, has been demonstrated in psoriasis patients. Appropriate screening tests should be performed. The etiology of psoriasis is still poorly understood, but there is clearly a genetic component to the disease. In various studies, 30–50% of patients with psoriasis report a positive family history. Psoriatic lesions contain infiltrates of activated T cells that are thought to elaborate cytokines responsible for keratinocyte hyperproliferation, which results in the characteristic clinical findings. Agents inhibiting T cell activation, clonal expansion, or release of proinflammatory cytokines are often effective for the treatment of severe psoriasis (see below).

TABLE 53-2  Papulosquamous Disorders Psoriasis

Lichen planus

Pityriasis rosea

Dermatophytosis

CLINICAL FEATURES Sharply demarcated, erythematous plaques with micalike scale; predominantly on elbows, knees, and scalp; atypical forms may localize to intertriginous areas; eruptive forms may be associated with infection Purple polygonal papules marked by severe pruritus; lacy white markings, especially associated with mucous membrane lesions Rash often preceded by herald patch; oval to round plaques with trailing scale; most often affects trunk; eruption lines up in skinfolds giving a “fir tree–like” appearance; generally spares palms and soles Polymorphous appearance depending on dermatophyte, body site, and host response; sharply defined to illdemarcated scaly plaques with or without inflammation; may be associated with hair loss

OTHER NOTABLE FEATURES May be aggravated by certain drugs, infection; severe forms seen in association with HIV

HISTOLOGIC FEATURES Acanthosis, vascular proliferation

Certain drugs may induce: thiazides, antimalarial drugs

Interface dermatitis

Variable pruritus; self-limited, resolving Pathologic features often nonspecific in 2–8 weeks; may be imitated by secondary syphilis KOH preparation may show branching hyphae; culture helpful

Hyphae and neutrophils in stratum corneum

Abbreviations: HIV, human immunodeficiency virus; KOH, potassium hydroxide.

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TREATMENT

Psoriasis

PART 2

Treatment of psoriasis depends on the type, location, and extent of disease. All patients should be instructed to avoid excess drying or irritation of their skin and to maintain adequate cutaneous hydration. Most cases of localized, plaque-type psoriasis can be managed with mid-potency topical glucocorticoids, although their long-term use is often accompanied by loss of effectiveness (tachyphylaxis) and atrophy of the skin. A topical vitamin D analogue (calcipotriene) and a retinoid (tazarotene) are also efficacious in the treatment of limited psoriasis and have largely replaced other topical agents such as coal tar, salicylic acid, and anthralin. Ultraviolet (UV) light, natural or artificial, is an effective therapy for many patients with widespread psoriasis. Ultraviolet B (UVB), narrowband UVB, and ultraviolet A (UVA) light with either oral or topical psoralens (PUVA) are used clinically. UV light’s immunosuppressive properties are thought to be responsible for its therapeutic activity in psoriasis. It is also mutagenic, potentially leading to an increased incidence of nonmelanoma and melanoma skin cancer. UV-light therapy is contraindicated in patients receiving cyclosporine and should be used with great care in all immunocompromised patients due to the increased risk of skin cancer. Various systemic agents can be used for severe, widespread psoriatic disease (Table 53-3). Oral glucocorticoids should not be used for the treatment of psoriasis due to the potential for development of life-threatening pustular psoriasis when therapy is discontinued. Methotrexate is an effective agent, especially in patients with PsA. The synthetic retinoid acitretin is useful, especially when immunosuppression must be avoided; however, teratogenicity limits its use. Apremilast is a new oral agent that inhibits phosphodiesterase type 4. It is approved for both psoriasis and PsA. It must be used cautiously in the presence of renal failure or depression. The evidence implicating psoriasis as a T cell–mediated disorder has directed therapeutic efforts to immunoregulation. Cyclosporine and other immunosuppressive agents can be very effective in the treatment of psoriasis, and much attention is currently directed toward the development of biologic agents with more selective immunosuppressive properties and better safety profiles (Table 53-4). Experience with some of these biologic agents is limited, and information regarding combination therapy and adverse events continues to emerge. These biologic agents appear to be quite efficacious in treatment of psoriasis and are well tolerated; however, caution with certain patient comorbidities must be exercised. Use of tumor necrosis factor-α (TNF-α) inhibitors may worsen congestive heart failure (CHF), and they should be used with caution in patients at risk for or known to have CHF. Further, none of the immunosuppressive agents used in the treatment of psoriasis should be initiated if the patient has a severe infection (including TB, HIV, hepatitis B or C); patients on such therapy should be routinely screened for tuberculosis. There have been reports of progressive multifocal leukoencephalopathy and lupus erythematosus in association with treatment with the TNF-α inhibitors. Malignancies, including a risk or history

of certain malignancies, may limit the use of these systemic agents. In general, immunosuppressive agents have also been linked to an increase risk of skin cancer and patients receiving these agents should be monitored for the development of skin cancer.

■■LICHEN PLANUS

Cardinal Manifestations and Presentation of Diseases

Lichen planus (LP) is a papulosquamous disorder that may affect the skin, scalp, nails, and mucous membranes. The primary cutaneous lesions are pruritic, polygonal, flat-topped, violaceous papules. Close examination of the surface of these papules often reveals a network of gray lines (Wickham’s striae). The skin lesions may occur anywhere but have a predilection for the wrists, shins, lower back, and genitalia (Fig. 53-5). Involvement of the scalp (lichen planopilaris) may lead to scarring alopecia, and nail involvement may lead to permanent deformity or loss of fingernails and toenails. LP commonly involves mucous membranes, particularly the buccal mucosa, where it can present on a spectrum ranging from a mild, white, reticulate eruption of the mucosa to a severe, erosive stomatitis. Erosive stomatitis may persist for years and may be linked to an increased risk of oral squamous cell carcinoma. Cutaneous eruptions clinically resembling LP have been observed after administration of numerous drugs, including thiazide diuretics, gold, antimalarial agents, penicillamine, and phenothiazines, and in patients with skin lesions of chronic graft-versus-host disease. In addition, LP may be associated with hepatitis C infection. The course of LP is variable, but most patients have spontaneous remissions 6 months to 2 years after the onset of disease. Topical glucocorticoids are the mainstay of therapy.

■■PITYRIASIS ROSEA

Pityriasis rosea (PR) is a papulosquamous eruption of unknown etiology occurring more commonly in the spring and fall. Its first manifestation is the development of a 2- to 6-cm annular lesion (the herald patch). This is followed in a few days to a few weeks by the appearance of many smaller annular or papular lesions with a predilection to occur on the trunk (Fig. 53-6). The lesions are generally oval, with their long axis parallel to the skinfold lines. Individual lesions may range in color from red to brown and have a trailing scale. PR shares many clinical features with the eruption of secondary syphilis, but palm and sole lesions are extremely rare in PR and common in secondary syphilis. The eruption tends to be moderately pruritic and lasts 3–8 weeks. Treatment is directed at alleviating pruritus and consists of oral antihistamines; mid-potency topical glucocorticoids; and, in some cases, UVB phototherapy.

CUTANEOUS INFECTIONS (TABLE 53-5) ■■IMPETIGO, ECTHYMA, AND FURUNCULOSIS

Impetigo is a common superficial bacterial infection of skin caused most often by S. aureus (Chap. 142) and in some cases by group A β-hemolytic streptococci (Chap. 143). The primary lesion is a superficial pustule that ruptures and forms a characteristic yellow-brown honey-colored crust (see Chap. 143, Fig. 143-3). Lesions may occur on normal skin (primary infection) or in areas already affected by another

TABLE 53-3  FDA-Approved Systemic Therapy for Psoriasis ADMINISTRATION AGENT Methotrexate

MEDICATION CLASS Antimetabolite

ROUTE Oral

FREQUENCY Weeklya

Acitretin

Retinoid

Oral

Daily

Cyclosporine

Calcineurin inhibitor

Oral

Twice daily

Apremilast

Phosphodiesterase type 4 inhibitor

Oral

Twice dailyb

ADVERSE EVENTS (SELECTED) Hepatotoxicity, pulmonary toxicity, pancytopenia, potential for increased malignancies, ulcerative stomatitis, nausea, diarrhea, teratogenicity Teratogenicity, hepatotoxicity, hyperostosis, hyperlipidemia/pancreatitis, depression, ophthalmologic effects, pseudotumor cerebri Renal dysfunction, hypertension, hyperkalemia, hyperuricemia, hypomagnesemia, hyperlipidemia, increased risk of malignancies Hypersensitivity reaction, depression, nausea, diarrhea, vomiting, dyspepsia, weight loss, headache, fatigue

Abbreviation: FDA, Food and Drug Administration. Initial test dose is required. bInitial dose escalation is required.

a

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335

TABLE 53-4  FDA-Approved Biologics for Psoriasis or Psoriatic Arthritis ADMINISTRATION AGENT Etanercept

MECHANISM OF ACTION

ROUTE SC

FREQUENCY Once or twice weeklya

Adalimumab

Anti-TNF-α

Ps, PsA

SC

Every other weeka

Infliximab

Anti-TNF-α

Ps, PsA

IV

Every 8 weeksa

Golimumab

Anti-TNF-α

PsA

SC

Every 4 or 8 weeks

Ustekinumab

Anti-IL-12 and anti-IL-23

Ps, PsA

SC

Every 12 weeksa

Certolizumab pegol

Anti-TNF-α

PsA

SC

Every 2 or 4 weeksa

Secukinumab

Anti-IL-17

Ps, PsA

SC

Every 4 weeksa

Ixekizumab

Anti-IL-17

Ps

SC

Every 4 weeksa

WARNINGS, SELECTED Serious infections, hepatotoxicity, CHF, hematologic events, hypersensitivity reactions, neurologic events, potential for increased malignancies Serious infections, hepatotoxicity, CHF, hematologic events, hypersensitivity reactions, neurologic events, potential for increased malignancies Serious infections, hepatotoxicity, CHF, hematologic events, hypersensitivity reactions, neurologic events, potential for increased malignancies Serious infections, hepatotoxicity, CHF, hypersensitivity reactions, neurologic events, potential for increased malignancies Serious infections, neurologic events, potential for increased malignancies Serious infections, CHF, hematologic events, hypersensitivity reactions, neurologic events, potential for increased malignancies, hepatotoxicity Serious infections, hypersensitivity reaction, inflammatory bowel disease Serious infections, hypersensitivity reaction, inflammatory bowel disease

Initial dose modifications required.

a

Abbreviations: CHF, congestive heart failure; IL, interleukin; IV, intravenous; Ps, psoriasis; PsA, psoriatic arthritis; SC, subcutaneous; TNF-α, tumor necrosis factor-α.

skin disease (secondary infection). Lesions caused by staphylococci may be tense, clear bullae, and this less common form of the disease is called bullous impetigo. Blisters are caused by the production of exfoliative toxin by S. aureus phage type II. This is the same toxin responsible for staphylococcal scalded-skin syndrome, often resulting in dramatic loss of the superficial epidermis due to blistering. The latter syndrome is much more common in children than in adults; however, it should be considered along with toxic epidermal necrolysis and severe drug eruptions in patients with widespread blistering of the skin. Ecthyma is a deep nonbullous variant of impetigo that causes punched-out ulcerative lesions. It is more often caused by a primary or secondary infection with Streptococcus pyogenes. Ecthyma is a deeper infection than typical impetigo and resolves with scars. Treatment of both ecthyma and impetigo involves gentle debridement of adherent crusts, which is facilitated by the use of soaks and topical antibiotics in conjunction with appropriate oral antibiotics. Furunculosis is also caused by S. aureus, and this disorder has gained prominence in the last decade because of CA-MRSA. A furuncle, or boil, is a painful, erythematous nodule that can occur on any

FIGURE 53-5  Lichen planus. An example of lichen planus showing multiple flat-topped, violaceous papules and plaques. Nail dystrophy, as seen in this patient’s thumbnail, may also be a feature. (Courtesy of Robert Swerlick, MD; with permission.)

Harrisons_20e_Part2_p0065-p0418.indd 335

cutaneous surface. The lesions may be solitary but are most often multiple. Patients frequently believe they have been bitten by spiders or insects. Family members or close contacts may also be affected. Furuncles can rupture and drain spontaneously or may need incision and drainage, which may be adequate therapy for small solitary furuncles without cellulitis or systemic symptoms. Whenever possible, lesional material should be sent for culture. Current recommendations for methicillin-sensitive infections are β-lactam antibiotics. Therapy for CA-MRSA is discussed previously (see “Atopic Dermatitis”). Warm compresses and nasal mupirocin are helpful therapeutic additions. Severe infections may require IV antibiotics.

■■ERYSIPELAS AND CELLULITIS See Chap. 124.

■■DERMATOPHYTOSIS

Dermatophytes are fungi that infect skin, hair, and nails and include members of the genera Trichophyton, Microsporum, and Epidermophyton (Chap. 214). Tinea corporis, or infection of the relatively hairless skin of the body (glabrous skin), may have a variable appearance depending

Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders

INDICATION Ps, PsA

CHAPTER 53

Anti-TNF-α

FIGURE 53-6  Pityriasis rosea. In this patient with pityriasis rosea, multiple round to oval erythematous patches with fine central scale are distributed along the skin tension lines on the trunk.

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336

TABLE 53-5  Common Skin Infections Impetigo

Dermatophytosis

Candidiasis

PART 2

Tinea versicolor

CLINICAL FEATURES Honey-colored crusted papules, plaques, or bullae

ETIOLOGIC AGENT Group A Streptococcus and Staphylococcus aureus

Inflammatory or noninflammatory annular scaly plaques; may involve hair loss; groin involvement spares scrotum; hyphae on KOH preparation Inflammatory papules and plaques with satellite pustules, frequently in intertriginous areas; may involve scrotum; pseudohyphae on KOH preparation Hyper- or hypopigmented scaly patches on trunk; characteristic mixture of hyphae and spores (“spaghetti and meatballs”) on KOH preparation

Trichophyton, Epidermophyton, or Microsporum spp.

TREATMENT Systemic or topical antistaphylococcal and antistreptococcal antibiotics Topical azoles, systemic griseofulvin, terbinafine, or azoles

Candida albicans and other Candida spp.

Topical nystatin or azoles; systemic azoles for resistant disease

Malassezia furfur

Topical selenium sulfide lotion or azoles

Abbreviation: KOH, potassium hydroxide.

Cardinal Manifestations and Presentation of Diseases

on the extent of the associated inflammatory reaction. Typical infections consist of erythematous, scaly plaques, with an annular appearance that accounts for the common name “ringworm.” Deep inflammatory nodules or granulomas occur in some infections, most often those inappropriately treated with mid- to high-potency topical glucocorticoids. Involvement of the groin (tinea cruris) is more common in males than in females. It presents as a scaling, erythematous eruption sparing the scrotum. Infection of the foot (tinea pedis) is the most common dermatophyte infection and is often chronic; it is characterized by variable erythema, edema, scaling, pruritus, and occasionally vesiculation. The infection may be widespread or localized but generally involves the web space between the fourth and fifth toes. Infection of the nails (tinea unguium or onychomycosis) occurs in many patients with tinea pedis and is characterized by opacified, thickened nails and subungual debris. The distal-lateral variant is most common. Proximal subungual onychomycosis may be a marker for HIV infection or other immunocompromised states. Dermatophyte infection of the scalp (tinea capitis) continues to be common, particularly affecting inner-city children but also affecting adults. The predominant organism is Trichophyton tonsurans, which can produce a relatively noninflammatory infection with mild scale and hair loss that is diffuse or localized. T. tonsurans and Microsporum canis can also cause a markedly inflammatory dermatosis with edema and nodules. This latter presentation is a kerion. The diagnosis of tinea can be made from skin scrapings, nail scrapings, or hair by culture or direct microscopic examination with KOH. Nail clippings may be sent for histologic examination with periodic acid–Schiff (PAS) stain.

TREATMENT

Dermatophytosis Both topical and systemic therapies may be used in dermatophyte infections. Treatment depends on the site involved and the type of infection. Topical therapy is generally effective for uncomplicated tinea corporis, tinea cruris, and limited tinea pedis. Topical agents are not effective as monotherapy for tinea capitis or onychomycosis (see below), and nystatin is not active against dermatophytes. Topicals are generally applied twice daily, and treatment should continue for 1 week beyond clinical resolution of the infection. Tinea pedis often requires longer treatment courses and frequently relapses. Oral antifungal agents may be required for recalcitrant tinea pedis or tinea corporis. For dermatophyte infections involving the hair and nails and for other infections unresponsive to topical therapy, oral antifungal agents are often used. Markedly inflammatory tinea capitis may result in scarring and hair loss, and a systemic antifungal agent plus systemic or topical glucocorticoids may be helpful in preventing these sequelae. A fungal etiology should be confirmed by direct microscopic examination or by culture before oral antifungal agents are prescribed for any infection. All of the oral agents may cause hepatotoxicity. They should not be used in women who are pregnant or breast-feeding.

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Griseofulvin is approved in the United States for dermatophyte infections involving the skin, hair, or nails. Common side effects of griseofulvin include gastrointestinal distress, headache, and urticaria. Two newer oral antifungal agents, itraconazole and terbinafine, are sometimes prescribed “off-label” for superficial fungal infections. Oral itraconazole is approved for onychomycosis. Itraconazole has the potential for serious interactions with other drugs requiring the P450 enzyme system for metabolism. Itraconazole should not be administered to patients with evidence of ventricular dysfunction or patients with known CHF. Terbinafine is also approved for onychomycosis, and the granule version is approved for treatment of tinea capitis. Terbinafine has fewer interactions with other drugs than itraconazole; however, caution should be used with patients who are on multiple medications. The risk/benefit ratio should be considered when an asymptomatic toenail infection is treated with systemic agents. The FDA has limited the use of a third oral agent due to potential hepatotoxicity and published the following: “Nizoral [ketoconazole] oral tablets should not be a first-line treatment for any fungal infection.” The topical form of ketoconazole is not affected by this action.

■■TINEA (PITYRIASIS) VERSICOLOR

Tinea versicolor is caused by a nondermatophytic, dimorphic fungus, Malassezia furfur, a normal inhabitant of the skin. The expression of infection is promoted by heat and humidity. The typical lesions consist of oval scaly macules, papules, and patches concentrated on the chest, shoulders, and back but only rarely on the face or distal extremities. On dark skin the lesions often appear as hypopigmented areas, whereas on light skin they are slightly erythematous or hyperpigmented. A KOH preparation from scaling lesions will demonstrate a confluence of short hyphae and round spores (“spaghetti and meatballs”). Lotions or shampoos containing sulfur, salicylic acid, or selenium sulfide are the treatments of choice and will clear the infection if used daily for 1–2 weeks and then weekly thereafter. These preparations are irritating if left on the skin for >10 min; thus, they should be washed off completely. Treatment with some oral antifungal agents is also effective, but they do not provide lasting results and are not FDA approved for this indication.

■■CANDIDIASIS

Candidiasis is a fungal infection caused by a related group of yeasts whose manifestations may be localized to the skin and mucous membranes or, rarely, may be systemic and life-threatening (Chap. 211). The causative organism is usually Candida albicans. These organisms are normal saprophytic inhabitants of the gastrointestinal tract but may overgrow due to broad-spectrum antibiotic therapy, diabetes mellitus, or immunosuppression and cause disease. Candidiasis is a very common infection in HIV-infected individuals (Chap. 197). The oral cavity is commonly involved. Lesions may occur on the tongue or buccal mucosa (thrush) and appear as white plaques. Fissured, macerated lesions at the corners of the mouth (perlèche) are often seen in individuals with poorly fitting dentures and may also be associated with candidal infection. In addition, candidal infections have an affinity for sites

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that are chronically wet and macerated, including the skin around nails (onycholysis and paronychia), and in intertriginous areas. Intertriginous lesions are characteristically edematous, erythematous, and scaly, with scattered “satellite pustules.” In males, there is often involvement of the penis and scrotum as well as the inner aspect of the thighs. In contrast to dermatophyte infections, candidal infections are frequently painful and accompanied by a marked inflammatory response. Diagnosis of candidal infection is based on the clinical pattern and demonstration of yeast on KOH preparation or culture.

Candidiasis

■■WARTS

Warts are cutaneous neoplasms caused by papillomaviruses. More than 100 different human papillomaviruses (HPVs) have been described. A typical wart, verruca vulgaris, is sessile, dome-shaped, and usually about a centimeter in diameter. Its surface is hyperkeratotic, consisting of many small filamentous projections. HPV also causes typical plantar warts, flat warts (verruca plana), and filiform warts. Plantar warts are endophytic and are covered by thick keratin. Paring of the wart will generally reveal a central core of keratinized debris and punctate bleeding points. Filiform warts are most commonly seen on the face, neck, and skinfolds, and present as papillomatous lesions on a narrow base. Flat warts are only slightly elevated and have a velvety, nonverrucous surface. They have a propensity for the face, arms, and legs, and are often spread by shaving. Genital warts begin as small papillomas that may grow to form large, fungating lesions. In women, they may involve the labia, perineum, or perianal skin. In addition, the mucosa of the vagina, urethra, and anus can be involved as well as the cervical epithelium. In men, the lesions often occur initially in the coronal sulcus but may be seen on the shaft of the penis, the scrotum, or the perianal skin or in the urethra. Appreciable evidence has accumulated indicating that HPV plays a role in the development of neoplasia of the uterine cervix and anogenital skin (Chap. 85). HPV types 16 and 18 have been most intensely studied and are the major risk factors for intraepithelial neoplasia and squamous cell carcinoma of the cervix, anus, vulva, and penis. The risk is higher among patients immunosuppressed after solid organ transplantation and among those infected with HIV. Recent evidence also implicates other HPV types. Histologic examination of biopsied samples from affected sites may reveal changes associated with typical warts and/or features typical of intraepidermal carcinoma (Bowen’s disease). Squamous cell carcinomas associated with HPV infections have also been observed in extragenital skin (Chap. 72), most commonly in patients immunosuppressed after organ transplantation. Patients on long-term immunosuppression should be monitored for the development of squamous cell carcinoma and other cutaneous malignancies.

TREATMENT

Warts Treatment of warts, other than anogenital warts, should be tempered by the observation that a majority of warts in normal individuals

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■■HERPES SIMPLEX See Chap. 187.

■■HERPES ZOSTER See Chap. 188.

ACNE ■■ACNE VULGARIS

Acne vulgaris is a self-limited disorder primarily of teenagers and young adults, although perhaps 10–20% of adults may continue to experience some form of the disorder. The permissive factor for the expression of the disease in adolescence is the increase in sebum production by sebaceous glands after puberty. Small cysts, called comedones, form in hair follicles due to blockage of the follicular orifice by retention of keratinous material and sebum. The activity of bacteria (Propionibacterium acnes) within the comedones releases free fatty acids from sebum, causes inflammation within the cyst, and results in rupture of the cyst wall. An inflammatory foreign-body reaction develops as result of extrusion of oily and keratinous debris from the cyst. The clinical hallmark of acne vulgaris is the comedone, which may be closed (whitehead) or open (blackhead). Closed comedones appear as 1- to 2-mm pebbly white papules, which are accentuated when the skin is stretched. They are the precursors of inflammatory lesions of acne vulgaris. The contents of closed comedones are not easily expressed. Open comedones, which rarely result in inflammatory acne lesions, have a large dilated follicular orifice and are filled with easily expressible oxidized, darkened, oily debris. Comedones are usually accompanied by inflammatory lesions: papules, pustules, or nodules. The earliest lesions seen in adolescence are generally mildly inflamed or noninflammatory comedones on the forehead. Subsequently, more typical inflammatory lesions develop on the cheeks, nose, and chin (Fig. 53-7). The most common location for acne is the face, but involvement of the chest and back is common. Most disease remains mild and does not lead to scarring. A small number of patients develop large inflammatory cysts and nodules, which may drain and result in significant scarring. Regardless of the severity, acne may affect a patient’s quality of life. With adequate treatment, this effect may be transient. In the case of severe, scarring acne, the effects can be permanent and profound. Early therapeutic intervention in severe acne is essential. Exogenous and endogenous factors can alter the expression of acne vulgaris. Friction and trauma (from headbands or chin straps of athletic helmets), application of comedogenic topical agents (cosmetics or hair preparations), or chronic topical exposure to certain industrial compounds may elicit or aggravate acne. Glucocorticoids, topical or systemic, may also elicit acne. Other systemic medications such as oral

Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders

Treatment involves removal of any predisposing factors such as antibiotic therapy or chronic wetness and the use of appropriate topical or systemic antifungal agents. Effective topicals include nystatin or azoles (miconazole, clotrimazole, econazole, or ketoconazole). The associated inflammatory response accompanying candidal infection on glabrous skin can be treated with a mild glucocorticoid lotion or cream (2.5% hydrocortisone). Systemic therapy is usually reserved for immunosuppressed patients or individuals with chronic or recurrent disease who fail to respond to appropriate topical therapy. Oral fluconazole is most commonly prescribed for cutaneous candidiasis. Oral nystatin is effective only for candidiasis of the gastrointestinal tract.

337

CHAPTER 53

TREATMENT

resolve spontaneously within 1–2 years. There are many modalities available to treat warts, but no single therapy is universally effective. Factors that influence the choice of therapy include the location of the wart, the extent of disease, the age and immunologic status of the patient, and the patient’s desire for therapy. Perhaps the most useful and convenient method for treating warts in almost any location is cryotherapy with liquid nitrogen. Equally effective for nongenital warts, but requiring much more patient compliance, is the use of keratolytic agents such as salicylic acid plasters or solutions. For genital warts, in-office application of a podophyllin solution is moderately effective but may be associated with marked local reactions. Prescription preparations of dilute, purified podophyllin are available for home use. Topical imiquimod, a potent inducer of local cytokine release, has been approved for treatment of genital warts. A new topical compound composed of green tea extracts (sinecatechins) is also available. Conventional and laser surgical procedures may be required for recalcitrant warts. Recurrence of warts appears to be common with all these modalities. A highly effective vaccine for selected types of HPV has been approved by the FDA, and its use is reported to reduce the incidence of anogenital and cervical carcinoma.

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338

PART 2 Cardinal Manifestations and Presentation of Diseases

FIGURE 53-7  Acne vulgaris. An example of acne vulgaris with inflammatory papules, pustules, and comedones. (Courtesy of Kalman Watsky, MD; with permission.)

FIGURE 53-8  Acne rosacea. Prominent facial erythema, telangiectasia, scattered papules, and small pustules are seen in this patient with acne rosacea. (Courtesy of Robert Swerlick, MD; with permission.)

contraceptive pills, lithium, isoniazid, androgenic steroids, halogens, phenytoin, and phenobarbital may produce acneiform eruptions or aggravate preexisting acne. Genetic factors and polycystic ovary disease may also play a role.

■■ACNE ROSACEA

TREATMENT

Acne Vulgaris Treatment of acne vulgaris is directed toward elimination of comedones by normalizing follicular keratinization and decreasing sebaceous gland activity, the population of P. acnes, and inflammation. Minimal to moderate pauci-inflammatory disease may respond adequately to local therapy alone. Although areas affected with acne should be kept clean, overly vigorous scrubbing may aggravate acne due to mechanical rupture of comedones. Topical agents such as retinoic acid, benzoyl peroxide, or salicylic acid may alter the pattern of epidermal desquamation, preventing the formation of comedones and aiding in the resolution of preexisting cysts. Topical antibacterial agents (such as azelaic acid, erythromycin, clindamycin, or dapsone) are also useful adjuncts to therapy. Benzoyl peroxide products should be used in combination with topical antibiotics (erythromycin and clindamycin) to prevent development of bacterial resistance. Patients with moderate to severe acne with a prominent inflammatory component will benefit from the addition of systemic therapy, such as tetracycline in doses of 250–500 mg bid or doxycycline in doses of 100 mg bid. Minocycline is also useful. Such antibiotics appear to have anti-inflammatory effects independent of their antibacterial effects. If the patient is not showing appropriate response within 3 months, changes in the plan should be considered. Female patients who do not respond to oral antibiotics may benefit from hormonal therapy. Several oral contraceptives are now approved by the FDA for use in the treatment of acne vulgaris. Patients with severe nodulocystic acne unresponsive to the therapies discussed above may benefit from treatment with the synthetic retinoid isotretinoin. Its dose is based on the patient’s weight, and it is given once daily for 5 months. Results are excellent in appropriately selected patients. Its use is highly regulated due to its potential for severe adverse events, primarily teratogenicity and depression. In addition, patients receiving this medication develop extremely dry skin and cheilitis and must be followed for development of hypertriglyceridemia. At present, prescribers must enroll in a program designed to prevent pregnancy and adverse events while patients are taking isotretinoin. These measures are imposed to ensure that all prescribers are familiar with the risks of isotretinoin, that all female patients have two negative pregnancy tests prior to initiation of therapy and a negative pregnancy test prior to each refill, and that all patients have been warned about the risks associated with isotretinoin.

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Acne rosacea, commonly referred to simply as rosacea, is an inflammatory disorder predominantly affecting the central face. Persons most often affected are Caucasians of northern European background, but rosacea also occurs in patients with dark skin. Rosacea is seen almost exclusively in adults, only rarely affecting patients contact >> stasis [with autosensitization] or seborrheic [primarily infants])a c.  Pityriasis rubra pilaris 2. Drugs 3.  Systemic diseases a. Cutaneous T cell lymphoma (Sézary syndrome, erythrodermic mycosis fungoides) b.  Other lymphomas 4.  Idiopathic (usually older men)

a Discussed in detail in Chap. 53; cardiovascular disease and the metabolic syndrome are comorbidities in psoriasis; primarily in Europe, hepatitis C virus is associated with oral lichen planus. bAssociated with chronic sun exposure more often than exposure to arsenic; usually one or a few lesions. cSee also Red Lesions in “Papulonodular Skin Lesions.” dAlso cutaneous lesions of HTLV1-associated adult T cell leukemia/lymphoma. eSee also Red-Brown Lesions in “Papulonodular Skin Lesions.”

Abbreviation: HIV, human immunodeficiency virus.

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Skin Manifestations of Internal Disease

PAPULOSQUAMOUS SKIN LESIONS

54

339

CHAPTER 54

It is a generally accepted concept in medicine that the skin can develop signs of internal disease. Therefore, in textbooks of medicine, one finds a chapter describing in detail the major systemic disorders that can be identified by cutaneous signs. The underlying assumption of such a chapter is that the clinician has been able to identify the specific disorder in the patient and needs only to read about it in the textbook. In reality, concise differential diagnoses and the identification of these disorders are actually difficult for the nondermatologist because he or she is not well-versed in the recognition of cutaneous lesions or their spectrum of presentations. Therefore, this chapter covers this particular topic of cutaneous medicine not by simply focusing on individual diseases, but by describing the various presenting clinical signs and symptoms that point to specific disorders. Concise differential diagnoses will be generated in which the significant diseases will be distinguished from the more common cutaneous disorders that have minimal or no significance with regard to associated internal disease. The latter disorders are reviewed in table form and always need to be excluded when considering the former. For a detailed description of individual diseases, the reader should consult a dermatologic text.

diseases—tinea, psoriasis, pityriasis rosea, and lichen planus—are primary cutaneous disorders (Chap. 53). When psoriatic lesions are accompanied by arthritis, the possibility of psoriatic arthritis or reactive arthritis should be considered. A history of oral ulcers, conjunctivitis, uveitis, and/or urethritis points to the latter diagnosis. Lithium, beta blockers, HIV or streptococcal infections, and a rapid taper of systemic glucocorticoids are known to exacerbate psoriasis; despite being used to treat psoriasis, TNF-α inhibitors can also induce psoriatic lesions. Comorbidities in patients with psoriasis include cardiovascular disease and metabolic syndrome. Whenever the diagnosis of pityriasis rosea or lichen planus is made, it is important to review the patient’s medications because the eruption may resolve by simply discontinuing the offending agent. Pityriasis rosea–like drug eruptions are seen most commonly with beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and metronidazole, whereas the drugs that can produce a lichenoid eruption include thiazides, antimalarials, quinidine, beta blockers, TNF-α inhibitors, anti-PD-1/PD-L1 Ab, and ACE inhibitors. In some populations, there is a higher prevalence of hepatitis C viral infection in patients with oral lichen planus. Lichen planus–like lesions are also observed in chronic graft-versus-host disease. In its early stages, the mycosis fungoides (MF) form of cutaneous T cell lymphoma (CTCL) may be confused with eczema or psoriasis, but it often fails to respond to appropriate therapy for those inflammatory diseases. MF can develop within lesions of large-plaque parapsoriasis and is suggested by an increase in the thickness of the lesions. The diagnosis of MF is established by skin biopsy in which collections of atypical T lymphocytes are found in the epidermis and dermis. As the disease progresses, cutaneous tumors and lymph node involvement may appear. In secondary syphilis, there are scattered red-brown papules with thin scale. The eruption often involves the palms and soles and can resemble pityriasis rosea. Associated findings are helpful in making the diagnosis and include annular plaques on the face, nonscarring alopecia, condyloma lata (broad-based and moist), and mucous patches as well as lymphadenopathy, malaise, fever, headache, and myalgias. The interval between the primary chancre and the secondary stage is usually 4–8 weeks, and spontaneous resolution without appropriate therapy occurs.

Bolognia JL, Jorizzo JL, Schaffer JV (eds): Dermatology, 3rd ed. Philadelphia, Saunders, 2012. Goldsmith LA et al (eds): Fitzpatrick’s Dermatology in General Medicine, 8th ed. New York, McGraw-Hill, 2012. James WD, Berger TG, Elston DM (eds): Andrew’s Diseases of the Skin Clinical Dermatology, 12th ed. Philadelphia, Elsevier, 2016. Wolff K, Johnson RA, Saavedra AP (eds): Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 7th ed. New York, McGraw-Hill, 2013.

a

Discussed in detail in Chap. 53.

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340

TABLE 54-3  Erythroderma (Primary Cutaneous Disorders)

Psoriasisa

INITIAL LESIONS Pink-red, silvery scale, sharply demarcated

LOCATION OF INITIAL LESIONS Elbows, knees, scalp, presacral area, intergluteal fold

OTHER FINDINGS Nail dystrophy, arthritis, pustules, SAPHO syndromeb

DIAGNOSTIC AIDS Skin biopsy

TREATMENT Topical glucocorticoids, vitamin D; UV-B (narrowband) > PUVA; oral retinoid; MTX, cyclosporine, anti-TNF agents, apremilast, anti-IL-12/23 Ab, anti-IL17A or -IL-17 receptor Ab Topical glucocorticoids, tacrolimus, pimecrolimus, tar, and antipruritics; oral antihistamines; open wet dressings; UV-B ± UV-A > PUVA; oral/IM glucocorticoids (shortterm); MTX; mycophenolate mofetil; azathioprine; cyclosporine; anti-IL-4/13 Ab Topical or oral antibiotics Remove irritant or allergen; topical glucocorticoids; oral antihistamines; oral/IM glucocorticoids (short-term)

Dermatitisa

PART 2 Cardinal Manifestations and Presentation of Diseases

Atopic

Acute: Antecubital and popliteal fossae, neck, hands, Erythema, fine scale, crust, indistinct borders, eyelids excoriations Chronic: Lichenification (increased skin markings), excoriations

Pruritus Personal and/or family history of atopy, including asthma, allergic rhinitis or conjunctivitis, and atopic dermatitis Exclude secondary infection with Staphylococcus aureus or HSV Exclude superimposed irritant or allergic contact dermatitis

Skin biopsy

Contact

Local: Erythema, crusting, vesicles, and bullae

Depends on offending agent

Patch testing; repeat open application test

Systemic: Erythema, fine scale, crust

Generalized vs major intertriginous zones (especially groin)

Seborrheic (rare in adults)

Pink-red to pink-orange, greasy scale

Scalp, nasolabial folds, eyebrows, intertriginous zones

Stasis (with autosensitization)

Erythema, crusting, excoriations

Lower extremities

Pityriasis rubra pilaris

Orange-red (salmoncolored), perifollicular papules

Generalized, but characteristic “skip” areas of normal skin

Irritant—onset often within hours Allergic—delayed-type hypersensitivity; lag time of 48 h with re-challenge Patient has history of allergic contact dermatitis to topical agent and then receives systemic medication that is structurally related, e.g., formaldehyde (skin), aspartame (oral) Flares with stress, HIV infection Associated with Parkinson’s disease Pruritus, lower extremity edema, varicosities, hemosiderin deposits, lipodermatosclerosis History of venous ulcers, thrombophlebitis, and/or cellulitis Exclude cellulitis Exclude superimposed contact dermatitis, e.g., topical neomycin Wax-like palmoplantar keratoderma Exclude cutaneous T cell lymphoma

Patch testing

Same as local

Skin biopsy

Topical glucocorticoids and imidazoles

Skin biopsy

Topical glucocorticoids; open wet dressings; leg elevation; pressure stockings; pressure wraps if associated ulcers

Skin biopsy

Isotretinoin or acitretin; MTX; perhaps anti-IL-12/23 Ab, anti-TNF agents, anti-IL-17 Ab

Discussed in detail in Chap. 53. bSAPHO syndrome occurs more commonly in patients with palmoplantar pustulosis than in those with erythrodermic psoriasis.

a

Abbreviations: Ab, antibody; HSV, herpes simplex virus; IL, interleukin; IM, intramuscular; MTX, methotrexate; PUVA, psoralens + ultraviolet A irradiation; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis (a subtype is chronic recurrent multifocal osteomyelitis); TNF, tumor necrosis factor; UV-A, ultraviolet A irradiation; UV-B, ultraviolet B irradiation.

changes such as pustules or erosions. Migratory waves of erythema studded with superficial pustules are seen in pustular psoriasis. Drug-induced erythroderma (exfoliative dermatitis) may begin as an exanthematous (morbilliform) eruption (Chap. 56) or may arise as diffuse erythema. A number of drugs can produce an erythroderma, including penicillins, sulfonamides, carbamazepine, phenytoin, and allopurinol. Fever and peripheral eosinophilia often accompany the eruption, and there may also be facial swelling, hepatitis, myocarditis, thyroiditis, and allergic interstitial nephritis; this constellation is frequently referred to as drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity reaction (DIHS). In addition, these reactions, especially to aromatic anticonvulsants, can lead to a pseudolymphoma syndrome (with adenopathy and circulating atypical lymphocytes), while reactions to allopurinol may be accompanied by gastrointestinal bleeding. The most common malignancy that is associated with erythroderma is CTCL; in some series, up to 25% of the cases of erythroderma were

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due to CTCL. The patient may progress from isolated plaques and tumors, but more commonly, the erythroderma is present throughout the course of the disease (Sézary syndrome). In Sézary syndrome, there are circulating clonal atypical T lymphocytes, pruritus, and lymphadenopathy. In cases of erythroderma where there is no apparent cause (idiopathic), longitudinal evaluation is mandatory to monitor for the possible development of CTCL. There have been isolated case reports of erythroderma secondary to some solid tumors—lung, liver, prostate, thyroid, and colon—but it is primarily during a late stage of the disease.

ALOPECIA

(Table 54-4) The two major forms of alopecia are scarring and nonscarring. Scarring alopecia is associated with fibrosis, inflammation, and loss of hair follicles. A smooth scalp with a decreased number of follicular openings is usually observed clinically, but in some patients, the changes are seen only in biopsy specimens from affected areas.

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TABLE 54-4  Causes of Alopecia

341

Skin Manifestations of Internal Disease

a Most patients with trichotillomania or early stages of traction alopecia and some patients with pressure-induced alopecia. bWhile the majority of patients with discoid lesions have only cutaneous disease, these lesions do represent one of the 11 American College of Rheumatology criteria (1982) for systemic lupus erythematosus. cCan involve underlying muscles and osseous structures and rarely in linear morphea of the frontal scalp (en coup de sabre), there is involvement of the meninges and brain.

In nonscarring alopecia, the hair shafts are absent or miniaturized, but the hair follicles are preserved, explaining the reversible nature of nonscarring alopecia. The most common causes of nonscarring alopecia include androgenetic alopecia, telogen effluvium, alopecia areata, tinea capitis, and the early phase of traumatic alopecia (Table 54-5). In women with androgenetic alopecia, an elevation in circulating levels of androgens may be seen as a result of ovarian or adrenal gland dysfunction or neoplasm. When there are signs of virilization, such as a deepened voice and enlarged clitoris, the possibility of an ovarian or adrenal gland tumor should be considered. Exposure to various drugs can also cause diffuse hair loss, usually by inducing a telogen effluvium. An exception is the anagen effluvium observed with antimitotic agents such as daunorubicin. Alopecia is a side effect of the following drugs: warfarin, heparin, propylthiouracil, carbimazole, isotretinoin, acitretin, lithium, beta blockers, interferons, colchicine, and amphetamines. Fortunately, spontaneous regrowth usually follows discontinuation of the offending agent. Less commonly, nonscarring alopecia is associated with lupus erythematosus and secondary syphilis. In systemic lupus there are two forms of alopecia—one is scarring secondary to discoid lesions (see below), and the other is nonscarring. The latter form coincides with flares of systemic disease and may involve the entire scalp or just the frontal scalp, with the appearance of multiple short hairs (“lupus hairs”) as a sign of initial regrowth. Scattered, poorly circumscribed patches of alopecia with a “moth-eaten” appearance are a manifestation of the secondary stage of syphilis. Diffuse thinning of the hair is also associated with hypothyroidism and hyperthyroidism (Table 54-4). Scarring alopecia is more frequently the result of a primary cutaneous disorder such as lichen planus, chronic cutaneous (discoid) lupus, central centrifugal cicatricial alopecia, folliculitis decalvans, or linear scleroderma (morphea) than it is a sign of systemic disease. Although the scarring lesions of discoid lupus can be seen in patients with systemic lupus, in the majority of patients, the disease process is limited to the skin. Less common causes of scarring alopecia include sarcoidosis (see “Papulonodular Skin Lesions,” below) and cutaneous metastases. In the early phases of discoid lupus, lichen planus, and folliculitis decalvans, there are circumscribed areas of alopecia. Fibrosis and

CHAPTER 54

I.  Nonscarring alopecia A.  Primary cutaneous disorders 1.  Androgenetic alopecia 2.  Telogen effluvium 3.  Alopecia areata 4.  Tinea capitis 5.  Traumatic alopeciaa 6.  Psoriasiform alopecia, including TNF-α inhibitor-induced B. Drugs C.  Systemic diseases 1.  Systemic lupus erythematosus 2.  Secondary syphilis 3. Hypothyroidism 4. Hyperthyroidism 5. Hypopituitarism 6.  Deficiencies of protein, biotin, zinc, and perhaps iron II.  Scarring alopecia A.  Primary cutaneous disorders 1.  Cutaneous lupus (chronic discoid lesions)b 2.  Lichen planus, including frontal fibrosing alopecia 3.  Central centrifugal cicatricial alopecia 4.  Folliculitis decalvans 5.  Linear morphea (linear scleroderma)c B.  Systemic diseases 1.  Discoid lesions in the setting of systemic lupus erythematosusb 2. Sarcoidosis 3.  Cutaneous metastases

TABLE 54-5  Nonscarring Alopecia (Primary Cutaneous Disorders) Telogen effluvium

CLINICAL CHARACTERISTICS Diffuse shedding of normal hairs Follows major stress (high fever, severe infection) or change in hormone levels (postpartum) Reversible without treatment

Androgenetic alopecia Miniaturization of hairs along the midline of the scalp (male pattern; female Recession of the anterior scalp line in men and some pattern) women

Alopecia areata

Well-circumscribed, circular areas of hair loss, 2–5 cm in diameter In extensive cases, coalescence of lesions and/or involvement of other hair-bearing surfaces of the body Pitting or sandpapered appearance of the nails

Tinea capitis

Varies from scaling with minimal hair loss to discrete patches with “black dots” (sites of broken infected hairs) to boggy plaque with pustules (kerion)b Broken hairs, often of varying lengths Irregular outline in trichotillomania and traction alopecia

Traumatic alopeciac

PATHOGENESIS Stress causes more of the asynchronous growth cycles of individual hairs to become synchronous; therefore, larger numbers of growing (anagen) hairs simultaneously enter the dying (telogen) phase Increased sensitivity of affected hairs to the effects of androgens Increased levels of circulating androgens (ovarian or adrenal source in women) The germinative zones of the hair follicles are surrounded by T lymphocytes Occasional associated diseases: hyperthyroidism, hypothyroidism, vitiligo, Down syndrome Invasion of hairs by dermatophytes, most commonly Trichophyton tonsurans Traction with curlers, rubber bands, tight braiding Exposure to heat or chemicals (e.g., hair straighteners) Mechanical pulling (trichotillomania)

TREATMENT Observation; discontinue any drugs that have alopecia as a side effect; must exclude underlying metabolic causes, e.g., hypothyroidism, hyperthyroidism

If no evidence of hyperandrogenemia, then topical minoxidil; finasteridea; spironolactone (women); hair transplant Topical anthralin or tazarotene; intralesional glucocorticoids; topical contact sensitizers; JAK inhibitors

Oral griseofulvin or terbinafine plus 2.5% selenium sulfide or ketoconazole shampoo; examine family members Discontinuation of offending hair style or chemical treatments; diagnosis of trichotillomania may require observation of shaved hairs (for growth) or biopsy, possibly followed by psychotherapy

a To date, Food and Drug Administration–approved for men. bScarring alopecia can occur at sites of kerions. cMay also be scarring, especially late-stage traction alopecia.

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342

subsequent loss of hair follicles are observed primarily in the center of these alopecic patches, whereas the inflammatory process is most prominent at the periphery. The areas of active inflammation in discoid lupus are erythematous with scale, whereas the areas of previous inflammation are often hypopigmented with a rim of hyperpigmentation. In lichen planus, perifollicular macules at the periphery are usually violetcolored. A complete examination of the skin and oral mucosa combined with a biopsy and direct immunofluorescence microscopy of inflamed skin will aid in distinguishing these two entities. The peripheral active lesions in folliculitis decalvans are follicular pustules; these patients can develop a reactive arthritis.

PART 2

FIGURATE SKIN LESIONS

Cardinal Manifestations and Presentation of Diseases

(Table 54-6) In figurate eruptions, the lesions form rings and arcs that are usually erythematous but can be skin-colored to brown. Most commonly, they are due to primary cutaneous diseases such as tinea, urticaria, granuloma annulare, and erythema annulare centrifugum (Chaps. 53 and 55). An underlying systemic illness is found in a second, less common group of migratory annular erythemas. It includes erythema migrans, erythema gyratum repens, erythema marginatum, and necrolytic migratory erythema. In erythema gyratum repens, one sees numerous mobile concentric arcs and wavefronts that resemble the grain in wood. A search for an underlying malignancy is mandatory in a patient with this eruption. Erythema migrans is the cutaneous manifestation of Lyme disease, which is caused by the spirochete Borrelia burgdorferi. In the initial stage (3–30 days after tick bite), a single annular lesion is usually seen, which can expand to ≥10 cm in diameter. Within several days, up to half of the patients develop multiple smaller erythematous lesions at sites distant from the bite. Associated symptoms include fever, headache, photophobia, myalgias, arthralgias, and malar rash. Erythema marginatum is seen in patients with rheumatic fever, primarily on the trunk. Lesions are pink-red in color, flat to minimally elevated, and transient. There are additional cutaneous diseases that present as annular eruptions but lack an obvious migratory component. Examples include CTCL, subacute cutaneous lupus, secondary syphilis, and sarcoidosis (see “Papulonodular Skin Lesions,” below). TABLE 54-6  Causes of Figurate Skin Lesions I.  Primary cutaneous disorders A. Tinea B.  Urticaria (primary in ≥90% of patients) C.  Granuloma annulare D.  Erythema annulare centrifugum E.  Psoriasis, annular pustular psoriasis F.  Interstitial granulomatous drug reaction II.  Systemic diseases A. Migratory 1.  Erythema migrans (CDC case definition is ≥5 cm in diameter) 2.  Urticaria (≤10% of patients) 3.  Erythema gyratum repens 4.  Erythema marginatum 5.  Pustular psoriasis (generalized and annular forms) 6.  Necrolytic migratory erythema (glucagonoma syndrome)a B. Nonmigratory 1. Sarcoidosis 2.  Subacute cutaneous lupus erythematosus, LE tumidus 3.  Annular erythema of Sjögren’s syndrome 4.  Secondary syphilis (especially the face) 5.  Cutaneous T cell lymphoma (especially mycosis fungoides) 6.  Interstitial granulomatous dermatitisb Migratory erythema with erosions; favors lower extremities and girdle area. Underlying diseases include rheumatoid arthritis, LE, and granulomatosis with polyangiitis. a b

Abbreviations: CDC, Centers for Disease Control and Prevention; LE, lupus erythematosus.

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TABLE 54-7  Causes of Acneiform Eruptions I.  Primary cutaneous disorders A.  Acne vulgaris B.  Acne rosacea II. Drugs, e.g., anabolic steroids, glucocorticoids, lithium, EGFR inhibitors, MEK inhibitors iodides III.  Systemic diseases A.  Increased androgen production 1.  Adrenal origin, e.g., Cushing’s disease, 21-hydroxylase deficiency 2. Ovarian origin, e.g., polycystic ovary syndrome, ovarian hyperthecosis B.  Cryptococcosis, disseminated C.  Dimorphic fungal infections D.  Behçet’s disease Abbreviation: EGFR, epidermal growth factor receptor; MEK, MAP (mitogen activated protein) kinase.

ACNE

(Table 54-7) In addition to acne vulgaris and acne rosacea, the two major forms of acne (Chap. 53), there are drugs and systemic diseases that can lead to acneiform eruptions. Patients with the carcinoid syndrome have episodes of flushing of the head, neck, and sometimes the trunk. Resultant skin changes of the face, in particular telangiectasias, may mimic the clinical appearance of erythematotelangiectatic acne rosacea.

PUSTULAR LESIONS

Acneiform eruptions (see “Acne,” above) and folliculitis represent the most common pustular dermatoses. An important consideration in the evaluation of follicular pustules is a determination of the associated pathogen, for example, normal flora (culture-negative), Staphylococcus aureus, Pseudomonas aeruginosa (“hot tub” folliculitis), Malassezia, dermatophytes (Majocchi’s granuloma), and Demodex spp. Noninfectious forms of folliculitis include HIV- or immunosuppression-associated eosinophilic folliculitis and folliculitis secondary to drugs such as glucocorticoids, lithium, and epidermal growth factor receptor (EGFR) or MEK inhibitors. Administration of high-dose systemic glucocorticoids can result in a widespread eruption of follicular pustules on the trunk, characterized by lesions in the same stage of development. With regard to underlying systemic diseases, nonfollicular-based pustules are a characteristic component of pustular psoriasis (sterile) and can be seen in septic emboli of bacterial or fungal origin (see “Purpura,” below). In patients with acute generalized exanthematous pustulosis (AGEP) due primarily to medications (e.g., cephalosporins), there are large areas of erythema studded with multiple sterile pustules in addition to neutrophilia.

TELANGIECTASIAS

(Table 54-8) To distinguish the various types of telangiectasias, it is important to examine the shape and configuration of the dilated blood vessels. Linear telangiectasias are seen on the face of patients with actinically damaged skin and acne rosacea, and they are found on the legs of patients with venous hypertension and first appear on the legs in generalized essential telangiectasia. Patients with an unusual form of mastocytosis (telangiectasia macularis eruptiva perstans) and the carcinoid syndrome (see “Acne,” above) also have linear telangiectasias. Lastly, linear telangiectasias are found in areas of cutaneous inflammation. For example, longstanding lesions of discoid lupus frequently have telangiectasias within them. Poikiloderma is a term used to describe a patch of skin with: (1) reticulated hypo- and hyperpigmentation, (2) wrinkling secondary to epidermal atrophy, and (3) telangiectasias. Poikiloderma does not imply a single disease entity—although it is becoming less common, it is seen in skin damaged by ionizing radiation as well as in patients with autoimmune connective tissue diseases, primarily dermatomyositis (DM), and rare genodermatoses (e.g., Kindler syndrome). In systemic sclerosis (scleroderma) the dilated blood vessels have a unique configuration and are known as mat telangiectasias. The lesions

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TABLE 54-8  Causes of Telangiectasias

punctum with radiating legs is seen. Although the degree of systemic involvement varies in this autosomal dominant disease (due primarily to mutations in either the endoglin or activin receptor–like kinase gene), the major symptoms are recurrent epistaxis and gastrointestinal bleeding. The fact that these mucosal telangiectasias are actually AV communications helps to explain their tendency to bleed.

HYPOPIGMENTATION

TABLE 54-9  Causes of Hypopigmentation I.  Primary cutaneous disorders A. Diffuse 1.  Generalized vitiligoa B. Localized 1.  Idiopathic guttate hypomelanosis 2. Postinflammatory 3.  Pityriasis (tinea) versicolor 4. Vitiligoa 5. Chemical- or drug-induced leukoderma, e.g., topical imiquimod, oral imatinib 6.  Nevus depigmentosus 7. Piebaldisma II.  Systemic diseases A. Diffuse 1.  Oculocutaneous albinismb 2.  Hermansky-Pudlak syndromeb,c 3.  Chédiak-Higashi syndromeb,d 4. Phenylketonuria B. Localized   1.  Systemic sclerosis (scleroderma)   2. Melanoma-associated leukoderma, spontaneous or immunotherapy-induced  3. Vogt-Koyanagi-Harada syndrome  4. Onchocerciasis  5. Sarcoidosis   6.  Cutaneous T cell lymphoma (especially mycosis fungoides)   7.  Tuberculoid and indeterminate leprosy   8.  Linear nevoid hypopigmentation (hypomelanosis of Ito)e   9.  Incontinentia pigmenti (stage IV) 10.  Tuberous sclerosis 11.  Waardenburg syndrome and Shah-Waardenburg syndrome

Becoming less common.

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Skin Manifestations of Internal Disease

(Table 54-9) Disorders of hypopigmentation are often classified as either diffuse or localized. The classic example of diffuse hypopigmentation is oculocutaneous albinism (OCA). The most common forms are due to mutations in the tyrosinase gene (type I) or the P gene (type II); patients with type IA OCA have a total lack of enzyme activity. At birth, different forms of OCA can appear similar—white hair, gray-blue eyes, and pink-white skin. However, the patients with no tyrosinase activity maintain this phenotype, whereas those with decreased activity will acquire some pigmentation of the eyes, hair, and skin as they age. The degree of pigment formation is also a function of racial background, and the pigmentary dilution is more readily apparent when patients are compared to their first-degree relatives. The ocular findings in OCA correlate with the degree of hypopigmentation and include decreased visual acuity, nystagmus, photophobia, strabismus, and a lack of normal binocular vision. The differential diagnosis of localized hypomelanosis includes the following primary cutaneous disorders: idiopathic guttate hypomelanosis, postinflammatory hypopigmentation, pityriasis (tinea) versicolor, vitiligo, chemical- or drug-induced leukoderma, nevus depigmentosus (see below),

a

are broad macules that usually measure 2–7 mm in diameter but occasionally are larger. Mats have a polygonal or oval shape, and their erythematous color may appear uniform, but, upon closer inspection, the erythema is the result of delicate telangiectasias. The most common locations for mat telangiectasias are the face, oral mucosa, and hands— peripheral sites that are prone to intermittent ischemia. The limited form of systemic sclerosis, often referred to as the CREST (calcinosis cutis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) variant (Chap. 353), is associated with a chronic course and anticentromere antibodies. Mat telangiectasias are an important clue to the diagnosis of this variant as well as the diffuse form of systemic sclerosis because they may be the only cutaneous finding. Cuticular telangiectasias are pathognomonic signs of the three major autoimmune connective tissue diseases: lupus erythematosus, systemic sclerosis, and DM. They are easily visualized by the naked eye and occur in at least two-thirds of these patients. In both DM and lupus, there is associated nailfold erythema, and in DM, the erythema is often accompanied by “ragged” cuticles and fingertip tenderness. Under 10× magnification, the blood vessels in the nailfolds of lupus patients are tortuous and resemble “glomeruli,” whereas in systemic sclerosis and DM, there is a loss of capillary loops and those that remain are markedly dilated. In hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease), the lesions usually appear during adolescence (mucosal) and adulthood (cutaneous) and are most commonly seen on the mucous membranes (nasal, orolabial), face, and distal extremities, including under the nails. They represent arteriovenous (AV) malformations of the dermal microvasculature, are dark red in color, and are usually slightly elevated. When the skin is stretched over an individual lesion, an eccentric

343

CHAPTER 54

I.  Primary cutaneous disorders A. Linear/branching 1.  Acne rosacea (face) 2.  Actinically damaged skin (face, neck, V of chest) 3.  Venous hypertension (legs) 4.  Generalized essential telangiectasia 5.  Cutaneous collagenous vasculopathy 6.  Within basal cell carcinomas or cutaneous lymphoma B. Poikiloderma 1.  Ionizing radiationa C.  Spider angioma 1. Idiopathic 2. Pregnancy II.  Systemic diseases A. Linear/branching 1.  Carcinoid (head, neck, upper trunk) 2.  Ataxia-telangiectasia (bulbar conjunctivae, head and neck) 3.  Mastocytosis (within lesions) B. Poikiloderma 1.  Dermatomyositis, lupus erythematosus 2.  Mycosis fungoides, patch stage 3.  Genodermatoses, e.g., xeroderma pigmentosum, Kindler syndrome C. Mat 1.  Systemic sclerosis (scleroderma) D. Cuticular/periungual 1.  Lupus erythematosus 2.  Systemic sclerosis (scleroderma) 3. Dermatomyositis 4.  Hereditary hemorrhagic telangiectasia E. Papular 1.  Hereditary hemorrhagic telangiectasia F.  Spider angioma 1. Cirrhosis

Absence of melanocytes in areas of leukoderma. bNormal number of melanocytes. cPlatelet storage defect and restrictive lung disease secondary to deposits of ceroid-like material or immunodeficiency; due to mutations in β or δ subunit of adaptor-related protein complex 3 as well as subunits of biogenesis of lysosome-related organelles complex (BLOC)-1, 2, and 3. dGiant lysosomal granules and recurrent infections. eMinority of patients in a nonreferral setting have systemic abnormalities (musculoskeletal, central nervous system, ocular). a

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344

TABLE 54-10  Hypopigmentation (Primary Cutaneous Disorders, Localized)

PART 2

  CLINICAL CHARACTERISTICS Idiopathic guttate Common; acquired; usually hypomelanosis 2–4 mm in diameter Shins and extensor forearms Postinflammatory Can develop within active hypopigmentation lesions, as in subacute cutaneous lupus, or after the lesion fades, as in atopic dermatitis

Cardinal Manifestations and Presentation of Diseases

Pityriasis (tinea) versicolor

Vitiligo

Chemical- or drug-induced leukoderma

Piebaldism

Common disorder Upper trunk and neck (shawllike distribution), groin Young adults Macules have fine white scale when scratched Acquired; progressive Symmetric areas of complete pigment loss Periorificial—around mouth, nose, eyes, nipples, umbilicus, anus Other areas—flexor wrists, extensor distal extremities Segmental form is less common—unilateral, dermatomal-like Similar appearance to vitiligo Often begins on hands when associated with chemical exposure Satellite lesions in areas not exposed to chemicals

Autosomal dominant Congenital, stable White forelock Areas of amelanosis contain normally pigmented and hyperpigmented macules of various sizes Symmetric involvement of central forehead, ventral trunk, and mid regions of upper and lower extremities

WOOD’S LAMP EXAMINATION (UV-A; PEAK = 365 NM) SKIN BIOPSY SPECIMEN Less enhancement Abrupt decrease in than vitiligo epidermal melanin content Depends on particular Type of inflammatory disease infiltrate depends on specific disease Usually less enhancement than in vitiligo

PATHOGENESIS Possible somatic mutations as a reflection of aging or UV exposure

TREATMENT None

Block in transfer of melanin from melanocytes to keratinocytes could be secondary to edema or decrease in contact time Destruction of melanocytes if inflammatory cells attack basal layer of epidermis Invasion of stratum corneum by the yeast Malassezia Yeast is lipophilic and produces C9 and C11 dicarboxylic acids, which in vitro inhibit tyrosinase

Treat underlying inflammatory disease

Selenium sulfide 2.5% shampoo; topical imidazoles; oral triazoles

Golden fluorescence

Hyphal forms and budding yeast in stratum corneum

More apparent Chalk-white

Absence of melanocytes in well-developed lesions Mild inflammation

Autoimmune phenomenon that results in destruction of melanocytes—primarily cellular (circulating skinhoming autoreactive T cells)

Topical glucocorticoids; topical calcineurin inhibitors; UV-B (narrowband); PUVA; JAK inhibitors transplants, if stable; depigmentation (topical MBEH), if widespread and treatment-resistant

More apparent Chalk-white

Decreased number or absence of melanocytes

Avoid exposure to offending agent, then treat as vitiligo Drug-induced variant may undergo repigmentation when medication is discontinued

Enhancement of leukoderma and hyperpigmented macules

Amelanotic areas—few to no melanocytes

Exposure to chemicals that selectively destroy melanocytes, in particular phenols and catechols (germicides; rubber products) or ingestion of drugs such as imatinib Release of cellular antigens and activation of circulating lymphocytes may explain satellite phenomenon Possible inhibition of KIT receptor Defect in migration of melanoblasts from neural crest to involved skin or failure of melanoblasts to survive or differentiate in these areas Mutations within the KIT protooncogene that encodes the tyrosine kinase receptor for stem cell growth factor (kit ligand)

None; occasionally transplants

Abbreviations: MBEH, monobenzylether of hydroquinone; UV-B, ultraviolet B irradiation; PUVA, psoralens + ultraviolet A irradiation.

and piebaldism (Table 54-10). In this group of diseases, the areas of involvement are macules or patches with a decrease or absence of pigmentation. Patients with vitiligo also have an increased incidence of several autoimmune disorders, including Hashimoto’s thyroiditis, Graves’ disease, pernicious anemia, Addison’s disease, uveitis, alopecia areata, chronic mucocutaneous candidiasis, and the autoimmune polyendocrine syndromes (types I and II). Diseases of the thyroid gland are the most frequently associated disorders, occurring in up to 30% of patients with vitiligo. Circulating autoantibodies are often found, and the most common ones are antithyroglobulin, antimicrosomal, and antithyroid-stimulating hormone receptor antibodies. There are four systemic diseases that should be considered in a patient with skin findings suggestive of vitiligo—Vogt-Koyanagi-Harada

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syndrome, systemic sclerosis, onchocerciasis, and melanoma-associated leukoderma. A history of aseptic meningitis, nontraumatic uveitis, tinnitus, hearing loss, and/or dysacousia points to the diagnosis of the Vogt-Koyanagi-Harada syndrome. In these patients, the face and scalp are the most common locations of pigment loss. The vitiligolike leukoderma seen in patients with systemic sclerosis has a clinical resemblance to idiopathic vitiligo that has begun to repigment as a result of treatment; that is, perifollicular macules of normal pigmentation are seen within areas of depigmentation. The basis of this leukoderma is unknown; there is no evidence of inflammation in areas of involvement, but it can resolve if the underlying connective tissue disease becomes inactive. In contrast to idiopathic vitiligo, melanomaassociated leukoderma often begins on the trunk, and its appearance,

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(Table 54-11) Disorders of hyperpigmentation are also divided into two major groups—localized and diffuse. The localized forms are due to an epidermal alteration, a proliferation of melanocytes, or an increase in pigment production. Both seborrheic keratoses and acanthosis nigricans belong to the first group. Seborrheic keratoses are common lesions, but in one rare clinical setting, they are a sign of systemic disease, and that setting is the sudden appearance of multiple lesions, often with an

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I.  Primary cutaneous disorders A. Localized 1.  Epidermal alteration a.  Seborrheic keratosis b.  Pigmented actinic keratosis 2.  Proliferation of melanocytes a. Lentigo b.  Melanocytic nevus (mole) c. Melanoma 3.  Increased pigment production a.  Ephelide (freckle) b.  Café au lait macule c.  Postinflammatory hyperpigmentation d. Melasma 4.  Dermal pigmentation a.  Fixed drug eruption B.  Localized and diffuse 1.  Drugs (e.g., minocycline, hydroxychloroquine, bleomycin) II.  Systemic diseases A. Localized 1.  Epidermal alteration a.  Seborrheic keratoses (sign of Leser-Trélat) b. Acanthosis nigricans (insulin resistance, other endocrine disorders, paraneoplastic) 2.  Proliferation of melanocytes a. Lentigines (Peutz-Jeghers and LEOPARD/Noonan with multiple lentigines syndromes; xeroderma pigmentosum) b. Melanocytic nevi (Carney complex [LAMB and NAME syndromes])a 3.  Increased pigment production a. Café au lait macules (neurofibromatosis, McCune-Albright syndromeb) b.  Urticaria pigmentosac 4.  Dermal pigmentation a.  Incontinentia pigmenti (stage III) b.  Dyskeratosis congenita B. Diffuse 1. Endocrinopathies a.  Addison’s disease b.  Nelson syndrome c.  Ectopic ACTH syndrome d. Hyperthyroidism 2. Metabolic a.  Porphyria cutanea tarda b. Hemochromatosis c.  Vitamin B12, folate deficiency d. Pellagra e.  Malabsorption, including Whipple’s disease 3.  Melanosis secondary to metastatic melanoma 4. Autoimmune a.  Biliary cirrhosis b.  Systemic sclerosis (scleroderma) c.  POEMS syndrome d.  Eosinophilia-myalgia syndromed 5.  Drugs (e.g. cyclophosphamide) and metals (e.g. silver)

Skin Manifestations of Internal Disease

HYPERPIGMENTATION

345

TABLE 54-11  Causes of Hyperpigmentation

CHAPTER 54

if spontaneous, should prompt a search for metastatic disease. It is also seen in patients undergoing immunotherapy for melanoma, including ipilimumab, with cytotoxic T lymphocytes presumably recognizing cell surface antigens common to melanoma cells and melanocytes, and is associated with a greater likelihood of a clinical response. There are two systemic disorders (neurocristopathies) that may have the cutaneous findings of piebaldism (Table 54-9). They are ShahWaardenburg syndrome and Waardenburg syndrome. A possible explanation for both disorders is an abnormal embryonic migration or survival of two neural crest–derived elements, one of them being melanocytes and the other myenteric ganglion cells (leading to Hirschsprung disease in Shah-Waardenburg syndrome) or auditory nerve cells (Waardenburg syndrome). The latter syndrome is characterized by congenital sensorineural hearing loss, dystopia canthorum (lateral displacement of the inner canthi but normal interpupillary distance), heterochromic irises, and a broad nasal root, in addition to the piebaldism. The facial dysmorphism can be explained by the neural crest origin of the connective tissues of the head and neck. Patients with Waardenburg syndrome have been shown to have mutations in four genes, including PAX-3 and MITF, all of which encode transcription factors, whereas patients with Hirschsprung disease plus white spotting have mutations in one of three genes—endothelin 3, endothelin B receptor, and SOX-10. In tuberous sclerosis, the earliest cutaneous sign is macular hypomelanosis, referred to as an ash leaf spot. These lesions are often present at birth and are usually multiple; however, detection may require Wood’s lamp examination, especially in fair-skinned individuals. The pigment within them is reduced, but not absent. The average size is 1–3 cm, and the common shapes are polygonal and lance-ovate. Examination of the patient for additional cutaneous signs such as multiple angiofibromas of the face (adenoma sebaceum), ungual and intraoral fibromas, fibrous cephalic plaques, and connective tissue nevi (shagreen patches) is recommended. It is important to remember that an ash leaf spot on the scalp will result in a circumscribed patch of lightly pigmented hair. Internal manifestations include seizures, intellectual disability, central nervous system (CNS) and retinal hamartomas, pulmonary lymphangioleiomyomatosis (women), renal angiomyolipomas, and cardiac rhabdomyomas. The latter can be detected in up to 60% of children (1.5 cm (see “Hyperpigmentation,” above), axillary freckling, and multiple Lisch nodules, are seen in von Recklinghausen’s disease (NF type I) (Chap. 86).

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TABLE 54-15  Papulonodular Skin Lesions According to Color Groups

PART 2

I. White A.  Calcinosis cutis B.  Osteoma cutis (also skin-colored or blue) II. Skin-colored A.  Rheumatoid nodules B.  Neurofibromas (von Recklinghausen’s disease [NF1]) C.  Angiofibromas (tuberous sclerosis, MEN syndrome, type 1) D.  Neuromas (MEN syndrome, type 2b) E.  Adnexal tumors 1.  Basal cell carcinomas (basal cell nevus syndrome) 2.  Tricholemmomas (Cowden disease) F.  Osteomas (arise in skull and jaw in Gardner syndrome) G.  Primary cutaneous disorders 1.  Epidermal inclusion cystsa 2. Lipomas III. Pink/translucentb A.  Amyloidosis, primary systemic B.  Papular mucinosis/scleromyxedema C.  Multicentric reticulohistiocytosis IV. Yellow A. Xanthomas B. Tophi C.  Necrobiosis lipoidica D.  Pseudoxanthoma elasticum E.  Sebaceous adenomas (Muir-Torre syndrome) V. Redb A. Papules 1.  Angiokeratomas (Fabry disease) 2.  Bacillary angiomatosis (primarily in AIDS) B. Papules/plaques 1.  Cutaneous lupus 2.  Lymphoma cutis 3.  Leukemia cutis 4.  Sweet syndrome C. Nodules 1. Panniculitis 2. Medium-sized vessel vasculitis (e.g., cutaneous polyarteritis nodosa) D.  Primary cutaneous disorders 1.  Arthropod bites 2.  Cherry hemangiomas 3.  Infections, e.g., streptococcal cellulitis, sporotrichosis 4.  Polymorphous light eruption 5. Cutaneous lymphoid hyperplasia (lymphocytoma cutis, pseudolymphoma) VI. Red-brownb A. Sarcoidosis B.  Urticaria pigmentosa C.  Erythema elevatum diutinum (chronic leukocytoclastic vasculitis) D.  Lupus vulgaris VII. Blueb A.  Venous malformations (e.g., blue rubber bleb syndrome) B.  Primary cutaneous disorders 1.  Venous lake 2.  Blue nevus VIII. Violaceous A.  Lupus pernio (sarcoidosis) B.  Lymphoma cutis C.  Cutaneous lupus IX. Purple A.  Kaposi’s sarcoma B. Angiosarcoma C.  Palpable purpura (see Table 54-16) X. Brown-blackc XI.  Any color A. Metastases

Cardinal Manifestations and Presentation of Diseases

If multiple with childhood onset, consider Gardner syndrome. bMay have darker hue in more darkly pigmented individuals. cSee also “Hyperpigmentation.”

a

Abbreviation: MEN, multiple endocrine neoplasia.

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In some patients, the neurofibromas are localized and unilateral due to somatic mosaicism. Angiofibromas are firm pink to skin-colored papules that measure from 3 mm to 1.5 cm in diameter. When multiple lesions are located on the central cheeks (adenoma sebaceum), the patient has tuberous sclerosis or multiple endocrine neoplasia (MEN) syndrome, type 1. The former is an autosomal disorder due to mutations in two different genes, and the associated findings are discussed in the section on ash leaf spots as well as in Chap. 86. Neuromas (benign proliferations of nerve fibers) are also firm, skin-colored papules. They are more commonly found at sites of amputations and in rudimentary polydacyly. However, when there are multiple neuromas on the eyelids, lips, distal tongue, and/or oral mucosa, the patient should be investigated for other signs of MEN syndrome, type 2b. Associated findings include marfanoid habitus, protuberant lips, intestinal ganglioneuromas, and medullary thyroid carcinoma (>75% of patients; Chap. 381). Adnexal tumors are derived from pluripotent cells of the epidermis that can differentiate toward hair, sebaceous, apocrine or eccrine glands, or remain undifferentiated. Basal cell carcinomas (BCCs) are examples of adnexal tumors that have little or no evidence of differentiation. Clinically, they are translucent papules with rolled borders, telangiectasias, and central erosion. BCCs commonly arise in sun-damaged skin of the head and neck as well as the upper trunk. When a patient has multiple BCCs, especially prior to age 30, the possibility of the basal cell nevus syndrome should be raised. It is inherited as an autosomal dominant trait and is associated with jaw cysts, palmar and plantar pits, frontal bossing, medulloblastomas, and calcification of the falx cerebri and diaphragma sellae. Tricholemmomas are also skin-colored adnexal tumors but differentiate toward hair follicles and can have a wartlike appearance. The presence of multiple tricholemmomas on the face and cobblestoning of the oral mucosa points to the diagnosis of Cowden disease (multiple hamartoma syndrome) due to mutations in the phosphatase and tensin homolog (PTEN) gene. Internal organ involvement (in decreasing order of frequency) includes fibrocystic disease and carcinoma of the breast, adenomas and carcinomas of the thyroid, and gastrointestinal polyposis. Keratoses of the palms, soles, and dorsal aspect of the hands are also seen.

■■PINK LESIONS

The cutaneous lesions associated with primary systemic amyloidosis are often pink to pink-orange in color and translucent. Common locations are the face, especially the periorbital and perioral regions, and flexural areas. On biopsy, homogeneous deposits of amyloid are seen in the dermis and in the walls of blood vessels; the latter lead to an increase in vessel wall fragility. As a result, petechiae and purpura develop in clinically normal skin as well as in lesional skin following minor trauma, hence the term pinch purpura. Amyloid deposits are also seen in the striated muscle of the tongue and result in macroglossia. Even though specific mucocutaneous lesions are present in only ~30% of the patients with primary systemic (AL) amyloidosis, the diagnosis can be made via histologic examination of abdominal subcutaneous fat, in conjunction with a serum free light chain assay. By special staining, amyloid deposits are seen around blood vessels or individual fat cells in 40–50% of patients. There are also three forms of amyloidosis that are limited to the skin and that should not be construed as cutaneous lesions of systemic amyloidosis. They are macular amyloidosis (upper back), lichen amyloidosis (usually lower extremities), and nodular amyloidosis. In macular and lichen amyloidosis, the deposits are composed of altered epidermal keratin. Early-onset macular and lichen amyloidosis have been associated with MEN syndrome, type 2a. Patients with multicentric reticulohistiocytosis also have pink-colored papules and nodules on the face and mucous membranes as well as on the extensor surface of the hands and forearms. They have a polyarthritis that can mimic rheumatoid arthritis clinically. On histologic examination, the papules have characteristic giant cells that are not seen in biopsies of rheumatoid nodules. Pink to skin-colored papules that are firm, 2–5 mm in diameter, and often in a linear arrangement are seen in patients with papular mucinosis. This disease is also referred to as

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scleromyxedema. The latter name comes from the induration of the face and extremities that may accompany the papular eruption. Biopsy specimens of the papules show localized mucin deposition, and serum protein electrophoresis plus immunofixation electrophoresis demonstrates a monoclonal spike of IgG, usually with a λ light chain.

■■YELLOW LESIONS

Skin Manifestations of Internal Disease

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Cutaneous lesions that are red in color have a wide variety of etiologies; in an attempt to simplify their identification, they will be subdivided into papules, papules/plaques, and subcutaneous nodules. Common red papules include arthropod bites and cherry hemangiomas; the latter are small, bright-red, dome-shaped papules that represent a benign proliferation of capillaries. In patients with AIDS (Chap. 197), the development of multiple red hemangioma-like lesions points to bacillary angiomatosis, and biopsy specimens show clusters of bacilli that stain positively with the Warthin-Starry stain; the pathogens have been identified as Bartonella henselae and Bartonella quintana. Disseminated visceral disease is seen primarily in immunocompromised hosts but can occur in immunocompetent individuals. Multiple angiokeratomas are seen in Fabry disease, an X-linked recessive lysosomal storage disease that is due to a deficiency of α-galactosidase A. The lesions are red to red-blue in color and can be quite small in size (1–3 mm), with the most common location being the lower trunk. Associated findings include chronic renal disease, peripheral neuropathy, and corneal opacities (cornea verticillata). Electron photomicrographs of angiokeratomas and clinically normal skin demonstrate lamellar lipid deposits in fibroblasts, pericytes, and endothelial cells that are diagnostic of this disease. Widespread acute eruptions of erythematous papules are discussed in the section on exanthems. There are several infectious diseases that present as erythematous papules or nodules in a lymphocutaneous or sporotrichoid pattern, that is, in a linear arrangement along the lymphatic channels. The two most common etiologies are Sporothrix schenckii (sporotrichosis) and the atypical mycobacterium Mycobacterium marinum. The organisms are introduced as a result of trauma, and a primary inoculation site is often seen in addition to the lymphatic nodules. Additional causes include Nocardia, Leishmania, and other atypical mycobacteria and dimorphic fungi; culture or PCR of lesional tissue will aid in the diagnosis. The diseases that are characterized by erythematous plaques with scale are reviewed in the papulosquamous section, and the various forms of dermatitis are discussed in the section on erythroderma. Additional disorders in the differential diagnosis of red papules/plaques include cellulitis, polymorphous light eruption (PMLE), cutaneous lymphoid hyperplasia (lymphocytoma cutis), cutaneous lupus, lymphoma cutis, and leukemia cutis. The first three diseases represent primary cutaneous disorders, although cellulitis may be accompanied by a bacteremia. PMLE is characterized by erythematous papules and plaques in a primarily sun-exposed distribution—dorsum of the hand, extensor forearm, and upper trunk. Lesions follow exposure to UV-B and/or UV-A, and in higher latitudes, PMLE is most severe in the late spring and early summer. A process referred to as “hardening” occurs with continued UV exposure, and the eruption fades, but in temperate climates, it recurs the next spring. PMLE must be differentiated from cutaneous lupus, and this is accomplished by observation of the natural history, histologic examination, and sometimes direct immunofluorescence of the lesions. Cutaneous lymphoid hyperplasia (pseudolymphoma) is a benign polyclonal proliferation of lymphocytes within the skin that presents as infiltrated pink-red to red-purple papules and plaques; it must be distinguished from lymphoma cutis. Several types of red plaques are seen in patients with systemic lupus, including (1) erythematous urticarial plaques across the cheeks and nose in the classic butterfly rash; (2) erythematous discoid lesions with fine or “carpet-tack” scale, telangiectasias, central hypopigmentation, peripheral hyperpigmentation, follicular plugging, and atrophy located on the scalp, face, external ears, arms, and upper trunk; and (3) psoriasiform or annular lesions of subacute cutaneous lupus with hypopigmented centers located primarily on the extensor arms and upper trunk. Additional mucocutaneous findings include (1) a violaceous flush on the face and V of the neck; (2) photosensitivity; (3) urticarial vasculitis (see “Urticaria,” above); (4) lupus panniculitis (see below); (5) diffuse alopecia; (6) alopecia secondary to discoid lesions; (7) cuticular telangiectasias and erythema; (8) EM- or TEN-like lesions that may become bullous; (9) oral or nasal ulcers; (10) livedo reticularis; and (11) distal ulcerations secondary to Raynaud’s phenomenon, vasculitis, or livedoid vasculopathy. Patients with only discoid lesions

CHAPTER 54

Several systemic disorders are characterized by yellow-colored cutaneous papules or plaques—hyperlipidemia (xanthomas), gout (tophi), diabetes (necrobiosis lipoidica), pseudoxanthoma elasticum, and MuirTorre syndrome (sebaceous tumors). Eruptive xanthomas are the most common form of xanthomas and are associated with hypertriglyceridemia (primarily hyperlipoproteinemia types I, IV, and V). Crops of yellow papules with erythematous halos occur primarily on the extensor surfaces of the extremities and the buttocks, and they spontaneously involute with a fall in serum triglycerides. Types II and III result in one or more of the following types of xanthoma: xanthelasma, tendon xanthomas, and plane xanthomas. Xanthelasma are found on the eyelids, whereas tendon xanthomas are frequently associated with the Achilles and extensor finger tendons; plane xanthomas are flat and favor the palmar creases and flexural folds. Tuberous xanthomas are frequently associated with hypercholesterolemia; however, they are also seen in patients with hypertriglyceridemia and are found most frequently over the large joints or hand. Biopsy specimens of xanthomas show collections of lipid-containing macrophages (foam cells). Patients with several disorders, including biliary cirrhosis, can have a secondary form of hyperlipidemia with associated tuberous and plane xanthomas. However, patients with plasma cell dyscrasias have normolipemic plane xanthomas. This latter form of xanthoma may be ≥12 cm in diameter and is most frequently seen on the neck, upper trunk, and flexural folds. It is important to note that the most common setting for eruptive xanthomas is uncontrolled diabetes mellitus. The least specific sign for hyperlipidemia is xanthelasma, because at least 50% of the patients with this finding have normal lipid profiles. In tophaceous gout, there are deposits of monosodium urate in the skin around the joints, particularly those of the hands and feet. Additional sites of tophi formation include the helix of the ear and the olecranon and prepatellar bursae. The lesions are firm, yellow to yellow-white in color, and occasionally discharge a chalky material. Their size varies from 1 mm to 7 cm, and the diagnosis can be established by polarized light microscopy of the aspirated contents of a tophus. Lesions of necrobiosis lipoidica are found primarily on the shins (90%), and patients can have diabetes mellitus or develop it subsequently. Characteristic findings include a central yellow color, atrophy (transparency), telangiectasias, and a red to red-brown border. Ulcerations can also develop within the plaques. Biopsy specimens show necrobiosis of collagen and granulomatous inflammation. In pseudoxanthoma elasticum (PXE), due to mutations in the gene ABCC6, there is an abnormal deposition of calcium on the elastic fibers of the skin, eye, and blood vessels. In the skin, the flexural areas such as the neck, axillae, antecubital fossae, and inguinal area are the primary sites of involvement. Yellow papules coalesce to form reticulated plaques that have an appearance similar to that of plucked chicken skin. In severely affected skin, hanging, redundant folds develop. Biopsy specimens of involved skin show swollen and irregularly clumped elastic fibers with deposits of calcium. In the eye, the calcium deposits in Bruch’s membrane lead to angioid streaks and choroiditis; in the arteries of the heart, kidney, gastrointestinal tract, and extremities, the deposits lead to angina, hypertension, gastrointestinal bleeding, and claudication, respectively. Adnexal tumors that have differentiated toward sebaceous glands include sebaceous adenoma, sebaceous carcinoma, and sebaceous hyperplasia. Except for sebaceous hyperplasia, which is commonly seen on the face, these tumors are fairly rare. Patients with Muir-Torre syndrome have one or more sebaceous adenoma(s), and they can also have sebaceous carcinomas and sebaceous hyperplasia as well as keratoacanthomas. The internal manifestations of Muir-Torre syndrome include multiple carcinomas of the gastrointestinal tract (primarily colon) as well as cancers of the genitourinary tract.

■■RED LESIONS

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usually have the form of lupus that is limited to the skin. However, up to 10–15% of these patients eventually develop systemic lupus. Direct immunofluorescence of involved skin, in particular discoid lesions, shows deposits of IgG or IgM and C3 in a granular distribution along the dermal-epidermal junction. In lymphoma cutis, there is a clonal proliferation of malignant lymphocytes within the skin, and the clinical appearance resembles that of cutaneous lymphoid hyperplasia—infiltrated pink-red to red-purple papules and plaques. Lymphoma cutis can occur anywhere on the surface of the skin, whereas the sites of predilection for lymphocytomas include the malar ridge, tip of the nose, and earlobes. Patients with non-Hodgkin’s lymphomas have specific cutaneous lesions more often than those with Hodgkin’s disease, and, occasionally, the skin nodules precede the development of extracutaneous non-Hodgkin’s lymphoma or represent the only site of involvement (e.g., primary cutaneous B cell lymphoma). Arcuate lesions are sometimes seen in lymphoma and lymphocytoma cutis as well as in CTCL. Adult T cell leukemia/lymphoma that develops in association with HTLV-1 infection is characterized by cutaneous plaques, hypercalcemia, and circulating CD25+ lymphocytes. Leukemia cutis has the same appearance as lymphoma cutis, and specific lesions are seen more commonly in monocytic leukemias than in lymphocytic or granulocytic leukemias. Cutaneous chloromas (granulocytic sarcomas) may precede the appearance of circulating blasts in acute myelogenous leukemia and, as such, represent a form of aleukemic leukemia cutis. Sweet syndrome is characterized by pink-red to red-brown edematous plaques that are frequently painful and occur primarily on the head, neck, and upper extremities. The patients also have fever, neutrophilia, and a dense dermal infiltrate of neutrophils in the lesions. In ~10% of the patients, there is an associated malignancy, most commonly acute myelogenous leukemia. Sweet syndrome has also been reported with inflammatory bowel disease, systemic lupus erythematosus, and solid tumors (primarily of the genitourinary tract) as well as drugs (e.g., all-trans-retinoic acid, granulocyte colony-stimulating factor [G-CSF]). The differential diagnosis includes neutrophilic eccrine hidradenitis; bullous forms of pyoderma gangrenosum; and, occasionally, cellulitis. Extracutaneous sites of involvement include joints, muscles, eyes, kidneys (proteinuria, occasionally glomerulonephritis), and lungs (neutrophilic infiltrates). The idiopathic form of Sweet syndrome is seen more often in women, following a respiratory tract infection. Common causes of erythematous subcutaneous nodules include inflamed epidermoid inclusion cysts, acne cysts, and furuncles. Panniculitis, an inflammation of the fat, also presents as subcutaneous nodules and is frequently a sign of systemic disease. There are several forms of panniculitis, including erythema nodosum, erythema induratum/nodular vasculitis, lupus panniculitis, lipodermatosclerosis, α1-antitrypsin deficiency, factitial, and fat necrosis secondary to pancreatic disease. Except for erythema nodosum, these lesions may break down and ulcerate or heal with a scar. The shin is the most common location for the nodules of erythema nodosum, whereas the calf is the most common location for lesions of erythema induratum. In erythema nodosum, the nodules are initially red but then develop a blue color as they resolve. Patients with erythema nodosum but no underlying systemic illness can still have fever, malaise, leukocytosis, arthralgias, and/or arthritis. However, the possibility of an underlying illness should be excluded, and the most common associations are streptococcal infections, upper respiratory viral infections, sarcoidosis, and inflammatory bowel disease, in addition to drugs (oral contraceptives, sulfonamides, penicillins, bromides, iodides, BRAF inhibitors). Less common associations include bacterial gastroenteritis (Yersinia, Salmonella) and coccidioidomycosis followed by tuberculosis, histoplasmosis, brucellosis, and infections with Chlamydophila pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae, or hepatitis B virus. Erythema induratum and nodular vasculitis have overlapping features clinically and histologically, and whether they represent two separate entities or the ends of a single disease spectrum is a point of debate; in general, the latter is usually idiopathic and the former is associated with the presence of Mycobacterium tuberculosis DNA by

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PCR within skin lesions. The lesions of lupus panniculitis are found primarily on the cheeks, upper arms, and buttocks (sites of abundant fat) and are seen in both the cutaneous and systemic forms of lupus. The overlying skin may be normal, erythematous, or have the changes of discoid lupus. The subcutaneous fat necrosis that is associated with pancreatic disease is presumably secondary to circulating lipases and is seen in patients with pancreatic carcinoma as well as in patients with acute and chronic pancreatitis. In this disorder, there may be an associated arthritis, fever, and inflammation of visceral fat. Histologic examination of deep incisional biopsy specimens will aid in the diagnosis of the particular type of panniculitis. Subcutaneous erythematous nodules are also seen in cutaneous polyarteritis nodosa and as a manifestation of systemic vasculitis when there is involvement of medium-sized vessels, for example, systemic polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis, or granulomatosis with polyangiitis (Chap. 356). Cutaneous polyarteritis nodosa presents with painful subcutaneous nodules and ulcers within a red-purple, netlike pattern of livedo reticularis. The latter is due to slowed blood flow through the superficial horizontal venous plexus. The majority of lesions are found on the lower extremities, and while arthralgias and myalgias may accompany cutaneous polyarteritis nodosa, there is no evidence of systemic involvement. In both the cutaneous and systemic forms of vasculitis, skin biopsy specimens of the associated nodules will show the changes characteristic of a necrotizing vasculitis and/or granulomatous inflammation.

■■RED-BROWN LESIONS

The cutaneous lesions in sarcoidosis (Chap. 360) are classically red to red-brown in color, and with diascopy (pressure with a glass slide), a yellow-brown residual color is observed that is secondary to the granulomatous infiltrate. The waxy papules and plaques may be found anywhere on the skin, but the face is the most common location. Usually there are no surface changes, but occasionally the lesions will have scale. Biopsy specimens of the papules show “naked” granulomas in the dermis, that is, granulomas surrounded by a minimal number of lymphocytes. Other cutaneous findings in sarcoidosis include annular lesions with an atrophic or scaly center, papules within scars, hypopigmented papules and patches, alopecia, acquired ichthyosis, erythema nodosum, and lupus pernio (see below). The differential diagnosis of sarcoidosis includes foreign-body granulomas produced by chemicals such as beryllium and zirconium, late secondary syphilis, and lupus vulgaris. Lupus vulgaris is a form of cutaneous tuberculosis that is seen in previously infected and sensitized individuals. There is often underlying active tuberculosis elsewhere, usually in the lungs or lymph nodes. Lesions occur primarily in the head and neck region and are red-brown plaques with a yellow-brown color on diascopy. Secondary scarring can develop within the central portion of the plaques. Cultures or PCR analysis of the lesions should be performed, along with an interferon γ release assay of peripheral blood, because it is rare for the acid-fast stain to show bacilli within the dermal granulomas. A generalized distribution of red-brown macules and papules is seen in the form of mastocytosis known as urticaria pigmentosa (Chap. 347). Each lesion represents a collection of mast cells in the dermis, with hyperpigmentation of the overlying epidermis. Stimuli such as rubbing cause these mast cells to degranulate, and this leads to the formation of localized urticaria (Darier’s sign). Additional symptoms can result from mast cell degranulation and include headache, flushing, diarrhea, and pruritus. Mast cells also infiltrate various organs such as the liver, spleen, and gastrointestinal tract, and accumulations of mast cells in the bones may produce either osteosclerotic or osteolytic lesions on radiographs. In the majority of these patients, however, the internal involvement remains indolent. A subtype of chronic cutaneous small-vessel vasculitis, erythema elevatum diutinum (EED), also presents with papules that are red-brown in color. The papules coalesce into plaques on the extensor surfaces of knees, elbows, and the small joints of the hand. Flares of EED have been associated with streptococcal infections.

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■■BLUE LESIONS

Violaceous papules and plaques are seen in lupus pernio, lymphoma cutis, and cutaneous lupus. Lupus pernio is a particular type of sarcoidosis that involves the tip and alar rim of the nose as well as the earlobes, with lesions that are violaceous in color rather than red-brown. This form of sarcoidosis is associated with involvement of the upper respiratory tract. The plaques of lymphoma cutis and cutaneous lupus may be red or violaceous in color and were discussed above.

■■PURPLE LESIONS

Purple-colored papules and plaques are seen in vascular tumors, such as Kaposi’s sarcoma (Chap. 197) and angiosarcoma, and when there is extravasation of red blood cells into the skin in association with inflammation, as in palpable purpura (see “Purpura,” below). Patients with congenital or acquired AV fistulas and venous hypertension can develop purple papules on the lower extremities that can resemble Kaposi’s sarcoma clinically and histologically; this condition is referred to as pseudo-Kaposi’s sarcoma (acral angiodermatitis). Angiosarcoma is found most commonly on the scalp and face of elderly patients or within areas of chronic lymphedema and presents as purple papules and plaques. In the head and neck region, the tumor often extends beyond the clinically defined borders and may be accompanied by facial edema.

■■BROWN AND BLACK LESIONS

Brown- and black-colored papules are reviewed in “Hyperpigmentation,” above.

■■CUTANEOUS METASTASES

These are discussed last because they can have a wide range of colors. Most commonly, they present as either firm, skin-colored subcutaneous nodules or firm, red to red-brown papulonodules while metastatic melanoma can be pink, blue, or black in color. Cutaneous metastases develop from hematogenous or lymphatic spread and are most often due to the following primary carcinomas: in men, melanoma, oropharynx, lung, and colon; and in women, breast, melanoma, and ovary. These metastatic lesions may be the initial presentation of the carcinoma, especially when the primary site is the lung.

PURPURA

(Table 54-16) Purpura are seen when there is an extravasation of red blood cells into the dermis and, as a result, the lesions do not blanch with pressure. This is in contrast to those erythematous or violetcolored lesions that are due to localized vasodilatation—they do blanch with pressure. Purpura (≥3 mm) and petechiae (≤2 mm) are divided into two major groups: palpable and nonpalpable. The most frequent causes of nonpalpable petechiae and purpura are primary cutaneous disorders such as trauma, solar (actinic) purpura, and capillaritis. Less common causes are steroid purpura and livedoid vasculopathy (see “Ulcers,” below). Solar purpura are seen primarily on the extensor forearms, whereas steroid purpura secondary to potent topical glucocorticoids or endogenous or exogenous Cushing’s syndrome can be more

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I.  Primary cutaneous disorders A. Nonpalpable 1. Trauma 2.  Solar (actinic, senile) purpura 3.  Steroid purpura 4. Capillaritis 5.  Livedoid vasculopathy in the setting of venous hypertensiona II.  Drugs (e.g. anti-platelet agents, anti-coagulants) III.  Systemic diseases A. Nonpalpable 1.  Clotting disturbances a.  Thrombocytopenia (including ITP) b.  Abnormal platelet function c.  Clotting factor defects 2.  Vascular fragility a.  Amyloidosis (within normal-appearing skin) b.  Ehlers-Danlos syndrome c. Scurvy 3. Thrombi a.  Disseminated intravascular coagulation b.  Warfarin (Coumadin®)-induced necrosis c.  Heparin-induced thrombocytopenia and thrombosis d.  Antiphospholipid antibody syndrome e.  Monoclonal cryoglobulinemia f.  Vasculopathy induced by levamisole-adulterated cocaine g.  Thrombotic thrombocytopenic purpura h. Thrombocytosis i.  Homozygous protein C or protein S deficiency 4. Emboli a. Cholesterol b. Fat 5.  Possible immune complex a.  Gardner-Diamond syndrome (autoerythrocyte sensitivity) b.  Waldenström’s hypergammaglobulinemic purpura B. Palpable 1. Vasculitis a. Cutaneous small-vessel vasculitis, including in the setting of systemic vasculitides 2. Embolib a.  Acute meningococcemia b.  Disseminated gonococcal infection c.  Rocky Mountain spotted fever d.  Ecthyma gangrenosum

Skin Manifestations of Internal Disease

■■VIOLACEOUS LESIONS

353

TABLE 54-16  Causes of Purpura

CHAPTER 54

Lesions that are blue in color are the result of vascular ectasias, hyperplasias and tumors or melanin pigment within the dermis. Venous lakes (ectasias) are compressible dark-blue lesions that are found commonly in the head and neck region. Venous malformations are also compressible blue papulonodules and plaques that can occur anywhere on the body, including the oral mucosa. When there are multiple papulonodules rather than a single congenital lesion, the patient may have the blue rubber bleb syndrome or Maffucci’s syndrome. Patients with the blue rubber bleb syndrome also have vascular anomalies of the gastrointestinal tract that may bleed, whereas patients with Maffucci’s syndrome have associated osteochondromas. Blue nevi (moles) are seen when there are collections of pigment-producing nevus cells in the dermis. These benign papular lesions are dome-shaped and occur most commonly on the dorsum of the hand or foot or in the head and neck region.

a Also associated with underlying disorders that lead to hypercoagulability/ thrombophilia, e.g., factor V Leiden, protein C dysfunction/deficiency. bBacterial (including rickettsial), fungal, or parasitic.

Abbreviation: ITP, idiopathic thrombocytopenic purpura.

widespread. In both cases, there is alteration of the supporting connective tissue that surrounds the dermal blood vessels. In contrast, the petechiae that result from capillaritis are found primarily on the lower extremities. In capillaritis, there is an extravasation of erythrocytes as a result of perivascular lymphocytic inflammation. The petechiae are bright red, 1–2 mm in size, and scattered within yellow-brown patches. The yellow-brown color is caused by hemosiderin deposits within the dermis. Systemic causes of nonpalpable purpura fall into several categories, and those secondary to clotting disturbances and vascular fragility will be discussed first. The former group includes thrombocytopenia (Chap. 111), abnormal platelet function as is seen in uremia, and clotting factor defects. The initial site of presentation for thrombocytopeniainduced petechiae is the distal lower extremity. Capillary fragility leads to nonpalpable purpura in patients with systemic amyloidosis

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(see “Papulonodular Skin Lesions,” above), disorders of collagen production such as Ehlers-Danlos syndrome, and scurvy. In scurvy, there are flattened corkscrew hairs with surrounding hemorrhage on the lower extremities, in addition to gingivitis. Vitamin C is a cofactor for lysyl hydroxylase, an enzyme involved in the posttranslational modification of procollagen that is necessary for cross-link formation. In contrast to the previous group of disorders, the noninflammatory purpura seen in the following group of diseases are associated with thrombi formation within vessels and have a retiform configuration. It is important to note that these thrombi are demonstrable in skin biopsy specimens. This group of disorders includes disseminated intravascular coagulation (DIC), monoclonal cryoglobulinemia, thrombocytosis, thrombotic thrombocytopenic purpura, antiphospholipid antibody syndrome, and reactions to warfarin and heparin (heparin-induced thrombocytopenia and thrombosis). DIC is triggered by several types of infection (gram-negative, gram-positive, viral, and rickettsial) as well as by tissue injury and neoplasms. Widespread purpura and hemorrhagic infarcts of the distal extremities are seen. Similar lesions are found in purpura fulminans, which is a form of DIC associated with fever and hypotension that occurs more commonly in children following an infectious illness such as varicella, scarlet fever, or an upper respiratory tract infection. In both disorders, hemorrhagic bullae can develop in involved skin. Monoclonal cryoglobulinemia is associated with plasma cell dyscrasias, chronic lymphocytic leukemia, and lymphoma. Purpura, primarily of the lower extremities, and hemorrhagic infarcts of the fingers, toes, and ears are seen in these patients. Exacerbations of disease activity can follow cold exposure or an increase in serum viscosity. Biopsy specimens show precipitates of the cryoglobulin within dermal vessels. Similar deposits have been found in the lung, brain, and renal glomeruli. Patients with thrombotic thrombocytopenic purpura can also have hemorrhagic infarcts as a result of intravascular thromboses. Additional signs include microangiopathic hemolytic anemia and fluctuating neurologic abnormalities, especially headaches and confusion. Administration of warfarin can result in painful areas of erythema that become purpuric and then necrotic with an adherent black eschar; the condition is referred to as warfarin-induced necrosis. This reaction is seen more often in women and in areas with abundant subcutaneous fat—breasts, abdomen, buttocks, thighs, and calves. The erythema and purpura develop between the third and tenth day of therapy, most likely as a result of a transient imbalance in the levels of anticoagulant and procoagulant vitamin K–dependent factors. Continued therapy does not exacerbate preexisting lesions, and patients with an inherited or acquired deficiency of protein C are at increased risk for this particular reaction as well as for purpura fulminans and calciphylaxis. Purpura secondary to cholesterol emboli are usually seen on the lower extremities of patients with atherosclerotic vascular disease. They often follow anticoagulant therapy or an invasive vascular procedure such as an arteriogram but also occur spontaneously from disintegration of atheromatous plaques. Associated findings include livedo reticularis, gangrene, cyanosis, and ischemic ulcerations. Multiple step sections of the biopsy specimen may be necessary to demonstrate the cholesterol clefts within the vessels. Petechiae are also an important sign of fat embolism and occur primarily on the upper body 2–3 days after a major injury. By using special fixatives, the emboli can be demonstrated in biopsy specimens of the petechiae. Emboli of tumor or thrombus are seen in patients with atrial myxomas and marantic endocarditis. In the Gardner-Diamond syndrome (autoerythrocyte sensitivity), female patients develop large ecchymoses within areas of painful, warm erythema. Intradermal injections of autologous erythrocytes or phosphatidyl serine derived from the red cell membrane can reproduce the lesions in some patients; however, there are instances where a reaction is seen at an injection site of the forearm but not in the midback region. The latter has led some observers to view Gardner-Diamond syndrome as a cutaneous manifestation of severe emotional stress. More recently, the possibility of platelet dysfunction (as assessed via aggregation studies) has been raised. Waldenström’s hypergammaglobulinemic purpura is a chronic disorder characterized by recurrent crops of petechiae and larger purpuric macules on the lower extremities. There

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are circulating complexes of IgG–anti-IgG molecules, and exacerbations are associated with prolonged standing or walking. Palpable purpura are further subdivided into vasculitic and embolic. In the group of vasculitic disorders, cutaneous small-vessel vasculitis, also known as leukocytoclastic vasculitis (LCV), is the one most commonly associated with palpable purpura (Chap. 356). Underlying etiologies include drugs (e.g., antibiotics), infections (e.g., hepatitis C virus), and autoimmune connective tissue diseases (e.g., rheumatoid arthritis, Sjögren’s syndrome, lupus). Henoch-Schönlein purpura (HSP) is a subtype of acute LCV that is seen more commonly in children and adolescents following an upper respiratory infection. The majority of lesions are found on the lower extremities and buttocks. Systemic manifestations include fever, arthralgias (primarily of the knees and ankles), abdominal pain, gastrointestinal bleeding, and nephritis. Direct immunofluorescence examination shows deposits of IgA within dermal blood vessel walls. Renal disease is of particular concern in adults with HSP. Several types of infectious emboli can give rise to palpable purpura. These embolic lesions are usually irregular in outline as opposed to the lesions of LCV, which are circular in outline. The irregular outline is indicative of a cutaneous infarct, and the size corresponds to the area of skin that received its blood supply from that particular arteriole or artery. The palpable purpura in LCV are circular because the erythrocytes simply diffuse out evenly from the postcapillary venules as a result of inflammation. Infectious emboli are most commonly due to gram-negative cocci (meningococcus, gonococcus), gram-negative rods (Enterobacteriaceae), and gram-positive cocci (Staphylococcus). Additional causes include Rickettsia and, in immunocompromised patients, Aspergillus and other opportunistic fungi. The embolic lesions in acute meningococcemia are found primarily on the trunk, lower extremities, and sites of pressure, and a gunmetal-gray color often develops within them. Their size varies from a few millimeters to several centimeters, and the organisms can be cultured from the lesions. Associated findings include a preceding upper respiratory tract infection; fever; meningitis; DIC; and, in some patients, a deficiency of the terminal components of complement. In disseminated gonococcal infection (arthritis-dermatitis syndrome), a small number of inflammatory papules and vesicopustules, often with central purpura or hemorrhagic necrosis, are found on the distal extremities. Additional symptoms include arthralgias, tenosynovitis, and fever. To establish the diagnosis, a Gram stain of these lesions should be performed. Rocky Mountain spotted fever is a tick-borne disease that is caused by Rickettsia rickettsii. A several-day history of fever, chills, severe headache, and photophobia precedes the onset of the cutaneous eruption. The initial lesions are erythematous macules and papules on the wrists, ankles, palms, and soles. With time, the lesions spread centripetally and become purpuric. Lesions of ecthyma gangrenosum begin as edematous, erythematous papules or plaques and then develop central purpura and necrosis. Bullae formation also occurs in these lesions, and they are frequently found in the girdle region. The organism that is classically associated with ecthyma gangrenosum is Pseudomonas aeruginosa, but other gram-negative rods such as Klebsiella, Escherichia coli, and Serratia can produce similar lesions. In immunocompromised hosts, the list of potential pathogens is expanded to include Candida and other opportunistic fungi (e.g., Aspergillus, Fusarium).

ULCERS

The approach to the patient with a cutaneous ulcer is outlined in Table 54-17. Peripheral vascular diseases of the extremities are reviewed in Chap. 275, as is Raynaud’s phenomenon. Livedoid vasculopathy (livedoid vasculitis; atrophie blanche) represents a combination of a vasculopathy plus intravascular thrombosis. Purpuric lesions and livedo reticularis are found in association with painful ulcerations of the lower extremities. These ulcers are often slow to heal, but when they do, irregularly shaped white scars form. The majority of cases are secondary to venous hypertension, but possible underlying illnesses include disorders of hypercoagulability, for example, antiphospholipid syndrome, factor V Leiden (Chaps. 113 and 350).

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TABLE 54-17  Causes of Mucocutaneous Ulcers

355

FEVER AND RASH

The major considerations in a patient with a fever and a rash are inflammatory diseases versus infectious diseases. In the hospital setting, the most common scenario is a patient who has a drug rash plus a fever secondary to an underlying infection. However, it should be emphasized that a drug reaction can lead to both a cutaneous eruption and a fever (“drug fever”), especially in the setting of DRESS, AGEP, or serum sickness–like reaction. Additional inflammatory diseases that are often associated with a fever include pustular psoriasis, erythroderma, and Sweet syndrome. Lyme disease, secondary syphilis, and viral and bacterial exanthems (see “Exanthems,” above) are examples of infectious diseases that produce a rash and a fever. Lastly, it is important to determine whether or not the cutaneous lesions represent septic emboli (see “Purpura,” above). Such lesions usually have evidence of ischemia in the form of purpura, necrosis, or impending necrosis (gunmetal-gray color). In the patient with thrombocytopenia, however, purpura can be seen in inflammatory reactions such as morbilliform drug eruptions and infectious lesions.

■■FURTHER READING

Bolognia JL, Schaffer JV, Cerroni L (eds): Dermatology, 4th ed. Philadelphia, Elsevier, 2018. Callen JP et al (eds): Dermatological Signs of Systemic Disease, 5th ed. Edinburgh, Elsevier, 2017. Rigopoulos D, Larios G, Katsambas A: Skin signs of systemic diseases. Clin Dermatol 29:531, 2011. Taylor SC et al (eds): Taylor and Kelly’s Dermatology for Skin of Color, 2nd ed. New York, McGraw-Hill, 2016. Thiers BH, Sahn RE, Callen JP: Cutaneous manifestations of internal malignancy. CA: Cancer J Clin 59:73, 2009.

55

Immunologically Mediated Skin Diseases

Underlying atherosclerosis. bAlso associated with underlying disorders that lead to hypercoagulability/thrombophilia, e.g., factor V Leiden, protein C dysfunction/ deficiency, antiphospholipid antibodies. cReviewed in section on Purpura. d Reviewed in section on Papulonodular Skin Lesions. eFavors plantar surface of the foot. fSign of immunosuppression.

bites, and factitial. In the myeloproliferative disorders, the ulcers may be more superficial with a pustulobullous border, and these lesions provide a connection between classic pyoderma gangrenosum and acute febrile neutrophilic dermatosis (Sweet syndrome).

CHAPTER 55

I.  Primary cutaneous disorders A.  Peripheral vascular disease (Chap. 275) 1. Venous 2. Arteriala B.  Livedoid vasculopathy in the setting of venous hypertensionb C.  Squamous cell carcinoma (e.g., within scars), basal cell carcinomas D.  Infections, e.g., ecthyma caused by Streptococcus (Chap. 143) E.  Physical, e.g., trauma, pressure F.  Drugs, e.g., hydroxyurea II.  Systemic diseases A.  Lower legs   1.  Small-vessel and medium-vessel vasculitisc  2. Hemoglobinopathies (Chap. 94)  3. Cryoglobulinemia,c cryofibrinogenemia  4. Cholesterol embolia,c  5. Necrobiosis lipoidicad  6. Antiphospholipid syndrome (Chap. 112)  7. Neuropathice (Chap. 396)  8. Panniculitis   9.  Kaposi’s sarcoma, acral angiodermatitis 10.  Diffuse dermal angiomatosis B.  Hands and feet 1.  Raynaud’s phenomenon (Chap. 275) 2.  Buerger disease C. Generalized 1.  Pyoderma gangrenosum, but most commonly legs 2. Calciphylaxis (Chap. 403) 3.  Infections, e.g., dimorphic fungi, leishmaniasis 4. Lymphoma D.  Face, especially perioral, and anogenital 1.  Chronic herpes simplexf III. Mucosal A.  Behçet’s syndrome (Chap. 357) B.  Erythema multiforme major, Stevens-Johnson syndrome, TEN C.  Primary blistering disorders (Chap. 55) D.  Lupus erythematosus, lichen planus E.  Inflammatory bowel disease F.  Acute HIV infection G.  Reactive arthritis

Immunologically Mediated Skin Diseases Kim B. Yancey, Thomas J. Lawley

a

Abbreviations: HIV, human immunodeficiency virus; TEN, toxic epidermal necrolysis.

In pyoderma gangrenosum, the border of untreated active ulcers has a characteristic appearance consisting of an undermined necrotic violaceous edge and a peripheral erythematous halo. The ulcers often begin as pustules that then expand rather rapidly to a size as large as 20 cm. Although these lesions are most commonly found on the lower extremities, they can arise anywhere on the surface of the body, including at sites of trauma (pathergy). An estimated 30–50% of cases are idiopathic, and the most common associated disorders are ulcerative colitis and Crohn’s disease. Less commonly, pyoderma gangrenosum is associated with seropositive rheumatoid arthritis, acute and chronic myelogenous leukemia, hairy cell leukemia, myelofibrosis, or a monoclonal gammopathy, usually IgA. Because the histology of pyoderma gangrenosum may be nonspecific (dermal infiltrate of neutrophils when in untreated state), the diagnosis requires clinicopathologic correlation, in particular, the exclusion of similar-appearing ulcers such as necrotizing vasculitis, Meleney’s ulcer (synergistic infection at a site of trauma or surgery), dimorphic fungi, cutaneous amebiasis, spider

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A number of immunologically mediated skin diseases and immunologically mediated systemic disorders with cutaneous manifestations are now recognized as distinct entities with consistent clinical, histologic, and immunopathologic findings. Clinically, these disorders are characterized by morbidity (pain, pruritus, disfigurement) and, in some instances, result in death (largely due to loss of epidermal barrier function and/or secondary infection). The major features of the more common immunologically mediated skin diseases are summarized in this chapter (Table 55-1), as are autoimmune systemic disorders with cutaneous manifestations.

AUTOIMMUNE CUTANEOUS DISEASES ■■PEMPHIGUS VULGARIS

Pemphigus refers to a group of autoantibody-mediated intraepidermal blistering diseases characterized by loss of cohesion between epidermal cells (a process termed acantholysis). Manual pressure to the skin of these patients may elicit the separation of the epidermis (Nikolsky’s sign). This finding, while characteristic of pemphigus, is not specific to this group of disorders and is also seen in toxic epidermal necrolysis, Stevens-Johnson syndrome, and a few other skin diseases. Pemphigus vulgaris (PV) is a mucocutaneous blistering disease that predominantly occurs in patients >40 years of age. PV typically begins on mucosal surfaces and often progresses to involve the skin.

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TABLE 55-1  Immunologically Mediated Blistering Diseases DISEASE Pemphigus vulgaris Pemphigus foliaceus

Paraneoplastic pemphigus

PART 2

Bullous pemphigoid Pemphigoid gestationis

Cardinal Manifestations and Presentation of Diseases

Dermatitis herpetiformis Linear IgA disease

Epidermolysis bullosa acquisita

Mucous membrane pemphigoid

CLINICAL MANIFESTATIONS Flaccid blisters, denuded skin, oromucosal lesions Crusts and shallow erosions on scalp, central face, upper chest, and back Painful stomatitis with papulosquamous or lichenoid eruptions that may progress to blisters Large tense blisters on flexor surfaces and trunk Pruritic, urticarial plaques rimmed by vesicles and bullae on the trunk and extremities Extremely pruritic small papules and vesicles on elbows, knees, buttocks, and posterior neck Pruritic small papules on extensor surfaces; occasionally larger, arciform blisters Blisters, erosions, scars, and milia on sites exposed to trauma; widespread, inflammatory, tense blisters may be seen initially Erosive and/or blistering lesions of mucous membranes and possibly the skin; scarring of some sites

HISTOLOGY Acantholytic blister formed in suprabasal layer of epidermis Acantholytic blister formed in superficial layer of epidermis

IMMUNOPATHOLOGY Cell surface deposits of IgG on keratinocytes Cell surface deposits of IgG on keratinocytes

AUTOANTIGENSa Dsg3 (plus Dsg1 in patients with skin involvement) Dsg1

Acantholysis, keratinocyte necrosis, and vacuolar interface dermatitis

Cell surface deposits of IgG and C3 on keratinocytes and (variably) similar immunoreactants in epidermal BMZ Linear band of IgG and/or C3 in epidermal BMZ Linear band of C3 in epidermal BMZ

Plakin protein family members and desmosomal cadherins (see text for details)

Granular deposits of IgA in dermal papillae

Epidermal transglutaminase

Linear band of IgA in epidermal BMZ

BPAG2 (see text for specific details)

Subepidermal blister with eosinophil-rich infiltrate Teardrop-shaped, subepidermal blisters in dermal papillae; eosinophilrich infiltrate Subepidermal blister with neutrophils in dermal papillae Subepidermal blister with neutrophil-rich infiltrate

BPAG1, BPAG2 BPAG2 (plus BPAG1 in some patients)

Subepidermal blister that may Linear band of IgG and/or C3 in or may not include a leukocytic epidermal BMZ infiltrate

Type VII collagen

Subepidermal blister that may Linear band of IgG, IgA, and/or C3 or may not include a leukocytic in epidermal BMZ infiltrate

BPAG2, laminin-332, or others

a Autoantigens bound by these patients’ autoantibodies are defined as follows: Dsg1, desmoglein 1; Dsg3, desmoglein 3; BPAG1, bullous pemphigoid antigen 1; BPAG2, bullous pemphigoid antigen 2.

Abbreviation: BMZ, basement membrane zone.

This disease is characterized by fragile, flaccid blisters that rupture to produce extensive denudation of mucous membranes and skin (Fig. 55-1). The mouth, scalp, face, neck, axilla, groin, and trunk are typically involved. PV may be associated with severe skin pain; some patients experience pruritus as well. Lesions usually heal without scarring except at sites complicated by secondary infection or mechanically induced dermal wounds. Postinflammatory hyperpigmentation is usually present for some time at sites of healed lesions. Biopsies of early lesions demonstrate intraepidermal vesicle formation secondary to loss of cohesion between epidermal cells (i.e., acantholytic blisters). Blister cavities contain acantholytic epidermal cells, which appear as round homogeneous cells containing hyperchromatic nuclei. Basal keratinocytes remain attached to the epidermal basement membrane; hence, blister formation takes place within the suprabasal portion of the epidermis. Lesional skin may contain focal collections of intraepidermal eosinophils within blister cavities; dermal alterations are slight, often limited to an eosinophil-predominant leukocytic infiltrate. Direct immunofluorescence microscopy of lesional or intact patient skin shows deposits of IgG on the surface of keratinocytes; deposits of complement components are typically found in lesional but not in uninvolved skin. Deposits of IgG on keratinocytes are derived from circulating autoantibodies to cell-surface autoantigens. Such circulating autoantibodies can be demonstrated in 80–90% of PV patients by indirect immunofluorescence microscopy; monkey esophagus is the optimal substrate for these studies. Patients with PV have IgG autoantibodies to desmogleins (Dsgs), transmembrane desmosomal glycoproteins that belong to the cadherin family of calcium-dependent adhesion molecules. Such autoantibodies can be precisely quantitated by enzyme-linked immunosorbent assay (ELISA). Patients with early PV (i.e., mucosal disease) have IgG autoantibodies to Dsg3; patients with advanced PV (i.e., mucocutaneous disease) have IgG autoantibodies to both Dsg3 and Dsg1. Experimental studies have shown that autoantibodies from patients with PV are pathogenic (i.e., responsible for blister formation) and that their titer correlates with disease activity. Recent studies have shown that the anti-Dsg autoantibody profile in

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these patients’ sera as well as the tissue distribution of Dsg3 and Dsg1 determine the site of blister formation in patients with PV. Coexpression of Dsg3 and Dsg1 by epidermal cells protects against pathogenic IgG antibodies to either of these cadherins but not against pathogenic autoantibodies to both. PV can be life-threatening. Prior to the availability of glucocorticoids, mortality rates ranged from 60% to 90%; the current figure is ~5%. Common causes of morbidity and death are infection and complications of treatment. Bad prognostic factors include advanced age, widespread involvement, and the requirement for high doses of glucocorticoids (with or without other immunosuppressive agents) for control of disease. The course of PV in individual patients is variable and difficult to predict. Some patients experience remission, while others may require long-term treatment or succumb to complications of their disease or its treatment. The mainstay of treatment is systemic glucocorticoids. Patients with moderate to severe PV are usually started on prednisone at 1 mg/kg per day. If new lesions continue to appear after 1–2 weeks of treatment, the dose may need to be increased and/or prednisone may need to be combined with other immunosuppressive agents such as azathioprine (2–2.5 mg/kg per day), mycophenolate mofetil (20–35 mg/kg per day), rituximab (375 mg/m2 per week × 4, or 1000 mg on days 1 and 15), or cyclophosphamide (1–2 mg/kg per day). Patients with severe, treatment-resistant disease may derive benefit from plasmapheresis (six high-volume exchanges [i.e., 2–3 L per exchange] over ~2 weeks) and/or IV immunoglobulin (IVIg) (2 g/kg over 3–5 days every 6–8 weeks). It is important to bring severe or progressive disease under control quickly in order to lessen the severity and/or duration of this disorder. Increasingly, rituximab and daily glucocorticoids are used early in PV patients to avert the development of advanced and/or treatment-resistant disease.

■■PEMPHIGUS FOLIACEUS

Pemphigus foliaceus (PF) is distinguished from PV by several features. In PF, acantholytic blisters are located high within the epidermis, usually just beneath the stratum corneum. Hence, PF is a more superficial

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A

Endemic forms of PF are found in south-central rural Brazil, where the disease is known as fogo salvagem (FS), as well as in selected sites in Latin America and Tunisia. Endemic PF, like other forms of this disease, is mediated by IgG autoantibodies to Dsg1. Clusters of FS overlap with those of leishmaniasis, a disease transmitted by bites of the sand fly Lutzomyia longipalis. Recent studies have shown that sand-fly salivary antigens (specifically, the LJM11 salivary protein) are recognized by IgG autoantibodies from FS patients (as well as by monoclonal antibodies to Dsg1 derived from these patients). Moreover, mice immunized with LJM11 produce antibodies to Dsg1. Thus, these findings suggest that insect bites may deliver salivary antigens that initiate a crossreactive humoral immune response, which may lead to FS in genetically susceptible individuals. Although pemphigus has been associated with several autoimmune diseases, its association with thymoma and/or myasthenia gravis is particularly notable. To date, >30 cases of thymoma and/or myasthenia gravis have been reported in association with pemphigus, usually with PF. Patients may also develop pemphigus as a consequence of drug exposure; drug-induced pemphigus usually resembles PF rather than PV. Drugs containing a thiol group in their chemical structure (e.g., penicillamine, captopril, enalapril) are most commonly associated with drug-induced pemphigus. Nonthiol drugs linked to pemphigus include penicillins, cephalosporins, and piroxicam. Some cases of drug-induced pemphigus are durable and require treatment with systemic glucocorticoids and/or immunosuppressive agents. PF is generally a less severe disease than PV and usually carries a better prognosis. Localized disease can sometimes be treated with topical or intralesional glucocorticoids; more active cases can usually be controlled with systemic glucocorticoids either alone or in combination with other immunosuppressive agents. Patients with severe, treatment-resistant disease may require more aggressive interventions, as described above for patients with PV.

■■PARANEOPLASTIC PEMPHIGUS

B FIGURE 55-1  Pemphigus vulgaris. A. Flaccid bullae are easily ruptured, resulting in multiple erosions and crusted plaques. B. Involvement of the oral mucosa, which is almost invariable, may present with erosions on the gingiva, buccal mucosa, palate, posterior pharynx, or tongue. (B, Courtesy of Robert Swerlick, MD; with permission.)

blistering disease than PV. The distribution of lesions in the two disorders is much the same, except that in PF mucous membranes are almost always spared. Patients with PF rarely have intact blisters but rather exhibit shallow erosions associated with erythema, scale, and crust formation. Mild cases of PF can resemble severe seborrheic dermatitis; severe PF may cause extensive exfoliation. Sun exposure (ultraviolet irradiation) may be an aggravating factor. PF has immunopathologic features in common with PV. Specifically, direct immunofluorescence microscopy of perilesional skin demonstrates IgG on the surface of keratinocytes. Similarly, patients with PF have circulating IgG autoantibodies directed against the surface of keratinocytes. In PF, autoantibodies are directed against Dsg1, a 160-kDa desmosomal cadherin. These autoantibodies can be quantitated by ELISA. As noted for PV, the autoantibody profile in patients with PF (i.e., anti-Dsg1 IgG) and the tissue distribution of this autoantigen (i.e., expression in oral mucosa that is compensated by coexpression of Dsg3) are thought to account for the distribution of lesions in this disease.

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Paraneoplastic pemphigus (PNP) is an autoimmune acantholytic mucocutaneous disease associated with an occult or confirmed neoplasm. Patients with PNP typically have painful stomatitis in association with papulosquamous and/or lichenoid eruptions that often progress to blisters. Palm and sole involvement are common in these patients and raise the possibility that prior reports of neoplasiaassociated erythema multiforme actually may have represented unrecognized cases of PNP. Biopsies of lesional skin from these patients show varying combinations of acantholysis, keratinocyte necrosis, and vacuolar-interface dermatitis. Direct immunofluorescence microscopy of a patient’s skin shows deposits of IgG and complement on the surface of keratinocytes and (variably) similar immunoreactants in the epidermal basement membrane zone. Patients with PNP have IgG autoantibodies to cytoplasmic proteins that are members of the plakin family (e.g., desmoplakins I and II, bullous pemphigoid antigen [BPAG]1, envoplakin, periplakin, and plectin) and to cell-surface proteins that are members of the cadherin family (e.g., Dsg1 and Dsg3). Passive transfer studies have shown that autoantibodies from patients with PNP are pathogenic in animal models. The predominant neoplasms associated with PNP are nonHodgkin’s lymphoma, chronic lymphocytic leukemia, thymoma, spindle cell tumors, Waldenström’s macroglobulinemia, and Castleman’s disease; the last-mentioned neoplasm is particularly common among children with PNP. Rare cases of seronegative PNP have been reported in patients with B cell malignancies previously treated with rituximab. In addition to severe skin lesions, many patients with PNP develop life-threatening bronchiolitis obliterans. PNP is generally resistant to conventional therapies (i.e., those used to treat PV); rarely, a patient’s disease may ameliorate or even remit following ablation or removal of underlying neoplasms.

■■BULLOUS PEMPHIGOID

Bullous pemphigoid (BP) is a polymorphic autoimmune subepidermal blistering disease usually seen in the elderly. Initial lesions may consist of urticarial plaques; most patients eventually display tense blisters on

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In some instances, azathioprine (2–2.5 mg/kg per day), mycophenolate mofetil (20–35 mg/kg per day), or rituximab (375 mg/m2 per week x 4, or 1000 mg on days 1 and 15) are necessary adjuncts.

■■PEMPHIGOID GESTATIONIS

PART 2 Cardinal Manifestations and Presentation of Diseases

FIGURE 55-2  Bullous pemphigoid with tense vesicles and bullae on erythematous, urticarial bases. (Courtesy of the Yale Resident’s Slide Collection; with permission.)

either normal-appearing or erythematous skin (Fig. 55-2). The lesions are usually distributed over the lower abdomen, groin, and flexor surface of the extremities; oral mucosal lesions are found in some patients. Pruritus may be nonexistent or severe. As lesions evolve, tense blisters tend to rupture and be replaced by erosions with or without surmounting crust. Nontraumatized blisters heal without scarring. The major histocompatibility complex class II allele HLA-DQβ1*0301 is prevalent in patients with BP. Despite isolated reports, several studies have shown that patients with BP do not have a higher incidence of malignancy than appropriately age- and gender-matched controls. Biopsies of early lesional skin demonstrate subepidermal blisters and histologic features that roughly correlate with the clinical character of the particular lesion under study. Lesions on normal-appearing skin generally contain a sparse perivascular leukocytic infiltrate with some eosinophils; conversely, biopsies of inflammatory lesions typically show an eosinophil-rich infiltrate at sites of vesicle formation and in perivascular areas. In addition to eosinophils, cell-rich lesions also contain mononuclear cells and neutrophils. It is not possible to distinguish BP from other subepidermal blistering diseases by routine histologic studies alone. Direct immunofluorescence microscopy of normal-appearing perilesional skin from patients with BP shows linear deposits of IgG and/ or C3 in the epidermal basement membrane. The sera of ~70% of these patients contain circulating IgG autoantibodies that bind the epidermal basement membrane of normal human skin in indirect immunofluorescence microscopy. IgG from an even higher percentage of patients reacts with the epidermal side of 1 M NaCl split skin (an alternative immunofluorescence microscopy test substrate used to distinguish circulating IgG autoantibodies to the basement membrane in patients with BP from those in patients with similar, yet different, subepidermal blistering diseases; see below). In BP, circulating autoantibodies recognize 230- and 180-kDa hemidesmosome-associated proteins in basal keratinocytes (i.e., BPAG1 and BPAG2, respectively). Autoantibodies to BPAG2 are thought to deposit in situ, activate complement, produce dermal mast-cell degranulation, and generate granulocyte-rich infiltrates that cause tissue damage and blister formation. BP may persist for months to years, with exacerbations or remissions. Extensive involvement may result in widespread erosions and compromise cutaneous integrity; elderly and/or debilitated patients may die. The mainstay of treatment is systemic glucocorticoids. Local or minimal disease can sometimes be controlled with topical glucocorticoids alone; more extensive lesions generally respond to systemic glucocorticoids either alone or in combination with other immunosuppressive agents. Patients usually respond to prednisone (0.75–1 mg/kg per day).

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Pemphigoid gestationis (PG), also known as herpes gestationis, is a rare, nonviral, subepidermal blistering disease of pregnancy and the puerperium. PG may begin during any trimester of pregnancy or present shortly after delivery. Lesions are usually distributed over the abdomen, trunk, and extremities; mucous membrane lesions are rare. Skin lesions in these patients may be quite polymorphic and consist of erythematous urticarial papules and plaques, vesiculopapules, and/or frank bullae. Lesions are almost always extremely pruritic. Severe exacerbations of PG frequently follow delivery, typically within 24–48 h. PG tends to recur in subsequent pregnancies, often beginning earlier during such gestations. Brief flare-ups of disease may occur with resumption of menses and may develop in patients later exposed to oral contraceptives. Occasionally, infants of affected mothers have transient skin lesions. Biopsies of early lesional skin show teardrop-shaped subepidermal vesicles forming in dermal papillae in association with an eosinophil-rich leukocytic infiltrate. Differentiation of PG from other subepidermal bullous diseases by light microscopy is difficult. However, direct immunofluorescence microscopy of perilesional skin from PG patients reveals the immunopathologic hallmark of this disorder: linear deposits of C3 in the epidermal basement membrane. These deposits develop as a consequence of complement activation produced by lowtiter IgG anti–basement membrane autoantibodies directed against BPAG2, the same hemidesmosome-associated protein that is targeted by autoantibodies in patients with BP—a subepidermal bullous disease that resembles PG clinically, histologically, and immunopathologically. The goals of therapy in patients with PG are to prevent the development of new lesions, relieve intense pruritus, and care for erosions at sites of blister formation. Many patients require treatment with moderate doses of daily glucocorticoids (i.e., 20–40 mg of prednisone) at some point in their course. Mild cases (or brief flare-ups) may be controlled by vigorous use of potent topical glucocorticoids. Infants born of mothers with PG appear to be at increased risk of being born slightly premature or “small for dates.” Current evidence suggests that there is no difference in the incidence of uncomplicated live births between PG patients treated with systemic glucocorticoids and those managed more conservatively. If systemic glucocorticoids are administered, newborns are at risk for development of reversible adrenal insufficiency.

■■DERMATITIS HERPETIFORMIS

Dermatitis herpetiformis (DH) is an intensely pruritic, papulovesicular skin disease characterized by lesions symmetrically distributed over extensor surfaces (i.e., elbows, knees, buttocks, back, scalp, and posterior neck) (see Fig. 52-8). Primary lesions in this disorder consist of papules, papulovesicles, or urticarial plaques. Because pruritus is prominent, patients may present with excoriations and crusted papules but no observable primary lesions. Patients sometimes report that their pruritus has a distinctive burning or stinging component; the onset of such local symptoms reliably heralds the development of distinct clinical lesions 12–24 h later. Almost all DH patients have associated, usually subclinical, gluten-sensitive enteropathy (Chap. 318), and >90% express the HLA-B8/DRw3 and HLA-DQw2 haplotypes. DH may present at any age, including in childhood; onset in the second to fourth decades is most common. The disease is typically chronic. Biopsy of early lesional skin reveals neutrophil-rich infiltrates within dermal papillae. Neutrophils, fibrin, edema, and microvesicle formation at these sites are characteristic of early disease. Older lesions may demonstrate nonspecific features of a subepidermal bulla or an excoriated papule. Because the clinical and histologic features of this disease can be variable and resemble those of other subepidermal blistering disorders, the diagnosis is confirmed by direct immunofluorescence microscopy of normal-appearing perilesional skin. Such studies demonstrate granular deposits of IgA (with or without complement

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Linear IgA disease, once considered a variant form of DH, is actually a separate and distinct entity. Clinically, patients with linear IgA disease may resemble individuals with DH, BP, or other subepidermal blistering diseases. Lesions typically consist of papulovesicles, bullae, and/ or urticarial plaques that develop predominantly on central or flexural sites. Oral mucosal involvement occurs in some patients. Severe pruritus resembles that is seen in patients with DH. Patients with linear IgA disease do not have an increased frequency of the HLA-B8/DRw3 haplotype or an associated enteropathy and therefore are not candidates for treatment with a gluten-free diet. Histologic alterations in early lesions may be virtually indistinguishable from those in DH. However, direct immunofluorescence microscopy of normal-appearing perilesional skin reveals a linear band of IgA (and often C3) in the epidermal basement membrane zone. Most patients with linear IgA disease have circulating IgA anti-basement membrane autoantibodies directed against neoepitopes in the proteolytically processed extracellular domain of BPAG2. These patients generally respond to treatment with dapsone (50–200 mg/d).

■■EPIDERMOLYSIS BULLOSA ACQUISITA

Epidermolysis bullosa acquisita (EBA) is a rare, noninherited, polymorphic, chronic, subepidermal blistering disease. (The inherited form is discussed in Chap. 406.) Patients with classic or noninflammatory EBA have blisters on noninflamed skin, atrophic scars, milia, nail dystrophy, and oral lesions. Because lesions generally occur at sites exposed to minor trauma, classic EBA is considered a mechanobullous disease. Other patients with EBA have widespread inflammatory scarring and bullous lesions that resemble severe BP. Inflammatory EBA may

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■■MUCOUS MEMBRANE PEMPHIGOID

Immunologically Mediated Skin Diseases

■■LINEAR IgA DISEASE

evolve into the classic, noninflammatory form of this disease. Rarely, 359 patients present with lesions that predominate on mucous membranes. The HLA-DR2 haplotype is found with increased frequency in EBA patients. Studies suggest that EBA is sometimes associated with inflammatory bowel disease (especially Crohn’s disease). The histology of lesional skin varies with the character of the lesion being studied. Noninflammatory bullae are subepidermal, feature a sparse leukocytic infiltrate, and resemble the lesions in patients with porphyria cutanea tarda. Inflammatory lesions consist of neutrophil-rich subepidermal blisters. EBA patients have continuous deposits of IgG (and frequently C3) in a linear pattern within the epidermal basement membrane zone. Ultrastructurally, these immunoreactants are found in the sublamina densa region in association with anchoring fibrils. Approximately 50% of EBA patients have demonstrable circulating IgG anti-basement membrane autoantibodies directed against type VII collagen—the collagen species that makes up anchoring fibrils. Such IgG autoantibodies bind the dermal side of 1 M NaCl split skin (in contrast to IgG autoantibodies in patients with BP). Studies have shown that passive transfer of experimental or patient IgG against type VII collagen can produce lesions in mice that clinically, histologically, and immunopathologically resemble those in patients with EBA. Treatment of EBA is generally unsatisfactory. Some patients with inflammatory EBA may respond to systemic glucocorticoids, either alone or in combination with immunosuppressive agents. Other patients (especially those with neutrophil-rich inflammatory lesions) may respond to dapsone. The chronic, noninflammatory form of EBA is largely resistant to treatment, although some patients may respond to cyclosporine, azathioprine, IVIg, or rituximab.

CHAPTER 55

components) in the papillary dermis and along the epidermal basement membrane zone. IgA deposits in the skin are unaffected by control of disease with medication; however, these immunoreactants diminish in intensity or disappear in patients maintained for long periods on a strict gluten-free diet (see below). Patients with DH have granular deposits of IgA in their epidermal basement membrane zone and should be distinguished from individuals with linear IgA deposits at this site (see below). Although most DH patients do not report overt gastrointestinal symptoms or have laboratory evidence of malabsorption, biopsies of the small bowel usually reveal blunting of intestinal villi and a lymphocytic infiltrate in the lamina propria. As is true for patients with celiac disease, this gastrointestinal abnormality can be reversed by a glutenfree diet. Moreover, if maintained, this diet alone may control the skin disease and eventuate in clearance of IgA deposits from these patients’ epidermal basement membrane zones. Subsequent gluten exposure in such patients alters the morphology of their small bowel, elicits a flare-up of their skin disease, and is associated with the reappearance of IgA in their epidermal basement membrane zones. As in patients with celiac disease, dietary gluten sensitivity in patients with DH is associated with IgA anti-endomysial autoantibodies that target tissue transglutaminase. Studies indicate that patients with DH also have high-avidity IgA autoantibodies to epidermal transglutaminase and that the latter is co-localized with granular deposits of IgA in the papillary dermis of DH patients. Patients with DH also have an increased incidence of thyroid abnormalities, achlorhydria, atrophic gastritis, and autoantibodies to gastric parietal cells. These associations likely relate to the high frequency of the HLA-B8/DRw3 haplotype in these patients, since this marker is commonly linked to autoimmune disorders. The mainstay of treatment of DH is dapsone, a sulfone. Patients respond rapidly (24–48 h) to dapsone (50–200 mg/d), but require careful pretreatment evaluation and close follow-up to ensure that complications are avoided or controlled. All patients taking dapsone at >100 mg/d will have some hemolysis and methemoglobinemia, which are expected pharmacologic side effects of this agent. Gluten restriction can control DH and lessen dapsone requirements; this diet must rigidly exclude gluten to be of maximal benefit. Many months of dietary restriction may be necessary before a beneficial result is achieved. Good dietary counseling by a trained dietitian is essential.

Mucous membrane pemphigoid (MMP) is a rare, acquired, subepithelial immunobullous disease characterized by erosive lesions of mucous membranes and skin that result in scarring of at least some sites of involvement. Common sites include the oral mucosa (especially the gingiva) and conjunctiva; other sites that may be affected include the nasopharyngeal, laryngeal, esophageal, and anogenital mucosa. Skin lesions (present in about one-third of patients) tend to predominate on the scalp, face, and upper trunk and generally consist of a few scattered erosions or tense blisters on an erythematous or urticarial base. MMP is typically a chronic and progressive disorder. Serious complications may arise as a consequence of ocular, laryngeal, esophageal, or anogenital lesions. Erosive conjunctivitis may result in shortened fornices, symblepharon, ankyloblepharon, entropion, corneal opacities, and (in severe cases) blindness. Similarly, erosive lesions of the larynx may cause hoarseness, pain, and tissue loss that, if unrecognized and untreated, may eventuate in complete destruction of the airway. Esophageal lesions may result in stenosis and/or strictures that could place patients at risk for aspiration. Strictures may also complicate anogenital involvement. Biopsies of lesional tissue generally show subepithelial vesiculobullae and a mononuclear leukocytic infiltrate. Neutrophils and eosinophils may be seen in biopsies of early lesions; older lesions may demonstrate a scant leukocytic infiltrate and fibrosis. Direct immunofluorescence microscopy of perilesional tissue typically reveals deposits of IgG, IgA, and/or C3 in the epidermal basement membrane. Because many patients with MMP exhibit no evidence of circulating anti-basement membrane autoantibodies, testing of perilesional skin is important diagnostically. Although MMP was once thought to be a single nosologic entity, it is now largely regarded as a disease phenotype that may develop as a consequence of an autoimmune reaction to a variety of molecules in the epidermal basement membrane (e.g., BPAG2, laminin-332, type VII collagen, α6β4 integrin) and other antigens yet to be completely defined. Studies suggest that MMP patients with autoantibodies to laminin-332 have an increased relative risk for cancer. Treatment of MMP is largely dependent upon the sites of involvement. Due to potentially severe complications, patients with ocular, laryngeal, esophageal, and/or anogenital involvement require aggressive systemic treatment with dapsone, prednisone, or the latter

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in combination with another immunosuppressive agent (e.g., azathioprine, mycophenolate mofetil, cyclophosphamide, or rituximab), or IVIg. Less threatening forms of the disease may be managed with topical or intralesional glucocorticoids.

AUTOIMMUNE SYSTEMIC DISEASES WITH PROMINENT CUTANEOUS FEATURES ■■DERMATOMYOSITIS

PART 2 Cardinal Manifestations and Presentation of Diseases

The cutaneous manifestations of dermatomyositis (Chap. 358) are often distinctive but at times may resemble those of systemic lupus erythematosus (SLE) (Chap. 349), scleroderma (Chap. 353), or other overlapping connective tissue diseases (Chap. 353). The extent and severity of cutaneous disease may or may not correlate with the extent and severity of the myositis. The cutaneous manifestations of dermatomyositis are similar, whether the disease appears in children or in the elderly, except that calcification of subcutaneous tissue is a common late sequela in childhood dermatomyositis. The cutaneous signs of dermatomyositis may precede or follow the development of myositis by weeks to years. Cases lacking muscle involvement (i.e., dermatomyositis sine myositis or amyopathic dermatomyositis) have also been reported. The most common manifestation is a purple-red discoloration of the upper eyelids, sometimes associated with scaling (“heliotrope” erythema; Fig. 55-3) and periorbital edema. Erythema on the cheeks and nose in a “butterfly” distribution may resemble the malar eruption of SLE. Erythematous or violaceous scaling patches are common on the upper anterior chest, posterior neck, scalp, and the extensor surfaces of the arms, legs, and hands. Erythema and scaling may be particularly prominent over the elbows, knees, and dorsal interphalangeal joints. Approximately one-third of patients have violaceous, flat-topped papules over the dorsal interphalangeal joints that are pathognomonic of dermatomyositis (Gottron’s papules) (Fig. 55-4). Thin violaceous papules and plaques on the elbows and knees of patients with dermatomyositis are referred to as Gottron’s sign (Fig. 55-4). These lesions can be contrasted with the erythema and scaling on the dorsum of the fingers that spares the skin over the interphalangeal joints of some SLE patients. Periungual telangiectases and edema may be prominent in patients with dermatomyositis. Lacy or reticulated erythema may be associated with fine scaling on the extensor and lateral surfaces of the thighs and upper arms. Other patients, particularly those with long-standing disease, develop areas of hypopigmentation, hyperpigmentation, mild atrophy, and telangiectasia known as poikiloderma. Poikiloderma is rare in both SLE and scleroderma and thus can serve as a clinical sign that distinguishes dermatomyositis from these two diseases. Cutaneous changes may be similar in dermatomyositis and various overlap syndromes where

FIGURE 55-3  Dermatomyositis. Periorbital violaceous erythema characterizes the classic heliotrope rash. (Courtesy of James Krell, MD; with permission.)

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FIGURE 55-4  Gottron’s papules. Dermatomyositis often involves the hands as erythematous flat-topped papules over the knuckles. Periungual telangiectases are also evident.

thickening and binding down of the skin of the hands (sclerodactyly) as well as Raynaud’s phenomenon can be seen. However, the presence of severe muscle disease, Gottron’s papules, heliotrope erythema, and poikiloderma serve to distinguish patients with dermatomyositis. Skin biopsy of the erythematous, scaling lesions of dermatomyositis may reveal only mild nonspecific inflammation, but sometimes may show changes indistinguishable from those found in cutaneous lupus erythematosus (LE), including epidermal atrophy, hydropic degeneration of basal keratinocytes, and dermal changes consisting of edema of the upper dermis, interstitial mucin deposition, and a mild mononuclear cell infiltrate. Direct immunofluorescence microscopy of lesional skin is usually negative, although granular deposits of immunoglobulin(s) and complement in the epidermal basement membrane zone have been described in some patients. Treatment should be directed at the systemic disease. Topical glucocorticoids are sometimes useful; patients should avoid exposure to ultraviolet irradiation and aggressively use photoprotective measures, including broad-spectrum sunscreens.

■■LUPUS ERYTHEMATOSUS

The cutaneous manifestations of LE (Chap. 349) can be divided into acute, subacute, and chronic or discoid types. Acute cutaneous LE is characterized by erythema of the nose and malar eminences in a “butterfly” distribution (Fig. 55-5A). The erythema is often sudden in onset, accompanied by edema and fine scale, and correlated with systemic involvement. Patients may have widespread involvement of the face as well as erythema and scaling of the extensor surfaces of the extremities and upper chest (Fig. 55-5B). These acute lesions, while sometimes evanescent, usually last for days and are often associated with exacerbations of systemic disease. Skin biopsy of acute lesions typically shows hydropic degeneration of basal keratinocytes, dermal edema, and (in some cases) a sparse infiltrate of mononuclear cells in the upper dermis as well as dermal mucin. Direct immunofluorescence microscopy of lesional skin frequently reveals deposits of immunoglobulin(s) and complement in the epidermal basement membrane zone. Treatment is aimed at control of systemic disease. Photoprotection is very important in this as well as in other forms of LE. Subacute cutaneous lupus erythematosus (SCLE) is characterized by a widespread photosensitive, nonscarring eruption. In most patients, renal and central nervous system involvement is mild or absent. SCLE may present as a papulosquamous eruption that resembles psoriasis or as annular polycyclic lesions. In the papulosquamous form, discrete erythematous papules arise on the back, chest, shoulders, extensor surfaces of the arms, and dorsum of the hands; lesions are uncommon on the central face and the flexor surfaces of the arms as well as below the waist. These slightly scaling papules tend to merge into large plaques, some with a reticulate appearance. The annular form involves the same areas and presents with erythematous papules that evolve into oval, circular, or polycyclic lesions. The lesions of SCLE are more widespread but have less tendency for scarring than lesions of discoid LE. In many

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CHAPTER 55 of Rheumatology criteria for SLE. Typical discoid lesions are frequently seen in patients with SLE. Biopsy of DLE lesions shows hyperkeratosis, follicular plugging, atrophy of the epidermis, hydropic degeneration of basal keratinocytes, thickening of the epidermal basement membrane zone, and a mononuclear cell infiltrate adjacent to epidermal, adnexal, and microvascular basement membranes. Direct immunofluorescence microscopy demonstrates immunoglobulin(s) and complement deposits at the basement membrane zone in ~90% of cases. Treatment is focused on control of local cutaneous disease and consists mainly of photoprotection and topical or intralesional glucocorticoids. If local therapy is ineffective, use of aminoquinoline antimalarial agents may be indicated.

Immunologically Mediated Skin Diseases

FIGURE 55-6 Discoid (chronic cutaneous) lupus erythematosus (LE). Violaceous, hyperpigmented, atrophic plaques, follicular plugging, and scarring are typical features of chronic cutaneous LE.

■■SCLERODERMA AND MORPHEA FIGURE 55-5  Acute cutaneous lupus erythematosus (LE). A. Acute cutaneous LE on the face, showing prominent, scaly, malar erythema. Involvement of other sun-exposed sites is also common. B. Acute cutaneous LE on the upper chest, demonstrating brightly erythematous and slightly edematous papules and plaques. (B, Courtesy of Robert Swerlick, MD; with permission.)

patients with SCLE, drugs (e.g., hydrochlorothiazide, calcium channel blockers, proton pump inhibitors) may induce or exacerbate disease. Skin biopsy typically reveals epidermal changes that include atrophy, hydropic degeneration of basal keratinocytes, and apoptosis accompanied by an infiltrate of mononuclear cells in the upper dermis. Direct immunofluorescence microscopy of lesional skin reveals deposits of immunoglobulin(s) in the epidermal basement membrane zone in about one-half of these cases. A particulate pattern of IgG deposition throughout the epidermis has been associated with SCLE. Most SCLE patients have anti-Ro autoantibodies. Local therapy alone is usually unsuccessful. Most patients require treatment with aminoquinoline antimalarial drugs. Low-dose therapy with oral glucocorticoids is sometimes necessary. Photoprotective measures against both ultraviolet B and ultraviolet A wavelengths are very important. Discoid lupus erythematosus (DLE, also called chronic cutaneous LE) is characterized by discrete lesions, most often found on the face, scalp, and/or external ears. The lesions are erythematous papules or plaques with a thick, adherent scale that occludes hair follicles (follicular plugging). When the scale is removed, its underside shows small excrescences that correlate with the openings of hair follicles (so-called “carpet tacking”), a finding relatively specific for DLE. Longstanding lesions develop central atrophy, scarring, and hypopigmentation but frequently have erythematous, sometimes raised borders (Fig. 55-6). These lesions persist for years and tend to expand slowly. Up to 15% of patients with DLE eventually meet the American College

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The skin changes of scleroderma (Chap. 353) usually begin on the fingers, hands, toes, feet, and face, with episodes of recurrent nonpitting edema. Sclerosis of the skin commences distally on the fingers (sclerodactyly) and spreads proximally, usually accompanied by resorption of bone of the fingertips, which may have punched out ulcers, stellate scars, or areas of hemorrhage (Fig. 55-7). The fingers may actually shrink and become sausage-shaped, and, because the fingernails are usually unaffected, they may curve over the end of the fingertips. Periungual telangiectases are usually present, but periungual erythema is rare. In advanced cases, the extremities show contractures and calcinosis cutis. Facial involvement includes a smooth, unwrinkled brow, taut skin over the nose, shrinkage of tissue around the mouth, and perioral

FIGURE 55-7  Scleroderma showing acral sclerosis and focal digital ulcers.

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PART 2 Cardinal Manifestations and Presentation of Diseases

FIGURE 55-8  Scleroderma often eventuates in development of an expressionless, masklike facies.

radial furrowing (Fig. 55-8). Matlike telangiectases are often present, particularly on the face and hands. Involved skin feels indurated, smooth, and bound to underlying structures; hyper- and hypopigmentation are common as well. Raynaud’s phenomenon (i.e., cold-induced blanching, cyanosis, and reactive hyperemia) is documented in almost all patients and can precede development of scleroderma by many years. Linear scleroderma is a limited form of disease that presents in a linear, bandlike distribution and tends to involve deep as well as superficial layers of skin. The combination of calcinosis cutis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectases has been termed as the CREST syndrome. Anti-centromere autoantibodies have been reported in a very high percentage of patients with CREST syndrome but in only a small minority of patients with scleroderma. Skin biopsy reveals thickening of the dermis, homogenization of collagen bundles, atrophic pilosebaceous and eccrine glands, and a sparse mononuclear cell infiltrate in the dermis and subcutaneous fat. Direct immunofluorescence microscopy of lesional skin is usually negative. Morphea is characterized by localized thickening and sclerosis of skin; it dominates on the trunk. This disorder may affect children or adults. Morphea begins as erythematous or flesh-colored plaques that become sclerotic, develop central hypopigmentation, and have an erythematous border. In most cases, patients have one or a few lesions, and the disease is termed localized morphea. In some patients, widespread cutaneous lesions may occur without systemic involvement (generalized morphea). Many adults with generalized morphea have concomitant rheumatic or other autoimmune disorders. Skin biopsy of morphea is generally indistinguishable from that of scleroderma. Scleroderma and morphea are usually quite resistant to therapy. For this reason, physical therapy to prevent joint contractures and to maintain function is employed and is often helpful. Treatment options for early, rapidly progressive disease include phototherapy (UVA1 [ultraviolet A1 irradiation] or PUVA [psoralens + ultraviolet A irradiation]) or methotrexate (15–20 mg/week) alone or in combination with daily glucocorticoids. Diffuse fasciitis with eosinophilia is a clinical entity that can sometimes be confused with scleroderma. There is usually a sudden onset of swelling, induration, and erythema of the extremities, frequently following significant physical exertion. The proximal portions of the extremities (upper arms, forearms, thighs, calves) are more often involved than are the hands and feet. While the skin is indurated, it usually displays a woody, dimpled, or “pseudocellulite” appearance rather than being bound down as in scleroderma; contractures may occur early secondary to fascial involvement. The latter may also cause muscle groups to be separated and veins to appear depressed (i.e., the “groove sign”). These skin findings are accompanied by peripheral-blood eosinophilia, increased erythrocyte sedimentation rate,

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and sometimes hypergammaglobulinemia. Deep biopsy of affected areas of skin reveals inflammation and thickening of the deep fascia overlying muscle. An inflammatory infiltrate composed of eosinophils and mononuclear cells is usually found. Patients with eosinophilic fasciitis appear to be at increased risk for developing bone marrow failure or other hematologic abnormalities. While the ultimate course of eosinophilic fasciitis is uncertain, many patients respond favorably to treatment with prednisone in doses of 40–60 mg/d. The eosinophilia-myalgia syndrome, a disorder with epidemic numbers of cases reported in 1989 and linked to ingestion of l-tryptophan manufactured by a single company in Japan, is a multisystem disorder characterized by debilitating myalgias and absolute eosinophilia in association with varying combinations of arthralgias, pulmonary symptoms, and peripheral edema. In a later phase (3–6 months after initial symptoms), these patients often develop localized sclerodermatous skin changes, weight loss, and/or neuropathy (Chap. 353). The precise cause of this syndrome, which may resemble other sclerotic skin conditions, is unknown. However, the implicated lots of l-tryptophan contained the contaminant 1,1-ethylidene bis[tryptophan]. This contaminant may be pathogenic or may be a marker for another substance that provokes the disorder.

■■FURTHER READING

Bolognia JL et al (eds): Dermatology, 4th ed. Philadelphia, Elsevier, 2018. Goldsmith LA et al (eds): Fitzpatrick’s Dermatology in General Medicine, 8th ed. New York, McGraw-Hill, 2012. Hammers CM, Stanley JR: Mechanisms of disease: Pemphigus and bullous pemphigoid. Annu Rev Pathol 11:175, 2016. Schmidt E, Zillikens D: Pemphigoid diseases. Lancet 381:320, 2013.

56

Cutaneous Drug Reactions Robert G. Micheletti, Misha Rosenbach, Bruce U. Wintroub, Kanade Shinkai

Cutaneous reactions are among the most frequent adverse reactions to drugs. Most are benign, but a few can be life threatening. Prompt recognition of severe reactions, drug withdrawal, and appropriate therapeutic interventions can minimize toxicity. This chapter focuses on adverse cutaneous reactions to systemic medications; it covers their incidence, patterns, and pathogenesis, and provides some practical guidelines on treatment, assessment of causality, and future use of drugs.

USE OF PRESCRIPTION DRUGS IN THE UNITED STATES

In the United States, more than 3 billion prescriptions for >60,000 drug products, which include >2000 different active agents, are dispensed annually. Hospital inpatients alone annually receive about 120 million courses of drug therapy, and half of adult Americans receive prescription drugs on a regular outpatient basis. Adverse effects of a prescription medication may result in 4.5 million urgent or emergency care visits each year in the United States. Many patients use over-thecounter medicines that may cause adverse cutaneous reactions.

INCIDENCE OF CUTANEOUS REACTIONS

Several large cohort studies established that acute cutaneous reactions to drugs affect about 3% of hospitalized patients. Reactions usually occur a few days to 4 weeks after initiation of therapy. Many drugs of common use are associated with a 1–2% rate of rashes during premarketing clinical trials. The risk is often higher when medications are used in general, unselected populations. The rate may reach 3–7% for amoxicillin, sulfamethoxazole, many anticonvulsants, and anti-HIV agents.

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KEY PATHWAY IgE

Type II

IgG-mediated cytotoxicity

Type III

Immune complex

Type IVa

T lymphocyte– mediated macrophage inflammation T lymphocyte– mediated eosinophil inflammation

Type IVb

Type IVc

T lymphocyte– mediated cytotoxic T lymphocyte inflammation

■■NONIMMUNOLOGIC DRUG REACTIONS

Type IVd

T lymphocyte– mediated neutrophil inflammation

Examples of nonimmunologic drug reactions are pigmentary changes due to dermal accumulation of medications or their metabolites, alteration of hair follicles by antimetabolites and signaling inhibitors, and lipodystrophy associated with metabolic effects of anti-HIV medications. These side effects are predictable and sometimes can be prevented.

■■IMMUNOLOGIC DRUG REACTIONS

Evidence suggests an immunologic basis for most acute drug eruptions. Drug reactions may result from immediate release of preformed mediators (e.g., urticaria, anaphylaxis), antibody-mediated reactions, immune complex deposition, and antigen-specific responses. Drug-specific T cell clones can be derived from the blood or from skin lesions of patients with a variety of drug allergies, strongly suggesting that these T cells mediate drug allergy in an antigen-specific manner. Specific clones are generated by medications that are frequently a cause of drug eruptions: penicillin G, amoxicillin, cephalosporins, sulfamethoxazole, phenobarbital, carbamazepine, and lamotrigine. Both CD4 and CD8 clones have been obtained; however, their specific roles in drug allergy have not been elucidated. Drug presentation to T cells is major histocompatibility complex (MHC)-restricted and likely involves drug-peptide complex recognition by specific T cell receptors (TCRs). Once a drug has induced an immune response, the final phenotype of the reaction is determined by the nature of effectors: cytotoxic (CD8+) T cells in blistering and certain hypersensitivity reactions, chemokines for reactions mediated by neutrophils or eosinophils, and B cell collaboration for production of specific antibodies for urticarial reactions. Immunologic reactions have recently been classified into further subtypes that provide a useful framework for designating adverse drug reactions based on involvement of specific immune pathways (Table 56-1).

Immediate Reactions  Immediate reactions depend on the

release of mediators of inflammation by tissue mast cells or circulating basophils. These mediators include histamine, leukotrienes, prostaglandins, bradykinins, platelet-activating factor, enzymes, and proteoglycans. Drugs can trigger mediator release either directly (“anaphylactoid” reaction) or through IgE-specific antibodies. These reactions usually manifest in the skin and gastrointestinal, respiratory, and cardiovascular systems (Chap. 346). Primary symptoms and signs include pruritus, urticaria, nausea, vomiting, abdominal cramps, bronchospasm, laryngeal edema, and, occasionally, anaphylactic shock with hypotension and death. They occur within minutes of drug exposure.

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KEY IMMUNE ADVERSE DRUG MEDIATORS REACTION TYPE IgE Urticaria, angioedema, anaphylaxis IgG Drug-induced hemolysis, thrombocytopenia (e.g., penicillin) IgG + antigen Vasculitis, serum sickness, drug-induced lupus Tuberculin skin test, IFN-γ, TNF-α contact dermatitis T 1 cells H

IL-4, IL-5, IL-13 TH2 cells Eosinophils Cytotoxic T lymphocytes Granzyme Perforin Granulysin (SJS/TEN] only) CXCL8, IL-17, GM-CSF Neutrophils

DIHS Morbilliform eruption

Cutaneous Drug Reactions

TYPE Type I

PATHOGENESIS OF DRUG REACTIONS

Adverse cutaneous responses to drugs can arise as a result of immunologic or nonimmunologic mechanisms.

363

TABLE 56-1  Classification of Adverse Drug Reactions Based on Immune Pathway

CHAPTER 56

In addition to acute eruptions, a variety of skin diseases can be induced or exacerbated by prolonged use of drugs (e.g., pruritus, pigmentation, nail or hair disorders, psoriasis, bullous pemphigoid, photosensitivity, and even cutaneous neoplasms). These drug reactions are not frequent, but neither their incidence nor their impact on public health has been evaluated. In a series of 48,005 inpatients over a 20-year period, morbilliform rash (91%) and urticaria (6%) were the most frequent skin reactions. Severe reactions are too rare to be detected in such cohorts. Although rare, severe cutaneous reactions to drugs have an important impact on health because of significant sequelae, including mortality. Adverse drug rashes are responsible for hospitalization, increase the duration of hospital stay, and can be life threatening. Some populations are at increased risk of drug reactions, including elderly patients, patients with autoimmune disease, hematopoietic stem cell transplant recipients, and those with acute Epstein-Barr virus (EBV) or human immunodeficiency virus (HIV) infection. The pathophysiology underlying this association is unknown but may be related to immunocompromise or immune dysregulation. Individuals with advanced HIV disease (e.g., CD4 T lymphocyte count 39°C (102.2°F); sore throat; conjunctivitis; and acute onset of painful dusky, atypical, target-like lesions (Fig. 56-11). Intestinal and upper respiratory tract involvement are associated with a poor prognosis, as are older age and greater extent of epidermal detachment. At least 10% of those with SJS and 30% of those with TEN die from the disease. Drugs that most commonly cause SJS/TEN are sulfonamides, allopurinol, antiepileptics (e.g., lamotrigine, phenytoin, carbamazepine), oxicam NSAIDs, β-lactam and other antibiotics, and nevirapine. Frozen-section skin biopsy may aid in rapid diagnosis. At this time, there is no consensus on the most effective treatment for SJS/TEN. The best outcomes stem from early diagnosis, immediate discontinuation of the suspected drug, and meticulous supportive therapy in an intensive care or burn unit. Issues such as fluid management, atraumatic wound care, infection prevention and treatment, and ophthalmologic and respiratory support are critical. Systemic glucocorticoid therapy (prednisone 1–2 mg/kg)

FIGURE 56-7  Stevens-Johnson syndrome (SJS).

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FIGURE 56-8  SJS-TEN overlap.

may be useful early in disease evolution; however, long-term or late systemic glucocorticoid use has been associated with increased mortality. After initial enthusiasm for the use of intravenous immunoglobulin (IVIG) in the treatment of SJS/TEN, more recent data question whether it is beneficial. There are emerging data to support treatment with cyclosporine and etanercept. Randomized studies to evaluate potential therapies are lacking and difficult to perform.

Pustular Eruptions  AGEP is a rare reaction pattern affecting 3–5 people per million per year. It is thought to be secondary to medication exposure in >90% of cases (Fig. 56-12). Patients typically present with diffuse erythema or erythroderma, as well as high spiking fevers, and

FIGURE 56-9  Toxic epidermal necrolysis, hand.

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CHAPTER 56

FIGURE 56-10  Toxic epidermal necrolysis.

leukocytosis. One to two days later, innumerable pinpoint pustules develop overlying the erythema. The pustules are most pronounced in body fold areas; however, they may become generalized and, when coalescent, can lead to superficial erosion. In such cases, differentiating the eruption from SJS in its initial stages may be difficult; in AGEP, any erosions tend to be more superficial, and prominent mucosal involvement is lacking. Skin biopsy shows collections of neutrophils and sparse necrotic keratinocytes in the upper part of the epidermis, unlike the full-thickness epidermal necrosis that characterizes SJS. Before the pustules appear, AGEP may also mimic DIHS due to the prominent fever and erythroderma. The principal differential diagnosis for AGEP is acute pustular psoriasis, which has an identical clinical and histologic appearance. Many patients with AGEP have a personal or family history of psoriasis. AGEP classically begins within 24–48 hours of drug exposure, though it may occur as much as 1–2 weeks later. β-Lactam antibiotics, calcium channel blockers, macrolide antibiotics, and other inciting agents (including radiocontrast and dialysates) have been reported. Patch testing with the responsible drug often results in a localized pustular eruption.

Overlap Hypersensitivity Syndromes  An important concept in the clinical approach to severe drug eruptions is the presence of overlap syndromes, most notably DIHS with TEN-like features, DIHS with pustular eruption (AGEP-like), and AGEP with TEN-like features. In several case series of AGEP, 50% of cases had TEN-like or DRESSlike features, and 20% of cases had mucosal involvement resembling SJS/TEN. In one study, up to 20% of all severe drug eruptions had overlap features, suggesting that AGEP, DIHS, and SJS/TEN represent a clinical spectrum with some common pathophysiologic mechanisms. Designation of a single diagnosis based on cutaneous and extracutaneous involvement may not always be possible in cases of hypersensitivity; in such instances, treatment should be geared toward addressing the dominant clinical features. The timing of rash onset with respect to drug administration, which is usually much more delayed in DIHS, and the presence of systemic manifestations such as hepatitis are helpful clues to that diagnosis.

Cutaneous Drug Reactions

FIGURE 56-12  Acute generalized exanthematous pustulosis.

Vasculitis  Cutaneous small-vessel vasculitis (CSVV) typically

presents with purpuric papules and macules involving the lower extremities and other dependent areas (Fig. 56-13) (Chap. 356). Pustular and hemorrhagic vesicles as well as rounded ulcers also occur. Importantly, vasculitis may involve other organs, including the kidneys, joints, gastrointestinal tract, and lungs, necessitating a thorough clinical evaluation for systemic involvement. Drugs are implicated as a cause of roughly 15% of all cases of small vessel vasculitis. Antibiotics, particularly β-lactams, are commonly implicated; however, almost any drug can cause vasculitis. Vasculitis may also be idiopathic or due to underlying infection, connective tissue disease, or (rarely) malignancy. Rare but important types of drug-induced vasculitis include drug-induced ANCA vasculitis. Such patients commonly present with cutaneous manifestations but can develop the full range of symptoms associated with ANCA vasculitis, including crescentic glomerulonephritis and alveolar hemorrhage. Propylthiouracil, methimazole, and hydralazine are common culprits. Drug-induced polyarteritis nodosa has been associated with long-term exposure to minocycline. The presence of perivascular eosinophils on skin biopsy can be a clue to possible drug etiology.

MANAGEMENT OF THE PATIENT WITH SUSPECTED DRUG ERUPTION

There are four main questions to answer regarding a suspected drug eruption:

FIGURE 56-11  Target-like lesion in SJS.

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1. Is the observed rash caused by a medication? 2. Is the reaction severe or evolving? 3. Which drug or drugs are suspected, and should they be withdrawn? 4. What recommendation can be made for future medication use?

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with their key features and commonly associated medications. Any concern for a serious reaction should prompt immediate consultation with a dermatologist and/or referral of the patient to a specialized center.

■■CONFIRMATION OF DRUG REACTION

PART 2

The probability of drug etiology varies with the pattern of the reaction. Only fixed drug eruptions are always drug-induced. Morbilliform eruptions are usually viral in children and drug-induced in adults. Among severe reactions, drugs account for 10–20% of anaphylaxis and vasculitis and between 70% and 90% of AGEP, DIHS, SJS, and TEN. Skin biopsy helps characterize the reaction but does not indicate drug causality. Blood counts and liver and renal function tests are important for evaluating organ involvement. The association of mild elevation of liver enzymes and high eosinophil count is frequent but not specific for a drug reaction. Blood tests that could identify an alternative cause, serologic tests (to rule out drug-induced lupus), and serology or polymerase chain reaction for infections may be of great importance to determine a cause.

Cardinal Manifestations and Presentation of Diseases

■■WHAT DRUG(S) TO SUSPECT AND WITHDRAW

FIGURE 56-13  Cutaneous small-vessel vasculitis (CSVV, leukocytoclastic vasculitis).

■■EARLY DIAGNOSIS OF SEVERE ERUPTIONS

Rapid recognition of potentially serious or life-threatening reactions is paramount. In this regard, a suspected drug eruption is best defined initially by what it is not (e.g., SJS/TEN, DIHS). Table 56-2 lists clinical and laboratory features that, if present, suggest the presence of a severe reaction. Table 56-3 lists the most important of these reactions, along TABLE 56-2  Clinical and Laboratory Findings Suggestive of Severe Cutaneous Adverse Drug Reaction Cutaneous Generalized erythema Facial edema Skin pain Palpable purpura Dusky or target-like lesions Skin necrosis Blisters or epidermal detachment Positive Nikolsky sign Mucous membrane erosions Swelling of lips or tongue General High fever Enlarged lymph nodes Arthralgias or arthritis Shortness of breath, hoarseness, wheezing, hypotension Laboratory Results Eosinophil count >1000/μL Lymphocytosis with atypical lymphocytes Abnormal liver or kidney function tests Source: Adapted from JC Roujeau, RS Stern: Severe adverse cutaneous reactions to drugs. N Engl J Med 331:1272, 1994.

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Most cases of drug eruptions occur during the first course of treatment with a new medication. A notable exception is IgE-mediated urticaria and anaphylaxis that need presensitization and develop a few minutes to a few hours after rechallenge. Characteristic timing of onset following drug administration is as follows: 4–14 days for morbilliform eruption, 2–4 days for AGEP, 5–28 days for SJS/TEN, and 14–48 days for DIHS. A drug chart, compiling information of all current and past medications/supplements and the timing of administration relative to the rash, is a key diagnostic tool for identifying the inciting drug. Medications introduced for the first time in the relevant time frame are prime suspects. Two other important elements to suspect causality at this stage are (1) previous experience with the drug in the population and (2) alternative etiologic candidates. The decision to continue or discontinue any medication depends on the severity of the reaction, the severity of the primary disease undergoing treatment, the degree of suspicion of causality, and the feasibility of finding an alternative safer treatment. In any potentially fatal drug reaction, elimination of all possible suspect drugs or unnecessary medications should be immediately attempted. Some rashes may resolve when “treating through” a benign drug-related eruption. The decision to treat through an eruption should, however, remain the exception and withdrawal of every suspect drug the general rule. On the other hand, drugs that are not suspected and are important for the patient (e.g., antihypertensive agents) generally should not be quickly withdrawn. This approach may permit judicious use of these agents in the future.

■■RECOMMENDATION FOR FUTURE USE OF DRUGS

The aims are to (1) prevent the recurrence of the drug eruption and (2) avoid compromising future treatment by inaccurately excluding otherwise useful medications. A thorough assessment of drug causality is based on timing of the reaction, evaluation of other possible causes, and effect of drug withdrawal or continuation. The RegiSCAR group has proposed the Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) to rank likelihood of drug causality in SJS/TEN; validation of this and other instruments, such as the Naranjo adverse drug reaction probability scale, is limited. Medication(s) with a “definite” or “probable” causality should be contraindicated, a warning card or medical alert tag (e.g., wristband) should be given to the patient, and the drugs should be listed in the patient’s medical chart as allergies.

■■CROSS-SENSITIVITY

Because of possible cross-sensitivity among chemically related drugs, many physicians recommend avoidance of not only the medication that induced the reaction but also all drugs of the same pharmacologic class. There are two types of cross-sensitivity. Reactions that depend on a pharmacologic interaction may occur with all drugs that target the same pathway, whether the drugs are structurally similar or not. This is the case with angioedema caused by NSAIDs and ACE inhibitors. In this situation, the risk of recurrence varies from drug to drug in a

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TABLE 56-3  Clinical Features of Severe Cutaneous Drug Reactions DIAGNOSIS Stevens-Johnson syndrome (SJS)

FREQUENT SIGNS AND SYMPTOMS Most cases involve fever

Nearly all cases involve fever, “acute skin failure,” leukopenia

MOST COMMON CULPRIT DRUGS Sulfonamides, anticonvulsants, allopurinol, nonsteroidal antiinflammatory drugs (NSAIDs) Same as for SJS

Anticonvulsants, sulfonamides, allopurinol, minocycline

Fever, arthralgias

Antithymocyte globulin, cephalosporins, monoclonal antibodies Warfarin, heparin

Pain in affected areas Respiratory distress, cardiovascular collapse

β-Lactam antibiotics, calcium channel blockers, macrolide antibiotics

Angiotensin-converting enzyme (ACE) inhibitors, NSAIDs, contrast dye

Cutaneous Drug Reactions

Fever, lymphadenopathy, hepatitis, nephritis, myocarditis, eosinophilia, atypical lymphocytosis High fever, leukocytosis (neutrophilia), hypocalcemia

CHAPTER 56

MUCOSAL LESIONS TYPICAL SKIN LESIONS Erosions usually at two or Small blisters form from dusky more sites macules or atypical targets; rare areas of confluence; detachment ≤10% body surface area Toxic epidermal necrolysis Erosions usually at two or Individual lesions like those seen in (TEN)a more sites SJS; confluent dusky erythema; large sheets of necrotic epidermis; total detachment of >30% body surface area Drug-induced hypersensitivity Mucositis reported in as Diffuse, deep red morbilliform eruption many as 30% with facial involvement; facial and syndrome/drug rash with eosinophilia and systemic acral swelling symptoms (DIHS/DRESS) Acute generalized Oral erosions in perhaps Innumerable pinpoint pustules exanthematous pustulosis 20% overlying a diffuse erythematous (AGEP) eruption; may develop superficial erosions Serum sickness or serum Absent Urticarial serpiginous or polycyclic sickness-like reaction rash; purpuric eruption along the sides of the feet and hands is characteristic Anticoagulant-induced Infrequent Purpura and necrosis, especially of necrosis central, fatty areas Angioedema Often involved Urticaria or swelling of the central face, other areas

Overlap of SJS and TEN have features of both, and attachment of 10–30% of body surface area may occur.

a

Source: Adapted from JC Roujeau, RS Stern: Severe adverse cutaneous reactions to drugs. N Engl J Med 331:1272, 1994.

particular class; however, avoidance of all drugs in the class is usually recommended. Immune recognition of structurally related drugs is the second mechanism by which cross-sensitivity occurs. A classic example is hypersensitivity to aromatic antiepileptics (barbiturates, phenytoin, carbamazepine) with up to 50% reaction to a second drug in patients who reacted to one. For other drugs, in vitro and in vivo data have suggested that cross-reactivity exists only between compounds with very similar chemical structures. Sulfamethoxazole-specific lymphocytes may be activated by other antibacterial sulfonamides but not diuretics, antidiabetic drugs, or anti-COX2 NSAIDs with a sulfonamide group. Approximately 10% of patients with penicillin allergies will also develop allergic reactions to cephalosporin class antibiotics. Recent data suggest that although the risk of developing a drug eruption to another drug is increased in persons with a prior reaction, “cross-sensitivity” is probably not the explanation. As an example, those with a history of an allergic-like reaction to penicillin are at greater risk of developing a reaction to antibacterial sulfonamides than to cephalosporins. These data suggest that the list of drugs to avoid after a drug reaction should be limited to the causative one(s) and to a few very similar medications. Because of growing evidence that some severe cutaneous reactions to drugs are associated with HLA genes, it is recommended that first-degree family members of patients with severe cutaneous reactions also should avoid causative agents. This may be most relevant for sulfonamides and antiepileptic medications.

■■ROLE OF TESTING FOR CAUSALITY AND DRUG RECHALLENGE

The usefulness of laboratory tests, skin-prick, or patch testing to determine causality is debated. Many in vitro immunologic assays have been developed for research purposes; however, the predictive value of these tests has not been validated in large series of affected patients. In some cases, diagnostic rechallenge may be appropriate, even for drugs with high rates of adverse reactions. Skin-prick testing has clinical value in limited settings. In patients with a history suggesting immediate IgE-mediated reactions to penicillin, skin-prick testing with penicillins or cephalosporins has proven useful for identifying patients at risk of anaphylactic reactions to these

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agents. Negative skin tests do not totally rule out IgE-mediated reactivity; however, the risk of anaphylaxis in response to penicillin administration in patients with negative skin tests is about 1%. In contrast, two-thirds of patients with a positive skin test experience an allergic response upon rechallenge. The skin tests themselves carry a small risk of anaphylaxis. For patients with delayed-type hypersensitivity, the clinical utility of skin tests remains questionable. At least one of a combination of several tests (prick, patch, and intradermal) is positive in 50–70% of patients with a reaction “definitely” attributed to a single medication. This low sensitivity corresponds to the observation that readministration of drugs with negative skin testing results in eruptions in 17% of cases. Desensitization can be considered in those with a history of reaction to a medication that must be used again. Efficacy of such procedures has been demonstrated in cases of immediate reaction to penicillin and positive skin tests, anaphylactic reactions to platinum chemotherapy, and delayed reactions to sulfonamides in patients with AIDS. Desensitization is often successful in HIV-infected patients with morbilliform eruptions to sulfonamides but is not recommended in HIV-infected patients who developed erythroderma or a bullous reaction in response to prior sulfonamide exposure. Various protocols are available, including oral and parenteral approaches. Oral desensitization appears to have a lower risk of serious anaphylactic reaction. Desensitization carries the risk of anaphylaxis regardless of how it is performed and should be performed in monitored clinical settings such as an intensive care unit. After desensitization, many patients experience nonlife-threatening reactions during therapy with the culprit drug.

■■REPORTING

Any severe reaction to drugs should be reported to a regulatory agency or to pharmaceutical companies. Because severe reactions are too rare to be detected in premarketing clinical trials, spontaneous reports are of critical importance for early detection of unexpected life-threatening events. To be useful, the report should contain enough details to permit ascertainment of severity and drug causality. Acknowledgments We acknowledge the contribution of Drs. Jean-Claude Roujeau and Robert S. Stern to this chapter in previous editions.

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■■FURTHER READING

PART 2 Cardinal Manifestations and Presentation of Diseases

Belum VR: Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 60:12, 2016. Cornejo-Garcia JA et al: The genetics of drug hypersensitivity reactions. J Investig Allergol Clin Immunol 26:222, 2016. Creamer D et al: U.K. guidelines for the management of StevensJohnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol 174:1194, 2016. Harp JL et al: Severe cutaneous adverse reactions: impact of immunology, genetics, and pharmacology. Semin Cutan Med Surg 33:17, 2014. Ko TM et al: Use of HLA-B*5801 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: National prospective cohort study. BMJ 351:h4848, 2015. Lacouture ME et al: Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol 71:161, 2014. Mayorga C et al: In vitro tests for drug hypersensitivity reactions: An ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 71:1103, 2016. Oussalah A et al: Genetic variants associated with drug-induced immediate hypersensitivity reactions: A PRISMA-compliant systematic review. Allergy 71:443, 2016. Petrelli F et al: Antibiotic prophylaxis for skin toxicity induced by antiepidermal growth factor receptor agents: A systematic review and meta-analysis. Br J Dermatol, 2016 ePub ahead of print. Accessed September 28, 2016. Sassolas B et al: ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson syndrome and toxic epidermal necrolysis: Comparison with case-control analysis. Clin Pharmacol Ther 88:60, 2010. White KD et al: Evolving models of the immunopathogenesis of T cell-mediated drug allergy: The role of host, pathogens, and drug response. J Allergy Clin Immunol 136:219, 2015. Wolverton SE: Practice gaps: Drug reactions. Dermatol Clin 34:311, 2016.

57

Photosensitivity and Other Reactions to Light

Alexander G. Marneros, David R. Bickers

SOLAR RADIATION

Sunlight is the most visible and obvious source of comfort in the environment. The sun provides the beneficial effects of warmth and vitamin D synthesis. However, acute and chronic sun exposure also has pathologic consequences. Cutaneous exposure to sunlight is a major cause of human skin cancer and can have immunosuppressive effects as well. The sun’s energy reaching the earth’s surface is limited to components of the ultraviolet (UV) spectrum, the visible spectrum, and portions of the infrared spectrum. The cutoff at the short end of the UV spectrum at ∼290 nm is due primarily to stratospheric ozone—formed by highly energetic ionizing radiation—that prevents penetration to the earth’s surface of the shorter, more energetic, potentially more harmful wavelengths of solar radiation. Indeed, concern about destruction of the ozone layer by chlorofluorocarbons released into the atmosphere has led to international agreements to reduce production of those chemicals. Measurements of solar flux showed a 20-fold regional variation in the amount of energy at 300 nm that reaches the earth’s surface. This variability relates to seasonal effects, the path that sunlight traverses through ozone and air, the altitude (a 4% increase for each 300 m of elevation), the latitude (increasing intensity with decreasing latitude), and the amount of cloud cover, fog, and pollution.

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The major components of the photobiologic action spectrum that are capable of affecting human skin include the UV and visible wavelengths between 290 and 700 nm. In addition, the wavelengths beyond 700 nm in the infrared spectrum primarily emit heat and in certain circumstances may exacerbate the pathologic effects of energy in the UV and visible spectra. The UV spectrum reaching the Earth represents 50%, thus making prolongation of clot formation due to a factor deficiency dependent on the factor missing from the added plasma. Testing for Antiphospholipid Antibodies  Antibodies to phospholipids (cardiolipin) or phospholipid-binding proteins (β2-microglobulin and others) are detected by enzyme-linked immunosorbent assay (ELISA). When these antibodies interfere with phospholipiddependent coagulation tests, they are termed lupus anticoagulants. The aPTT has variability sensitivity to lupus anticoagulants, depending in part on the aPTT reagents used. An assay using a sensitive reagent has been termed an LA-PTT. The dilute Russell viper venom test (dRVVT) and the tissue thromboplastin inhibition (TTI) test are modifications of standard tests with the phospholipid reagent decreased, thus increasing the sensitivity to antibodies that interfere with the phospholipid component. The tests, however, are not specific for lupus anticoagulants, because factor deficiencies or other inhibitors will also result in prolongation. Documentation of a lupus anticoagulant requires not only prolongation of a phospholipiddependent coagulation test but also lack of correction when mixed with normal plasma and correction with the addition of activated platelet membranes or certain phospholipids (e.g., hexagonal phase). Other Coagulation Tests  The thrombin time and the reptilase time measure fibrinogen conversion to fibrin and are prolonged when

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the fibrinogen level is low (usually 25% in the sum of the products of the perpendicular diameters of all measurable lesions (or an increase of 20% in the sums of the ■■MANAGEMENT OF DISEASE AND TREATMENT longest diameters by RECIST). Tumor shrinkage or growth that does COMPLICATIONS Because cancer therapies are toxic (Chap. 69), patient management not meet any of these criteria is considered stable disease. Some sites of involves addressing complications of both the disease and its treat- involvement (e.g., bone) or patterns of involvement (e.g., lymphangitic ment as well as the complex psychosocial problems associated with lung or diffuse pulmonary infiltrates) are considered unmeasurable. cancer. In the short term during a course of curative therapy, the No response is complete without biopsy documentation of their resopatient’s functional status may decline. Treatment-induced toxicity is lution, but partial responses may exclude their assessment unless clear less acceptable if the goal of therapy is palliation. The most common objective progression has occurred. For some hematologic neoplasms, flow cytometric and genetic assays may determine the presence of residual tumor cells that escape microscopic detection. In general, these techniques can reliably detect TABLE 65-4  Karnofsky Performance Index as few as 1 tumor cell among 10,000 cells. If such tests do not detect PERFORMANCE tumor cells, the patient is said to have minimal residual disease negSTATUS FUNCTIONAL CAPABILITY OF THE PATIENT ativity, a finding generally associated with more durable remissions. 100 Normal; no complaints; no evidence of disease Accumulating data are defining interventions in patients with minimal 750

PART 4 Oncology and Hematology

86.3 80.3 105.3 114.6 155.4 148.9 153.6 171.4 119.3 156.1 162.3 187.9 114.7 200.9 194.9 202.6 205.0 209.8 189.7 221.5 174.1 223.9 211.2 224.0 189.5 251.7 227.9 256.2 190.7 259.6 212.1 260.3 224.2 265.6 221.3 272.2 220.9 276.2 162.7 281.9 274.3 283.0 270.7 288.0 246.7 290.6 246.4 293.8 187.2 298.5 251.1 299.0 204.8 325.2 266.3 331.8 239.7 332.0 240.7 332.9 288.0 348.0 265.9 273.5 354.0 285.2 358.2 302.3 378.1 246.3 385.3 270.1 453.3

Algeria, Setif India, Chennai Ecuador, Quito Uganda, Kyadondo Egypt, Gharbiah Pakistan, South Karachi Turkey, Izmir Zimbabwe, Harare: African Philippines, Manila Singapore China, Shanghai Colombia, Cali Russia, St Petersburg Argentina, Bahia Blanca China, Hong Kong Brazil, Goiania Poland, Cracow Finland USA, SEER 14 (Hispanic) Korea Denmark Israel The Netherlands Norway Japan, Miyagi UK, Merseyside and Cheshire Spain, Navarra Canada Czech Republic Germany, Saarland Italy, Parma Switzerland, Geneva Australia, South New Zealand USA, SEER 14 (White) France, Bas-Rhin USA, SEER 14 (Black)

Rate per 100,000

Females Males

90 80

70 60 50 40 30 20 10 0

Able to carry on normal activity; minor signs or symptoms of disease Normal activity with effort; some signs or symptoms of disease Cares for self; unable to carry on normal activity or do active work Requires occasional assistance but is able to care for most needs Requires considerable assistance and frequent medical care Disabled; requires special care and assistance Severely disabled; hospitalization is indicated, although death is not imminent Very sick; hospitalization is necessary; active supportive treatment is necessary Moribund, fatal processes progressing rapidly Dead

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TABLE 65-5  The Eastern Cooperative Oncology Group (ECOG) Performance Scale ECOG Grade 0: Fully active, able to carry on all predisease performance without restriction ECOG Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work ECOG Grade 2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about >50% of waking hours ECOG Grade 3: Capable of only limited self-care, confined to bed or chair >50% of waking hours ECOG Grade 4: Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair ECOG Grade 5: Dead Source: From MM Oken et al: Am J Clin Oncol 5:649, 1982.

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TUMOR MARKERS

CANCER

NONNEOPLASTIC CONDITIONS

Hormones Human chorionic gonadotropin Calcitonin Catecholamines

Gestational trophoblastic disease, gonadal germ cell tumor Medullary cancer of the thyroid Pheochromocytoma

Pregnancy

Hepatocellular carcinoma, gonadal germ cell tumor Adenocarcinomas of the colon, pancreas, lung, breast, ovary

Cirrhosis, hepatitis

Prostate cancer

Prostatitis, prostatic hypertrophy  

   

Oncofetal Antigens α Fetoprotein Carcinoembryonic antigen

Pancreatitis, hepatitis, inflammatory bowel disease, smoking

Enzymes Prostatic acid phosphatase Neuron-specific enolase Lactate dehydrogenase

Small-cell cancer of the lung, neuroblastoma Lymphoma, Ewing’s sarcoma

Hepatitis, hemolytic anemia, many others

Tumor-Associated Proteins Prostate-specific antigen Prostate cancer Monoclonal immunoglobulin CA-125 CA 19-9 CD30

CD25

Myeloma Ovarian cancer, some lymphomas Colon, pancreatic, breast cancer Hodgkin’s disease, anaplastic large-cell lymphoma Hairy cell leukemia, adult T-cell leukemia/ lymphoma

Prostatitis, prostatic hypertrophy Infection, MGUS Menstruation, peritonitis, pregnancy Pancreatitis, ulcerative colitis —

—

Abbreviation: MGUS, monoclonal gammopathy of uncertain significance.

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■■LONG-TERM FOLLOW-UP/LATE COMPLICATIONS

At the completion of treatment, sites originally involved with tumor are reassessed, usually by radiography or imaging techniques, and any persistent abnormality is biopsied. If disease persists, the multidisciplinary team discusses a new salvage treatment plan. If the patient has been rendered disease-free by the original treatment, the patient is followed regularly for disease recurrence. The optimal guidelines for follow-up care are not known. For many years, a routine practice has been to follow the patient monthly for 6–12 months, then every other month for a year, every 3 months for a year, every 4 months for a year, every 6 months for a year, and then annually. At each visit, a battery of laboratory and radiographic and imaging tests were obtained on the assumption that it is best to detect recurrent disease before it becomes symptomatic. However, where follow-up procedures have been examined, this assumption has been found to be untrue. Studies of breast cancer, melanoma, lung cancer, colon cancer, and lymphoma have all failed to support the notion that asymptomatic relapses are more readily cured by salvage therapy than symptomatic relapses. In view of the enormous cost of a full battery of diagnostic tests and their manifest lack of impact on survival, new guidelines are emerging for less frequent follow-up visits, during which the history and physical examination are the major investigations performed. As time passes, the likelihood of recurrence of the primary cancer diminishes. For many types of cancer, survival for 5 years without recurrence is tantamount to cure. However, important medical problems can occur in patients treated for cancer and must be examined (Chap. 91). Some problems emerge as a consequence of the disease and some as a consequence of the treatment. An understanding of these disease- and treatment-related problems may help in their detection and management. Despite these concerns, most patients who are cured of cancer return to normal lives.

Approach to the Patient with Cancer

TABLE 65-6  Tumor Markers

resolution of symptoms. If therapy is unsuccessful, other classes of antidepressants may be used. In addition to medication, psychosocial interventions such as support groups, psychotherapy, and guided imagery may be of benefit. Many patients opt for unproven or unsound approaches to treatment when it appears that conventional medicine is unlikely to be curative. Those seeking such alternatives are often well educated and may be early in the course of their disease. Unsound approaches are usually hawked on the basis of unsubstantiated anecdotes and not only cannot help the patient but may be harmful. Physicians should strive to keep communications open and nonjudgmental, so that patients are more likely to discuss with the physician what they are actually doing. The appearance of unexpected toxicity may be an indication that a supplemental therapy is being taken.2

CHAPTER 65

residual disease positivity that can extend remission duration and survival. Tumor markers may be useful in patient management in certain tumors. Response to therapy may be difficult to gauge with certainty. However, some tumors produce or elicit the production of markers that can be measured in the serum or urine, and in a particular patient, rising and falling levels of the marker are usually associated with increasing or decreasing tumor burden, respectively. Some clinically useful tumor markers are shown in Table 65-6. Tumor markers are not in themselves specific enough to permit a diagnosis of malignancy to be made, but once a malignancy has been diagnosed and shown to be associated with elevated levels of a tumor marker, the marker can be used to assess response to treatment. The recognition and treatment of depression are important components of management. The incidence of depression in cancer patients is ~25% overall and may be greater in patients with greater debility. This diagnosis is likely in a patient with a depressed mood (dysphoria) and/or a loss of interest in pleasure (anhedonia) for at least 2 weeks. In addition, three or more of the following symptoms are usually present: appetite change, sleep problems, psychomotor retardation or agitation, fatigue, feelings of guilt or worthlessness, inability to concentrate, and suicidal ideation. Patients with these symptoms should receive therapy. Medical therapy with a serotonin reuptake inhibitor such as fluoxetine (10–20 mg/d), sertraline (50–150 mg/d), or paroxetine (10–20 mg/d) or a tricyclic antidepressant such as amitriptyline (50–100 mg/d) or desipramine (75–150 mg/d) should be tried, allowing 4–6 weeks for response. Effective therapy should be continued at least 6 months after

■■SUPPORTIVE CARE

In many ways, the success of cancer therapy depends on the success of the supportive care. Failure to control the symptoms of cancer and its treatment may lead patients to abandon curative therapy. Of equal importance, supportive care is a major determinant of quality of life. Even when life cannot be prolonged, the physician must strive to preserve its quality. Quality-of-life measurements have become common endpoints of clinical research studies. Furthermore, palliative care has been shown to be cost-effective when approached in an organized fashion. A credo for oncology could be to cure sometimes, to extend life often, and to comfort always.

Pain  Pain occurs with variable frequency in the cancer patient:

25–50% of patients present with pain at diagnosis, 33% have pain associated with treatment, and 75% have pain with progressive disease. The pain may have several causes. In ~70% of cases, pain is caused by the tumor itself—by invasion of bone, nerves, blood vessels, or Information about unsound methods may be obtained from the National Council Against Health Fraud, Box 1276, Loma Linda, CA 92354, or from the Center for Medical Consumers and Health Care Information, 237 Thompson Street, New York, NY 10012.

2

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PART 4

mucous membranes or obstruction of a hollow viscus or duct. In ~20% of cases, pain is related to a surgical or invasive medical procedure, to radiation injury (mucositis, enteritis, or plexus, or spinal cord injury), or to chemotherapy injury (mucositis, peripheral neuropathy, phlebitis, steroid-induced aseptic necrosis of the femoral head). In 10% of cases, pain is unrelated to cancer or its treatment. Assessment of pain requires the methodical investigation of the history of the pain, its location, character, temporal features, provocative and palliative factors, and intensity (Chap. 10); a review of the oncologic history and past medical history as well as personal and social history; and a thorough physical examination. The patient should be given a 10-division visual analogue scale on which to indicate the severity of the pain. The clinical condition is often dynamic, making it necessary to reassess the patient frequently. Pain therapy should not be withheld while the cause of pain is being sought. A variety of tools are available with which to address cancer pain. About 85% of patients will have pain relief from pharmacologic intervention. However, other modalities, including antitumor therapy (such as surgical relief of obstruction, radiation therapy, and strontium-89 or samarium-153 treatment for bone pain), neurostimulatory techniques, regional analgesia, or neuroablative procedures, are effective in an additional 12% or so. Thus, very few patients will have inadequate pain relief if appropriate measures are taken. A specific approach to pain relief is detailed in Chap. 9.

Nausea  Emesis in the cancer patient is usually caused by chemo-

Oncology and Hematology

therapy (Chap. 69). Its severity can be predicted from the drugs used to treat the cancer. Three forms of emesis are recognized on the basis of their timing with regard to the noxious insult. Acute emesis, the most common variety, occurs within 24 h of treatment. Delayed emesis occurs 1–7 days after treatment; it is rare, but, when present, usually follows cisplatin administration. Anticipatory emesis occurs before administration of chemotherapy and represents a conditioned response to visual and olfactory stimuli previously associated with chemotherapy delivery. Acute emesis is the best understood form. Stimuli that activate signals in the chemoreceptor trigger zone in the medulla, the cerebral cortex, and peripherally in the intestinal tract lead to stimulation of the vomiting center in the medulla, the motor center responsible for coordinating the secretory and muscle contraction activity that leads to emesis. Diverse receptor types participate in the process, including dopamine, serotonin, histamine, opioid, and acetylcholine receptors. The serotonin receptor antagonists ondansetron and granisetron are effective drugs against highly emetogenic agents, as are neurokinin receptor antagonists like aprepitant and fosaprepitant (see Chap. 69). As with the analgesia ladder, emesis therapy should be tailored to the situation. For mildly and moderately emetogenic agents, prochlorperazine, 5–10 mg PO or 25 mg PR, is effective. Its efficacy may be enhanced by administering the drug before the chemotherapy is delivered. Dexamethasone, 10–20 mg IV, is also effective and may enhance the efficacy of prochlorperazine. For highly emetogenic agents such as cisplatin, mechlorethamine, dacarbazine, and streptozocin, combinations of agents work best and administration should begin 6–24 h before treatment. Ondansetron, 8 mg PO every 6 h the day before therapy and IV on the day of therapy, plus dexamethasone, 20 mg IV before treatment, is an effective regimen. Addition of oral aprepitant (a substance P/neurokinin 1 receptor antagonist) to this regimen (125 mg on day 1, 80 mg on days 2 and 3) further decreases the risk of both acute and delayed vomiting. Like pain, emesis is easier to prevent than to alleviate. Delayed emesis may be related to bowel inflammation from the therapy and can be controlled with oral dexamethasone and oral metoclopramide, a dopamine receptor antagonist that also blocks serotonin receptors at high dosages. The best strategy for preventing anticipatory emesis is to control emesis in the early cycles of therapy to prevent the conditioning from taking place. If this is unsuccessful, prophylactic antiemetics the day before treatment may help. Experimental studies are evaluating behavior modification.

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Effusions  Fluid may accumulate abnormally in the pleural cavity,

pericardium, or peritoneum. Asymptomatic malignant effusions may not require treatment. Symptomatic effusions occurring in tumors responsive to systemic therapy usually do not require local treatment but respond to the treatment for the underlying tumor. Symptomatic effusions occurring in tumors unresponsive to systemic therapy may require local treatment in patients with a life expectancy of at least 6 months. Pleural effusions due to tumors may or may not contain malignant cells. Lung cancer, breast cancer, and lymphomas account for ~75% of malignant pleural effusions. Their exudative nature is usually gauged by an effusion/serum protein ratio of ≥0.5 or an effusion/serum lactate dehydrogenase ratio of ≥0.6. When the condition is symptomatic, thoracentesis is usually performed first. In most cases, symptomatic improvement occurs for non-Jewish white > African American > Hispanic > Asian Female/male ratio 0.51–1.58 0.34–1.65 Smoking May prevent disease May cause disease (odds ratio 0.58) (odds ratio 1.76) Oral contraceptives No increased risk Hazard ratio 2.82 Appendectomy Protective (risk reduction Not protective 13–26%) Monozygotic twins 6–18% concordance 38–58% concordance Dizygotic twins 0–2% concordance 4% concordance Antibiotic use in the first 2.9× the risk of developing childhood IBD year of life   Abbreviation: IBD, inflammatory bowel disease.

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immigrated to Westernized countries and then returned to their country of birth also continue to demonstrate an increased risk of developing IBD. Peak incidence of UC and CD is in the second to fourth decades, with 78% of CD studies and 51% of UC studies reporting the highest incidence among those age 20–29 years old. A second modest rise in incidence occurs between the seventh and ninth decades of life. The female-to-male ratio ranges from 0.51 to 1.58 for UC studies and 0.34 to 1.65 for CD studies, suggesting that the diagnosis of IBD is not gender-specific. Pediatric IBD (patients 60). One study noted an OR of 1.72 for vertebral fracture and an OR of 1.59 for hip fracture. The disease severity predicted the risk of a fracture. Only 13% of IBD patients who had a fracture were on any kind of antifracture treatment. Up to 20% of bone mass can be lost per year with chronic glucocorticoid use. The effect is dosage-dependent. Budesonide may also suppress the pituitary-adrenal axis and thus carries a risk of causing osteoporosis. Osteonecrosis is characterized by death of osteocytes and adipocytes and eventual bone collapse. The pain is aggravated by motion and swelling of the joints. It affects the hips more often than knees and shoulders, and in one series, 4.3% of patients developed osteonecrosis within 6 months of starting glucocorticoids. Diagnosis is made by bone scan or MRI, and treatment consists of pain control, cord decompression, osteotomy, and joint replacement.

CHAPTER 319 Inflammatory Bowel Disease

The incidence of ocular complications in IBD patients is 1–10%. The most common are conjunctivitis, anterior uveitis/iritis, and episcleritis. Uveitis is associated with both UC and Crohn’s colitis, may be found during periods of remission, and may develop in patients following bowel resection. Symptoms include ocular pain, photophobia, blurred vision, and headache. Prompt intervention, sometimes with systemic glucocorticoids, is required to prevent scarring and visual impairment. Episcleritis is a benign disorder that presents with symptoms of mild ocular burning. It occurs in 3–4% of IBD patients, more commonly in Crohn’s colitis, and is treated with topical glucocorticoids.

lifetime risk of developing cholangiocarcinoma and then cannot be 2269 transplanted. Patients with IBD and PSC are at increased risk of colon cancer and should be surveyed yearly by colonoscopy and biopsy. In addition, cholangiography is normal in a small percentage of patients who have a variant of PSC known as small duct primary sclerosing cholangitis. This variant (sometimes referred to as “pericholangitis”) is probably a form of PSC involving small-caliber bile ducts. It has similar biochemical and histologic features to classic PSC. It appears to have a significantly better prognosis than classic PSC, although it may evolve into classic PSC. Granulomatous hepatitis and hepatic amyloidosis are much rarer extraintestinal manifestations of IBD.

■■THROMBOEMBOLIC DISORDERS

Patients with IBD have an increased risk of both venous and arterial thrombosis even if the disease is not active. Factors responsible for the hypercoagulable state have included abnormalities of the platelet-endothelial interaction, hyperhomocysteinemia, alterations in the coagulation cascade, impaired fibrinolysis, involvement of tissue factor-bearing microvesicles, disruption of the normal coagulation system by autoantibodies, and a genetic predisposition. A spectrum of vasculitides involving small, medium, and large vessels has also been observed.

■■OTHER DISORDERS

More common cardiopulmonary manifestations include endocarditis, myocarditis, pleuropericarditis, and interstitial lung disease. A secondary or reactive amyloidosis can occur in patients with long-standing IBD, especially in patients with CD. Amyloid material is deposited systemically and can cause diarrhea, constipation, and renal failure. The renal disease can be successfully treated with colchicine. Pancreatitis is a rare extraintestinal manifestation of IBD and results from duodenal fistulas; ampullary CD; gallstones; PSC; drugs such as 6-mercaptopurine, azathioprine, or, very rarely, 5-ASA agents; autoimmune pancreatitis; and primary CD of the pancreas.

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TREATMENT

Inflammatory Bowel Disease

PART 10 Disorders of the Gastrointestinal System

5-ASA AGENTS These agents are effective at inducing and maintaining remission in UC. They may have a limited role in inducing remission in CD but no clear role in maintenance of CD. Newer sulfa-free aminosalicylate preparations deliver increased amounts of the pharmacologically active ingredient of sulfasalazine (5-ASA, mesalamine) to the site of active bowel disease while limiting systemic toxicity. Peroxisome proliferator activated receptor γ (PPAR-γ) may mediate 5-ASA therapeutic action by decreasing nuclear localization of NF-κB. Sulfafree aminosalicylate formulations include alternative azo-bonded carriers, 5-ASA dimers, and delayed-release and controlled-release preparations. Each has the same efficacy as sulfasalazine when equimolar concentrations are used. Sulfasalazine’s molecular structure provides a convenient delivery system to the colon by allowing the intact molecule to pass through the small intestine after only partial absorption and to be broken down in the colon by bacterial azo reductases that cleave the azo bond linking the sulfa and 5-ASA moieties. Sulfasalazine is effective treatment for mild to moderate UC and is occasionally used in Crohn’s colitis, but its high rate of side effects limits its use. Although sulfasalazine is more effective at higher doses, at 6 or 8 g/d up to 30% of patients experience allergic reactions or intolerable side effects such as headache, anorexia, nausea, and vomiting that are attributable to the sulfapyridine moiety. Hypersensitivity reactions, independent of sulfapyridine levels, include rash, fever, hepatitis, agranulocytosis, hypersensitivity pneumonitis, pancreatitis, worsening of colitis, and reversible sperm abnormalities. Sulfasalazine can also impair folate absorption, and patients should be given folic acid supplements. Balsalazide contains an azo bond binding mesalamine to the carrier molecule 4-aminobenzoyl-β-alanine; it is effective in the colon. Delzicol and Asacol HD (high dose) are enteric-coated forms of mesalamine with the 5-ASA being released at pH >7. They disintegrate with complete breakup of the tablet occurring in many different parts of the gut ranging from the small intestine to the splenic flexure; they have increased gastric residence when taken with a meal. Asacol has been discontinued and replaced with Delzicol, which lacks dibutyl phthalate (DBP), an inactive ingredient in Asacol’s enteric coating. DBP has been associated with adverse effects on the male reproductive system in animals at very high doses. Lialda is a once-a-day formulation of mesalamine (Multi-Matrix System [MMX]) designed to release mesalamine in the colon. The MMX technology incorporates mesalamine into a lipophilic matrix

within a hydrophilic matrix encapsulated in a polymer resistant to degradation at a low pH (6. In addition, there is a polymer matrix core that aids in sustained release throughout the colon. Because Lialda and Apriso are given once daily, an anticipated benefit is improved compliance compared with two to four daily doses required for other mesalamine preparations. Pentasa is another mesalamine formulation that uses an ethylcellulose coating to allow water absorption into small beads containing the mesalamine. Water dissolves the 5-ASA, which then diffuses out of the bead into the lumen. Disintegration of the capsule occurs in the stomach. The microspheres then disperse throughout the entire GI tract from the small intestine through the distal colon in both fasted and fed conditions. Salofalk® Granu-Stix, an unencapsulated version of mesalamine, has been in use in Europe for induction and maintenance of remission for several years. Appropriate doses of the 5-ASA compounds are shown in Table 319-7. Some 50–75% of patients with mild to moderate UC improve when treated with 5-ASA doses equivalent to 2 g/d of mesalamine; the dose response continues up to at least 4.8 g/d. More common side effects of the 5-ASA medications include headaches, nausea, hair loss, and abdominal pain. Rare side effects of the 5-ASA medications include renal impairment, hematuria, pancreatitis, and paradoxical worsening of colitis. Renal function tests and urinalysis should be checked yearly. Topical Rowasa enemas are composed of mesalamine and are effective in mild-to-moderate distal UC. Combination therapy with mesalamine in both oral and enema form is more effective than either treatment alone for both distal and extensive UC. Canasa suppositories composed of mesalamine are effective in treating proctitis. GLUCOCORTICOIDS The majority of patients with moderate to severe UC benefit from oral or parenteral glucocorticoids. Prednisone is usually started at doses of 40–60 mg/d for active UC that is unresponsive to 5-ASA therapy. Parenteral glucocorticoids may be administered as hydrocortisone, 300 mg/d, or methylprednisolone, 40–60 mg/d. A new glucocorticoid for UC, budesonide (Uceris), is released entirely in the colon and has minimal to no glucocorticoid side effects. The dose is 9 mg/d for 8 weeks, and no taper is required. Topically applied

TABLE 319-7  Oral 5-ASA Preparations PREPARATION

FORMULATION

DELIVERY

DOSING PER DAY

Sulfapyridine-5-ASA   Aminobenzoyl-alanine–5-ASA

Colon   Colon

3–6 g (acute) 2–4 g (maintenance) 6.75–9 g

Eudragit S (pH 7)   MMX mesalamine (SPD476)

Distal ileum-colon   Ileum-colon

2.4–4.8 g (acute) 1.6–4.8 g (maintenance) 2.4–4.8 g

Ethylcellulose microgranules  

Stomach-colon  

2–4 g (acute) 1.5–4 g (maintenance)

Intellicor extended-release mechanism

Ileum-colon

1.5 g (maintenance)

Azo-Bond Sulfasalazine (500 mg) (Azulfidine)   Balsalazide (750 mg) (Colazal) Delayed-Release Mesalamine (400, 800 mg) (Delzicol, Asacol HD)   Mesalamine (1.2 g) (Lialda) Controlled-Release Mesalamine (250, 500, 1000 mg) (Pentasa)   Delayed- and Extended-Release Mesalamine (0.375 g) (Apriso)

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glucocorticoids are also beneficial for distal colitis and may serve as an adjunct in those who have rectal involvement plus more proximal disease. Hydrocortisone enemas or foam may control active disease, although they have no proven role as maintenance therapy. These glucocorticoids are significantly absorbed from the rectum and can lead to adrenal suppression with prolonged administration. Topical 5-ASA therapy is more effective than topical steroid therapy in the treatment of distal UC. Glucocorticoids are also effective for treatment of moderate to severe CD and induce a 60–70% remission rate compared to a 30% placebo response. The systemic effects of standard glucocorticoid formulations have led to the development of more potent formulations that are less well-absorbed and have increased first-pass metabolism. Controlled ileal-release budesonide has been nearly equal to prednisone for ileocolonic CD with fewer glucocorticoid side effects. Budesonide is used for 2–3 months at a dose of 9 mg/d, and then tapered. Glucocorticoids play no role in maintenance therapy in either UC or CD. Once clinical remission has been induced, they should be tapered according to the clinical activity, normally at a rate of no more than 5 mg/week. They can usually be tapered to 20 mg/d within 4–5 weeks but often take several months to be discontinued altogether. The side effects are numerous, including fluid retention, abdominal striae, fat redistribution, hyperglycemia, subcapsular cataracts, osteonecrosis, osteoporosis, myopathy, emotional disturbances, and withdrawal symptoms. Most of these side effects, aside from osteonecrosis, are related to the dose and duration of therapy.

AZATHIOPRINE AND 6-MERCAPTOPURINE Azathioprine and 6-mercaptopurine (6-MP) are purine analogues used concomitantly with biologic therapy or, less often, as the sole immunosuppressants. Azathioprine is rapidly absorbed and converted to 6-MP, which is then metabolized to the active end product, thioinosinic acid, an inhibitor of purine ribonucleotide synthesis and cell proliferation. Efficacy can be seen as early as 3–4 weeks but can take up to 4–6 months. Adherence can be monitored by measuring the levels of 6-thioguanine and 6-methyl-mercaptopurine, end products of 6-MP metabolism. The doses used range from 2–3 mg/kg per day for azathioprine and 1–1.5 mg/kg per day for 6-MP. Although azathioprine and 6-MP are usually well tolerated, pancreatitis occurs in 3–4% of patients, typically presents within the first few weeks of therapy, and is completely reversible when the drug is stopped. Other side effects include nausea, fever, rash, and hepatitis. Bone marrow suppression (particularly leukopenia) is dose-related and often delayed, necessitating regular monitoring of the complete blood cell count (CBC). Additionally, 1 in 300 individuals lacks thiopurine methyltransferase, the enzyme responsible for drug metabolism to inactive end-products (6-methylmercaptopurine); an additional 11% of the population are heterozygotes with intermediate enzyme activity. Both are at increased risk of toxicity because of increased accumulation of active 6-thioguanine

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METHOTREXATE MTX inhibits dihydrofolate reductase, resulting in impaired DNA synthesis. Additional anti-inflammatory properties may be related to decrease in the production of IL-1. It is used most often concomitantly with biologic therapy to decrease antibody formation and improve disease response. Intramuscular (IM) or subcutaneous (SC) doses range from 15 to 25 mg/week. Potential toxicities include leukopenia and hepatic fibrosis, necessitating periodic evaluation of CBCs and liver enzymes. The role of liver biopsy in patients on long-term MTX is uncertain but is probably limited to those with increased liver enzymes. Hypersensitivity pneumonitis is a rare but serious complication of therapy. CYCLOSPORINE CSA is a lipophilic peptide with inhibitory effects on both the cellular and humoral immune systems. CSA blocks the production of IL-2 by T helper lymphocytes. CSA binds to cyclophilin, and this complex inhibits calcineurin, a cytoplasmic phosphatase enzyme involved in the activation of T cells. CSA also indirectly inhibits B cell function by blocking helper T cells. CSA has a more rapid onset of action than 6-MP and azathioprine. CSA is most effective when given at 2–4 mg/kg per day IV in severe UC that is refractory to IV glucocorticoids, with 82% of patients responding. CSA can be an alternative to colectomy. The long-term success of oral CSA is not as dramatic, but if patients are started on 6-MP or azathioprine at the time of hospital discharge, remission can be maintained. For the 2 mg/kg dose, levels as measured by monoclonal radioimmunoassay or by the highperformance liquid chromatography assay should be maintained between 150 and 350 ng/mL. CSA may cause significant toxicity; renal function should be monitored frequently. Hypertension, gingival hyperplasia, hypertrichosis, paresthesias, tremors, headaches, and electrolyte abnormalities are common side effects. Creatinine elevation calls for dose reduction or discontinuation. Seizures may also complicate therapy, especially if the patient is hypomagnesemic or if serum cholesterol levels are 8%. In patients with concurrent symptoms of dyspepsia, upper GI radiographs or esophagogastroduodenoscopy may be advisable. In patients with postprandial right upper quadrant pain, an ultrasonogram of the gallbladder should be obtained. Laboratory features that argue against IBS include evidence of anemia, elevated sedimentation rate, presence of leukocytes or blood in stool, and stool volume >200–300 mL/d. These findings would necessitate other diagnostic considerations.

CHAPTER 320 Irritable Bowel Syndrome

IBS include the following: recurrence of lower abdominal pain with altered bowel habits over a period of time without progressive deterioration, onset of symptoms during periods of stress or emotional upset, absence of other systemic symptoms such as fever and weight loss, and small-volume stool without any evidence of blood. On the other hand, the appearance of the disorder for the first time in old age, progressive course from time of onset, persistent diarrhea after a 48-h fast, and presence of nocturnal diarrhea or steatorrheal stools argue against the diagnosis of IBS. Because the major symptoms of IBS—abdominal pain, abdominal bloating, and alteration in bowel habits—are common complaints of many GI organic disorders, the list of differential diagnoses is a long one. The quality, location, and timing of pain may be helpful to suggest specific disorders. Pain due to IBS that occurs in the epigastric or periumbilical area must be differentiated from biliary tract disease, peptic ulcer disorders, intestinal ischemia, and carcinoma of the stomach and pancreas. If pain occurs mainly in the lower abdomen, the possibility of diverticular disease of the colon, inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), and carcinoma of the colon must be considered. Postprandial pain accompanied by bloating, nausea, and vomiting suggests gastroparesis or partial intestinal obstruction. Intestinal infestation with Giardia lamblia or other parasites may cause similar symptoms. When diarrhea is the major complaint, the possibility of lactase deficiency, laxative abuse, malabsorption, celiac sprue, hyperthyroidism, inflammatory bowel disease, and infectious diarrhea must be ruled out. On the other hand, constipation may be a side effect of many different drugs, such as anticholinergic, antihypertensive, and antidepressant medications. Endocrinopathies such as hypothyroidism and hypoparathyroidism must also be considered in the differential diagnosis of constipation, particularly if other systemic signs or symptoms of these endocrinopathies are present. In addition, acute intermittent porphyria and lead poisoning may present in a fashion similar to IBS, with painful constipation as the major complaint. These possibilities are suspected on the basis of their clinical presentations and are confirmed by appropriate serum and urine tests. Few tests are required for patients who have typical IBS symptoms and no alarm features. Unnecessary investigations may be costly and even harmful. The American Gastroenterological Association has delineated factors to be considered when determining the aggressiveness of the diagnostic evaluation. These include the duration of symptoms, the change in symptoms over time, the age and sex of the patient, the referral status of the patient, prior diagnostic studies, a family history of colorectal malignancy, and

TREATMENT

Irritable Bowel Syndrome Patient Counseling and Dietary Alterations  Reassurance and careful explanation of the functional nature of the disorder and of how to avoid obvious food precipitants are important first steps in patient counseling and dietary change. Occasionally, a meticulous dietary history may reveal substances (such as coffee, disaccharides, legumes, and cabbage) that aggravate symptoms. Excessive fructose and artificial sweeteners, such as sorbitol or mannitol, may cause diarrhea, bloating, cramping, or flatulence. As a therapeutic trial, patients should be encouraged to eliminate any foodstuffs that appear to produce symptoms. However patients should avoid

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TABLE 320-2  Some Common Food Sources of FODMAPs FOOD TYPE Fruits

FREE FRUCTOSE LACTOSE Apple, cherry, mango,   pear, watermelon

FRUCTANS Peach, persimmon, watermelon

GALACTO-OLIGOSACCHARIDES  

Vegetables

Asparagus, artichokes, sugar snap peas  

 

 

 

Artichokes, beetroot, Brussels sprout, chicory, fennel, garlic, leek, onion, peas Wheat, rye, barley

 

 

 

 

Pistachios

 

 

 

Milk, yogurt, ice cream, custard, soft cheeses    

 

 

 

Legumes, lentils, chickpeas Chicory drinks

Legumes, chickpeas, lentils  

   

 

Inulin, FOS

 

Sorbitol, mannitol, maltitol, xylitol, isomalt

Grains and cereals Nuts and seeds Milk and milk products Legumes Other

  Honey, high-fructose corn syrup Food additives  

POLYOLS Apple, apricot, pear, avocado, blackberries, cherry, nectarine, plum, prune Cauliflower, mushroom, snow peas

Abbreviations: FODMAPs, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; FOS, fructo-oligosaccharides. Source: Adapted from PR Gibson et al: Am J Gastroenterol 107:657, 2012.

nutritionally depleted diets. A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) (Table 320-2) has been shown to be helpful in IBS patients (see Low FODMAP Diet).

PART 10 Disorders of the Gastrointestinal System

Stool-Bulking Agents  High-fiber diets and bulking agents, such as bran or hydrophilic colloid, are frequently used in treating IBS. The water-holding action of fibers may contribute to increased stool bulk because of the ability of fiber to increase fecal output of bacteria. Fiber also speeds up colonic transit in most persons. In diarrhea-prone patients, whole-colonic transit is faster than average; however, dietary fiber can delay transit. Furthermore, because of their hydrophilic properties, stool-bulking agents bind water and thus prevent both excessive hydration and dehydration of stool. The latter observation may explain the clinical experience that a high-fiber diet relieves diarrhea in some IBS patients. Fiber supplementation with psyllium has been shown to reduce perception of rectal distention, indicating that fiber may have a positive effect on visceral afferent function. The beneficial effects of dietary fiber on colonic physiology suggest that dietary fiber should be an effective treatment for IBS patients, but controlled trials of dietary fiber have produced variable results. This is not surprising since IBS is a heterogeneous disorder, with some patients being constipated and other having predominant diarrhea. Most investigations report increases in stool weight, decreases in colonic transit times, and improvement in constipation. Others have noted benefits in patients with alternating diarrhea and constipation, pain, and bloating. However, most studies observe no responses in patients with diarrhea- or pain-predominant IBS. It is possible that different fiber preparations may have dissimilar effects on selected symptoms in IBS. A cross-over comparison of different fiber preparations found that psyllium produced greater improvements in stool pattern and abdominal pain than bran. Furthermore, psyllium preparations tend to produce less bloating and distention. Despite the equivocal data regarding efficacy, most gastroenterologists consider stool-bulking agents worth trying in patients with IBS-C. Fiber should be started at a nominal dose and slowly titrated up as tolerated over the course of several weeks to a targeted dose of 20–30 g of total dietary and supplementary fiber per day. Even when used judiciously, fiber can exacerbate bloating, flatulence, constipation, and diarrhea. Antispasmodics  Clinicians have observed that anticholinergic drugs may provide temporary relief for symptoms such as painful cramps related to intestinal spasm. Although controlled clinical trials have produced mixed results, evidence generally supports

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beneficial effects of anticholinergic drugs for pain. A meta-analysis of 26 double-blind clinical trials of antispasmodic agents in IBS reported better global improvement (62%) and abdominal pain reductions (64%) compared to placebo (35 and 45%, respectively), suggesting efficacy in some patients. The drugs are most effective when prescribed in anticipation of predictable pain. Physiologic studies demonstrate that anticholinergic drugs inhibit the gastrocolic reflex; hence, postprandial pain is best managed by giving antispasmodics 30 min before meals so that effective blood levels are achieved shortly before the anticipated onset of pain. Most anticholinergics contain natural belladonna alkaloids, which may cause xerostomia, urinary hesitancy and retention, blurred vision, and drowsiness. They should be used in the elderly with caution. Some physicians prefer to use synthetic anticholinergics such as dicyclomine that have less effect on mucous membrane secretions and produce fewer undesirable side effects. Antidiarrheal Agents  Peripherally acting opiate-based agents are the initial therapy of choice for IBS-D. Physiologic studies demonstrate increases in segmenting colonic contractions, delays in fecal transit, increases in anal pressures, and reductions in rectal perception with these drugs. When diarrhea is severe, especially in the painless diarrhea variant of IBS, small doses of loperamide, 2–4 mg every 4–6 h up to a maximum of 12 g/d, can be prescribed. These agents are less addictive than paregoric, codeine, or tincture of opium. In general, the intestines do not become tolerant of the antidiarrheal effect of opiates, and increasing doses are not required to maintain antidiarrheal potency. These agents are most useful if taken before anticipated stressful events that are known to cause diarrhea. However, not infrequently, a high dose of loperamide may cause cramping because of increases in segmenting colonic contractions. Another antidiarrheal agent that may be used in IBS patients is the bile acid binder cholestyramine resin as up to 30% of IBS-D patients may have bile acid malabsorption. Antidepressant Drugs  In addition to their mood-elevating effects, antidepressant medications have several physiologic effects that suggest they may be beneficial in IBS. In IBS-D patients, the tricyclic antidepressant imipramine slows jejunal migrating motor complex transit propagation and delays orocecal and whole-gut transit, indicative of a motor inhibitory effect. Some studies also suggest that tricyclic agents may alter visceral afferent neural function. A number of studies indicate that tricyclic antidepressants may be effective in some IBS patients. In a 2-month study of desipramine, abdominal pain improved in 86% of patients compared to 59% given placebo. Another study of desipramine in 28 IBS patients showed

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improvement in stool frequency, diarrhea, pain, and depression. When stratified according to the predominant symptoms, improvements were observed in IBS-D patients, with no improvement being noted in IBS-C patients. The beneficial effects of the tricyclic compounds in the treatment of IBS appear to be independent of their effects on depression. The therapeutic benefits for the bowel symptoms occur faster and at a lower dosage. The efficacy of antidepressant agents in other chemical classes in the management of IBS is less well evaluated. In contrast to tricyclic agents, the selective serotonin reuptake inhibitor (SSRI) paroxetine accelerates orocecal transit, raising the possibility that this drug class may be useful in IBS-C patients. The SSRI citalopram blunts perception of rectal distention and reduces the magnitude of the gastrocolonic response in healthy volunteers. A small placebo-controlled study of citalopram in IBS patients reported reductions in pain. However, these findings could not be confirmed in another randomized controlled trial that showed that citalopram at 20 mg/d for 4 weeks was not superior to placebo in treating nondepressed IBS patients. Hence, the efficacy of SSRIs in the treatment of IBS needs further confirmation.

Modulation of Gut Flora  Because altered colonic flora (gut dysbiosis) may contribute to the pathogenesis of IBS, this has led to great interest in using antibiotics, prebiotics, and probiotics to treat IBS (Fig. 320-3). Antibiotics  Antibiotic treatment benefits a subset of IBS patients. In a double-blind, randomized, placebo-controlled study, neomycin dosed at 500 mg twice daily for 10 days was more effective than placebo at improving symptom scores among IBS patients. The nonabsorbed oral antibiotic rifaximin is the most thoroughly studies antibiotic of the treatment of IBS. In a double-blind, placebocontrolled study, patients receiving rifaximin at a dose of 550 mg two times daily for 2 weeks experienced substantial improvement of global IBS symptoms over placebo. Rifaximin is the only antibiotic with demonstrated sustained benefit beyond therapy cessation in IBS patients. The drug has a favorable safety and tolerability profile compared with systemic antibiotics. A systemic review and meta-analysis of five studies of IBS patients found that rifaximin is more effective than placebo for global symptoms and bloating (odds ratio 1.57) with a number needed to treat (NNT) of 10.2. The

Probiotics

Probiotics  These are defined as live microorganisms that when administered in adequate amounts confer a health benefit on the host. A meta-analysis of 10 probiotic studies in IBS patients found significant relief of pain and bloating with the use of Bifidobacterium breve, B longum, and Lactobacillus acidophilus species compared to placebo. However, there was no change in stool frequency or consistency. Large-scale studies of well-phenotyped IBS patients are needed to establish the efficacy of these probiotics. Low FODMAP Diet  A diet rich in FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) often triggers symptoms in IBS patients. FODMAPs are poorly absorbed by the small intestine and fermented by bacteria in the colon to produce gas and osmotically active carbohydrates (Fig. 320-4). At the same time, on entering the colon, FODMAPs may serve as nutrient for the colonic bacteria and promote the growth of gram negative commensal bacteria which may induce epithelial damage and subclinical mucosa inflammation. Fructose and fructans induce IBS symptoms in a dose-dependent manner. In contrast, a low FODMAP diet reduces IBS symptoms. A randomized controlled trial showed a 4-week low FODMAP diet improved symptoms in 68% of IBS patients compared with 23% on a habitual diet. Low FOMAP diets appeared to be superior to national guidelines for IBS management. These observations were confirmed by a double blind controlled study of 30 IBS patients and 18 healthy controls, in which a low FODMAP diet significantly reduced bloating, pain, passage of gas, and diarrhea. A double blind randomized control trial involving 92 IBS patients showed >50% of patients on the low FODMAP diet had major improvement of their abdominal pain compared

Small poorly absorbed carbohydrates

Food source for bacteria

Laxative effect

Water in intestines

Gas production

Abdominal distention

Bloating, abdominal discomfort, flatulence, diarrhea Antibiotics

FIGURE 320-3  Gut dysbiosis: a potential treatment target. Prebiotics, probiotics, and low FODMAP diet may be used to modulate gut flora and treat IBS.

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Prebiotics  These are nondigestible food ingredients that stimulate growth and/or activity of bacteria in the GI tract. There have been four randomized trials to examine the effects of prebiotics. Three of the four studies reported that prebiotics worsened or did not improve IBS symptoms. This is not surprising given the adverse effects of high carbohydrate diet on IBS symptoms.

Prebiotics

Dysbiosis Diet

2281

CHAPTER 320 Irritable Bowel Syndrome

Antiflatulence Therapy  The management of excessive gas is seldom satisfactory, except when there is obvious aerophagia or disaccharidase deficiency. Patients should be advised to eat slowly and not chew gum or drink carbonated beverages. Bloating may decrease if an associated gut syndrome such as IBS or constipation is improved. If bloating is accompanied by diarrhea and worsens after ingesting dairy products, fresh fruits, vegetables, or juices, further investigation or a dietary exclusion trial may be worthwhile. Avoiding flatogenic foods, exercising, losing excess weight, and taking activated charcoal are safe but unproven remedies. A low FODMAP diet has been shown to be quite effective to reduce gas and bloating (see Low FODMAP Diet). Data regarding the use of surfactants such as simethicone are conflicting. Antibiotics may help in a subgroup of IBS patients with predominant symptoms of bloating. Beano, an over-the-counter oral β-glycosidase solution, may reduce rectal passage of gas without decreasing bloating and pain. Pancreatic enzymes reduce bloating, gas, and fullness during and after high-calorie, high-fat meal ingestion.

modest therapeutic gain was similar to that yielded by other current available therapies for IBS. However, currently there are still insufficient data to recommend routine use of this antibiotic in the treatment of IBS.

FIGURE 320-4  Pathogenesis of FODMAP-related symptoms. FODMAPs are poorly absorbed by the small intestine and fermented by gut bacteria to produce gas and osmotically active carbohydrates. These events act in concert to cause bloating, flatulence, and diarrhea. FODMAP may also serve as nutrients for colonic bacteria which may induce mucosa inflammation. (Figure created using data from http:// www.nutritiontoyou.com/wp-content/uploads/2014/06/IBS-symptoms.png.)

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with 20% of the control group. These observations demonstrate the impressive efficacy of low FODMAP diet for many IBS patients, and if confirmed may justify the recommendation of a low FODMAP diet as first-line treatment for IBS patients.

PART 10

Serotonin Receptor Agonist and Antagonists  Serotonin receptor antagonists have been evaluated as therapies for IBS-D. Serotonin acting on 5-HT3 receptors enhances the sensitivity of afferent neurons projecting from the gut. In humans, a 5-HT3 receptor antagonist such as alosetron reduces perception of painful visceral stimulation in IBS. It also induces rectal relaxation, increases rectal compliance, and delays colonic transit. Meta-analysis of 14 randomized controlled trials of alosetron or cilansetron showed that these antagonists are more effective than placebo in achieving global improvement in IBS symptoms and relief of abdominal pain and discomfort. These agents are more likely to cause constipation in IBS patients with diarrhea alternating with constipation. Also, 0.2% of patients using 5-HT3 antagonists developed ischemic colitis versus none in the control group. In postrelease surveillance, 84 cases of ischemic colitis were observed, including 44 cases that required surgery and 4 deaths. As a consequence, the medication was voluntarily withdrawn by the manufacturer in 2000. Alosetron has been reintroduced under a new risk-management program where patients have to sign a patient-physician agreement. This has significantly limited its usage. Novel 5-HT4 receptor agonists such as tegaserod exhibit prokinetic activity by stimulating peristalsis. In IBS patients with constipation, tegaserod accelerated intestinal and ascending colon transit. Clinical trials involving >4000 IBS-C patients reported reductions in discomfort and improvements in constipation and bloating, compared to placebo. Diarrhea is the major side effect. However, tegaserod has been withdrawn from the market; a meta-analysis revealed an increase in serious cardiovascular events.

Disorders of the Gastrointestinal System

Chloride Channel Activators  Lubiprostone is a bicyclic fatty acid that stimulates chloride channels in the apical membrane of intestinal epithelial cells. Chloride secretion induces passive movement of sodium and water into the bowel lumen and improves bowel function. Oral lubiprostone was effective in the treatment of patients with constipation-predominant IBS in large phase II and phase III randomized, double-blinded, placebo-controlled multicenter trials. Responses were significantly greater in patients receiving lubiprostone 8 μg twice daily for 3 months than in those receiving placebo. In general, the drug was quite well tolerated. The major side effects are nausea and diarrhea. Lubiprostone is a new class of compounds for treatment of chronic constipation with or without IBS. Guanylate Cyclase-C Agonist  Linaclotide is a minimally absorbed 14-amino-acid peptide guanylate cyclase-C (GC-C) agonist that binds to and activates GC-C on the luminal surface of intestinal epithelium. Activation of GC-C results in generation of cyclic guanosine monophosphate (cGMP), which triggers secretion of fluid, sodium, and bicarbonate. In animal models, linaclotide accelerates GI transit and reduces visceral nociception. The analgesic action of linaclotide appears to be mediated by cGMP acting on afferent pain fibers innervating the GI tract. A phase III, double-blind, controlled trial showed that linaclotide, 290 μg given once daily, significantly improved abdominal pain, bloating, and spontaneous TABLE 320-3  Spectrum of Severity in IBS  

MILD

MODERATE

SEVERE

70% +++

25% ++

5% +

0 0 + Primary

+ + ++ Specialty

+++ +++ +++ Referral

Clinical Features Prevalence Correlations with gut physiology Symptoms constant Psychosocial difficulties Health care issues Practice type

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TABLE 320-4  Possible Drugs for a Dominant Symptom in IBS SYMPTOM Diarrhea     Constipation                 Abdominal pain    Gas and bloating    a

DRUG Loperamide

DOSE 2–4 mg when necessary/ maximum 12 g/d Cholestyramine resin 4 g with meals Alosetrona 0.5–1 mg bid (for severe IBS, women) Psyllium husk 3–4 g bid with meals, then adjust Methylcellulose 2 g bid with meals, then adjust Calcium polycarbophil 1 g qd to qid Lactulose syrup 10–20 g bid 70% sorbitol 15 mL bid Polyethylene glycol 3350 17 g in 250 mL water qd Lubiprostone (Amitiza) 24 mg bid Magnesium hydroxide 30–60 mL qd Linaclotide 290 μg qd Smooth-muscle relaxant qd to qid ac Tricyclic antidepressants Start 25–50 mg hs, then adjust Selective serotonin Begin small dose, increase as reuptake inhibitors needed Low FODMAP diet   Probiotics qd Rifaximin 550 mg bid

Available only in the United States.

Abbreviation: FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. Source: Adapted from GF Longstreth et al: Gastroenterology 130:1480, 2006.

bowel movement. The only significant side effect was diarrhea, which occurred in 4.5% of the patients. The drug has been approved for treatment of constipation in IBS-C patients. Summary  The treatment strategy of IBS depends on the severity of the disorder (Table 320-3). Most IBS patients have mild symptoms. They are usually cared for in primary care practices, have little or no psychosocial difficulties, and do not seek health care often. Treatment usually involves education, reassurance, and dietary/ lifestyle changes. A smaller portion have moderate symptoms that are usually intermittent and correlate with altered gut physiology, e.g., worsened with eating or stress and relieved by defecation. For IBS-D patients, treatments include gut-acting pharmacologic agents such as antispasmodics, antidiarrheals, bile acid binders, and the newer gut serotonin modulators (Table 320-4). In IBS-C patients, increased fiber intake and the use of osmotic agents such as polyethylene glycol may achieve satisfactory results. For patients with more severe constipation, a chloride channel opener (lubiprostone) or GC-C agonist (linaclotide) may be considered. For IBS patients with predominant gas and bloating, a low-FODMAP diet may provide significant relief. Some patients may benefit from probiotics and rifaximin treatment. A small proportion of IBS patients have severe and refractory symptoms, are usually seen in referral centers, and frequently have constant pain and psychosocial difficulties. This group of patients is best managed with antidepressants and other psychological treatments (Table 320-4). Clinical trials demonstrating success of low FODMAP diet in improving IBS symptoms and quality of life provide strong evidence supporting the use of this dietary approach in the treatment of IBS. These observations, if confirmed, may lead to the use of low FODMAP diet as the first line of treatment of IBS patients with moderate to severe symptoms.

■■FURTHER READING

Barbara G et al: The immune system in irritable bowel syndrome. J Neurogastroenterol Motil 17:349, 2011. Drossman DA: Functional gastrointestinal disorders: History, pathophysiology, clinical features, and Rome IV. Gastroenterology 150:1262, 2016.

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Eswaran SL et al: A randomized controlled trial comparing the low FODMAP diet vs. modified NICE guidelines in US adults with IBS-D. Am J Gastroenterol 111:1824, 2016. Mayer EA et al: Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology 146:1500; 2014. Mayer EA et al: Towards a systems view of IBS. Nar Rev Gastroenterol Hepatol 12:592, 2015. Natividad JM, Verdu EF: Modulation of intestinal barrier by intestinal microbiota: Pathological and therapeutic implications. Pharmacological Research 69:42, 2013. Simren M et al: Intestinal microbiota in functional bowel disorders: A Rome foundation report. Gut 62:159, 2013. Talley NJ, Fodor AA: Bugs, stool, and the irritable bowel syndrome: Too much is as bad as too little? Gastroenterology 141:1555, 2011.

Disease 321 Diverticular and Common Anorectal Disorders

Rizwan Ahmed, Susan L. Gearhart

Incidence and Epidemiology  In the United States,

diverticulosis affects 60% of the population aged >60 and up to 30% of individuals with diverticular disease will experience recurrent symptoms. Diverticular disease has become the fifth most costly gastrointestinal disorder in the United States and is the leading indication for elective colon resection. The incidence of diverticular disease is on the rise. Fortunately, only 20% of patients with diverticulosis develop diverticular disease and 4% require hospitalization. Previously overlooked, the majority of patients with diverticular disease report a lower health-related quality of life and more depression as compared to matched controls, thus adding to health care costs. Formerly, diverticular disease was confined to developed countries; however, with the adoption of westernized diets in underdeveloped countries, diverticulosis is on the rise across the globe. Immigrants to the United States develop diverticular disease at the same rate as U.S. natives. Although the prevalence among females and males is similar, males tend to present at a younger age. The mean age at presentation is now shifting to affect younger populations.

Anatomy and Pathophysiology  Two types of diverticula occur

in the intestine: true and false (or pseudo diverticula). A true diverticulum is a saclike herniation of the entire bowel wall, whereas a pseudo diverticulum involves only a protrusion of the mucosa and submucosa through the muscularis propria of the colon (Fig. 321-1). The type of diverticulum most commonly affecting the colon is the pseudo diverticulum. Diverticula commonly affect the left and sigmoid colon; the rectum is always spared. However, in Asian populations, 70% of diverticula are seen in the right colon and cecum as well. Yamanda et al. found right-side colonic diverticulosis in 22% of Japanese patients undergoing colonoscopy. Diverticulitis is inflammation of a diverticulum. Previous understanding of the pathogenesis of diverticulosis attributed a low-fiber diet as the sole culprit, and onset of diverticulitis would occur acutely when these diverticula become obstructed. However, evidence now suggests that the pathogenesis is more complex and multifactorial. The diverticula occur at the point where the nutrient artery, or vasa recti, penetrates through the muscularis propria, resulting in a break in the integrity of the colonic wall. This anatomic restriction may be a result of the relative high-pressure zone within the muscular sigmoid colon. Thus, higher-amplitude contractions

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FIGURE 321-1  Gross and microscopic view of sigmoid diverticular disease. Arrows mark an inflamed diverticulum with the diverticular wall made up only of mucosa.

combined with constipated, high-fat-content stool within the sigmoid lumen in an area of weakness in the colonic wall results in the creation of these diverticula. Consequently, the vasa recti is either compressed or eroded, leading to either perforation or bleeding. Chronic low-grade inflammation is thought to play a key role in neuronal degeneration leading to dysmotility and high intraluminal pressure. As a consequence, pockets or outpouchings develop in the colonic wall where it is weakest. Furthermore, better understanding of the gut microbiota suggests that dysbiosis is an important aspect of disease.

CHAPTER 321 Diverticular Disease and Common Anorectal Disorders

■■DIVERTICULAR DISEASE

Presentation, Evaluation, and Management of Diverticular Bleeding  Hemorrhage from a colonic diverticulum is the most

common cause of hematochezia in patients >60 years, yet only 20% of patients with diverticulosis will have gastrointestinal bleeding. Patients at increased risk for bleeding tend to be hypertensive, have atherosclerosis, and regularly use aspirin and nonsteroidal anti-inflammatory agents. Most bleeds are self-limited and stop spontaneously with bowel rest. The lifetime risk of rebleeding is 25%. Initial localization of diverticular bleeding may include colonoscopy, multiplanar computed tomography (CT) angiogram, or nuclear medicine tagged red cell scan. If the patient is stable, ongoing bleeding is best managed by angiography. If mesenteric angiography can localize the bleeding site, the vessel can be occluded successfully with a coil in

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colonoscopy, if necessary, looking for evidence of colonic ischemia. Alternatively, a segmental resection of the colon can be undertaken to eliminate the risk of further bleeding. This may be advantageous in patients on chronic anticoagulation. However, with highly selective coil embolization, the rate of colonic ischemia is 10 units of blood.

Abscess

I

Feces

Presentation, Evaluation, and Staging of Diverticulitis 

PART 10 Disorders of the Gastrointestinal System

Acute uncomplicated diverticulitis (also known as Symptomatic Uncomplicated Diverticular Disease, SUDD) characteristically presents with fever, anorexia, left lower quadrant abdominal pain, and obstipation (Table 321-1). In 4 mm, and inflammation within the periodic fat ± the collection of contrast material or fluid. In up to 20% of patients, an abdominal abscess may be present. Symptoms of irritable bowel syndrome (Chap. 320) may mimic those of diverticulitis. Therefore, suspected diverticulitis that does not meet CT criteria or is not associated with a leukocytosis or fever is not diverticular disease. Other conditions that can mimic diverticular disease include an ovarian cyst, endometriosis, acute appendicitis, and pelvic inflammatory disease. Although the benefit of colonoscopy in the evaluation of patients with diverticular disease has been called into question, its use is still considered important in the exclusion of colorectal cancer. The parallel epidemiology of colorectal cancer and diverticular disease provides enough concern for an endoscopic evaluation before operative management. Therefore, a colonoscopy should be performed ~6 weeks after an attack of diverticular disease. Complicated diverticular disease is defined as diverticular disease associated with an abscess or perforation and less commonly with a fistula (Table 321-1). Perforated diverticular disease is staged using the Hinchey classification system (Fig. 321-2). This staging system was TABLE 321-1  Presentation of Diverticular Disease Uncomplicated Diverticular Disease—75% Abdominal pain Fever Leukocytosis Anorexia/obstipation Complicated Diverticular Disease—25% Abscess 16% Perforation 10% Stricture 5% Fistula 2%

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II

III

IV

FIGURE 321-2  Hinchey classification of diverticulitis. Stage I: Perforated diverticulitis with a confined paracolic abscess. Stage II: Perforated diverticulitis that has closed spontaneously with distant abscess formation. Stage III: Noncommunicating perforated diverticulitis with fecal peritonitis (the diverticular neck is closed off, and, therefore, contrast will not freely expel on radiographic images). Stage IV: Perforation and free communication with the peritoneum, resulting in fecal peritonitis.

developed to predict outcomes following the surgical management of complicated diverticular disease. In recent years, the Hinchey staging system has been modified to include the development of a phlegmon or early abscess (Hinchey stage Ia). A pericolic abscess is then considered Hinchey stage Ib. In complicated diverticular disease with fistula formation, common locations include cutaneous, vaginal, or vesicle fistulas. These conditions present with either passage of stool through the skin or vagina or the presence of air in the urinary stream (pneumaturia). Colovaginal fistulas are more common in women who have undergone a hysterectomy.

TREATMENT

Diverticular Disease MEDICAL MANAGEMENT Asymptomatic diverticular disease discovered on imaging studies or at the time of colonoscopy is best managed by lifestyle changes. Although the data regarding dietary risks and symptomatic diverticular disease are limited (see Table 321-2), patients may benefit from a fiber-enriched diet that includes 30 g of fiber each day. Supplementary fiber products such as Metamucil, Fibercon, or Citrucel are useful. The use of fiber increases colonic transit time, and, therefore, preventing increased intraluminal pressure leading to the development of diverticulosis. The incidence of complicated diverticular disease appears to also be increased in patients who smoke. Therefore, patients should be encouraged to refrain from smoking. The historical recommendation to avoid eating nuts is based on no more than anecdotal data. SUDD with confirmation of inflammation and infection within the colon should be treated initially with bowel rest. The routine use of antibiotics in uncomplicated diverticular disease did not demonstrate any benefit in time to symptom resolution, complications, or risk of recurrence. However, the data are limited and antibiotics remain in the treatment paradigm. Hospitalization is recommended if the patient is unable to take oral therapy, affected by several comorbidities, fails to improve with outpatient therapy,

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TABLE 321-2  The Use of Fiber in the Management of Diverticular Disease JOURNAL, STUDY YEAR Lancet, 1977 BMJ, 1981 J Gastroenterol, 1977 BMJ, 2011 Gastroenterology, 2012 Jama, 2008

PATIENTS (n) 18 58 30 47,033 2104 47,288

INTERVENTION Wheat or bran crisp bread Bran, ispaghula, placebo Methylcellulose Vegetarian vs nonvegetarian Fiber consumption Nut, corn, popcorn consumption

STUDY LENGTH 3 months 16 weeks 3 months 11.6 years 12 years 18 years

Ann R Coll Surg Engl, 1985

56

Fiber consumption

66 months

FINDINGS Significant reduction of symptoms score No difference Significant reduction in symptoms Vegetarians had a 31% lower risk of DD Fiber associated with great risk of DD Higher nut, corn, and popcorn had lower risk of recurrence Higher fiber associated with 19% reduction in symptom recurrence

Modified from A Turis, A Papa, S Danese: Review Article: The pathophysiology and medical management of diverticulosis and diverticular disease of the colon. Aliment Parmacol Ther 42:664, 2015.

SURGICAL MANAGEMENT Preoperative risk factors influencing postoperative mortality rates include higher American Society of Anesthesiologists (ASA) physical status class (Table 321-3) and preexisting organ failure. In patients who are low risk (ASA P1 and P2), surgical therapy can be offered to those who do not rapidly improve on medical therapy. For uncomplicated diverticular disease, medical therapy can be continued beyond two attacks without an increased risk of perforation requiring a colostomy. However, patients on immunosuppressive therapy, in chronic renal failure, or with a collagen-vascular disease have a fivefold greater risk of perforation during recurrent attacks. Surgical therapy is indicated in all low-surgical-risk patients with complicated diverticular disease.

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The goals of surgical management of diverticular disease include controlling sepsis, eliminating complications such as fistula or obstruction, removing the diseased colonic segment, and restoring intestinal continuity. These goals must be obtained while minimizing morbidity rate, length of hospitalization, and cost in addition to maximizing survival and quality of life. Table 321-4 lists the operations most commonly indicated based on the Hinchey classification and the predicted postoperative outcomes. The current options for uncomplicated diverticular disease include an open or a laparoscopic resection of the diseased area with reanastomosis to the rectosigmoid. Preservation of portions of the sigmoid colon may lead to early recurrence of the disease. The benefits of laparoscopic resection over open surgical techniques include early discharge (by at least 1 day), less narcotic use, less postoperative complications, and an earlier return to work. The options for the surgical management of complicated diverticular disease (Fig. 321-3) include the following open or laparoscopic procedures: (1) proximal diversion of the fecal stream with an ileostomy or colostomy and sutured omental patch with drainage, (2) resection with colostomy and mucous fistula or closure of distal bowel with formation of a Hartmann’s pouch (Hartmann’s procedure), (3) resection with anastomosis (coloproctostomy), or (4) resection with anastomosis and diversion (coloproctostomy with loop ileostomy or colostomy). (5) Laparoscopic technique of washout and drainage without diversion has been described for Hinchey III patients; however, a threefold increased risk of recurrent peritonitis requiring reoperation with washout alone has been reported. Patients with Hinchey stage Ia are managed with antibiotic therapy only followed by resection with anastomosis at 6 weeks. Patients with Hinchey stages Ib and II disease are managed with percutaneous drainage followed by resection with anastomosis about 6 weeks later. Current guidelines put forth by the American Society of Colon and Rectal Surgeons suggest, in addition to antibiotic therapy, CT-guided percutaneous drainage of diverticular abscesses that are >3 cm and have a well-defined wall. Abscesses that are 2 per year). Newer directions are targeted at colonic inflammation and dysbiosis. Diverticular disease is now considered a functional bowel disorder associated with low-grade inflammation. However, the use of anti-inflammatory medications (mesalazine) in randomized clinical trials has not demonstrated any effect on recurrence rates over placebo alone. Some authors have suggested that the use of anti-inflammatory medications is most helpful in patients with diverticular disease who also have segmental colitis (Segmental Colitis-Associated Diverticular Disease [SCADD]). Treatment strategies targeting dysbiosis in diverticular disease have also been evaluated using polymerase chain reaction (PCR) on stool specimens. Stool samples from consumers of a high-fiber diet have different bacterial content than stool samples from consumers of a low-fiber, high-fat diet. Probiotics are increasingly used by gastroenterologists for multiple bowel disorders and may prevent recurrence of diverticulitis. Specifically, probiotics containing Lactobacillus acidophilus and Bifidobacterium strains may be beneficial, however, a recent systematic review was unable to show any benefit to the use of probiotics. Rifaximin (a poorly absorbed broadspectrum antibiotic), when compared to fiber alone for the treatment of SUDD, is associated with 30% less frequent recurrent symptoms from uncomplicated diverticular disease.

TABLE 321-3  American Society of Anesthesiologists Physical Status Classification System P1 P2 P3 P4 P5 P6

A normal healthy patient A patient with mild systemic disease A patient with severe systemic disease A patient with severe systemic disease that is a constant threat to life A moribund patient who is not expected to survive without the operation A declared brain-dead patient whose organs are being removed for donor purposes

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TABLE 321-4  Outcome Following Surgical Therapy for Complicated Diverticular Disease Based Upon Modified Hinchey Staging HINCHEY STAGE Ia (pericolic phlegmon) Ib (pericolic abscess) II III

IV

OPERATIVE PROCEDURE Laparoscopic or open colon resection Percutaneous drainage followed by laparoscopic or open colon resection Percutaneous drainage followed by laparoscopic or open colon resection +/− proximal diversion with an ostomy Laparoscopic washout and drainage or Laparoscopic or open resection with proximal diversion (ostomy) or Hartmann’s procedure Hartmann’s procedure or Washout with proximal diversion

PART 10 Disorders of the Gastrointestinal System

diverticular abscess is associated with a 20–25% failure rate. Urgent operative intervention is undertaken if percutaneous drainage fails and patients develop generalized peritonitis, and most will need to be managed with a Hartmann’s procedure (resection of the sigmoid colon with end colostomy and rectal stump). In selected cases, nonoperative therapy may be considered. In one nonrandomized study, nonoperative management of isolated paracolic abscesses (Hinchey stage I) was associated with only a 20% recurrence rate at 2 years. More than 80% of patients with distant abscesses (Hinchey stage II) required surgical resection for recurrent symptoms. The management of Hinchey stage III disease is under debate. In this population of patients, no fecal peritonitis is present and it is presumed that the perforation has sealed. Historically, Hinchey stage III has been managed with a Hartmann’s procedure or with primary anastomosis and proximal diversion. Several studies have examined short- and long-term outcomes for laparoscopic peritoneal lavage to remove the peritoneal contamination and place drainage catheters should a communication to the bowel still exist. However, this procedure has been associated with an increased risk of requiring reoperation for ongoing peritonitis. Overall, ostomy rates are lower with the use of laparoscopic peritoneal lavage. No anastomosis of any type should be attempted in Hinchey stage IV disease, or the presence of fecal peritonitis. A limited approach to these patients is associated with a decreased mortality rate.

ANASTOMOTIC LEAK RATE, % 43 3

OVERALL MORBIDITY RATE, % 15 15

3

15

3

30% risk of peritonitis requiring reoperation if no resection is performed. Overall morbidity 50% Overall mortality 15%

—

Overall morbidity 50% Overall mortality 15%

congenital hypothyroidism, Hirschsprung’s disease, dementia, mental retardation, and schizophrenia.

Anatomy and Pathophysiology  Rectal prolapse (procidentia) is

a circumferential, full-thickness protrusion of the rectal wall through the anal orifice. It is often associated with a redundant sigmoid colon, pelvic laxity, and a deep rectovaginal septum (pouch of Douglas). Initially, rectal prolapse was felt to be the result of early internal rectal intussusception, which occurs in the upper to mid rectum. This was considered to be the first step in an inevitable progression to fullthickness external prolapse. However, only 1 of 38 patients with internal prolapse followed for >5 years developed full-thickness prolapse. Others have suggested that full-thickness prolapse is the result of damage to the nerve supply to the pelvic floor muscles or pudendal nerves from repeated stretching with straining to defecate. Damage to the pudendal nerves would weaken the pelvic floor muscles, including

Recurrent Symptoms  Recurrent abdominal symptoms following surgical resection for diverticular disease occur in 10% of patients. Recurrent diverticular disease develops in patients following inadequate surgical resection. A retained segment of diseased rectosigmoid colon is associated with twice the incidence of recurrence. The presence of irritable bowel syndrome may also cause recurrence of initial symptoms. Patients undergoing surgical resection for presumed diverticulitis and symptoms of chronic abdominal cramping and irregular loose bowel movements consistent with irritable bowel syndrome have poorer functional outcomes.

COMMON DISEASES OF THE ANORECTUM ■■RECTAL PROLAPSE (PROCIDENTIA) Incidence and Epidemiology  Rectal prolapse is six times more common in women than in men. The incidence of rectal prolapse peaks in women >60 years. Women with rectal prolapse have a higher incidence of associated pelvic floor disorders including urinary incontinence, rectocele, cystocele, and enterocele. About 20% of children with rectal prolapse will have cystic fibrosis. All children presenting with prolapse should undergo a sweat chloride test. Less common associations include Ehlers-Danlos syndrome, solitary rectal ulcer syndrome,

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FIGURE 321-3  Methods of surgical management of complicated diverticular disease. 1. Drainage, omental pedicle graft, and proximal diversion. 2. Hartmann’s procedure. 3. Sigmoid resection with coloproctostomy. 4. Sigmoid resection with coloproctostomy and proximal diversion.

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the external anal sphincter muscles. Bilateral pudendal nerve injury is more significantly associated with prolapse and incontinence than unilateral injury.

TREATMENT

Presentation and Evaluation  In external prolapse, the majority of patient complaints include anal mass, bleeding per rectum, and poor perianal hygiene. Prolapse of the rectum usually occurs following defecation and will spontaneously reduce or require the patient to manually reduce the prolapse. Constipation occurs in ~30–67% of patients with rectal prolapse. Differing degrees of fecal incontinence occur in 50–70% of patients. Patients with internal rectal prolapse will present with symptoms of both constipation and incontinence. Other associated findings include outlet obstruction (anismus) in 30%, colonic inertia in 10%, and solitary rectal ulcer syndrome in 12%. Office evaluation is best performed after the patient has been given an enema, which enables the prolapse to protrude. An important distinction should be made between full-thickness rectal prolapse and isolated mucosal prolapse associated with hemorrhoidal disease (Fig. 321-4). Mucosal prolapse is known for radial grooves rather than circumferential folds around the anus and is due to increased laxity of the connective tissue between the submucosa and underlying muscle of the anal canal. The evaluation of prolapse should also include cystoproctography and colonoscopy. These examinations evaluate for associated pelvic floor disorders and rule out a malignancy or a polyp as the lead point for prolapse. If rectal prolapse is associated with chronic constipation, the patient should undergo a defecating proctogram and a sitzmark study. This will evaluate for the presence of anismus or colonic inertia. Anismus is the result of attempting to defecate against a closed pelvic floor and is also known as nonrelaxing puborectalis. This can be seen when straightening of the rectum fails to occur on fluoroscopy while the patient is attempting to defecate. In colonic inertia, a sitzmark study will demonstrate retention of >20% of markers on abdominal x-ray 5 days after swallowing. For patients with fecal incontinence, endoanal ultrasound and manometric evaluation, including pudendal nerve testing of their anal sphincter muscles, may be performed before surgery for prolapse (see “Fecal Incontinence,” below).

The medical approach to the management of rectal prolapse is limited and includes stool-bulking agents or fiber supplementation to ease the process of evacuation. Surgical correction of rectal prolapse is the mainstay of therapy. Two approaches are commonly considered, transabdominal and transperineal. Transabdominal approaches have been associated with lower recurrence rates, but some patients with significant comorbidities are better served by a transperineal approach. Common transperineal approaches include a transanal proctectomy (Altmeier procedure), mucosal proctectomy (Delorme procedure), or placement of a Tirsch wire encircling the anus. The goal of the transperineal approach is to remove the redundant rectosigmoid colon. Common transabdominal approaches include presacral suture or mesh rectopexy (Ripstein) with (Frykman-Goldberg) or without resection of the redundant sigmoid. Colon resection, in general, is reserved for patients with constipation and outlet obstruction. Ventral rectopexy is an effective method of abdominal repair of full-thickness prolapse that does not require sigmoid resection (see description below). This repair may have improved functional results over other abdominal repairs. Transabdominal procedures can be performed effectively with laparoscopic and, more recently, robotic techniques without increased incidence of recurrence. The goal of the transabdominal approach is to restore normal anatomy by removing redundant bowel and reattaching the supportive tissue of the rectum to the presacral fascia. The final alternative is abdominal proctectomy with end-sigmoid colostomy. If total colonic inertia is present, as defined by a history of constipation and a positive sitzmark study, a subtotal colectomy with an ileosigmoid or rectal anastomosis may be required at the time of rectopexy. Previously, the presence of internal rectal prolapse identified on imaging studies has been considered a nonsurgical disorder, and biofeedback was recommended. However, only one-third of patients will have successful resolution of symptoms from biofeedback. Two surgical procedures more effective than biofeedback are the Stapled Transanal Rectal Resection (STARR) and the Laparoscopic Ventral Rectopexy (LVR). The STARR procedure (Fig. 321-5) is performed through the anus in patients with internal prolapse. A circular stapling device is inserted through the anus; the internal prolapse is identified and ligated with the stapling device. LVR (Fig. 321-6) is performed through an abdominal approach. An opening in the

C

B

D

FIGURE 321-4  Degrees of rectal prolapse. Mucosal prolapse only (A, B, sagittal view). Full-thickness prolapse associated with redundant rectosigmoid and deep pouch of Douglas (C, D, sagittal view).

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CHAPTER 321 Diverticular Disease and Common Anorectal Disorders

A

Rectal Prolapse

FIGURE 321-5  Stapled transanal rectal resection. Schematic of placement of the circular stapling device.

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TABLE 321-5  Medical Conditions That Contribute to Symptoms of Fecal Incontinence Neurologic Disorders •  Dementia •  Brain tumor •  Stroke •  Multiple sclerosis •  Tabes dorsalis •  Cauda equina lesions Skeletal Muscle Disorders •  Myasthenia gravis •  Myopathies, muscular dystrophy Miscellaneous •  Hypothyroidism •  Irritable bowel syndrome •  Diabetes •  Severe diarrhea •  Scleroderma

muscle fibers anteriorly at the time of the delivery. This results in an obvious anterior defect on endoanal ultrasound. Injury may also be the result of stretching of the pudendal nerves during pregnancy or delivery of the fetus through the birth canal.

PART 10

FIGURE 321-6  Laparoscopic ventral rectopexy (LVR). To reduce the internal prolapse and close any rectovaginal septal defect, the pouch of Douglas is opened and mesh is secured to the anterolateral rectum, vaginal fornix, and sacrum. (From A D’Hoore et al: Br J Surg 91:1500, 2004.)

Disorders of the Gastrointestinal System

peritoneum is created on the left side of the rectosigmoid junction, and this opening continues down anterior on the rectum into the pouch of Douglas. No rectal mobilization is performed, thus avoiding any autonomic nerve injury. Mesh is secured to the anterior and lateral portion of the rectum, the vaginal fornix, and the sacral promontory, allowing for closure of the rectovaginal septum and correction of the internal prolapse. In both procedures, recurrence at 1 year was low (65. A higher incidence of incontinence is seen among parous women. One-half of patients with fecal incontinence also suffer from urinary incontinence. The majority of incontinence is a result of obstetric injury to the pelvic floor, either while carrying a fetus or during the delivery. An anatomic sphincter defect may occur in up to 32% of women following childbirth regardless of visible damage to the perineum. Risk factors at the time of delivery include prolonged labor, the use of forceps, and the need for an episiotomy. Symptoms of incontinence can present after two or more decades following obstetric injury. Medical conditions known to contribute to the development of fecal incontinence are listed in Table 321-5.

Anatomy and Pathophysiology  The anal sphincter complex

is made up of the internal and external anal sphincter. The internal sphincter is smooth muscle and a continuation of the circular fibers of the rectal wall. It is innervated by the intestinal myenteric plexus and is therefore not under voluntary control. The external anal sphincter is formed in continuation with the levator ani muscles and is under voluntary control. The pudendal nerve supplies motor innervation to the external anal sphincter. Obstetric injury may result in tearing of the

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Presentation and Evaluation  Patients may suffer with varying degrees of fecal incontinence. Minor incontinence includes incontinence to flatus and occasional seepage of liquid stool. Major incontinence is frequent inability to control solid waste. As a result of fecal incontinence, patients suffer from poor perianal hygiene. Beyond the immediate problems associated with fecal incontinence, these patients are often withdrawn and suffer from depression. For this reason, quality-of-life measures are an important component in the evaluation of patients with fecal incontinence. The evaluation of fecal incontinence should include a thorough history and physical examination including digital rectal examination (DRE). Weak sphincter tone on DRE and loss of the “anal wink” reflex (S1-level control) may indicate a neurogenic dysfunction. Perianal scars may represent surgical injury. Other studies helpful in the diagnosis of fecal incontinence include anal manometry, pudendal nerve terminal motor latency (PNTML), and endoanal ultrasound. Centers that care for patients with fecal incontinence will have an anorectal physiology laboratory that uses standardized methods of evaluating anorectal physiology. Anorectal manometry (ARM) measures resting and squeeze pressures within the anal canal using an intraluminal water-perfused catheter. Current methods of ARM include use of a three-dimensional, high-resolution system with a 12-catheter perfusion system, which allows physiologic delineation of anatomic abnormalities. Pudendal nerve studies evaluate the function of the nerves innervating the anal canal using a finger electrode placed in the anal canal. Stretch injuries to these nerves will result in a delayed response of the sphincter muscle to a stimulus, indicating a prolonged latency. Finally, endoanal ultrasound will evaluate the extent of the injury to the sphincter muscles before surgical repair. Unfortunately, all of these investigations are user-dependent, and very few studies demonstrate that these studies predict outcome following an intervention. Magnetic resonance imaging (MRI) has been used, but its routine use for imaging in fecal incontinence is not well established. Rarely does a pelvic floor disorder exist alone. The majority of patients with fecal incontinence will have some degree of urinary incontinence. Similarly, fecal incontinence is a part of the spectrum of pelvic organ prolapse. For this reason, patients may present with symptoms of obstructed defecation as well as fecal incontinence. Careful evaluation including dynamic MRI or cinedefecography should be performed to search for other associated defects. Surgical repair of incontinence without attention to other associated defects may decrease the success of the repair.

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TREATMENT

Fecal Incontinence

■■HEMORRHOIDAL DISEASE Incidence and Epidemiology  Symptomatic hemorrhoids affect >1 million individuals in the Western world per year. The prevalence of hemorrhoidal disease is not selective for age or sex. However, age is known to be a risk factor. The prevalence of hemorrhoidal disease is less in underdeveloped countries. The typical low-fiber, high-fat Western diet is associated with constipation and straining and the development of symptomatic hemorrhoids. Anatomy and Pathophysiology  Hemorrhoidal cushions are a

normal part of the anal canal. The vascular structures contained within this tissue aid in continence by preventing damage to the sphincter muscle. Three main hemorrhoidal complexes traverse the anal canal— the left lateral, the right anterior, and the right posterior. Engorgement and straining lead to prolapse of this tissue into the anal canal. Over time, the anatomic support system of the hemorrhoidal complex weakens, exposing this tissue to the outside of the anal canal where it is

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STAGE I

DESCRIPTION OF CLASSIFICATION Enlargement with bleeding

II

Protrusion with spontaneous reduction

III

Protrusion requiring manual reduction

IV

Irreducible protrusion

TREATMENT Fiber supplementation Short course of cortisone suppository Sclerotherapy Infared coagulation Fiber supplementation Short course of cortisone suppository Sclerotherapy Infared coagulation Fiber supplementation Short course of cortisone suppository Rubber band ligation Operative hemorrhoidectomy Fiber supplementation Cortisone suppository Operative hemorrhoidectomy

susceptible to injury. Hemorrhoids are commonly classified as external or internal. External hemorrhoids originate below the dentate line and are covered with squamous epithelium and are associated with an internal component. External hemorrhoids are painful when thrombosed. Internal hemorrhoids originate above the dentate line and are covered with mucosa and transitional zone epithelium and represent the majority of hemorrhoids. The standard classification of hemorrhoidal disease is based on the progression of the disease from their normal internal location to the prolapsing external position (Table 321-6).

Presentation and Evaluation  Patients commonly present to a physician for two reasons: bleeding and protrusion. Pain is less common than with fissures and, if present, is described as a dull ache from engorgement of the hemorrhoidal tissue. Severe pain may indicate a thrombosed hemorrhoid. Hemorrhoidal bleeding is described as painless bright red blood seen either in the toilet or upon wiping. Occasional patients can present with significant bleeding, which may be a cause of anemia; however, the presence of a colonic neoplasm must be ruled out in anemic patients. Patients who present with a protruding mass complain about inability to maintain perianal hygiene and are often concerned about the presence of a malignancy. The diagnosis of hemorrhoidal disease is made on physical examination. Inspection of the perianal region for evidence of thrombosis or excoriation is performed, followed by a careful digital examination. Anoscopy is performed paying particular attention to the known position of hemorrhoidal disease. The patient is asked to strain. If this is difficult for the patient, the maneuver can be performed while sitting on a toilet. The physician is notified when the tissue prolapses. It is important to differentiate the circumferential appearance of a full-thickness rectal prolapse from the radial nature of prolapsing hemorrhoids (see “Rectal Prolapse,” above). The stage and location of the hemorrhoidal complexes are defined.

CHAPTER 321 Diverticular Disease and Common Anorectal Disorders

Medical management of fecal incontinence includes strategies to bulk up the stool, which help in increasing fecal sensation. These include fiber supplementation, loperamide, diphenoxylate, and bile acid binders. These agents harden the stool and delay frequency of bowel movements and are helpful in patients with minimal to mild symptoms. Furthermore, patients can be offered a form of physical therapy called biofeedback. This therapy helps strengthen the external sphincter muscle while training the patient to relax with defecation to avoid unnecessary straining and further injury to the sphincter muscles. Biofeedback has had variable success and is dependent on the motivation of the patient. At a minimum, biofeedback is risk-free. Most patients will have some improvement. For this reason, it should be incorporated into the initial recommendation to all patients with fecal incontinence. Historically, the “gold standard” for the treatment of fecal incontinence with an isolated sphincter defect has been the overlapping sphincteroplasty. The external anal sphincter muscle and scar tissue as well as any identifiable internal sphincter muscle are dissected free from the surrounding adipose and connective tissue and then an overlapping repair is performed in an attempt to rebuild the muscular ring and restore its function. However, long-term results following overlapping sphincteroplasty have been poor with a 50% failure rate over 5 years. Alternative therapies such as Sacral Nerve Stimulation (SNS), collagen-enhancing injectables, and magnetic “Fenix” ring are other options. SNS is an adaptation of a procedure developed for the management of urinary incontinence. SNS is ideally suited for patients with intact but weak anal sphincters. A temporary nerve stimulator is placed on the third sacral nerve. If there is at least a 50% improvement in symptoms, a permanent nerve stimulator is placed under the skin. Long-term results for sacral stimulation have been promising, with nearly 80% of patients having a reduction in incontinence episodes by at least 50%. This reduction has been sustainable in studies out to 5 years. Collagen-enhancing injectables have been around for several years. More than 50% of incontinent patients treated with nonanimal stabilized hyaluronic acid (NASHA/DX) achieved a 50% reduction in incontinence episodes, and these results were sustainable up to 2 years. Currently, this injectable is not universally available. The Fenix is a magnetic ring that is implanted around the anal sphincter muscles. Its long-term outcomes are still being studied and it is currently only available for compassionate use. Finally, the use of stem cells to increase the bulk of the sphincter muscles is currently being tested. Stem cells can be harvested from the patient’s own muscle, grown, and then implanted into their sphincter complex. Concern for cost and the need for an additional procedure dampen enthusiasm. Trial results are awaited.

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TABLE 321-6  The Staging and Treatment of Hemorrhoids

TREATMENT

Hemorrhoidal Disease The treatment for bleeding hemorrhoids is based on the stage of the disease (Table 321-6). In all patients with bleeding, the possibility of other causes must be considered. In young patients without a family history of colorectal cancer, the hemorrhoidal disease may be treated first and a colonoscopic examination performed if the bleeding continues. Older patients who have not had colorectal cancer screening should undergo colonoscopy or flexible sigmoidoscopy.

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PART 10 Disorders of the Gastrointestinal System

With rare exceptions, the acutely thrombosed hemorrhoid can be excised within the first 72 h by performing an elliptical excision. Sitz baths, fiber, and stool softeners are prescribed. Additional therapy for bleeding hemorrhoids includes the office procedures of rubber band ligation, infrared coagulation, and sclerotherapy. Sensation begins at the dentate line; therefore, all procedures can be performed without discomfort either endoscopically or in the office. Bands are placed around the engorged tissue, causing ischemia and fibrosis. This aids in fixing the tissue proximally in the anal canal. Patients may complain of a dull ache for 24 h following band application. During sclerotherapy, 1–2 mL of a sclerosant (usually sodium tetradecyl sulfate) is injected using a 25-gauge needle into the submucosa of the hemorrhoidal complex. Care must be taken not to inject the anal canal circumferentially, or stenosis may occur. For surgical management of hemorrhoidal disease, excisional hemorrhoidectomy, transhemorrhoidal dearterialization (THD), or stapled hemorrhoidectomy (“the procedure for prolapse or hemorrhoids” [PPH]) is the procedure of choice. All surgical methods of management are equally effective in the treatment of symptomatic third- and fourth-degree hemorrhoids. However, because the sutured hemorrhoidectomy involves the removal of redundant tissue down to the anal verge, unpleasant anal skin tags are removed as well. The stapled hemorrhoidectomy is associated with less discomfort; however, this procedure does not remove anal skin tags and an increased number of complications are associated with use of the stapling device. THD uses ultrasound guidance to ligate the blood supply to the anal tissue, hence reducing hemorrhoidal engorgement. No procedures on hemorrhoids should be done in patients who are immunocompromised or who have active proctitis. Furthermore, emergent hemorrhoidectomy for bleeding hemorrhoids is associated with a higher complication rate. Acute complications associated with the treatment of hemorrhoids include pain, infection, recurrent bleeding, and urinary retention. Care should be taken to place bands properly and to avoid overhydration in patients undergoing operative hemorrhoidectomy. Late complications include fecal incontinence as a result of injury to the sphincter during the dissection. Anal stenosis may develop from overzealous excision, with loss of mucosal skin bridges for reepithelialization. Finally, an ectropion (prolapse of rectal mucosa from the anal canal) may develop. Patients with an ectropion complain of a “wet” anus as a result of inability to prevent soiling once the rectal mucosa is exposed below the dentate line.

■■ANORECTAL ABSCESS Incidence and Epidemiology  The development of a perianal abscess is more common in men than women by a ratio of 3:1. The peak incidence is in the third to fifth decade of life. Perianal pain associated with the presence of an abscess accounts for 15% of office visits to a colorectal surgeon. The disease is more prevalent in immunocompromised patients such as those with diabetes, hematologic disorders, or inflammatory bowel disease (IBD) and persons who are HIV positive. These disorders should be considered in patients with recurrent perianal infections. Anatomy and Pathophysiology  An anorectal abscess is an abnormal fluid-containing cavity in the anorectal region. Anorectal abscess results from an infection involving the glands surrounding the anal canal. Normally, these glands release mucus into the anal canal, which aids in defecation. When stool accidentally enters the anal glands, the glands become infected and an abscess develops. Anorectal abscesses are perianal in 40–50% of patients, ischiorectal in 20–25%, intersphincteric in 2–5%, and supralevator in 2.5% (Fig. 321-7). Presentation and Evaluation  Perianal pain and fever are the hallmarks of an abscess. Patients may have difficulty voiding and have blood in the stool. A prostatic abscess may present with similar complaints, including dysuria. Patients with a prostatic abscess will often have a history of recurrent sexually transmitted diseases. On physical examination, a large fluctuant area is usually readily visible. Routine

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Abscesses Supralevator

Fistula tracts 4

Intersphincteric Ischiorectal Perianal

3 2

1

1 Intersphincteric

2

3 4 Extrasphincteric Suprasphincteric

Trans-sphincteric

FIGURE 321-7  Common locations of anorectal abscess (left) and fistula in ano (right).

laboratory evaluation shows an elevated white blood cell count. Diagnostic procedures are rarely necessary unless evaluating a recurrent abscess. A CT scan or MRI has an accuracy of 80% in determining incomplete drainage. If there is a concern about the presence of IBD, a rigid or flexible sigmoidoscopic examination may be done at the time of drainage to evaluate for inflammation within the rectosigmoid region. A more complete evaluation for Crohn’s disease would include a full colonoscopy and small-bowel series.

TREATMENT

Anorectal Abscess As with all abscesses, the “gold standard” is drainage. Office drainage of an uncomplicated anorectal abscess may suffice. A small incision close to the anal verge is made, and a Mallenkot drain is advanced into the abscess cavity. For patients who have a complicated abscess or who are diabetic or immunocompromised, drainage should be performed in an operating room under anesthesia. These patients are at greater risk for developing necrotizing fasciitis. The role of antibiotics in the management of anorectal abscesses is limited. Antibiotics are only warranted in patients who are immunocompromised or have prosthetic heart valves, artificial joints, diabetes, or IBD.

■■FISTULA IN ANO Incidence and Epidemiology  The incidence and prevalence of fistulating perianal disease parallel the incidence of anorectal abscess, estimating to be 1 in 10,000 individuals. Some 30–40% of abscesses will give rise to fistula in ano. Although the majority of the fistulas are cryptoglandular in origin, 10% are associated with IBD, tuberculosis, malignancy, and radiation. Anatomy and Pathophysiology  A fistula in ano is defined as a communication of an abscess cavity with an identifiable internal opening within the anal canal. This identifiable opening is most commonly located at the dentate line where the anal glands enter the anal canal. Patients experiencing continuous drainage following the treatment of a perianal abscess likely have a fistula in ano. These fistulas are classified by their relationship to the anal sphincter muscles, with 70% being intersphincteric, 23% transsphincteric, 5% suprasphincteric, and 2% extrasphincteric (Fig. 321-7). Presentation and Evaluation  A patient with a fistula in ano will complain of constant drainage from the perianal region associated with a firm mass. The drainage may increase with defecation. Perianal hygiene is difficult to maintain. Examination under anesthesia is the

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best way to evaluate a fistula. At the time of the examination, anoscopy is performed to look for an internal opening. Diluted hydrogen peroxide will aid in identifying such an opening. In lieu of anesthesia, MRI with an endoanal coil will also identify tracts in 80% of the cases. After drainage of an abscess with insertion of a Mallenkot catheter, a fistulagram through the catheter can be obtained in search of an occult fistula tract. Goodsall’s rule states that a posterior external fistula will enter the anal canal in the posterior midline, whereas an anterior fistula will enter at the nearest crypt. A fistula exiting >3 cm from the anal verge may have a complicated upward extension and may not obey Goodsall’s rule.

TREATMENT

Fistula in Ano

■■ANAL FISSURE Incidence and Epidemiology  Anal fissures occur at all ages

but are more common in the third through the fifth decades. A fissure is the most common cause of rectal bleeding in infancy. The prevalence is equal in males and females. It is associated with constipation, diarrhea, infectious etiologies, perianal trauma, and Crohn’s disease.

TREATMENT

Anal Fissure The management of the acute fissure is conservative. Stool softeners for those with constipation, increased dietary fiber, topical anesthetics, glucocorticoids, and sitz baths are prescribed and will heal 60–90% of fissures. Chronic fissures are those present for >6 weeks. These can be treated with modalities aimed at decreasing the anal canal resting pressure including nifedipine ointment applied three times a day and botulinum toxin type A, up to 20 units, injected into the internal sphincter on each side of the fissure. Surgical management includes anal dilatation and lateral internal sphincterotomy. Usually, one-third of the internal sphincter muscle is divided; it is easily identified because it is hypertrophied. Recurrence rates from medical therapy are higher, but this is offset by a risk of incontinence following sphincterotomy. Lateral internal sphincterotomy may lead to incontinence more commonly in women. Acknowledgment We would like to thank Cory Sandore for providing some illustrations for this chapter. Gregory Bulkley, MD, contributed to this chapter in an earlier edition and some of that material has been retained here.

■■FURTHER READING

Bharucha AE , Rao SSC, Shin AS: Surgical interventions and the use of device-aided therapy for the treatment of fecal incontinence and defecatory disorders. Clin Gastroenterol Hepatol 15:1844, 2017. Cotter TG et al: Approach to the patient with hematochezia. Mayo Clin Proc 92:797, 2017. Guttenplan M: The evaluation and office management of hemorrhoids for the gastroenterologist. Curr Gastroenterol Rep 19:30, 2017. Prichard D, Bharucha AE: Management of pelvic floor disorders: Biofeedback and more. Curr Treat Options Gastroenterol 12:456, 2014. Salfity HV et al: Minimally invasive incision and drainage technique in the treatment of simple subcutaneous abscess in adults. Am Surg 83:699, 2017. Sugrue J et al: Sphincter-sparing anal fistula repair: Are we getting better? Dis Colon Rectum 60:1071, 2017. Tursi A: Dietary pattern and colonic diverticulosis. Curr Opin Clin Nutr Metab Care 20:409, 2017.

CHAPTER 322 Mesenteric Vascular Insufficiency

A newly diagnosed draining fistula is best managed with placement of a seton, a vessel loop or silk tie placed through the fistula tract, which maintains the tract open and quiets down the surrounding inflammation that occurs from repeated blockage of the tract. Once the inflammation is less, the exact relationship of the fistula tract to the anal sphincters can be ascertained. A simple fistulotomy can be performed for intersphincteric and low (less than one-third of the muscle) transsphincteric fistulas without compromising continence. For a higher transsphincteric fistula, an anorectal advancement flap in combination with a drainage catheter or fibrin glue may be used. Very long (>2 cm) and narrow tracts respond better to fibrin glue than shorter tracts. Simple ligation of the internal fistula tract (LIFT procedure) has also been used in the management of simple fistula with good success. Patients should be maintained on stool-bulking agents, nonnarcotic pain medication, and sitz baths following surgery for a fistula. Early complications from these procedures include urinary retention and bleeding. Later complications are rare (75% of cases, emboli originate from the heart and preferentially lodge in the superior mesenteric artery (SMA) just distal to the origin of the middle colic artery. Progressive thrombosis of at least two of the major vessels supplying the intestine is required for the development of chronic intestinal angina. Nonocclusive ischemia is disproportionate mesenteric vasoconstriction (arteriolar vasospasm) in response to a severe physiologic stress such as shock. If left untreated, early mucosal stress ulceration will progress to full-thickness injury. Even in the early stages of ischemia, there is translocation of bacteria across the intestinal mucosa, resulting in bacteremia that can lead to sepsis.

■■PRESENTATION, EVALUATION, AND MANAGEMENT

Intestinal ischemia remains one of the most challenging diagnoses. The mortality rate is >50%. The most significant indicator of survival is the timeliness of diagnosis and treatment. An overview of diagnosis and management of each form of intestinal ischemia is given in Table 322-1. Acute mesenteric ischemia resulting from arterial embolus or thrombosis presents with severe acute, nonremitting abdominal pain strikingly out of proportion to the physical findings. Associated symptoms may include nausea and vomiting, transient diarrhea, anorexia, and bloody stools. With the exception of minimal abdominal distention and hypoactive bowel sounds, early abdominal examination is unimpressive. Later findings will demonstrate peritonitis and cardiovascular collapse. In the evaluation of acute intestinal ischemia, routine laboratory tests should be obtained, including complete blood count, serum chemistry, coagulation profile, arterial blood gas, amylase, lipase, lactic acid, blood type and cross match, and cardiac enzymes. Regardless of the need for urgent surgery, emergent admission to a monitored bed or intensive care unit is recommended for resuscitation and further evaluation. If the diagnosis of intestinal ischemia is being considered, consultation with a surgical service is necessary. Often the decision to operate is made on a high index of suspicion from the history and physical examination despite normal laboratory findings. Other diagnostic modalities that may be useful in diagnosis but should not delay surgical therapy include electrocardiogram (ECG), echocardiogram, abdominal radiographs, computed tomography (CT), and mesenteric angiography. More recently, mesentery duplex scanning and visible light spectroscopy during colonoscopy have been demonstrated to be beneficial. The ECG may demonstrate an arrhythmia, indicating the possible source of the emboli. A plain abdominal film may show evidence of free intraperitoneal air, indicating a perforated viscus and the need for emergent exploration. Earlier features of intestinal ischemia seen on abdominal radiographs include bowel-wall edema, known as “thumbprinting.” If the ischemia progresses, air can be seen within the bowel wall (pneumatosis intestinalis) and within the portal venous system. Other features include calcifications of the aorta and its tributaries, indicating atherosclerotic disease. With the administration of oral and IV contrast, dynamic CT angiography with three-dimensional reconstruction is a highly sensitive test for intestinal ischemia. In acute embolic disease, mesenteric angiography is best performed intraoperatively. A mesenteric duplex scan demonstrating a high peak velocity of flow in the SMA is associated with an ~80% positive predictive value of mesenteric ischemia. More significantly, a negative duplex scan virtually precludes the diagnosis of mesenteric ischemia. Duplex imaging serves as a screening test; however, further investigations with angiography are usually needed. One of the biggest limitations of duplex scanning is patients’ body habitus. The duplex imaging yields poor results in obese patients. Nevertheless, “food fear” in patients with chronic disease often leads to a decreased appetite and lower abdominal fat, thus, yielding high duplex imaging results. The endoscopic techniques such as visible light spectroscopy can also be used in the diagnosis of chronic ischemia. When suspecting mesenteric ischemia involving the colon, performing an endoscopy to evaluate up to the splenic flexure is high yield. This is often an excellent diagnostic tool in patients with chronic renal insufficiency who cannot tolerate IV contrast.

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TABLE 322-1  Overview of the Management of Acute Intestinal Ischemia CONDITION Arterioocclusive mesenteric ischemia 1.  Arterial embolus

KEY TO EARLY DIAGNOSIS Computed tomography (CT) angiography Early laparotomy

TREATMENT OF UNDERLYING CAUSE Anticoagulation Cardioversion Proximal thrombectomy

2.  Arterial thrombosis

Duplex ultrasound Angiography

Anticoagulation Hydration

Endovascular approach: thrombolysis, angioplasty and stenting Endarterectomy/thrombectomy or vascular bypass Assess viability and resect dead bowel

Mesenteric venous thrombosis Venous thrombosis

Spiral CT Angiography with venous phase

Anticoagulation Massive hydration

Anticoagulation ± laparotomy/ thrombectomy/catheter-directed thrombolysis Assess viability and resect dead bowel

Nonocclusive mesenteric ischemia

Vasospasm: Angiography Hypoperfusion: Spiral CT or colonoscopy

Ensure hydration Support cardiac output Avoid vasoconstrictors

Vasospasm Intraarterial vasodilators Hypoperfusion Delayed laparotomy Assess viability and resect dead bowel

TREATMENT OF SPECIFIC LESION Laparotomy Embolectomy Vascular bypass Assess viability and resect dead bowel

TREATMENT OF SYSTEMIC CONSEQUENCE Ensure hydration Give antibiotics Reverse acidosis Optimize oxygen delivery Avoid vasoconstrictors Give antibiotics Reverse acidosis Optimize oxygen delivery Support cardiac output Avoid vasoconstrictors Give antibiotics Reverse acidosis Optimize oxygen delivery Support cardiac output Avoid vasoconstrictors Ensure hydration Give antibiotics Reverse acidosis Optimize oxygen delivery Support cardiac output Avoid vasoconstrictors

The “gold standard” for the diagnosis of acute arterial occlusive disease is angiography, and management is laparotomy. Surgical exploration should not be delayed if suspicion of acute occlusive mesenteric ischemia is high or evidence of clinical deterioration or frank peritonitis is present. The goal of operative exploration is to resect compromised bowel and restore blood supply. The entire length of the small and large bowel beginning at the ligament of Treitz should be evaluated. The pattern of intestinal ischemia may indicate the level of arterial occlusion. In the case of SMA occlusion where the embolus usually lies just proximal to the origin of the middle colic artery, the proximal jejunum is often spared while the remainder of the small bowel up to the transverse colon will be ischemic. The surgical management of acute mesenteric ischemia of the small bowel is embolectomy via arteriotomy; a small incision is made in the artery through which the clot is retrieved. Another way to manage acute thrombosis is thrombolysis therapy and angioplasty with stent placement. However, this approach is more commonly applied to treat chronic mesenteric ischemia. If this is unsuccessful, a bypass from the aorta or iliac artery to the SMA is performed. Nonocclusive or vasospastic mesenteric ischemia presents with generalized abdominal pain, anorexia, bloody stools, and abdominal distention. Often these patients are obtunded, and physical findings may not assist in the diagnosis. The presence of a leukocytosis, metabolic acidosis, elevated amylase or creatinine phosphokinase levels, and/or lactic acidosis is useful in support of the diagnosis of advanced intestinal ischemia; however, these markers may not be indicative of either reversible ischemia or frank necrosis. Investigational markers for intestinal ischemia include d-dimer, glutathione S-transferase, plateletactivating factor (PAF), and mucosal pH monitoring. Regardless of the need for urgent surgery, emergent admission to a monitored bed or intensive care unit is recommended for resuscitation and further evaluation. Early manifestations of intestinal ischemia include fluid sequestration within the bowel wall leading to a loss of interstitial volume. Aggressive fluid resuscitation may be necessary. To optimize oxygen delivery, nasal O2 and blood transfusions may be given. Broad-spectrum antibiotics should be given to provide sufficient coverage for enteric

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pathogens, including gram-negative and anaerobic organisms. Frequent monitoring of the patient’s vital signs, urine output, blood gases, and lactate levels is paramount, as is frequent abdominal examination. All vasoconstricting agents should be avoided; fluid resuscitation is the intervention of choice to maintain hemodynamics. If ischemic colitis is a concern, colonoscopy should be performed to assess the integrity of the colon mucosa. Visualization of the rectosigmoid region may demonstrate decreased mucosal integrity, associated more commonly with nonocclusive mesenteric ischemia, or, on occasion, occlusive disease as a result of acute loss of inferior mesenteric arterial flow following aortic surgery. Ischemia of the colonic mucosa is graded as mild with minimal mucosal erythema or as moderate with pale mucosal ulcerations and evidence of extension to the muscular layer of the bowel wall. Severe ischemic colitis presents with severe ulcerations resulting in black or green discoloration of the mucosa, consistent with full-thickness bowel-wall necrosis. The degree of reversibility can be predicted from the mucosal findings: mild erythema is nearly 100% reversible, moderate is ~50% reversible, and frank necrosis is simply dead bowel. Follow-up colonoscopy can be performed to rule out progression of ischemic colitis. Laparotomy for nonocclusive mesenteric ischemia is warranted in patients with signs of peritonitis or worsening endoscopic findings and if the patient’s condition does not improve with aggressive resuscitation. Ischemic colitis is optimally treated with resection of the ischemic bowel and formation of a proximal stoma. Primary anastomosis should not be performed in patients with acute intestinal ischemia. Patients with mesenteric venous thrombosis may present with a gradual or sudden onset of pain. Symptoms include vague abdominal pain, nausea, and vomiting. Physical examination findings include abdominal distention with mild to moderate tenderness and signs of dehydration. The diagnosis of mesenteric thrombosis is frequently made on abdominal spiral CT with oral and IV contrast. Findings on CT angiography with venous phase include bowel-wall thickening and ascites. IV contrast will demonstrate a delayed arterial phase and clot within the superior mesenteric vein. The goal of management is to optimize hemodynamics and correct electrolyte abnormalities

CHAPTER 322 Mesenteric Vascular Insufficiency

Source: Modified from GB Bulkley, in JL Cameron (ed): Current Surgical Therapy, 2nd ed. Toronto, BC Decker, 1986.

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2294 with massive fluid resuscitation. Intravenous antibiotics as well as

PART 10 Disorders of the Gastrointestinal System

anticoagulation should be initiated. If laparotomy is performed and mesenteric venous thrombosis is suspected, heparin anticoagulation is immediately initiated, and compromised bowel is resected. Of all acute intestinal disorders, mesenteric venous insufficiency is associated with the best prognosis. Chronic intestinal ischemia presents with intestinal angina or postprandial abdominal pain associated with increased need of blood flow to the intestine following meals. Patients report abdominal cramping and pain following ingestion of a meal. Weight loss and chronic diarrhea may also be noted. Abdominal pain without weight loss is not chronic mesenteric angina. Physical examination will often reveal a malnourished patient with an abdominal bruit as well as other manifestations of atherosclerosis. Duplex ultrasound evaluation of the mesenteric vessels has gained in popularity. It is important to perform the test while the patient is fasting because the presence of increased bowel gas prevents adequate visualization of flow disturbances within the vessels or the lack of a vasodilation response to feeding during the test. This tool is frequently used as a screening test for patients with symptoms suggestive of chronic mesenteric ischemia. The gold standard for confirmation of mesenteric arterial occlusion is mesenteric angiography. Evaluation with mesenteric angiography allows for identification and possible intervention for the treatment of atherosclerosis within the vessel lumen and will also evaluate the patency of remaining mesenteric vessels. The use of mesenteric angiography may be limited in the presence of renal failure or contrast allergy. Magnetic resonance angiography is an alternative if the administration of contrast dye is contraindicated. The management of chronic intestinal ischemia includes medical management of atherosclerotic disease by exercise, cessation of smoking, and antiplatelet and lipid-lowering medications. A full cardiac evaluation should be performed before intervention on chronic mesenteric ischemia. Newer endovascular procedures may avoid an operative intervention in selected patient populations. Angioplasty with endovascular stenting in the treatment of chronic mesenteric ischemia is associated with an 80% long-term success rate. In patients requiring surgical exploration, the approach used is determined by findings of the mesenteric angiogram. The entire length of the small and large bowel should be evaluated, beginning at the ligament of Treitz. Restoration of blood flow at the time of laparotomy is accomplished with mesenteric vessel endarterectomy or bypass. Determination of intestinal viability intraoperatively in patients with suspected intestinal ischemia can be challenging. After revascularization, peristalsis and return of a pink color of the bowel wall should be observed. Palpation of major arterial mesenteric vessels can be performed, as well as applying a Doppler flowmeter to the antimesenteric border of the bowel wall, but neither is a definitive indicator of viability. In equivocal cases, 1 g of IV sodium fluorescein is administered, and the pattern of bowel reperfusion is observed under ultraviolet illumination with a standard (3600 A) Wood’s lamp. An area of nonfluorescence >5 mm in diameter suggests nonviability. If doubt persists, reexploration performed 24–48 h following surgery will allow demarcation of nonviable bowel. Primary intestinal anastomosis in patients with ischemic bowel is always worrisome; thus, delayed bowel reconstruction and reanastomosis should be deferred to the time of second-look laparotomy. acknowledgments

We thank Cory Sandore for providing the illustration for this chapter. Susan Gearhart contributed to this chapter in the 18th edition and Rizwan Ahmed contributed to the 19th edition.

■■FURTHER READING

Deng QW et al: Risk factors for postoperative acute mesenteric ischemia among adult patients undergoing cardiac surgery: A systematic review and meta-analysis. J Crit Care 42:294, 2017. Salsano G et al: What is the best revascularization strategy for acute occlusive arterial mesenteric ischemia: Systematic review and meta-analysis. Cardiovasc Intervent Radiol 41:27, 2018. Sise MJ: Acute mesenteric ischemia. Surg Clin North Am 94:165–81, 2014.

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Intestinal 323 Acute Obstruction Danny O. Jacobs

■■EPIDEMIOLOGY

Morbidity and mortality from acute intestinal obstruction have been decreasing over the past several decades. Nevertheless, the diagnosis can still be challenging, and the type of complications that patients suffer has not changed significantly. The extent of mechanical obstruction is typically described as partial, high-grade, or complete—generally correlating with the risk of complications and the urgency with which the underlying disease process must be addressed. Obstruction is also commonly described as being either “simple” or, alternatively, “strangulated” if vascular insufficiency and intestinal ischemia are evident. Acute intestinal obstruction occurs either mechanically from blockage or from intestinal dysmotility when there is no blockage. In the latter instance, the abnormality is described as being functional. Mechanical bowel obstruction may be caused by extrinsic processes, intrinsic abnormalities of the bowel wall, or intraluminal abnormalities (Table 323-1). Within each of these broad categories are many diseases that can impede intestinal propulsion. Intrinsic diseases that can cause intestinal obstruction are usually congenital, inflammatory, neoplastic, or traumatic in origin, although intussusception and radiation injury can also be etiologic. Acute intestinal obstruction accounts for ~1–3% of all hospitalizations and a quarter of all urgent or emergent general surgery admissions. Approximately 80% of cases involve the small bowel, and about onethird of these patients show evidence of significant ischemia. The mortality rate for patients with strangulation who are operated on within 24–30 h of the onset of symptoms is ~8% but triples shortly thereafter. Extrinsic diseases most commonly cause mechanical obstruction of the small intestine. In the United States and Europe, almost all cases are caused by postoperative adhesions, carcinomatosis, or herniation of the anterior abdominal wall. Carcinomatosis most often originates from the ovary, pancreas, stomach, or colon, although rarely, metastasis from distant organs like the breast and skin can occur. Adhesions are responsible for the majority of cases of early postoperative obstruction that require intervention. It is important to note many patients who are successfully treated for adhesive small-bowel instruction will recur. Approximately 20% of patients who were treated conservatively and TABLE 323-1  Most Common Causes of Acute Intestinal Obstruction Extrinsic Disease Adhesions (especially due to previous abdominal surgery), internal or external hernias, neoplasms (including carcinomatosis and extraintestinal malignancies, mostly commonly ovarian), endometriosis or intraperitoneal abscesses, and idiopathic sclerosis Intrinsic Disease Congenital (e.g., malrotation, atresia, stenosis, intestinal duplication, cyst formation, and congenital bands—the latter rarely in adults) Inflammation (e.g., inflammatory bowel disease, especially Crohn’s disease, but also diverticulitis, radiation, tuberculosis, lymphogranuloma venereum, and schistosomiasis) Neoplasia (note: primary small-bowel cancer is rare; obstructive colon cancer may mimic small-bowel obstruction if the ileocecal valve is incompetent) Traumatic (e.g., hematoma formation, anastomotic strictures) Other, including intussusception (where the lead point is typically a polyp or tumor in adults), volvulus, obstruction of duodenum by superior mesenteric artery, radiation or ischemic injury, and aganglionosis, which is Hirschsprung’s disease Intraluminal Abnormalities Bezoars, feces, foreign bodies including inspissated barium, gallstones (entering the lumen via a cholecystoenteric fistula), enteroliths

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TABLE 323-2  Acute Small-Intestinal and Colonic Obstruction Incidences CAUSE Postoperative adhesions Neoplasms Hernias (especially ventral or internal types, where the risk of strangulation is increased) Inflammatory bowel disease, other inflammation (obstruction may resolve if acute inflammation and edema subside) Intussusception, volvulus, other miscellaneous diseases

INCIDENCE >50% ~20% ~10%  ~5%  2.5 cm in diameter with little or no air seen in the colon are classical findings in patients with small-bowel obstruction, although findings may be equivocal in some patients with documented disease. Little bowel gas appears in patients with proximal bowel obstruction or in patients whose intestinal lumens are filled with fluid. Upright plain films of the abdomen of patients with large-bowel obstruction typically show colon dilatation. Small-bowel air-fluid levels will not be obvious if the ileocecal valve is competent. Although it can be difficult to distinguish from ileus, small-bowel obstruction is more likely when air-fluid levels are seen without significant colonic distension. Free air suggests that perforation has occurred in patients who have not recently undergone surgical procedures. A gas-filled, “coffee bean”–shaped dilated shadow may be seen in patients with volvulus. More sophisticated imaging, which may be unnecessarily time consuming and expensive, can nevertheless be beneficial when the diagnosis is unclear. Computed tomography (CT) is the most commonly used imaging modality. Its sensitivity for detecting bowel obstruction is ~95% (78–100%) in patients with high-grade obstruction, with a specificity of 96% and an accuracy of ≥95%. Its accuracy in diagnosing closed-loop obstruction is much lower (60%). CT may also provide useful information regarding location or to identify particular circumstances where surgical intervention is needed urgently. Patients who have evidence of contrast appearing within the cecum within 4–24 h of oral administration of water-soluble contrast can be expected to improve with high sensitivity and specificity (~95% each). For example, contrast studies may demonstrate a “bird’s beak,” a “c-loop,” or “whorl” deformity on CT imaging at the site where twisting obstructs the lumen when a colonic volvulus is present. Although abdominal radiography is usually the initial examination, unlike CT imaging, it may not accurately distinguish obstruction from other causes of colonic dysmotility. Examples of some CT images are reproduced in Fig. 323-2. Ultrasonographic evaluations are especially difficult to interpret but may be sensitive and appropriate studies to evaluate patients who are pregnant or for whom x-ray exposure is otherwise contraindicated or inappropriate. CT imaging with enteral and IV contrast can also identify ischemia. Altered bowel wall enhancement is the most specific early finding, but its sensitivity is low. Mesenteric venous gas, pneumoperitoneum, and pneumatosis intestinalis are late findings indicating the presence of bowel necrosis. CT scanning after a water-soluble contrast enema may help distinguish ileus or pseudo-obstruction from distal large-bowel obstruction in patients who present with evidence of small-bowel and colonic distention. CT enteroclysis, though rarely performed, can accurately identify neoplasia as a cause of bowel obstruction. Contrast enemas or colonoscopies are almost always needed to identify causes of acute colonic obstruction. Barium studies are generally contraindicated in patients with firm evidence of complete or high-grade bowel obstruction, especially when they present acutely. Barium should never be given orally to a patient with possible obstruction until that diagnosis has been excluded. In every other case, such investigations should only be performed in exceptional circumstances and with great caution because patients with significant obstruction may develop barium concretions as an additional source of blockage and some who would have otherwise recovered will require operative intervention. Barium opacification also renders cross-sectional imaging studies or angiography uninterpretable.

FIGURE 323-2  Computed tomography with oral and intravenous contrast demonstrating (A) evidence of small-bowel dilatation with air-fluid levels consistent with a small-bowel obstruction; (B) a partial small-bowel obstruction from an incarcerated ventral hernia (arrow); and (C) decompressed bowel seen distal to the hernia (arrow). (From W Silen: Acute intestinal obstruction, in DL Longo et al [eds]: Harrison’s Principles of Internal Medicine, 18th ed. New York, McGrawHill, 2012.)

TREATMENT

Acute Intestinal Obstruction An improved understanding of the pathophysiology of bowel obstruction and the importance of fluid resuscitation, electrolyte repletion, intestinal decompression, and the selected use of antibiotics have likely contributed to a reduction in mortality from acute bowel obstruction. Every patient should be stabilized as quickly

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as possible. Nasogastric tube suction decompresses the stomach, minimizes further distention from swallowed air, improves patient comfort, and reduces the risk of aspiration. Urine output should be assessed using a Foley catheter. In some cases, for example, in patients with cardiac disease, central venous pressures should be monitored. The use of antibiotics is controversial, although prophylactic administration may be warranted if operation is anticipated. Complete bowel obstruction is an indication for intervention. Stenting may be possible and warranted for some patients with highgrade obstruction due to unresectable stage IV malignancy. Stenting may also allow elective mechanical bowel preparation before surgery is undertaken. Because treatment options are so variable, it is helpful to make as precise a diagnosis as possible preoperatively. ILEUS Patients with ileus are treated supportively with intravenous fluids and nasogastric decompression while any underlying pathology is treated. Pharmacologic therapy is not yet proven to be efficacious or cost-effective. However, peripherally active μ-opioid receptor antagonists (e.g., alvimopan and methylnaltrexone) may accelerate gastrointestinal recovery in some patients who have undergone abdominal surgery.

PART 10 Disorders of the Gastrointestinal System

COLONIC PSEUDO-OBSTRUCTION (OGILVIE’S DISEASE) Neostigmine is an acetylcholinesterase inhibitor that increases cholinergic (parasympathetic) activity, which can stimulate colonic motility. Some studies have shown it to be moderately effective in alleviating acute colonic pseudo-obstruction. It is the most common therapeutic approach and can be used once it is certain that there is no mechanical obstruction. Cardiac monitoring is required, and atropine should be immediately available. Intravenous administration induces defecation and flatus within 10 min in the majority of patients who will respond. Sympathetic blockade by epidural anesthesia can successfully ameliorate pseudo-obstruction in some patients. VOLVULUS Patients with sigmoid volvulus can often be decompressed using a flexible tube inserted through a rigid proctoscope or using a flexible sigmoidoscope. Successful decompression results in sudden release of gas and fluid with evidence of decreased abdominal distension and allows definitive correction to be scheduled electively. Cecal volvulus most often requires laparotomy or laparoscopic correction. INTRAOPERATIVE STRATEGIES Approximately 60–80% of selected patients with mechanical bowel obstruction can be successfully treated conservatively. Indeed, most cases of radiation-induced obstruction should also be managed nonoperatively if possible. In most circumstances, early consultation with a surgeon is prudent when there is concern about strangulation obstruction or other abnormality that needs to be addressed urgently. Deterioration signifies a need for intervention. At this time, the decision as to whether the patient can continue to be treated nonoperatively can only be based on clinical judgment, although, as described earlier, imaging studies can sometimes be helpful. The frequency of major complications after operation ranges from 12 to 47%, with greater risk being attributed to resection therapies and the patient’s overall health. Risk is increased for patients with American Society of Anesthesiologists (ASA) class III or higher. At operation, dilation proximal to the site of blockage with distal collapse is a defining feature of bowel obstruction. Intraoperative strategies depend on the underlying problem and range from lysis of adhesions to resection with or without diverting ostomy to primary resection with anastomosis. Resection is warranted when there is concern about the bowel’s viability after the obstructive process is relieved. Laparoscopic approaches can be useful for patients with early obstruction when extensive adhesions are not expected to be present. Some patients with high-grade obstruction secondary to malignant disease that is not amendable to resection will benefit from bypass procedures.

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ADULT INTUSSUSCEPTION AND GALLSTONE ILEUS Primary resection is prudent. Careful manual reduction of any involved bowel may limit the amount of intestine that needs to be removed. A proximal ostomy may be required if unprepped colon is involved. The most common site of intestinal obstruction in patients with gallstone “ileus” is the ileum (60% of patients). The gallstone enters the intestinal tract most often via a cholecystoduodenal fistula. It can usually be removed by operative enterolithotomy. Addressing the gallbladder disease during urgent or emergent surgery is not recommended. POSTOPERATIVE BOWEL OBSTRUCTION Early postoperative mechanical bowel obstruction is that which occurs within the first 6 weeks of operation. Most are partial and can be expected to resolve spontaneously. It tends to respond and behave differently from classic mechanical bowel obstruction and may be very difficult to distinguish from postoperative ileus. A higher index of suspicion for a definitive site of obstruction is warranted for patients who undergo laparoscopic surgical procedures. Patients who first had ileus and then subsequently develop obstructive symptoms after an initial return of normal bowel function are more likely to have true postoperative small-bowel obstruction. The longer it takes for a patient’s obstructive symptoms to resolve after hospitalization, the more likely the patient is to require surgical intervention. Acknowledgment The wisdom and expertise of Dr. William Silen are gratefully acknowledged.

■■FURTHER READING

Catena F et al: Adhesive small bowel adhesions obstruction: Evolutions in diagnosis, management and prevention. World J Gastrointest Surg 27:222, 2016. Ferrada P et al: Surgery or stenting for colonic obstruction: A practice management guideline from the Eastern Association for the Surgery of Trauma. J Trauma Acute Care Surg 80:659, 2016. Jaffe T, Thompson WM: Large-bowel obstruction in the adults: Classic radiographic and CT findings, etiology and mimics. Radiology 275:651, 2015. Paulson EK, Thompson WM: Review of small-bowel obstruction: The diagnosis and when to worry. Radiology 275:332, 2015. Perry H et al: Relative accuracy of emergency CT in adults with non-traumatic abdominal pain. Brit Inst Rad 89:20150416, 2016. Taylor MR, Lalani N: Adult small bowel obstruction. Acad Emerg Med 20:528, 2013.

Appendicitis and 324 Acute Peritonitis Danny O. Jacobs

ACUTE APPENDICITIS ■■INCIDENCE AND EPIDEMIOLOGY

Appendicitis occurs more frequently in Westernized societies but its incidence is decreasing for uncertain reasons. Nevertheless, acute appendicitis remains the most common emergency general surgical disease affecting the abdomen, with a rate of ~100 per 100,000 person-years in Europe and the Americas or about 11 cases per 10,000 people annually. Approximately 9% of men and 7% of women will experience an episode during their lifetime. Appendicitis occurs most commonly in 10- to 19-year-olds; however, the average age at diagnosis appears to be gradually increasing, as is the frequency of the

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disease in African Americans, Asians, and Native Americans. Overall, 70% of patients are 70% 4–16% 4–16% 10–20% 50–60% >65% 50–75%

FREQUENCY (%) >95% >90% 30–70% 30–40% 30% ~10% 3–5% 5–10% 5% 38.3°C (~101°F) and if there are rigors. Patients with appendicitis will be found to lie quite still to avoid peritoneal irritation caused by movement, and some will report discomfort caused by a bumpy car ride on the way to the hospital or clinic, coughing, sneezing, or other actions that replicate a Valsalva maneuver. The entire abdomen should be examined systematically starting in an area where the patient does not report discomfort if possible. Classically, maximal tenderness is identified in the right lower quadrant at or near McBurney’s point, which is located approximately one-third of the way along a line originating at the anterior iliac spine and running to the umbilicus. Gentle pressure in the left lower quadrant may elicit pain in the right lower quadrant if the appendix is located there. This is Rovsing’s sign (Table 324-4). Evidence of parietal peritoneal irritation is often best elicited by gentle abdominal percussion, jiggling the patient’s gurney or bed, or mildly bumping the feet. Atypical presentation and pain patterns are common, especially in the very old or the very young. Diagnosing appendicitis in children can be especially challenging because they tend to respond so dramatically to stimulation and obtaining an accurate history may be difficult. In addition, it is important to remember that the smaller omentum found in children may be less likely to wall off an appendiceal perforation. Observing the child in a quiet surrounding may be helpful. Signs and symptoms of appendicitis can be subtle in the elderly who may not react as vigorously to appendicitis as younger people. Pain, if noticed, may be minimal and have originated in the right lower quadrant or, otherwise, where the appendix is located. It may never have been noticed to be intermittent, or there may only be significant discomfort with deep palpation. Nausea, anorexia, and emesis may be the predominant complaints. The rare patient may even present with signs and symptoms of distal bowel obstruction secondary to appendiceal inflammation and phlegmon or abscess formation.

■■LABORATORY TESTING

Laboratory testing does not identify patients with appendicitis. The white blood cell count is only mildly to moderately elevated in ~70% of patients TABLE 324-4  Classic Signs of Appendicitis in Patients with Abdominal Pain MANEUVER Rovsing’s sign Obturator sign Iliopsoas sign

FINDINGS Palpating in the left lower quadrant causes pain in the right lower quadrant Internal rotation of the hip causes pain, suggesting the possibility of an inflamed appendix located in the pelvis Extending the right hip causes pain along posterolateral back and hip, suggesting retrocecal appendicitis

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with simple appendicitis (with a leukocytosis of 10,000–18,000 cells/μL). A “left shift” toward immature polymorphonuclear leukocytes is present in >95% of cases. A sickle cell preparation may be prudent to obtain in those of African, Spanish, Mediterranean, or Indian ancestry. Serum amylase and lipase levels should be measured. Urinalysis is indicated to help exclude genitourinary conditions that may mimic acute appendicitis, but a few red or white blood cells may be present as a nonspecific finding. However, an inflamed appendix that abuts the ureter or bladder may cause sterile pyuria or hematuria. Every woman of childbearing age should have a pregnancy test. Cervical cultures are indicated if pelvic inflammatory disease is suspected. Anemia and guaiac-positive stools should raise concern about the presence of other diseases or complications such as cancer.

■■IMAGING

FIGURE 324-3  Computed tomography with oral and intravenous contrast of acute appendicitis. There is thickening of the wall of the appendix and periappendiceal stranding (arrow).

in patients who present with abdominal pain, fever, and neutropenia due to chemotherapy. CT imaging may be very helpful, although it is important not to be overly cautious and delay operative intervention for those patients who are believed to have appendicitis.

TREATMENT

Acute Appendicitis In the absence of contraindications, most patients who have strongly suggestive medical histories and physical examinations with supportive laboratory findings are candidates for appendectomy. In many instances, imaging studies are not required but are often obtained before surgical consultation is requested. Certainly, imaging and further study is appropriate in patients whose evaluations are suggestive but not convincing. CT may accurately indicate the presence of appendicitis or other intraabdominal processes that warrant intervention. Whenever the diagnosis is uncertain, it is prudent to observe the patient and repeat the abdominal examination over 6–8 h. Any evidence of progression

CHAPTER 324 Acute Appendicitis and Peritonitis

Plain films of the abdomen are rarely helpful and so are not routinely obtained unless the clinician is worried about other conditions such as intestinal obstruction, perforated viscus, or ureterolithiasis. Less than 5% of patients will present with an opaque fecalith in the right lower quadrant. The presence of a fecalith is not diagnostic of appendicitis, although its presence in an appropriate location where the patient complains of pain is suggestive and is associated with a greater likelihood of complications. The effectiveness of ultrasonography as a tool to diagnosis appendicitis is highly operator dependent. Even in very skilled hands, the appendix may not be visualized. Its overall sensitivity is 0.86, with a specificity of 0.81. Ultrasonography, especially intravaginal techniques, appears to be most useful for identifying pelvic pathology in women. Ultrasonographic findings suggesting the presence of appendicitis include wall thickening, an increased appendiceal diameter, and the presence of free fluid. Current practice in many institutions is to first perform ultrasonography and progress to other imaging studies only if the findings are equivocal. The sensitivity and specificity of CT are at least 0.94 and 0.95, respectively. Thus, CT imaging, given its high negative predictive value, may be helpful if the diagnosis is in doubt, although studies performed early in the course of disease may not have any typical radiographic findings. In patients where the diagnosis is uncertain, delaying operation at the time of presentation to obtain CT does not appear to increase the risk of perforation. CT scanning is a superior method for assessing the severity of acute appendicitis in the absence of peritoneal findings indicative of perforation, abscess, or suspicion of an associated malignancy. Suggestive findings on CT examination include dilatation >6 mm with wall thickening, a lumen that does not fill with enteric contrast, and fatty tissue stranding or air surrounding the appendix, which suggests inflammation (Figs. 324-3 and 324-4). The presence of luminal air or contrast is not consistent with a diagnosis of appendicitis. Furthermore, nonvisualization of the appendix is a nonspecific finding that should not be used to rule out the presence of appendiceal or periappendiceal inflammation.

■■SPECIAL PATIENT POPULATIONS

Appendicitis in the most common extrauterine general surgical emergency observed during pregnancy. Early symptoms of appendicitis such as nausea and anorexia may be overlooked. Diagnosing appendicitis in pregnant patients may be especially difficult because as the uterus enlarges the appendix may be pushed higher along the right flank even to the right upper quadrant or because the gravid uterus may obscure typical physical findings. Ultrasonography may facilitate early diagnosis. A high index of suspicion is required because of the effects of unrecognized and untreated appendicitis on the fetus. For example, the fetal mortality rate is four times greater (from 5 to 20%) in patients with perforation. Immunocompromised patients may present with only mild tenderness and may have many other disease processes in their differential diagnosis, including atypical infections from mycobacteria, Cytomegalovirus, or other fungi. Enterocolitis is a concern and may be present

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FIGURE 324-4  Appendiceal fecalith (arrow).

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PART 10

is an indication for operation. Narcotics can be given to patients with severe discomfort. All patients should be fully prepared for surgery and have any fluid and electrolyte abnormalities corrected. Either laparoscopic or open appendectomy is a satisfactory choice for patients with uncomplicated appendicitis though most procedures are performed in a minimally invasive fashion. Management of those who present with a mass representing a phlegmon or abscess can be more difficult. Such patients are best served by treatment with broad-spectrum antibiotics, drainage if there is an abscess >3 cm in diameter, and parenteral fluids and bowel rest if they appear to respond to conservative management. The appendix can then be more safely removed 6–12 weeks later when inflammation has diminished. Laparoscopic appendectomy now accounts for the majority of all appendectomies performed in Western cultures and is associated with less postoperative pain, shorter lengths of stay, faster return to normal activity and likely fewer superficial wound complications—although the risk of intraabdominal abscess formation may be higher. A laparoscopic approach may also be useful when the exact diagnosis is uncertain. A laparoscopic approach may also facilitate exposure in those who are very obese. Absent complications, most patients can be discharged within 24–40 h of operation. The most common postoperative complications are fever and leukocytosis. Continuation of these findings beyond 5 days should raise concern for the presence of an intraabdominal abscess. The mortality rate for uncomplicated, nonperforated appendicitis is 0.1–0.5%, which approximates the overall risk of general anesthesia. The mortality rate for perforated appendicitis or other complicated disease is much higher, ranging from 3% overall to a high as 15% in the elderly.

ACUTE PERITONITIS

Disorders of the Gastrointestinal System

Acute peritonitis, or inflammation of the visceral and parietal peritoneum, is most often but not always infectious in origin, resulting from perforation of a hollow viscus. This is called secondary peritonitis, as opposed to primary or spontaneous peritonitis, when a specific intraabdominal source cannot be identified. In either instance, the inflammation can be localized or diffuse.

■■ETIOLOGY

Infective organisms may contaminate the peritoneal cavity after spillage from a hollow viscus, because of a penetrating wound of the abdominal wall, or because of the introduction of a foreign object like a peritoneal dialysis catheter or port that becomes infected. Secondary peritonitis most commonly results from perforation of the appendix, colonic diverticuli, or the stomach and duodenum. It may also occur as a complication of bowel infarction or incarceration, cancer, inflammatory bowel disease, and intestinal obstruction or volvulus. Conditions that may cause secondary bacterial peritonitis and their mechanisms are listed in Table 324-5. Over 90% of the cases of primary or spontaneous bacterial peritonitis occur in patients with ascites or hypoproteinemia (70 y

Females

9–13 y 14–18 y 19–30 y 31–50 y 51–70 y >70 y

Males

1–3 y 4–8 y

Children

Birth to 6 mo 6–12 mo

Infants

VITAMIN A (lg/d)a

TABLE 325-1  Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes for Vitamins

LIFE-STAGE GROUP

CHAPTER 325 Nutrient Requirements and Dietary Assessment

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2305

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Disorders of the Gastrointestinal System

Harrisons_20e_Part10_p2177-p2450.indd 2306

1300 1300 1000 1000 1200 1200

1300 1300 1000 1000 1000 1200

1300 1000 1000

1300 1000 1000

44* 45* 45*

29* 30* 30* 1300 1300 1300

1000 1000 1000

700 890 900 900 900 900

700 890 900 900 900 900

340 440

220*

200*

3* 3* 3*

3* 3* 3*

2* 3* 3* 3* 3* 3*

2* 3* 4* 4* 4* 4*

0.7* 1*

0.5*

0.01*

FLUORIDE (mg/d)

290 290 290

220 220 220

120 150 150 150 150 150

120 150 150 150 150 150

90 90

130*

110*

IODINE (lg/d)

10 9 9

27 27 27

8 15 18 18 8 8

8 11 8 8 8 8

360 310 320

400 350 360

240 360 310 320 320 320

240 410 400 420 420 420

80 130

75*

11 7 10

30*

MAGNESIUM (mg/d)

0.27*

IRON (mg/d)

2.6* 2.6* 2.6*

2.0* 2.0* 2.0*

1.6* 1.6* 1.8* 1.8* 1.8* 1.8*

1.9* 2.2* 2.3* 2.3* 2.3* 2.3*

1.2* 1.5*

0.6*

0.003*

50 50 50

50 50 50

34 43 45 45 45 45

34 43 45 45 45 45

17 22

3*

2*

1250 700 700

1250 700 700

1250 1250 700 700 700 700

1250 1250 700 700 700 700

460 500

275*

100*

MANGANESE MOLYBDENUM PHOSPHORUS (mg/d) (lg/d) (mg/d)

70 70 70

60 60 60

40 55 55 55 55 55

40 55 55 55 55 55

20 30

20*

15*

13 12 12

12 11 11

8 9 8 8 8 8

8 11 11 11 11 11

3 5

3

2*

SELENIUM ZINC (lg/d) (mg/d)

5.1* 5.1* 5.1*

4.7* 4.7* 4.7*

4.5* 4.7* 4.7* 4.7* 4.7* 4.7*

4.5* 4.7* 4.7* 4.7* 4.7* 4.7*

3.0* 3.8*

0.7*

0.4*

1.5* 1.5* 1.5*

1.5* 1.5* 1.5*

1.5* 1.5* 1.5* 1.5* 1.3* 1.2*

1.5* 1.5* 1.5* 1.5* 1.3* 1.2*

1.0* 1.2*

0.37*

0.12*

POTASSIUM SODIUM (g/d) (g/d)

2.3* 2.3* 2.3*

2.3* 2.3* 2.3*

2.3* 2.3* 2.3* 2.3* 2.0* 1.8*

2.3* 2.3* 2.3* 2.3* 2.0* 1.8*

1.5* 1.9*

0.57*

0.18*

CHLORIDE (g/d)

Sources: Food and Nutrition Board, Institute of Medicine, National Academies (http://www.iom.edu/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx), based on: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (1997); Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1998); Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000); and Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc (2001); Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (2005); and Dietary Reference Intakes for Calcium and Vitamin D (2011). These reports can be accessed via www.nap.edu.

Note: This table (taken from the DRI reports; see www.nap.edu) presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type followed by an asterisk (*). An RDA is the average daily dietary intake level sufficient to meet the nutrient requirements of nearly all healthy individuals (97–98%) in a group. The RDA is calculated from an estimated average requirement (EAR). If sufficient scientific evidence is not available to establish an EAR and thus to calculate an RDA, an AI is usually developed. For healthy breast-fed infants, an AI is the mean intake. The AI for other life-stage and sex-specific groups is believed to cover the needs of all healthy individuals in those groups, but lack of data or uncertainty in the data makes it impossible to specify with confidence the percentage of individuals covered by this intake.

14–18 y 19–30 y 31–50 y

Lactating Women

14–18 y 19–30 y 31–50 y

21* 24* 25* 25* 20* 20*

25* 35* 35* 35* 30* 30*

11* 15*

5.5*

260*

700 1000

0.2*

CHROMIUM COPPER (lg/d) (lg/d)

200*

Pregnant Women

9–13 y 14–18 y 19–30 y 31–50 y 51–70 y >70 y

Females

9–13 y 14–18 y 19–30 y 31–50 y 51–70 y >70 y

Males

1–3 y 4–8 y

Children

Birth to 6 mo 6–12 mo

Infants

CALCIUM (mg/d)

TABLE 325-2  Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes for Elements

PART 10

LIFE-STAGE GROUP

2306

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2307

TABLE 325-3  Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes for Total Water and Macronutrients LIFE-STAGE GROUP

CARBOHYDRATE (g/d)

TOTAL FIBER (g/d)

FAT (g/d)

LINOLEIC ACID (g/d)

`-LINOLENIC ACID (g/d)

PROTEINb (g/d)

0.7* 0.8*

60* 95*

NDc ND

31* 30*

4.4* 4.6*

0.5* 0.5*

9.1* 11.0

1.3* 1.7*

130 130

19* 25*

ND ND

7* 10*

0.7* 0.9*

13 19

2.4* 3.3* 3.7* 3.7* 3.7* 3.7*

130 130 130 130 130 130

31* 38* 38* 38* 30* 30*

ND ND ND ND ND ND

12* 16* 17* 17* 14* 14*

1.2* 1.6* 1.6* 1.6* 1.6* 1.6*

34 52 56 56 56 56

2.1* 2.3* 2.7* 2.7* 2.7* 2.7*

130 130 130 130 130 130

26* 26* 25* 25* 21* 21*

ND ND ND ND ND ND

10* 11* 12* 12* 11* 11*

1.0* 1.1* 1.1* 1.1* 1.1* 1.1*

34 46 46 46 46 46

3.0* 3.0* 3.0*

175 175 175

28* 28* 28*

ND ND ND

13* 13* 13*

1.4* 1.4* 1.4*

71 71 71

3.8* 3.8* 3.8*

210 210 210

29* 29* 29*

ND ND ND

13* 13* 13*

1.3* 1.3* 1.3*

71 71 71

TOTAL WATER (L/d)

a

Infants Birth to 6 mo 6–12 mo Children 1–3 y 4–8 y Males 9–13 y 14–18 y 19–30 y 31–50 y 51–70 y >70 y Females 9–13 y 14–18 y 19–30 y 31–50 y 51–70 y >70 y Pregnant Women

Lactating Women 14–18 19–30 y 31–50 y

Note: This table (taken from the DRI reports; see www.nap.edu) presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type followed by an asterisk (*). An RDA is the average daily dietary intake level sufficient to meet the nutrient requirements of nearly all healthy individuals (97–98%) in a group. The RDA is calculated from an estimated average requirement (EAR). If sufficient scientific evidence is not available to establish an EAR and thus to calculate an RDA, an AI is usually developed. For healthy breast-fed infants, an AI is the mean intake. The AI for other life-stage and sex-specific groups is believed to cover the needs of all healthy individuals in those groups, but lack of data or uncertainty in the data make it impossible to specify with confidence the percentage of individuals covered by this intake. a Total water includes all water contained in food, beverages, and drinking water. bBased on grams of protein per kilogram of body weight for the reference body weight (e.g., for adults: 0.8 g/kg body weight for the reference body weight). cNot determined.

Source: Food and Nutrition Board, Institute of Medicine, National Academies (http://www.iom.edu/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx), based on: Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (2002/2005) and Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (2005). These reports can be accessed via www.nap.edu.

and pellagra (niacin and tryptophan deficiency) (Chaps. 326 and 327). Each deficiency disease is characterized by imbalances at the cellular level between the supply of nutrients or energy and the body’s nutritional needs for growth, maintenance, and other functions. Imbalances and excesses in nutrient intakes are recognized as risk factors for certain chronic degenerative diseases, such as saturated fat and cholesterol in coronary artery disease; sodium in hypertension; obesity in hormonedependent cancers (endometrial and breast); and ethanol in alcoholism. Diet is only one of many risk factors because the etiology and pathogenesis of these disorders are multifactorial. Osteoporosis, for example, is associated with calcium deficiency, sometimes secondary to vitamin D deficiency, as well as with environment related risk factors (e.g., smoking, sedentary lifestyle), physiology (e.g., estrogen deficiency), genetic determinants (e.g., defects in collagen metabolism), and drug use (chronic steroid and aromatase inhibitors) (Chap. 404).

■■DIETARY ASSESSMENT Nutrition assessment in clinical situations is an iterative process that involves: (1) screening for malnutrition, (2) assessing the diet and other data to establish either the absence or the presence of malnutrition and its possible causes, (3) planning and implementing the most appropriate nutritional therapy, and (4) reassessing intakes to make sure that

Harrisons_20e_Part10_p2177-p2450.indd 2307

they have been consumed. Some disease states affect the bioavailability, requirements, use, or excretion of specific nutrients. In these circumstances, specific measurements of various nutrients or their biomarkers may be required to ensure adequate replacement (Chap. 326). Most health care facilities have nutrition-screening processes in place for identifying possible malnutrition after hospital admission. Nutritional screening is required by the Joint Commission, which accredits and certifies health care organizations in the United States. However, no universally recognized or validated standards exist. The factors that are usually assessed include abnormal weight for height or body mass index (e.g., BMI 25); reported weight change (involuntary loss or gain of >5 kg in the past 6 months) (Chap. 43); diagnoses with known nutritional implications (e.g., metabolic disease, any disease affecting the gastrointestinal tract, alcoholism); present therapeutic dietary prescription; chronic poor appetite; presence of chewing and swallowing problems or major food intolerances; need for assistance with preparing or shopping for food, eating, or other aspects of self-care; and social isolation. The nutritional status of hospitalized patients should be reassessed periodically—at least once every week. A more complete dietary assessment is indicated for patients who exhibit a high risk of or frank malnutrition on nutritional screening. The type of assessment varies with the clinical setting, the severity of the patient’s illness, and the stability of the patient’s condition.

CHAPTER 325 Nutrient Requirements and Dietary Assessment

14–18 y 19–30 y 31–50 y

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2308

Acute-Care Settings  In acute-care settings, anorexia, various

PART 10 Disorders of the Gastrointestinal System

other diseases, test procedures, and medications can compromise dietary intake. Under such circumstances, the goal is to identify and avoid inadequate intake and to assure appropriate alimentation. Dietary assessment focuses on what patients are currently eating, whether or not they are able and willing to eat, and whether or not they experience any problems with eating. Dietary intake assessment is based on information from observed intakes; medical records; history; clinical examination; and anthropometric, biochemical, and functional status evaluations. The objective is to gather enough information to establish the likelihood of malnutrition due to poor dietary intake or other causes in order to assess whether nutritional therapy is indicated (Chap. 328). Simple observations may suffice to suggest inadequate oral intake. These include dietitians’ and nurses’ notes; observation of a patient’s frequent refusal to eat or the amount of food eaten on trays; the frequent performance of tests and procedures that are likely to cause meals to be skipped; adherence to nutritionally inadequate diet orders (e.g., clear liquids or full liquids) for more than a few days; the occurrence of fever, gastrointestinal distress, vomiting, diarrhea, or a comatose state; and the presence of diseases or use of treatments that involve any part of the alimentary tract. Acutely ill patients with diet-related diseases such as diabetes need assessment because an inappropriate diet may exacerbate these conditions and adversely affect other therapies. Abnormal biochemical values (serum albumin levels 14 drinks per week), while women are at increased risk for liver injury by consuming >7 drinks per week. Gender-dependent

Harrisons_20e_Part10_p2177-p2450.indd 2399

RISK FACTOR Quantity

Gender

Hepatitis C

Genetics

Fatty liver

COMMENT In men, 40–80 g/d of ethanol produces fatty liver; 160 g/d for 10–20 years causes hepatitis or cirrhosis. Only 15% of alcoholics develop alcoholic liver disease. Women exhibit increased susceptibility to alcoholic liver disease at amounts >20 g/d; two drinks per day is probably safe. HCV infection concurrent with alcoholic liver disease is associated with younger age for severity, more advanced histology, and decreased survival. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) has been associated with alcoholic cirrhosis. Alcohol injury does not require malnutrition, but obesity and nonalcoholic fatty liver are risk factors. Patients should receive vigorous attention to nutritional support.

differences result from poorly understood effects of estrogen, proportion of body fat, and the gastric metabolism of alcohol. Obesity, a highfat diet, and the protective effect of coffee have been postulated to play a part in the development of the pathogenic process. Chronic infection with hepatitis C virus (HCV) (Chap. 334) is an important comorbidity in the progression of alcoholic liver disease to cirrhosis in chronic drinkers. Even light to moderate alcohol intake of 15–30 g/d increases the risk of cirrhosis and hepatocellular cancer in HCV-infected individuals. Patients with both alcoholic liver injury and HCV infection develop decompensated liver disease at a younger age and have poorer overall survival. Increased liver iron stores and, rarely, porphyria cutanea tarda can occur as a consequence of the overlapping injurious processes secondary to alcohol and HCV infection. The pathogenesis of alcoholic liver injury is unclear. The present conceptual foundation is that alcohol acts as a direct hepatotoxin and that malnutrition does not have a major role. Ingestion of alcohol initiates an inflammatory cascade by its metabolism, resulting in a variety of metabolic responses. Steatosis from lipogenesis, fatty acid synthesis, and depression of fatty acid oxidation appears secondary to effects on sterol regulatory transcription factor and peroxisome proliferator-activated receptor α (PPAR-α). Intestinal-derived endotoxin initiates a pathogenic process through toll-like receptor 4 and tumor necrosis factor α (TNF-α) that facilitates hepatocyte apoptosis and necrosis. The cell injury and endotoxin release initiated by ethanol and its metabolites also activate innate and adaptive immunity pathways releasing proinflammatory cytokines (e.g., TNF-α), chemokines, and proliferation of T and B cells. The effect of chronic ethanol ingestion on intestinal permeability influences liposaccharide hepatic influx as well as microbiome dysbiosis, further contributing to the pathogenic process. The production of toxic protein-aldehyde adducts, generation of reducing equivalents, and oxidative stress also play a role. Hepatocyte injury and impaired regeneration following chronic alcohol ingestion are ultimately associated with stellate cell activation and collagen production; key events in fibrogenesis. The resulting fibrosis from continuing alcohol use determines the architectural derangement of the liver and associated pathophysiology.

CHAPTER 335 Alcoholic Liver Disease

Chronic and excessive alcohol ingestion is a major cause of liver disease and is responsible for nearly 50% of the mortality from all cirrhosis. The pathology of alcoholic liver disease consists of three major lesions, with the progressive injury rarely existing in a pure form: (1) fatty liver, (2) alcoholic hepatitis, and (3) cirrhosis. Fatty liver is present in >90% of daily as well as binge drinkers. A much smaller percentage of heavy drinkers will progress to alcoholic hepatitis, thought to be a precursor to cirrhosis. The prognosis of severe alcoholic liver disease is dismal; the mortality of patients with alcoholic hepatitis concurrent with cirrhosis is nearly 60% at 4 years. Although alcohol is considered a direct hepatotoxin, only between 10 and 20% of alcoholics will develop alcoholic hepatitis. The explanation for this apparent paradox is unclear but involves the complex interaction of facilitating factors such as drinking patterns, diet, obesity, and gender. There are no diagnostic tools that can predict individual susceptibility to alcoholic liver disease.

2399

TABLE 335-1  Risk Factors for Alcoholic Liver Disease

■■PATHOLOGY

The liver has a limited repertoire in response to injury. Fatty liver is the initial and most common histologic response to hepatotoxic stimuli, including excessive alcohol ingestion. The accumulation of fat within the perivenular hepatocytes coincides with the location of alcohol dehydrogenase, the major enzyme responsible for alcohol metabolism. Continuing alcohol ingestion results in fat accumulation throughout the entire hepatic lobule. Despite extensive fatty change and distortion of the hepatocytes with macrovesicular fat, the cessation of drinking results in normalization of hepatic architecture and fat content. Alcoholic fatty liver has traditionally been regarded as entirely benign, but similar to the spectrum of nonalcoholic fatty liver disease, the appearance of steatohepatitis and certain

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2400 pathologic features such as giant mitochondria, perivenular fibrosis, and

macrovesicular fat may be associated with progressive liver injury. The transition between fatty liver and the development of alcoholic hepatitis is blurred. The hallmark of alcoholic hepatitis is hepatocyte injury characterized by ballooning degeneration, spotty necrosis, polymorphonuclear infiltrate, and fibrosis in the perivenular and perisinusoidal space of Disse. Mallory-Denk bodies are often present in florid cases but are neither specific nor necessary to establish the diagnosis. Alcoholic hepatitis is thought to be a precursor to the development of cirrhosis. However, like fatty liver, it is potentially reversible with cessation of drinking. Cirrhosis is present in up to 50% of patients with biopsy-proven alcoholic hepatitis, and its regression is uncertain, even with abstention.

■■CLINICAL FEATURES

■■LABORATORY FEATURES Disorders of the Gastrointestinal System

Patients with alcoholic liver disease are often identified through routine screening tests. The typical laboratory abnormalities seen in fatty liver are nonspecific and include modest elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase (GGTP), often accompanied by hypertriglyceridemia and hyperbilirubinemia. In alcoholic hepatitis and in contrast to other causes of fatty liver, AST and ALT are usually elevated two- to sevenfold. They are rarely >400 IU, and the AST/ALT ratio is >1 (Table 335-2). Hyperbilirubinemia is accompanied by modest increases in the alkaline phosphatase level. Derangement in hepatocyte synthetic function indicates more serious disease. Hypoalbuminemia and coagulopathy are common in advanced liver injury. Ultrasonography is useful in detecting fatty infiltration of the liver and determining liver size. The demonstration by ultrasound of portal vein flow reversal, ascites, and intraabdominal venous collaterals indicates serious liver injury with less potential for complete reversal.

TREATMENT

Alcoholic Liver Disease Complete abstinence from alcohol is the cornerstone in the treatment of alcoholic liver disease. Improved survival and the potential for reversal of histologic injury regardless of the initial clinical presentation are associated with total avoidance of alcohol ingestion. Referral of patients to experienced alcohol counselors and/or alcohol treatment programs should be routine in the management of patients with alcoholic liver disease. Attention should be directed to the nutritional and psychosocial states during the evaluation and treatment periods. Because of data suggesting that the pathogenic mechanisms in alcoholic hepatitis involve cytokine release and the perpetuation of injury by immunologic processes, glucocorticoids have been extensively evaluated in the treatment of alcoholic hepatitis. Patients with severe alcoholic hepatitis, defined as a discriminant function >32 or MELD >20, should be given prednisone, 40 mg/d, or prednisolone, 32 mg/d, for 4 weeks, followed by a steroid taper (Fig. 335-1). Exclusion criteria include active gastrointestinal bleeding, renal failure, or pancreatitis. Patients with infection can be concurrently treated with antibiotics and steroids. Women with encephalopathy from severe alcoholic hepatitis may be particularly good candidates for glucocorticoids. A Lille score >0.45, at http:// www.lillemodel.com, uses pretreatment variables plus the change in total bilirubin at day 7 of glucocorticoids to identify those patients unresponsive to therapy. The role of TNF-α expression and receptor activity in alcoholic liver injury has led to an examination of pentoxifylline, the nonspecific TNF inhibitor, either by itself, or with glucocorticoids for severe alcoholic hepatitis. In one study, pentoxifylline demonstrated an improved survival in the therapy of severe alcoholic hepatitis, primarily due to a decrease in hepatorenal syndrome. Subsequent clinical trials failed to find an increased benefit from pentoxifylline, either by itself or in combination with prednisolone (Fig. 335-2).

100

■■PROGNOSIS

Critically ill patients with alcoholic hepatitis have short-term (30-day) mortality rates >50%. Severe alcoholic hepatitis is heralded by coagulopathy (prothrombin time increased >5 s), anemia, serum albumin concentrations 137 μmol/L (8 mg/dL), renal failure, and ascites. A discriminant function calculated TABLE 335-2  Laboratory Diagnosis of Alcoholic Fatty Liver and Alcoholic Hepatitis TEST AST ALT AST/ALT GGTP Bilirubin

COMMENT Increased two- to sevenfold, 6 weeks) and a lack of response to symptomatic measures. The extent and nature of the additional investigation should be dictated by the clinical features and suspected pathologic process. Laboratory tests should be used to confirm a specific clinical diagnosis and not be used to screen or evaluate patients with vague rheumatic complaints. Indiscriminate use of broad batteries of diagnostic tests and radiographic procedures is rarely a useful or cost-effective means to establish a diagnosis. Besides a complete blood count, including a white blood cell (WBC) and differential count, the routine evaluation should include a determination of an acute-phase reactant such as the ESR or CRP, which can be useful in discriminating inflammatory from noninflammatory disorders. Both are inexpensive, easily obtained, and may be elevated with infection, inflammation, autoimmune disorders, neoplasia, pregnancy, renal insufficiency, advanced age, or hyperlipidemia. Extreme elevation of the acute-phase reactants (CRP, ESR) is seldom seen without evidence of serious illness (e.g., sepsis, pleuropericarditis, polymyalgia rheumatica, giant cell arteritis, adult Still’s disease). Serum uric acid determinations are useful in the diagnosis of gout and in monitoring the response to urate-lowering therapy. Uric acid, the end product of purine metabolism, is primarily excreted in the urine. Serum values range from 238 to 516 μmol/L (4.0–8.6 mg/dL) in men; the lower values (178–351 μmol/L [3.0–5.9 mg/dL]) seen in women are caused by the uricosuric effects of estrogen. Urinary uric acid levels are normally 535 μmol/L [>9 mg/dL]) is associated with an increased incidence of gout and nephrolithiasis, levels may not correlate with the severity of articular disease. Uric acid levels (and the risk of gout) may be increased by inborn errors of metabolism (Lesch-Nyhan syndrome), disease states (renal insufficiency, myeloproliferative disease, psoriasis), or drugs (alcohol, cytotoxic therapy, thiazides). Although nearly all patients with gout will demonstrate hyperuricemia at some time during their illness, up to 50% of patients with an acute gouty attack will have normal serum uric acid levels. Monitoring serum uric acid is useful in assessing the response to urate-lowering therapy or chemotherapy, with the target goal being a serum urate 2000/μL? No

is desired for what appears to be a chronic process. However, in acute inflammatory arthritis, early radiography is rarely helpful in establishing a diagnosis and may only reveal soft tissue swelling or juxtaarticular demineralization. As the disease progresses, calcification (of soft tissues, cartilage, or bone), joint space narrowing, erosions, bony ankylosis, new bone formation (sclerosis, osteophytes, or periostitis), or subchondral cysts may develop and suggest specific clinical entities. Consultation with a radiologist will help define the optimal imaging modality, technique, or positioning and prevent the need for further studies. Additional imaging techniques may possess greater diagnostic sensitivity and facilitate early diagnosis in a limited number of articular disorders and in selected circumstances and are indicated when conventional radiography is inadequate or nondiagnostic (Table 363-5). Ultrasonography is useful in the detection of soft tissue abnormalities,

METHOD Ultrasound

IMAGING TIME, H 70. Aging increases joint vulnerability through several mechanisms. Whereas dynamic loading of joints stimulates cartilage matrix synthesis by chondrocytes in young cartilage, aged cartilage is less responsive to these stimuli. Partly because of this failure to synthesize matrix with loading, cartilage thins with age, and thinner cartilage experiences higher shear stress and is at greater risk of cartilage damage. Also, joint protectors fail more often with age. Muscles that bridge the joint become weaker with age and also respond less quickly to oncoming impulses. Sensory nerve input slows with age, retarding the feedback loop of mechanoreceptors to muscles and tendons related to their tension and position. Ligaments stretch with age, making them less able to absorb impulses. These factors work in concert to increase the vulnerability of older joints to OA.

Harrisons_20e_Part11_p2451-p2648.indd 2626

Intrinsic joint vulnerabilities (local environment) Previous damage (e.g., meniscectomy) Bridging muscle weakness Increasing bone density Malalignment Proprioceptive deficiences Systemic factors affecting joint vulnerability

Use (loading) factors acting on joints

Increased age Female gender Racial/ethnic factors Genetic susceptibility Nutritional factors

Obesity Injurious physical activities

Susceptibility to OA

Osteoarthritis or its progression

FIGURE 364-4  Risk factors for osteoarthritis (OA) either contribute to the susceptibility of the joint (systemic factors or factors in the local joint environment) or increase risk by the load they put on the joint. Usually a combination of loading and susceptibility factors is required to cause disease or its progression.

Older women are at high risk of OA in all joints, a risk that emerges as women reach their sixth decade. Although hormone loss with menopause may contribute to this risk, there is little understanding of the unique vulnerability of older women versus men to OA.

■■HERITABILITY AND GENETICS

OA is a highly heritable disease, but its heritability is joint specific. Fifty percent of the hand and hip OA in the community is attributable to inheritance, that is, to disease present in other members of the family. However, the heritable proportion of knee OA is at most 30%, with some studies suggesting no heritability at all. Whereas many people with OA have disease in multiple joints, this “generalized OA” phenotype is rarely inherited and is more often a consequence of aging. Emerging evidence has identified genetic mutations that confer a high risk of OA, the best replicated is a polymorphism within the growth differentiation factor 5 (GDF5) gene. This polymorphism diminishes the quantity of GDF5; GDF5 has its main influence on joint shape which is likely to be the mechanism by which genes predisposing to OA increase risk of disease.

■■GLOBAL CONSIDERATIONS

With the aging of the populations, both the prevalence of OA and the amount of disability worldwide related to OA have been increasing especially in developed countries where many are living into old age. Hip OA is rare in China and in immigrants from China to the United States. However, OA in the knees is at least as common, if not more so, in Chinese than in whites from the United States, and knee OA represents a major cause of disability in China, especially in rural areas. Anatomic differences between Chinese and white hips may account for much of the difference in hip OA prevalence, with white hips having a higher prevalence of anatomic predispositions to the development of OA.

■■RISK FACTORS IN THE JOINT ENVIRONMENT

Some risk factors increase vulnerability of the joint through local effects on the joint environment. With changes in joint anatomy, for example, load across the joint is no longer distributed evenly across the joint surface, but rather shows an increase in focal stress. In the hip, three uncommon developmental abnormalities occurring in utero or in childhood, congenital dysplasia, Legg-Perthes disease, and slipped capital femoral epiphysis, leave a child with distortions of hip joint anatomy that often lead to OA later in life. Girls are predominantly affected by

6/1/18 2:41 PM

Varus

Knock knees (valgus)

acetabular dysplasia, a mild form of congenital dislocation, whereas the other abnormalities more often affect boys. Depending on the severity of the anatomic abnormalities, hip OA occurs either in young adulthood (severe abnormalities) or middle age (mild abnormalities). Femoroacetabular impingement can develop during adolescence. It is a clinical syndrome in which anatomic abnormalities of the femoral head and/or the acetabulum result in abnormal contact between the two bones especially during hip flexion and rotation, leading to cartilage and labral damage and hip pain and ultimately in later life to possible hip OA. Major injuries to a joint also can produce anatomic abnormalities that leave the joint susceptible to OA. For example, a fracture through the joint surface often causes OA in joints in which the disease is otherwise rare such as the ankle and the wrist. Avascular necrosis can lead to collapse of dead bone at the articular surface, producing anatomic irregularities and subsequent OA. Tears of ligamentous and fibrocartilaginous structures that protect the joints, such as the meniscus in the knee and the labrum in the hip, can lead to premature OA. Meniscal tears increase with age and when chronic are often asymptomatic but lead to adjacent cartilage damage and accelerated OA. Even injuries in which the affected person never received a diagnosis may increase risk of OA. For example, in the Framingham Study subjects, men with a history of major knee injury, but no surgery, had a 3.5-fold increased risk for subsequent knee OA. Another source of anatomic abnormality is malalignment across the joint (Fig. 364-5). This factor has been best studied in the knee, which is the fulcrum of the longest lever arm in the body. Varus (bowlegged) knees with OA are at exceedingly high risk of cartilage loss in the medial or inner compartment of the knee, whereas valgus (knockkneed) malalignment predisposes to rapid cartilage loss in the lateral compartment. Malalignment causes this effect by increasing stress on a focal area of cartilage, which then breaks down. There is evidence that malalignment in the knee not only causes cartilage loss but leads to underlying bone damage, producing bone marrow lesions seen on magnetic resonance imaging (MRI). Malalignment in the knee often produces such a substantial increase in focal stress within the knee (as evidenced by its destructive effects on subchondral bone) that severely malaligned knees may be destined to progress regardless of the status of other risk factors. Weakness in the quadriceps muscles bridging the knee increases the risk of the development of painful OA in the knee. The role of bone in serving as a shock absorber for impact load is not well understood, but persons with increased bone density are at high risk of OA, suggesting that the resistance of bone to impact during joint use may play a role in disease development.

CHAPTER 364 Osteoarthritis

Normal

FIGURE 364-5  The two types of limb malalignment in the frontal plane: varus, in which the stress is placed across the medial compartment of the knee joint, and valgus, which places excess stress across the lateral compartment of the knee.

overweight persons during walking. Obesity is a well-recognized and 2627 potent risk factor for the development of knee OA and, less so, for hip OA. Obesity precedes the development of disease and is not just a consequence of the inactivity present in those with disease. It is a stronger risk factor for disease in women than in men, and in women, the relationship of weight to the risk of disease is linear, so that with each pound increase in weight, there is a commensurate increase in risk. Weight loss in women lowers the risk of developing symptomatic disease. Not only is obesity a risk factor for OA in weight-bearing joints, but obese persons have more severe symptoms from the disease. Obesity’s effect on the development and progression of disease is mediated mostly through the increased loading in weight-bearing joints that occurs in overweight persons. However, a modest association of obesity with an increased risk of hand OA suggests that systemic products of adipose tissue such as adipokines may affect disease risk also.

Repeated Use of Joint and Exercise  There are two categories

of repetitive joint use, occupational use and leisure time physical activities. Workers performing repetitive tasks as part of their occupations for many years are at high risk of developing OA in the joints they use repeatedly. For example, farmers are at high risk for hip OA, and miners have high rates of OA in knees and spine. Workers whose jobs require regular knee bending or lifting or carrying heavy loads have a high rate of knee OA. One reason why workers may get disease is that during long days at work, their muscles may gradually become exhausted, no longer serving as effective joint protectors. It is widely recommended for people to adopt an exercise-filled lifestyle, and long-term studies of exercise suggest no consistent association of exercise with OA risk in the majority of persons. However, persons who already have injured joints may put themselves at greater risk by engaging in certain types of exercise. For example, persons who have already sustained major knee injuries are at increased risk of progressive knee OA as a consequence of running. In addition, compared to nonrunners, elite runners (professional runners and those on Olympic teams) have high risks of both knee and hip OA. Lastly, although recreational runners are not at increased risk of knee OA, studies suggest that they have a modest increased risk of disease in the hip.

PATHOLOGY

The pathology of OA provides evidence of the involvement of many joint structures in disease. Cartilage initially shows surface fibrillation and irregularity. As disease progresses, focal erosions develop there, and these eventually extend down to the subjacent bone. With further progression, cartilage erosion down to bone expands to involve a larger proportion of the joint surface, even though OA remains a focal disease with nonuniform loss of cartilage (Fig. 364-6).

■■LOADING FACTORS Obesity  Three to six times body weight is transmitted across

the knee during single-leg stance. Any increase in weight may be multiplied by this factor to reveal the excess force across the knee in

Harrisons_20e_Part11_p2451-p2648.indd 2627

FIGURE 364-6  Pathologic changes of osteoarthritis in a toe joint. Note the nonuniform loss of cartilage (arrowhead vs solid arrow), the increased thickness of the subchondral bone envelope (solid arrow), and the osteophyte (open arrow). (© 2018 American College of Rheumatology. Used with permission.)

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After an injury to cartilage, chondrocytes undergo mitosis and clustering. Although the metabolic activity of these chondrocyte clusters is high, the net effect of this activity is to promote proteoglycan depletion in the matrix surrounding the chondrocytes. This is because the catabolic activity is greater than the synthetic activity. As disease develops, collagen matrix becomes damaged, the negative charges of proteoglycans get exposed, and cartilage swells from ionic attraction to water molecules. Because in damaged cartilage proteoglycans are no longer forced into close proximity, cartilage does not bounce back after loading as it did when healthy, and cartilage becomes vulnerable to further injury. Chondrocytes at the basal level of cartilage undergo apoptosis. With loss of cartilage comes alteration in subchondral bone. Stimulated by growth factors and cytokines, osteoclasts and osteoblasts in the subchondral bony plate, just underneath cartilage, become activated. Bone formation produces a thickening and stiffness of the subchondral plate that occurs even before cartilage ulcerates. Trauma to bone during joint loading may be the primary factor driving this bone response, with healing from injury (including microcracks) producing stiffness. Small areas of osteonecrosis usually exist in joints with advanced disease. Bone death may also be caused by bone trauma with shearing of microvasculature, leading to a cutoff of vascular supply to some bone areas. At the margin of the joint, near areas of cartilage loss, osteophytes form. These start as outgrowths of new cartilage, and with neurovascular invasion from the bone, this cartilage ossifies. Osteophytes are an important radiographic hallmark of OA. The synovium produces lubricating fluids that minimize shear stress during motion. In healthy joints, the synovium consists of a single discontinuous layer filled with fat and containing two types of cells, macrophages and fibroblasts, but in OA, it can sometimes become edematous and inflamed. There is a migration of macrophages from the periphery into the tissue, and cells lining the synovium proliferate. Inflammatory cytokines and alarmins secreted by the synovium activate chondrocytes to produce enzymes which accelerate destruction of matrix. Additional pathologic changes occur in the capsule, which stretches, becomes edematous, and can become fibrotic. The pathology of OA is not identical across joints. In hand joints with severe OA, for example, there are often cartilage erosions in the center of the joint probably produced by bony pressure from the opposite side of the joint. Basic calcium phosphate and calcium pyrophosphate dihydrate crystals are present microscopically in most joints with end-stage OA. Their role in osteoarthritic cartilage is unclear, but their release from cartilage into the joint space and joint fluid likely triggers synovial inflammation, which can, in turn, produce release of cytokines and trigger nociceptive stimulation.

SOURCES OF PAIN

Because cartilage is aneural, cartilage loss in a joint is not accompanied by pain. Thus, pain in OA likely arises from structures outside the cartilage. Innervated structures in the joint include the synovium, ligaments, joint capsule, muscles, and subchondral bone. Most of these are not visualized by the x-ray, and the severity of x-ray changes in OA correlates poorly with pain severity. However, in later stages of OA, loss of cartilage integrity that is accompanied by neurovascular invasion may contribute to pain. Based on MRI studies in osteoarthritic knees comparing those with and without pain and on studies mapping tenderness in unanesthetized joints, likely sources of pain include synovial inflammation, joint effusions, and bone marrow edema. Modest synovitis develops in many but not all osteoarthritic joints. The presence of synovitis on MRI is correlated with the presence and severity of knee pain. Capsular stretching from fluid in the joint stimulates nociceptive fibers there, inducing pain. Increased focal loading as part of the disease not only damages cartilage but probably also injures the underlying bone. As a consequence, bone marrow edema appears on the MRI; histologically, this edema signals the presence of microcracks and scar, which are the

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consequences of trauma. These lesions may stimulate bone nociceptive fibers. Pain may arise from outside the joint also, including bursae near the joints. Common sources of pain near the knee are anserine bursitis and iliotibial band syndrome. The pathologic changes of OA may eventually lead to alterations in nervous system signaling. Specifically, peripheral nociceptors can become more responsive to sensory input, known as peripheral sensitization, and there can also be an increase in central ascending nociceptive pathway activity, known as central sensitization. Individuals with OA may also have insufficient descending inhibitory modulation. Some individuals may be genetically predisposed to becoming sensitized; however, regardless of the etiology, these nervous system alterations are associated with more severe pain severity, and may contribute to the presence of allodynia and hyperalgesia in patients with OA.

CLINICAL FEATURES

Joint pain from OA is primarily activity-related in the early stages of the disease. Pain comes on either during or just after joint use and then gradually resolves. Examples include knee or hip pain with going up or down stairs, pain in weight-bearing joints when walking, and, for hand OA, pain when cooking. Early in disease, pain is episodic, triggered often by overactive use of a diseased joint, such as a person with knee OA taking a long run and noticing a few days of pain thereafter. As disease progresses, the pain becomes continuous and even begins to be bothersome at night. Stiffness of the affected joint may be prominent, but morning stiffness is usually brief (45, but the differential diagnosis is long. Inflammatory arthritis is likely if there is prolonged morning stiffness and many other joints are affected. Bursitis occurs commonly around knees and hips. A physical examination should focus on whether tenderness is over the joint line (at the junction of the two bones around which the joint is articulating) or outside of it. Anserine bursitis, medial and distal to the knee, is an extremely common cause of chronic knee pain that may respond to a glucocorticoid injection. Prominent nocturnal pain in the absence of end-stage OA merits a distinct workup. For hip pain, OA can be detected by loss of internal rotation on passive movement, and pain isolated to an area lateral to the hip joint usually reflects the presence of trochanteric bursitis. No blood tests are routinely indicated for workup of patients with OA unless symptoms and signs suggest inflammatory arthritis. Examination of the synovial fluid is often more helpful diagnostically than an x-ray. If the synovial fluid white count is >1000/μL, inflammatory arthritis or gout or pseudogout is likely, the latter two being also identified by the presence of crystals. X-rays are indicated to evaluate the possibility of OA only when joint pain and physical findings are not typical of OA or if pain persists after inauguration of treatment effective for OA. In OA, radiographic findings (Fig. 364-7) correlate poorly with the presence and severity of pain. Further, in both knees and hips, radiographs may be normal in early disease as they are insensitive to cartilage loss and other early findings. Although MRI may reveal the extent of pathology in an osteoarthritic joint, it is not indicated as part of the diagnostic workup. Findings such as meniscal tears and cartilage and bone lesions occur not only in most patients with OA in the knee, but also in most older persons without joint pain. MRI findings almost never warrant a change in therapy.

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FIGURE 364-7  X-ray of knee with medial osteoarthritis. Note the narrowed joint space on medial side of the joint only (white arrow), the sclerosis of the bone in the medial compartment providing evidence of cortical thickening (black arrow), and the osteophytes in the medial femur (white wedge).

TREATMENT

Osteoarthritis The goals of the treatment of OA are to alleviate pain and minimize loss of physical function. To the extent that pain and loss of function are consequences of inflammation, of weakness across the joint, and of laxity and instability, the treatment of OA involves addressing each of these impairments. Comprehensive therapy consists of a multimodality approach including nonpharmacologic and pharmacologic elements. Patients with mild and intermittent symptoms may need only reassurance or nonpharmacologic treatments. Patients with ongoing, disabling pain are likely to need both nonpharmacotherapy and pharmacotherapy. Treatments for knee OA have been more completely evaluated than those for hip and hand OA or for disease in other joints. Thus, although the principles of treatment are identical for OA in all joints, we shall focus below on the treatment of knee OA, noting specific recommendations for disease in other joints, especially when they differ from those for the knee. NONPHARMACOTHERAPY Because OA is a mechanically driven disease, the mainstay of treatment involves altering loading across the painful joint and improving the function of joint protectors, so they can better distribute load across the joint. Ways of lessening focal load across the joint include: 1. avoiding painful activities as these are usually activities that overload the joint; 2. improving the strength and conditioning of muscles that bridge the joint, so as to optimize their function; and 3.  unloading the joint, either by redistributing load within the joint with a brace or a splint or by unloading the joint during weight bearing with a cane or a crutch. The simplest treatment for many patients is to avoid activities that precipitate pain. For example, for the middle-aged patient whose long-distance running brings on symptoms of knee OA, a less demanding form of weight-bearing activity may alleviate all symptoms. For an older person whose daily walks up and down hills bring on knee pain, routing these away from hills might eliminate symptoms. Since the loading effect of each pound of weight is multiplied across the knee three- to sixfold, each pound of weight loss may have a commensurate multiplier effect, unloading both knees and hips and probably relieving pain in those joints. In hand joints affected by OA, splinting, by limiting motion, often minimizes pain for patients with involvement especially in

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Exercise  Osteoarthritic pain in knees or hips during weight bearing results in lack of activity and poor mobility, and because OA is so common, the inactivity that results increases the risk of cardiovascular disease and obesity. Aerobic capacity is poor in most elders with symptomatic knee OA, worse than others of the same age. Weakness in muscles that bridge osteoarthritic joints is multifactorial in etiology. First, there is a decline in strength with age. Second, with limited mobility comes disuse muscle atrophy. Third, patients with painful knee or hip OA alter their gait so as to lessen loading across the affected joint, and this further diminishes muscle use. Fourth, “arthrogenous inhibition” may occur, whereby contraction of muscles bridging the joint is inhibited by a nerve afferent feedback loop emanating in a swollen and stretched joint capsule; this prevents maximal attainment of voluntary maximal strength. Because adequate muscle strength and conditioning are critical to joint protection, weakness in a muscle that bridges a diseased joint makes the joint more susceptible to further damage and pain. The degree of weakness correlates strongly with the severity of joint pain and the degree of physical limitation. One of the cardinal elements of the treatment of OA is to improve the functioning of muscles surrounding the joint. Trials in knee and hip OA have shown that exercise lessens pain and improves physical function. Most effective exercise regimens consist of aerobic and/or resistance training, the latter of which focuses on strengthening muscles across the joint. Exercises are likely to be effective especially if they train muscles for the activities a person performs daily. Activities that increase pain in the joint should be avoided, and the exercise regimen needs to be individualized to optimize effectiveness. Range-of-motion exercises, which do not strengthen muscles, and isometric exercises that strengthen muscles, but not through range of motion, are unlikely to be effective by themselves. Low-impact exercises, including water aerobics and water resistance training, are often better tolerated by patients than exercises involving impact loading, such as running or treadmill exercises. A patient should be referred to an exercise class or to a therapist who can create an individualized regimen. In addition to conventional exercise regimens, tai chi may be effective for knee OA. However, there is no strong evidence that patients with hand OA benefit from therapeutic exercise. Adherence over the long term is the major challenge to an exercise prescription. In trials involving patients with knee OA, who are engaged in exercise treatment, from a third to over half of patients stopped exercising by 6 months. Less than 50% continued regular exercise at 1 year. The strongest predictor of a patient’s continued exercise is a previous personal history of successful exercise. Physicians should reinforce the exercise prescription at each clinic visit, help the patient recognize barriers to ongoing exercise, and identify convenient times for exercise to be done routinely. The combination of exercise with calorie restriction and weight loss is especially effective in lessening pain.

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CHAPTER 364 Osteoarthritis

the base of the thumb. Weight-bearing joints such as knees and hips can be unloaded by using a cane in the hand opposite the affected joint for partial weight bearing. A physical therapist can help teach the patient how to use the cane optimally, including ensuring that its height is optimal for unloading. Crutches or walkers can serve a similar beneficial function.

Correction of Malalignment  Malalignment in the frontal plane (varus-valgus) markedly increases the stress across the joint, which can lead to progression of disease and to pain and disability (Fig. 364-5). Correcting varus-valgus malalignment, either surgically or with bracing, may relieve pain in persons whose knees are malaligned. However, correcting malalignment is often very challenging. Fitted braces that straighten varus knees by putting valgus stress across the knee can be effective. Unfortunately, many patients are unwilling to wear a realigning knee brace; in addition, in patients with obese legs, braces may slip with usage and lose their realigning effect. Braces are indicated for willing patients who can learn to put them on correctly and on whom they do not slip.

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Pain from the patellofemoral compartment of the knee can be caused by tilting of the patella or patellar malalignment with the patella riding laterally in the femoral trochlear groove. Using a patellar brace to realign the patella, or tape to pull the patella back into the trochlear sulcus or reduce its tilt, has been shown, when compared to control in clinical trials, to lessen patellofemoral pain. However, patients may find it difficult to apply tape, and skin irritation from the tape is common and like realigning braces, patellar braces may slip. Although their effect on malalignment is questionable, neoprene sleeves pulled up to cover the knee lessen pain and are easy to use and popular among patients. The explanation for their therapeutic effect on pain is unclear. In patients with knee OA, acupuncture produces modest pain relief compared to placebo needles and may be an adjunctive treatment. PHARMACOTHERAPY Although nonpharmacologic approaches to therapy constitute its mainstay, pharmacotherapy serves an important adjunctive role in OA treatment for symptom management. Available drugs are administered using oral, topical, and intraarticular routes. To date, there are no available drugs that alter the disease process itself. Acetaminophen, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), and Cyclooxygenase-2 (COX-2) Inhibitors  Acetaminophen (paracetamol) is the initial analgesic of choice for patients with OA in knees, hips, or hands, even though its treatment effect in OA is small (Table 364-1). For a minority of patients, it is adequate to control symptoms, in which case more toxic drugs such as NSAIDs can be avoided. NSAIDs are the most popular drugs to treat osteoarthritic pain. They can be administered either topically or orally. In clinical trials, oral NSAIDs produce ~30% greater improvement in pain than high-dose acetaminophen. Occasional patients treated with NSAIDs experience dramatic pain relief, whereas others experience little improvement. Initially, NSAIDs should be administered topically or taken orally on an “as needed” basis because side effects are less frequent with low intermittent doses. If occasional medication use is insufficiently effective, then daily treatment may be indicated, with an anti-inflammatory dose selected (Table 364-1). Patients should be reminded to take low-dose aspirin and ibuprofen or naproxen at different times to eliminate a drug interaction.

NSAIDs taken orally have substantial and frequent side effects, the most common of which is upper gastrointestinal (GI) toxicity, including dyspepsia, nausea, bloating, GI bleeding, and ulcer disease. Thirty to forty percent of patients experience upper GI side effects so severe as to require discontinuation of medication. To minimize the risk of nonsteroidal-related GI side effects, patients should take NSAIDs after food; if risk is high, patients should take a gastroprotective agent, such as a proton pump inhibitor. Certain oral agents are safer to the stomach than others, including nonacetylated salicylates and nabumetone. Major NSAID-related GI side effects can occur in patients who do not complain of upper GI symptoms. In one study of patients hospitalized for GI bleeding, 81% had no premonitory symptoms. Because of the increased rates of cardiovascular events associated with conventional NSAIDs such as diclofenac, many of these drugs are not appropriate long-term treatment choices for older persons with OA, especially those at high risk of heart disease or stroke. The American Heart Association has identified rofecoxib and all other COX-2 inhibitors as putting patients at high risk, although low doses of celecoxib (≤200 mg/d of celecoxib) are not associated with an elevation of risk. The only conventional NSAID that appears safe from a cardiovascular perspective is naproxen, but it does have GI toxicity. There are other common side effects of NSAIDs, including the tendency to develop edema because of prostaglandin inhibition of afferent blood supply to glomeruli in the kidneys and, for similar reasons, a predilection toward reversible renal insufficiency. Blood pressure may increase modestly in some NSAID-treated patients. Oral NSAIDs should not be used in patients with stage IV or V renal disease and should be used with caution in those with stage III disease. NSAIDs can be placed into a gel or topical solution with another chemical modality that enhances penetration of the skin barrier creating a topical NSAID. When absorbed through the skin, plasma concentrations are an order of magnitude lower than with the same amount of drug administered orally or parenterally. However, when these drugs are administered topically in proximity to a superficial joint (knees, hands, but not hips), the drug can be found in joint tissues such as the synovium and cartilage. Trial results have varied but generally have found that topical NSAIDs are slightly less efficacious than oral agents, but have far fewer GI and systemic side effects. Unfortunately, topical NSAIDs often cause local skin

TABLE 364-1  Pharmacologic Treatment for Osteoarthritis TREATMENT Acetaminophen

DOSAGE Up to 1 g tid

Oral NSAIDs and COX-2 inhibitors  Naproxen  Salsalate  Ibuprofen  Celecoxib Topical NSAIDs Diclofenac Na 1% gel Opiates

375–500 mg bid 1500 mg bid 600–800 mg 3–4 times a day 100–200 mg qd   4 g qid (for knees, hands) Various

Capsaicin Intraarticular injections  Steroids   Hyaluronans

COMMENTS Prolongs half-life of warfarin. Make sure patient is not taking other treatments containing acetaminophen to avoid hepatic toxicity. Take with food. Increased risk of myocardial infarction and stroke for some NSAIDs and especially COX-2 inhibitors. High rates of gastrointestinal side effects, including ulcers and bleeding, occur. Patients at high risk for gastrointestinal side effects should also take either a proton pump inhibitor or misoprostol.a There is an increase in gastrointestinal side effects or bleeding when taken with acetylsalicylic acid. Can also cause edema and renal insufficiency.

Rub onto joint. Few systemic side effects. Skin irritation common.   Common side effects include dizziness, sedation, nausea or vomiting, dry mouth, constipation, urinary retention, and pruritus. Respiratory and central nervous system depression can occur. 0.025–0.075% cream 3–4 times Can irritate mucous membranes. a day   Varies from 3 to 5 weekly injections depending on preparation

  Mild to moderate pain at injection site. Controversy exists regarding efficacy.

a Patients at high risk include those with previous gastrointestinal events, persons ≥60 years, and persons taking glucocorticoids. Trials have shown the efficacy of proton pump inhibitors and misoprostol in the prevention of ulcers and bleeding. Misoprostol is associated with a high rate of diarrhea and cramping; therefore, proton pump inhibitors are more widely used to reduce NSAID-related gastrointestinal symptoms.

Abbreviations: COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal anti-inflammatory drugs. Source: Adapted from DT Felson: N Engl J Med 354:841, 2006.

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irritation where the medication is applied, inducing redness, burning, or itching (see Table 364-1).

Other Classes of Drugs and Nutraceuticals  For patients with symptomatic knee or hip OA who have not had an adequate response to the treatments above and are either unwilling to undergo or are not candidates for total joint arthroplasty, opioid analgesics have shown modest efficacy and can be tried. Opioid management plans and patient selection are critical. Another option is the use of duloxetine, which has demonstrated modest efficacy in OA. Recent guidelines recommend against the use of glucosamine or chondroitin for OA. Large publicly supported trials have failed to show that, compared with placebo, these compounds relieve pain in persons with disease. Optimal nonsurgical therapy for OA is often achieved by trial and error, with each patient having idiosyncratic responses to specific treatments. Placebo (or contextual) effects may account for 50% of more of treatment effects in OA and certain modes of treatment delivery including intraarticular injections have greater contextual effects than others such as pills. When medical therapies have failed and the patient has an unacceptable reduction in their quality of life and ongoing pain and disability, then at least for knee and hip OA, total joint arthroplasty is indicated. SURGERY For knee OA, several operations are available. Arthroscopic debridement and lavage have diminished in popularity after randomized trials evaluating this operation have showed that its efficacy is no greater than that of sham surgery for relief of pain or disability. Although arthroscopic meniscectomy is indicated for acute meniscal tears in which symptoms such as locking and acute pain are clearly related temporally to a knee injury that produced the tear, recent trials show that doing a partial meniscectomy in persons with OA and a symptomatic meniscal tear does not relieve knee pain or improve function or even lead to resolution of catching or locking of the knee. For patients with knee OA isolated to the medial compartment, operations to realign the knee to lessen medial loading can relieve pain. These include a high tibial osteotomy, in which the tibia is broken just below the tibial plateau and realigned so as to load the lateral, nondiseased compartment, or a unicompartmental replacement with realignment. Each surgery may provide the patient with years of pain relief before a total knee replacement is required. Ultimately, when the patient with knee or hip OA has failed nonsurgical treatment modalities with limitations of pain or function that compromise the quality of life, the patients with reasonable expectations and readiness for surgery should be referred for total knee or hip arthroplasty. These are highly efficacious operations that relieve pain and improve function in the vast majority of patients, although rates of success are higher for hip than knee replacement. Currently, failure rates for both are ~1% per year, although these rates are higher in obese patients. The chance of surgical success is greater in centers where at least 25 such operations are performed yearly or with surgeons who perform multiple operations annually.

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Cartilage Regeneration  Chondrocyte transplantation has not been found to be efficacious in OA, perhaps because OA includes pathology of joint mechanics, which is not corrected by chondrocyte transplants. Similarly, abrasion arthroplasty (chondroplasty) has not been well studied for efficacy in OA, but it produces fibrocartilage in place of damaged hyaline cartilage. Both of these surgical attempts to regenerate and reconstitute articular cartilage may be more likely to be efficacious early in disease when joint malalignment and many of the other noncartilage abnormalities that characterize OA have not yet developed.

■■FURTHER READING

Felson D: Safety of nonsteroidal antiinflammatory drugs. N Engl J Med 375:2595, 2016. Glyn-Jones S et al: Osteoarthritis. Lancet 386:376, 2015. McAlindon TE et al: Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: A randomized clinical trial. JAMA 317:1967, 2017. McAlindon TE et al: OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 22:363, 2014. Neogi T et al: Sensitivity and sensitisation in relation to pain severity in knee osteoarthritis: Trait or state? Ann Rheum Dis 74:682, 2015. O’Neill TW et al: Synovial tissue volume: A treatment target in knee osteoarthritis (OA). Ann Rheum Dis 75:84, 2016.

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CHAPTER 365 Gout and Other Crystal-Associated Arthropathies

Intraarticular Injections: Glucocorticoids and Hyaluronic Acid  Because synovial inflammation is likely to be a major cause of pain in patients with OA, local anti-inflammatory treatments administered intraarticularly may be effective in ameliorating pain, at least temporarily. Glucocorticoid injections provide such efficacy, but response is variable, with some patients having little relief of pain, whereas others experience pain relief lasting several months. Synovitis, a major cause of joint pain in OA, may abate after an injection, and this correlates with the reduction in knee pain severity. Glucocorticoid injections are useful to get patients over acute flares of pain, but their effects usually last less than 3 months. Repeated injections may cause minor amounts of cartilage loss with probably unimportant clinical consequences. Hyaluronic acid injections can be given for treatment of symptoms in knee and hip OA, but there is controversy as to whether they have efficacy versus placebo (Table 364-1).

The timing of knee or hip replacement is critical. If the patient suffers for many years until their functional status has declined substantially, with considerable muscle weakness, postoperative functional status may not improve to a level achieved by others who underwent operation earlier in their disease course.

and Other 365 Gout Crystal-Associated Arthropathies

H. Ralph Schumacher1, Lan X. Chen

The use of polarizing light microscopy during synovial fluid analysis in 1961 by McCarty and Hollander and the subsequent application of other crystallographic techniques, such as electron microscopy, energy-dispersive elemental analysis, and x-ray diffraction, have allowed investigators to identify the roles of different microcrystals, including monosodium urate (MSU), calcium pyrophosphate (CPP), calcium apatite (apatite), and calcium oxalate (CaOx), in inducing acute or chronic arthritis or periarthritis. The clinical events that result from deposition of MSU, CPP, apatite, and CaOx have many similarities but also have important differences. Because of often similar clinical presentations, the need to perform synovial fluid analysis to distinguish the type of crystal involved must be emphasized. Polarized light microscopy alone can identify most typical crystals; apatite, however, is an exception. Aspiration and analysis of effusions are also important to assess the possibility of infection. Apart from the identification of specific microcrystalline materials or organisms, synovial fluid characteristics in crystal-associated diseases are nonspecific, and synovial fluid can be inflammatory or noninflammatory. Without crystal identification, these diseases can be confused with rheumatoid or other types of arthritis. A list of possible musculoskeletal manifestations of crystal-associated arthritis is shown in Table 365-1.

GOUT

Gout is a metabolic disease that most often affects middle-aged to elderly men and postmenopausal women. It results from an increased body pool of urate with hyperuricemia. It typically is characterized 1

Deceased

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TABLE 365-1  Musculoskeletal Manifestations of Crystal-Induced Arthritis

PART 11

Acute mono- or polyarthritis Bursitis Tendinitis Enthesitis Tophaceous deposits

Destructive arthropathies Chronic inflammatory arthritis Spinal arthritis Peculiar type of osteoarthritis Carpal tunnel syndrome

Immune-Mediated, Inflammatory, and Rheumatologic Disorders

by episodic acute arthritis or chronic arthritis caused by deposition of MSU crystals in joints and connective tissue tophi and the risk for deposition in kidney interstitium or uric acid nephrolithiasis (Chap. 410).

■■ACUTE AND CHRONIC ARTHRITIS

Acute arthritis is the most common early clinical manifestation of gout. Usually, only one joint is affected initially, but polyarticular acute gout can occur in subsequent episodes. The metatarsophalangeal joint of the first toe often is involved, but tarsal joints, ankles, and knees also are affected commonly. Especially in elderly patients or in advanced disease, finger joints may be involved. Inflamed Heberden’s or Bouchard’s nodes may be a first manifestation of gouty arthritis. The first episode of acute gouty arthritis frequently begins at night with dramatic joint pain and swelling. Joints rapidly become warm, red, and tender, with a clinical appearance that often mimics that of cellulitis. Early attacks tend to subside spontaneously within 3–10 days, and most patients have intervals of varying length with no residual symptoms until the next episode. Several events may precipitate acute gouty arthritis: dietary excess, trauma, surgery, excessive ethanol ingestion, hypouricemic therapy, and serious medical illnesses such as myocardial infarction and stroke. After many acute mono- or oligoarticular attacks, a proportion of gouty patients may present with a chronic nonsymmetric synovitis, causing potential confusion with rheumatoid arthritis (Chap. 351). Less commonly, chronic gouty arthritis will be the only manifestation, and, more rarely, the disease will manifest only as periarticular tophaceous deposits in the absence of synovitis. Women represent only 5–20% of all patients with gout. Most women with gouty arthritis are postmenopausal and elderly, have osteoarthritis and arterial hypertension that causes mild renal insufficiency, and usually are receiving diuretics. Premenopausal gout is rare. Kindreds of precocious gout in young women caused by decreased renal urate clearance and renal insufficiency have been described.

Laboratory Diagnosis  Even if the clinical appearance strongly

suggests gout, the presumptive diagnosis ideally should be confirmed by needle aspiration of acutely or chronically involved joints or tophaceous deposits. Acute septic arthritis, several of the other crystalline- associated arthropathies, palindromic rheumatism, and psoriatic arthritis may present with similar clinical features. During acute gouty attacks, needle-shaped MSU crystals typically are seen both intracellularly and extracellularly (Fig. 365-1). With compensated polarized light, these crystals are brightly birefringent with negative elongation. Synovial fluid leukocyte counts are elevated from 2000 to 60,000/μL. Effusions appear cloudy due to the increased numbers of leukocytes. Large amounts of crystals occasionally produce a thick pasty or chalky joint fluid. Bacterial infection can coexist with urate crystals in synovial fluid; if there is any suspicion of septic arthritis, joint fluid must be cultured. MSU crystals also can often be demonstrated in the first metatarsophalangeal joint and in knees not acutely involved with gout. Arthrocentesis of these joints is a useful technique to establish the diagnosis of gout between attacks. Serum uric acid levels can be normal or low at the time of an acute attack, as inflammatory cytokines can be uricosuric and effective initiation of hypouricemic therapy can precipitate attacks. This limits the value of serum uric acid determinations for the diagnosis of gout. Nevertheless, serum urate levels are almost always elevated at some time and are important to use to follow the course of hypouricemic therapy.

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FIGURE 365-1  Extracellular and intracellular monosodium urate crystals, as seen in a fresh preparation of synovial fluid, illustrate needle- and rod-shaped crystals. These crystals are strongly negative birefringent crystals under compensated polarized light microscopy; 400×.

A 24-h urine collection for uric acid can, in some cases, be useful in assessing the risk of stones, elucidating overproduction or underexcretion of uric acid, and deciding whether it may be appropriate to use a uricosuric therapy (Chap. 410). Excretion of >800 mg of uric acid per 24 h on a regular diet suggests that causes of overproduction of purine should be considered. Urinalysis, serum creatinine, hemoglobin, white blood cell (WBC) count, liver function tests, and serum lipids should be obtained because of possible pathologic sequelae of gout and other associated diseases requiring treatment and as baselines because of possible adverse effects of gout treatment.

Radiographic Features  Cystic changes, well-defined erosions

with sclerotic margins (often with overhanging bony edges), and soft tissue masses are characteristic radiographic features of advanced chronic tophaceous gout. Ultrasound may aid earlier diagnosis by showing a double contour sign overlying the articular cartilage. Dual-energy computed tomography (CT) can show specific features establishing the presence of urate crystals.

TREATMENT

Gout ACUTE GOUTY ARTHRITIS The mainstay of treatment during an acute attack is the administration of anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or glucocorticoids. NSAIDs are used most often in individuals without complicating comorbid conditions. Both colchicine and NSAIDs may be poorly tolerated and dangerous in the elderly and in the presence of renal insufficiency and gastrointestinal disorders. Ice pack applications and rest of the involved joints can be helpful. Colchicine given orally is a traditional and effective treatment if used early in an attack. Useful regimens are one 0.6-mg tablet given every 8 h with subsequent tapering or 1.2 mg followed by 0.6 mg in 1 h with subsequent day dosing depending on response. This is generally better tolerated than the formerly advised higher dose regimens. The drug must be at least temporarily discontinued promptly at the first sign of loose stools, and symptomatic treatment must be given for the diarrhea. Intravenous colchicine has been taken off the market. NSAIDs given in full anti-inflammatory doses are effective in ~90% of patients, and the resolution of signs and symptoms usually occurs in 5–8 days. The most effective drugs are any of those with a short half-life and include indomethacin, 25–50 mg tid; naproxen, 500 mg bid; ibuprofen, 800 mg tid; diclofenac, 50 mg tid; and celecoxib 800 mg followed by 400 mg 12 h later, then 400 mg bid. Glucocorticoids given as an intramuscular injection or orally, for example, prednisone, 30–50 mg/d as the initial dose and gradually

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HYPOURICEMIC THERAPY Ultimate control of gout requires correction of the basic underlying defect: the hyperuricemia. Attempts to normalize serum uric acid to 535 μmol/L [>9.0 mg/dL]), the patient’s willingness to commit to lifelong therapy, or the presence of uric acid stones. Urate-lowering therapy should be initiated in any patient who already has tophi or chronic gouty arthritis. Uricosuric agents such as probenecid can be used in patients with good renal function who underexcrete uric acid, with 85 years. In most cases, this process is asymptomatic, and the cause of CPPD is uncertain. Because >80% of patients are >60 years and 70% have preexisting joint damage from other conditions, it is likely that biochemical changes in aging or diseased cartilage favor crystal nucleation. In patients with CPPD arthritis, there is increased production of inorganic pyrophosphate and decreased levels of pyrophosphatases in cartilage extracts. Mutations in the ANKH gene, as described in both familial and sporadic cases, can increase elaboration and extracellular transport of pyrophosphate. The increase in pyrophosphate production appears to be related to enhanced activity of ATP pyrophosphohydrolase and 5′-nucleotidase, which catalyze the reaction of ATP to adenosine and pyrophosphate. This pyrophosphate could combine with calcium to form CPP crystals in matrix vesicles or on collagen fibers. There are decreased levels of cartilage glycosaminoglycans that normally inhibit and regulate crystal nucleation. High activities of transglutaminase enzymes also may contribute to the deposition of CPP crystals. Release of CPP crystals into the joint space is followed by the phagocytosis of those crystals by monocyte-macrophages and neutrophils, which respond by releasing chemotactic and inflammatory substances and, as with MSU crystals, activating the inflammasome. A minority of patients with CPPD arthropathy have metabolic abnormalities or hereditary CPP disease (Table 365-2). These associations suggest that a variety of different metabolic products may enhance CPP crystal deposition either by directly altering cartilage or by inhibiting inorganic pyrophosphatases. Included among these conditions are hyperparathyroidism, hemochromatosis, hypophosphatasia, and hypomagnesemia. The presence of CPPD arthritis in individuals aged 80% of patients with plantar fasciitis. Initial treatment consists of ice, heat, massage, stretching, and eliminating activities that can exacerbate plantar fasciitis. Orthotics provide medial arch support and can be effective. Some patients may benefit from foot strapping or taping or by wearing a night splint designed to keep the ankle in a neutral position. A short course of NSAIDs can be given to patients when the benefits outweigh the risks. Local glucocorticoid injections have also been shown to be efficacious but may carry an increased risk for plantar fascia rupture. Plantar fasciotomy is reserved for those patients who have failed to improve after at least 6–12 months of conservative treatment.

■■FURTHER READING

Buchbinder R: Plantar fasciitis. N Engl J Med 350:2159, 2004. Greis AC et al: Evaluation and nonsurgical management of rotator cuff calcific tendinopathy. Orthop Clin North Am 46:293, 2015. Harrison AK, Flatow EL: Subacromial impingement syndrome. J Am Acad Orthop Surg 19:701, 2011. Kirchgesner T et al: Drug-induced tendinopathy: From physiology to clinical applications. Joint Bone Spine 81:485, 2014. Neviaser AS, Neviaser RJ: Adhesive capsulitis of the shoulder. J Am Acad Orthop Surg 19:536, 2011.

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Endocrinology and Metabolism PART 12 Section 1 Endocrinology

to the Patient 369 Approach with Endocrine Disorders J. Larry Jameson

The management of endocrine disorders requires a broad understanding of intermediary metabolism, reproductive physiology, bone metabolism, and growth. Accordingly, the practice of endocrinology is intimately linked to a conceptual framework for understanding hormone secretion, hormone action, and principles of feedback control (Chap. 370). The endocrine system is evaluated primarily by measuring hormone concentrations, arming the clinician with valuable diagnostic information. Most disorders of the endocrine system are amenable to effective treatment once the correct diagnosis is established. Endocrine deficiency disorders are treated with physiologic hormone replacement; hormone excess conditions, which usually are caused by benign glandular adenomas, are managed by removing tumors surgically or reducing hormone levels medically.

SCOPE OF ENDOCRINOLOGY

The specialty of endocrinology encompasses the study of glands and the hormones they produce. The term endocrine was coined by Starling to contrast the actions of hormones secreted internally (endocrine) with those secreted externally (exocrine) or into a lumen, such as the gastrointestinal tract. The term hormone, derived from a Greek phrase meaning “to set in motion,” aptly describes the dynamic actions of hormones as they elicit cellular responses and regulate physiologic processes through feedback mechanisms. Unlike many other specialties in medicine, it is not possible to define endocrinology strictly along anatomic lines. The classic endocrine glands—pituitary, thyroid, parathyroid, pancreatic islets, adrenals, and gonads—communicate broadly with other organs through the nervous system, hormones, cytokines, and growth factors. In addition to its traditional synaptic functions, the brain produces a vast array of peptide hormones, and this has led to the discipline of neuroendocrinology. Through the production of hypothalamic releasing factors, the central nervous system (CNS) exerts a major regulatory influence over pituitary hormone secretion (Chap. 371). The peripheral nervous system stimulates the adrenal medulla. The immune and endocrine systems are also intimately intertwined. The adrenal hormone cortisol is a powerful immunosuppressant. Cytokines and interleukins (ILs) have profound effects on the functions of the pituitary, adrenal, thyroid, and gonads. Common endocrine diseases such as autoimmune thyroid disease and type 1 diabetes mellitus are caused by dysregulation of immune surveillance and tolerance. Less common diseases such as polyglandular failure, Addison’s disease, and lymphocytic hypophysitis also have an immunologic basis. The interdigitation of endocrinology with physiologic processes in other specialties sometimes blurs the role of hormones. For example, hormones play an important role in maintenance of blood pressure, intravascular volume, and peripheral resistance in the cardiovascular system. Vasoactive substances such as catecholamines, angiotensin II, endothelin, and nitric oxide are involved in dynamic changes of vascular tone in addition to their multiple roles in other tissues. The heart is the principal source of atrial natriuretic peptide, which acts in classic endocrine fashion to induce natriuresis at a distant target organ (the kidney). Erythropoietin, a traditional circulating hormone, is made in the kidney and stimulates erythropoiesis in bone marrow (Chap. 59).

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The kidney is also integrally involved in the renin-angiotensin axis (Chap. 379) and is a primary target of several hormones, including parathyroid hormone (PTH), mineralocorticoids, and vasopressin. The gastrointestinal tract produces a vast array of peptide hormones, such as cholecystokinin, ghrelin, gastrin, secretin, and vasoactive intestinal peptide, among many others. Carcinoid and islet tumors can secrete excessive amounts of these hormones, leading to specific clinical syndromes (Chap. 80). Many of these gastrointestinal hormones are also produced in the CNS, where their functions are poorly understood. Adipose tissue produces leptin, which acts centrally to control appetite, along with adiponectin, resistin, and other hormones that regulate metabolism. As hormones such as inhibin, ghrelin, and leptin are discovered, they become integrated into the science and practice of medicine on the basis of their functional roles rather than their tissues of origin. Characterization of hormone receptors frequently reveals unexpected relationships to factors in nonendocrine disciplines. The growth hormone (GH) and leptin receptors, for example, are members of the cytokine receptor family. The G protein–coupled receptors (GPCRs), which mediate the actions of many peptide hormones, are used in numerous physiologic processes, including vision, smell, and neurotransmission.

PATHOLOGIC MECHANISMS OF ENDOCRINE DISEASE

Endocrine diseases can be divided into three major types of conditions: (1) hormone excess, (2) hormone deficiency, and (3) hormone resistance (Table 369-1).

■■CAUSES OF HORMONE EXCESS

Syndromes of hormone excess can be caused by neoplastic growth of endocrine cells, autoimmune disorders, and excess hormone administration. Benign endocrine tumors, including parathyroid, pituitary, and adrenal adenomas, often retain the capacity to produce hormones, reflecting the fact that these tumors are relatively well differentiated. Many endocrine tumors exhibit subtle defects in their “set points” for feedback regulation. For example, in Cushing’s disease, impaired feedback inhibition of adrenocorticotropic hormone (ACTH) secretion is associated with autonomous function. However, the tumor cells are not completely resistant to feedback, as evidenced by ACTH suppression by higher doses of dexamethasone (e.g., high-dose dexamethasone test) (Chap. 379). Similar set point defects are also typical of parathyroid adenomas and autonomously functioning thyroid nodules. The molecular basis of some endocrine tumors, such as the multiple endocrine neoplasia (MEN) syndromes (MEN1, 2A, 2B), has provided important insights into tumorigenesis (Chap. 381). MEN1 is characterized primarily by the triad of parathyroid, pancreatic islet, and pituitary tumors. MEN2 predisposes to medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. The MEN1 gene, located on chromosome 11q13, encodes a putative tumor-suppressor gene, menin. Analogous to the paradigm first described for retinoblastoma, the affected individual inherits a mutant copy of the MEN1 gene, and tumorigenesis ensues after a somatic “second hit” leads to loss of function of the normal MEN1 gene (through deletion or point mutations). In contrast to inactivation of a tumor-suppressor gene, as occurs in MEN1 and most other inherited cancer syndromes, MEN2 is caused by activating mutations in a single allele. In this case, activating mutations of the RET protooncogene, which encodes a receptor tyrosine kinase, leads to thyroid C cell hyperplasia in childhood before the development of medullary thyroid carcinoma. Elucidation of this pathogenic mechanism has allowed early genetic screening for RET mutations in individuals at risk for MEN2, permitting identification of those who may benefit from prophylactic thyroidectomy and biochemical screening for pheochromocytoma and hyperparathyroidism.

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TABLE 369-1  Causes of Endocrine Dysfunction TYPE OF ENDOCRINE DISORDER

EXAMPLES

Hyperfunction

PART 12

Neoplastic  Benign  Malignant  Ectopic   Multiple endocrine neoplasia (MEN) Autoimmune Iatrogenic Infectious/inflammatory Activating receptor mutations

Pituitary adenomas, hyperparathyroidism, autonomous thyroid or adrenal nodules, pheochromocytoma Adrenal cancer, medullary thyroid cancer, carcinoid Ectopic ACTH, SIADH secretion MEN1, MEN2 Graves’ disease Cushing’s syndrome, hypoglycemia Subacute thyroiditis LH, TSH, Ca2+, PTH receptors, Gsα

Hypofunction 

Endocrinology and Metabolism

Autoimmune Iatrogenic Infectious/inflammatory Hormone mutations Enzyme defects Developmental defects Nutritional/vitamin deficiency Hemorrhage/infarction

Hashimoto’s thyroiditis, type 1 diabetes mellitus, Addison’s disease, polyglandular failure Radiation-induced hypopituitarism, hypothyroidism, surgical Adrenal insufficiency, hypothalamic sarcoidosis GH, LHβ, FSHβ, vasopressin 21-Hydroxylase deficiency Kallmann’s syndrome, Turner’s syndrome, transcription factors Vitamin D deficiency, iodine deficiency Sheehan’s syndrome, adrenal insufficiency

Hormone Resistance

 

Receptor mutations  Membrane  Nuclear Signaling pathway mutations Postreceptor

GH, vasopressin, LH, FSH, ACTH, GnRH, GHRH, PTH, leptin, Ca2+ AR, TR, VDR, ER, GR, PPARγ Albright’s hereditary osteodystrophy Type 2 diabetes mellitus, leptin resistance

Abbreviations: ACTH, adrenocorticotropic hormone; AR, androgen receptor; ER, estrogen receptor; FSH, follicle-stimulating hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; GR, glucocorticoid receptor; LH, luteinizing hormone; PPAR, peroxisome proliferator activated receptor; PTH, parathyroid hormone; SIADH, syndrome of inappropriate antidiuretic hormone; TR, thyroid hormone receptor; TSH, thyroid-stimulating hormone; VDR, vitamin D receptor.

Mutations that activate hormone receptor signaling have been identified in several GPCRs. For example, activating mutations of the luteinizing hormone (LH) receptor cause a dominantly transmitted form of male-limited precocious puberty, reflecting premature stimulation of testosterone synthesis in Leydig cells (Chap. 384). Activating mutations in these GPCRs are located predominantly in the transmembrane domains and induce receptor coupling to Gsα even in the absence of hormone. Consequently, adenylate cyclase is activated, and cyclic adenosine monophosphate (AMP) levels increase in a manner that mimics hormone action. A similar phenomenon results from activating mutations in Gsα. When these mutations occur early in development, they cause McCune-Albright syndrome. When they occur only in somatotropes, the activating Gsα mutations cause GH-secreting tumors and acromegaly (Chap. 373). In autoimmune Graves’ disease, antibody interactions with the thyroid-stimulating hormone (TSH) receptor mimic TSH action, leading to hormone overproduction (Chap. 375). Analogous to the effects of activating mutations of the TSH receptor, these stimulating autoantibodies induce conformational changes that release the receptor from a constrained state, thereby triggering receptor coupling to G proteins.

■■CAUSES OF HORMONE DEFICIENCY

Most examples of hormone deficiency states can be attributed to glandular destruction caused by autoimmunity, surgery, infection, inflammation, infarction, hemorrhage, or tumor infiltration (Table 369-1). Autoimmune damage to the thyroid gland (Hashimoto’s thyroiditis) and pancreatic islet β cells (type 1 diabetes mellitus) is a prevalent cause of endocrine disease. Mutations in a number of hormones, hormone receptors, transcription factors, enzymes, and channels can also lead to hormone deficiencies.

■■HORMONE RESISTANCE

Most severe hormone resistance syndromes are due to inherited defects in membrane receptors, nuclear receptors, or the pathways

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that transduce receptor signals. These disorders are characterized by defective hormone action despite the presence of increased hormone levels. In complete androgen resistance, for example, mutations in the androgen receptor result in a female phenotypic appearance in genetic (XY) males, even though LH and testosterone levels are increased (Chap. 381). In addition to these relatively rare genetic disorders, more common acquired forms of functional hormone resistance include insulin resistance in type 2 diabetes mellitus, leptin resistance in obesity, and GH resistance in catabolic states. The pathogenesis of functional resistance involves receptor downregulation and postreceptor desensitization of signaling pathways; functional forms of resistance are generally reversible.

■■CLINICAL EVALUATION OF ENDOCRINE DISORDERS

Because most glands are relatively inaccessible, the physical examination usually focuses on the manifestations of hormone excess or deficiency as well as direct examination of palpable glands, such as the thyroid and gonads. For these reasons, it is important to evaluate patients in the context of their presenting symptoms, review of systems, family and social history, and exposure to medications that may affect the endocrine system. Astute clinical skills are required to detect subtle symptoms and signs suggestive of underlying endocrine disease. For example, a patient with Cushing’s syndrome may manifest specific findings, such as central fat redistribution, skin striae, and proximal muscle weakness, in addition to features seen commonly in the general population, such as obesity, plethora, hypertension, and glucose intolerance. Similarly, the insidious onset of hypothyroidism—with mental slowing, fatigue, dry skin, and other features—can be difficult to distinguish from similar, nonspecific findings in the general population. Clinical judgment that is based on knowledge of disease prevalence and pathophysiology is required to decide when to embark on more extensive evaluation of these disorders. Laboratory testing plays an essential role in endocrinology by allowing quantitative assessment of hormone levels and dynamics. Radiologic imaging tests such as

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computed tomography (CT) scan, magnetic resonance imaging (MRI), thyroid scan, and ultrasound are also used for the diagnosis of endocrine disorders. However, these tests generally are employed only after a hormonal abnormality has been established by biochemical testing.

■■HORMONE MEASUREMENTS AND ENDOCRINE TESTING

CHAPTER 369 Approach to the Patient with Endocrine Disorders

Immunoassays are the most important diagnostic tool in endocrinology, as they allow sensitive, specific, and quantitative determination of steady-state and dynamic changes in hormone concentrations. Immunoassays use antibodies to detect specific hormones. For many peptide hormones, these measurements are now configured to use two different antibodies to increase binding affinity and specificity. There are many variations of these assays; a common format involves using one antibody to capture the antigen (hormone) onto an immobilized surface and a second antibody, coupled to a chemiluminescent (immunochemiluminescent assay [ICMA]) or radioactive (immunoradiometric assay [IRMA]) signal, to detect the antigen. These assays are sensitive enough to detect plasma hormone concentrations in the picomolar to nanomolar range, and they can readily distinguish structurally related proteins, such as PTH from PTH-related peptide (PTHrP). A variety of other techniques are used to measure specific hormones, including mass spectroscopy, various forms of chromatography, and enzymatic methods; bioassays are now used rarely. Most hormone measurements are based on plasma or serum samples. However, urinary hormone determinations remain useful for the evaluation of some conditions. Urinary collections over 24 h provide an integrated assessment of the production of a hormone or metabolite, many of which vary during the day. It is important to ensure complete collections of 24-h urine samples; simultaneous measurement of creatinine provides an internal control for the adequacy of collection and can be used to normalize some hormone measurements. A 24-h urine-free cortisol measurement largely reflects the amount of unbound cortisol, thus providing a reasonable index of biologically available hormone. Other commonly used urine determinations include 17-hydroxycorticosteroids, 17-ketosteroids, vanillylmandelic acid, metanephrine, catecholamines, 5-hydroxyindoleacetic acid, and calcium. The value of quantitative hormone measurements lies in their correct interpretation in a clinical context. The normal range for most hormones is relatively broad, often varying by a factor of two- to tenfold. The normal ranges for many hormones are sex- and age-specific. Thus, using the correct normative database is an essential part of interpreting hormone tests. The pulsatile nature of hormones and factors that can affect their secretion, such as sleep, meals, and medications, must also

be considered. Cortisol values increase fivefold between midnight 2651 and dawn; reproductive hormone levels vary dramatically during the female menstrual cycle. For many endocrine systems, much information can be gained from basal hormone testing, particularly when different components of an endocrine axis are assessed simultaneously. For example, low testosterone and elevated LH levels suggest a primary gonadal problem, whereas a hypothalamic-pituitary disorder is likely if both LH and testosterone are low. Because TSH is a sensitive indicator of thyroid function, it is generally recommended as a first-line test for thyroid disorders. An elevated TSH level is almost always the result of primary hypothyroidism, whereas a low TSH is most often caused by thyrotoxicosis. These predictions can be confirmed by determining the free thyroxine level. In the less common circumstance when free thyroxine and TSH are both low, it is important to consider secondary hypopituitarism caused by hypothalamic-pituitary disease. Elevated calcium and PTH levels suggest hyperparathyroidism, whereas PTH is suppressed in hypercalcemia caused by malignancy or granulomatous diseases. A suppressed ACTH in the setting of hypercortisolemia, or increased urine-free cortisol, is seen with hyperfunctioning adrenal adenomas. It is not uncommon, however, for baseline hormone levels associated with pathologic endocrine conditions to overlap with the normal range. In this circumstance, dynamic testing is useful to separate the two groups further. There are a multitude of dynamic endocrine tests, but all are based on principles of feedback regulation, and most responses can be rationalized based on principles that govern the regulation of endocrine axes. Suppression tests are used in the setting of suspected endocrine hyperfunction. An example is the dexamethasone suppression test used to evaluate Cushing’s syndrome (Chaps. 373 and 379). Stimulation tests generally are used to assess endocrine hypofunction. The ACTH stimulation test, for example, is used to assess the adrenal gland response in patients with suspected adrenal insufficiency. Other stimulation tests use hypothalamic-releasing factors such as corticotropin-releasing hormone (CRH) and growth hormone– releasing hormone (GHRH) to evaluate pituitary hormone reserve (Chap. 373). Insulin-induced hypoglycemia evokes pituitary ACTH and GH responses. Stimulation tests based on reduction or inhibition of endogenous hormones are now used infrequently. Examples include metyrapone inhibition of cortisol synthesis and clomiphene inhibition of estrogen feedback.

■■SCREENING AND ASSESSMENT OF COMMON ENDOCRINE DISORDERS

Many endocrine disorders are prevalent in the adult population (Table 369-2) and can be diagnosed and managed by general internists,

TABLE 369-2  Examples of Prevalent Endocrine and Metabolic Disorders in the Adult DISORDER Obesity

APPROX. PREVALENCE IN ADULTSa 36% BMI ≥30 70% BMI ≥25

Type 2 diabetes mellitus

>8%

Hyperlipidemia

20–25%

SCREENING/TESTING RECOMMENDATIONSb Calculate BMI Measure waist circumference Exclude secondary causes Consider comorbid complications Beginning at age 45, screen every 3 years, or earlier in high-risk groups: FPG >126 mg/dL Random plasma glucose >200 mg/dL An elevated HbA1C Consider comorbid complications Cholesterol screening at least every 5 years; more often in high-risk groups Lipoprotein analysis (LDL, HDL) for increased cholesterol, CAD, diabetes Consider secondary causes

CHAPTER(S) 395

396

400

(Continued)

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2652

TABLE 369-2  Examples of Prevalent Endocrine and Metabolic Disorders in the Adult (Continued) DISORDER

APPROX. PREVALENCE IN ADULTSa

SCREENING/TESTING RECOMMENDATIONSb

CHAPTER(S)

Metabolic syndrome Hypothyroidism

35% 5–10%, women 0.5–2%, men 1–3%, women 0.1%, men 2–5% palpable >25% by ultrasound 5–10%, women 2–5%, men

Measure waist circumference, FPG, BP, lipids TSH; confirm with free T4 Screen women after age 35 and every 5 years thereafter TSH, free T4

401 377

Physical examination of thyroid Fine-needle aspiration biopsy Bone mineral density measurements in women >65 years or in postmenopausal women or men at risk Exclude secondary causes Serum calcium PTH, if calcium is elevated Assess comorbid conditions Investigate both members of couple Semen analysis in male Assess ovulatory cycles in female Specific tests as indicated Free testosterone, DHEAS Consider comorbid conditions Free testosterone, DHEAS Exclude secondary causes Additional tests as indicated FSH PRL level MRI, if not medication-related Careful history, PRL, testosterone Consider secondary causes (e.g., diabetes) Testosterone, LH Often, no tests are indicated Consider Klinefelter’s syndrome Consider medications, hypogonadism, liver disease Karyotype Testosterone Measure serum 25-OH vitamin D Consider secondary causes Karyotype Consider comorbid conditions

378

Graves’ disease Thyroid nodules and neoplasia

PART 12

Osteoporosis

Endocrinology and Metabolism

Hyperparathyroidism

0.1–0.5%, women > men

Infertility

10%, couples

Polycystic ovarian syndrome

5–10%, women

Hirsutism

5–10%

Menopause Hyperprolactinemia

Median age, 51 15% in women with amenorrhea or galactorrhea

Erectile dysfunction

10–25%

Hypogonadism, male Gynecomastia

1–2% 15%

Klinefelter’s syndrome

0.2%, men

Vitamin D deficiency

10%

Turner’s syndrome

0.03%, women

376

404

403

384, 385

385 387

388 373 390 384 384

383 402 383

a The prevalence of most disorders varies among ethnic groups and with aging. Data based primarily on U.S. population. bSee individual chapters for additional information on evaluation and treatment. Early testing is indicated in patients with signs and symptoms of disease and in those at increased risk.

Abbreviations: BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; DHEAS, dehydroepiandrosterone; FPG, fasting plasma glucose; FSH, folliclestimulating hormone; HbA1C, hemoglobin A1C; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LH, luteinizing hormone; MRI, magnetic resonance imaging; PRL, prolactin; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone.

family practitioners, or other primary health care providers. The high prevalence and clinical impact of certain endocrine diseases justifies vigilance for features of these disorders during routine physical examinations; laboratory screening is indicated in selected high-risk populations.

■■FURTHER READING

Golden SH et al: Prevalence and incidence of endocrine and metabolic disorders in the United States: A comprehensive review. J Clin Endocrinol Metab 94:1853, 2009.

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Golden SH et al: Health disparities in endocrine disorders: Biological, clinical, and nonclinical factors—an Endocrine Society Scientific Statement. J Clin Endocrinol Metab 97:E1579, 2012. Jameson JL, DeGroot LJ (eds): Endocrinology: Adult and Pediatric, 7th ed. Philadelphia, Elsevier, 2016. Loriaux DL: A Biographical History of Endocrinology. Hoboken, Wiley Blackwell, 2016. Melmed S, Polonsky KS, Larsen PR, Kronenberg HM (eds): Williams Textbook of Endocrinology, 13th ed. Philadelphia, Elsevier, 2016.

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of Hormone 370 Mechanisms Action J. Larry Jameson

CLASSES OF HORMONES

Hormones can be divided into five major types: (1) amino acid derivatives such as dopamine, catecholamine, and thyroid hormone; (2) small neuropeptides such as gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), somatostatin, and vasopressin; (3) large proteins such as insulin, luteinizing hormone (LH), and parathyroid hormone (PTH); (4) steroid hormones such as cortisol and estrogen that are synthesized from cholesterol-based precursors; and (5) vitamin derivatives such as retinoids (vitamin A) and vitamin D. A variety of peptide growth factors, most of which act locally, share actions with hormones. As a rule, amino acid derivatives and peptide hormones interact with cell-surface membrane receptors. Steroids, thyroid hormones, vitamin D, and retinoids are lipid-soluble and interact with intracellular nuclear receptors, although many also interact with membrane receptors or intracellular signaling proteins as well.

■■HORMONE AND RECEPTOR FAMILIES

Hormones and receptors can be grouped into families, reflecting structural similarities and evolutionary origins (Table 370-1). The evolution of these families generates diverse but highly selective pathways of hormone action. Recognition of these relationships has proven useful for extrapolating information gleaned from one hormone or receptor to other family members. The glycoprotein hormone family, consisting of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), LH, and human chorionic gonadotropin (hCG), illustrates many features of evolutionarily related hormones. The glycoprotein hormones are heterodimers that share the α subunit in common; the β subunits are distinct and confer specific biologic actions. The overall three-dimensional architecture of the β subunits is similar, reflecting the locations of conserved disulfide bonds that restrain protein conformation. The cloning of the β-subunit genes from multiple species suggests that this family arose from a common ancestral gene, probably by gene duplication and subsequent divergence to evolve new biologic functions. As hormone families enlarge and diverge, their receptors must co-evolve to derive new biologic functions. Related G protein–coupled receptors (GPCRs), for example, have evolved for each of the glycoprotein hormones. These receptors are also structurally similar, and each is coupled predominantly to the Gsα signaling pathway. However, there is minimal overlap of hormone binding. For example, TSH binds with high specificity to the TSH receptor but interacts minimally with the LH or FSH receptors. Nonetheless, there can be subtle physiologic consequences of hormone cross-reactivity with other receptors. Very high levels of hCG during pregnancy stimulate the TSH receptor and

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RECEPTORS

EFFECTORS

SIGNALING PATHWAYS

G Protein–Coupled Seven-Transmembrane Receptor (GPCR) β-Adrenergic, LH, FSH, TSH Glucagon, PTH, PTHrP, ACTH, MSH, GHRH, CRH α-Adrenergic, somatostatin

TRH, GnRH

Gsα, adenylate cyclase Ca2+ channels Giα

Gq, G11

Stimulation of cyclic AMP production, protein kinase A Calmodulin, Ca2+-dependent kinases Inhibition of cyclic AMP production Activation of K+, Ca2+ channels Phospholipase C, diacyl-glycerol, IP3, protein kinase C, voltage-dependent Ca2+ channels

Receptor Tyrosine Kinase Insulin, IGF-I

Tyrosine kinases, IRS

EGF, NGF

Tyrosine kinases, ras

MAP kinases, PI 3-kinase; AKT Raf, MAP kinases, RSK

Cytokine Receptor–Linked Kinase GH, PRL

JAK, tyrosine kinases

STAT, MAP kinase, PI 3-kinase, IRS-1

Serine kinase

Smads

Serine Kinase Activin, TGF-β, MIS

CHAPTER 370 Mechanisms of Hormone Action

Hormones function as a communication system within the body. The endocrine system, composed of various glands and the hormones they produce, interacts with essentially all other physiologic systems to regulate growth, metabolism, homeostasis, and reproduction. Because hormones circulate and act via receptors in target tissues, they serve to integrate physiologic responses to external or internal cues. For example, the light-dark cycle, sensed through the visual system, modulates hypothalamic corticotopin-releasing hormone (CRH), which increases pituitary adrenocorticotropin hormone (ACTH) production, leading to increased adrenal cortisol production before the time of waking in the morning. Increased cortisol, in turn, circulates throughout the body, acting via the nuclear glucocorticoid receptor, to activate numerous genetic programs that influence metabolism, the cardiovascular system, behavior, and the immune system. This chapter provides an overview of the different types of hormones and how they function at the cellular level to control myriad physiologic processes.

2653

TABLE 370-1  Examples of Membrane Receptor Families and Signaling Pathways

Abbreviations: IP3, inositol triphosphate; IRS, insulin receptor substrates; MAP, mitogen-activated protein; MSH, melanocyte-stimulating hormone; NGF, nerve growth factor; PI, phosphatidylinositol; RSK, ribosomal S6 kinase; TGF-β, transforming growth factor β. For all other abbreviations, see text. Note that most receptors interact with multiple effectors and activate networks of signaling pathways.

increase thyroid hormone levels, resulting via feedback inhibition in a compensatory decrease in TSH. Insulin and insulin-like growth factor I (IGF-I) and IGF-II have structural similarities that are most apparent when precursor forms of the proteins are compared. In contrast to the high degree of specificity seen with the glycoprotein hormones, there is moderate cross-talk among the members of the insulin/IGF family. High concentrations of an IGF-II precursor produced by certain tumors (e.g., sarcomas) can cause hypoglycemia, partly because of binding to insulin and IGF-I receptors (Chap. 403). High concentrations of insulin also bind to the IGF-I receptor, perhaps accounting for some of the clinical manifestations seen in conditions with chronic hyperinsulinemia. Another important example of receptor cross-talk is seen with PTH and parathyroid hormone–related peptide (PTHrP) (Chap. 403). PTH is produced by the parathyroid glands, whereas PTHrP is expressed at high levels during development and by a variety of tumors (Chap. 89). These hormones have amino acid sequence similarity, particularly in their amino-terminal regions. Both hormones bind to the PTH1R receptor that is expressed in bone and kidney. Hypercalcemia and hypophosphatemia therefore may result from excessive production of either hormone, making it difficult to distinguish hyperparathyroidism from hypercalcemia of malignancy solely on the basis of serum chemistries. However, sensitive and specific assays for PTH and PTHrP now allow these disorders to be distinguished more readily. Based on their specificities for DNA-binding sites, the nuclear receptor family can be subdivided into type 1 receptors (glucocorticoid receptor, mineralocorticoid receptor, androgen receptor, estrogen receptor, progesterone receptor) that bind steroids and type 2 receptors (thyroid hormone receptor, vitamin D receptor, retinoic acid receptor, peroxisome proliferator activated receptor) that bind thyroid hormone, vitamin D, retinoic acid, or lipid derivatives, respectively. Certain functional domains in nuclear receptors, such as the zinc finger DNA-binding domains, are highly conserved. However, selective amino acid differences within this domain confer DNA sequence specificity. The hormone-binding domains are more variable, providing great diversity in the array of small molecules that bind to different nuclear receptors. With few

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2654 exceptions, hormone binding is highly specific for a single type of

PART 12 Endocrinology and Metabolism

nuclear receptor. One exception involves the glucocorticoid and mineralocorticoid receptors. Because the mineralocorticoid receptor also binds glucocorticoids with high affinity, an enzyme (11β-hydroxysteroid dehydrogenase) in renal tubular cells inactivates glucocorticoids, allowing selective responses to mineralocorticoids such as aldosterone. However, when very high glucocorticoid concentrations occur, as in Cushing’s syndrome, the glucocorticoid degradation pathway becomes saturated, allowing excessive cortisol levels to bind mineralocorticoid receptors leading to sodium retention and potassium wasting. This phenomenon is particularly pronounced in ectopic adrenocorticotropic hormone (ACTH) syndromes (Chap. 379). Another example of relaxed nuclear receptor specificity involves the estrogen receptor, which can bind an array of compounds, some of which have little apparent structural similarity to the high-affinity ligand estradiol. This feature of the estrogen receptor makes it susceptible to activation by “environmental estrogens” such as resveratrol, octylphenol, and many other aromatic hydrocarbons. However, this lack of specificity provides an opportunity to synthesize a remarkable series of clinically useful antagonists (e.g., tamoxifen) and selective estrogen response modulators (SERMs) such as raloxifene. These compounds generate distinct conformations that alter receptor interactions with components of the transcription machinery (see below), thereby conferring their unique actions.

■■HORMONE SYNTHESIS AND PROCESSING

The synthesis of peptide hormones and their receptors occurs through a classic pathway of gene expression: transcription → mRNA → protein → posttranslational protein processing → intracellular sorting, followed by membrane integration or secretion. Many hormones are embedded within larger precursor polypeptides that are proteolytically processed to yield the biologically active hormone. Examples include proopiomelanocortin (POMC) → ACTH; proglucagon → glucagon; proinsulin → insulin; and pro-PTH → PTH, among others. In many cases, such as POMC and proglucagon, these precursors generate multiple biologically active peptides. It is provocative that hormone precursors are typically inactive, presumably adding an additional level of regulatory control. Prohormone conversion occurs not only for peptide hormones but also for certain steroids (testosterone → dihydrotestosterone) and thyroid hormone (T4 → T3). Peptide precursor processing is intimately linked to intracellular sorting pathways that transport proteins to appropriate vesicles and enzymes, resulting in specific cleavage steps, followed by protein folding and translocation to secretory vesicles. Hormones destined for secretion are translocated across the endoplasmic reticulum under the guidance of an amino-terminal signal sequence that subsequently is cleaved. Cell-surface receptors are inserted into the membrane via short segments of hydrophobic amino acids that remain embedded within the lipid bilayer. During translocation through the Golgi and endoplasmic reticulum, hormones and receptors are subject to a variety of posttranslational modifications, such as glycosylation and phosphorylation, which can alter protein conformation, modify circulating halflife, and alter biologic activity. Synthesis of most steroid hormones is based on modifications of the precursor, cholesterol. Multiple regulated enzymatic steps are required for the synthesis of testosterone (Chap. 384), estradiol (Chap. 385), cortisol (Chap. 379), and vitamin D (Chap. 402). This large number of synthetic steps predisposes to multiple genetic and acquired disorders of steroidogenesis. Endocrine genes contain regulatory DNA elements similar to those found in many other genes, but their exquisite control by hormones reflects the presence of specific hormone response elements. For example, the TSH genes are repressed directly by thyroid hormones acting through the thyroid hormone receptor (TR), a member of the nuclear receptor family. Steroidogenic enzyme gene expression requires specific transcription factors, such as steroidogenic factor-1 (SF-1), acting in conjunction with signals transmitted by trophic hormones (e.g., ACTH or LH). Once activated, SF-1 functions as a master regulator, inducing a large array of genes required for steroidogenic and metabolic pathways

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required for steroid synthesis. For some hormones, substantial regulation occurs at the level of translational efficiency. Insulin biosynthesis, although it requires ongoing gene transcription, is regulated primarily at the translational and secretory levels in response to elevated levels of glucose or amino acids.

■■HORMONE SECRETION, TRANSPORT, AND DEGRADATION

The circulating level of a hormone is determined by its rate of secretion and its half-life. After protein processing, peptide hormones (e.g., GnRH, insulin, growth hormone [GH]) are stored in secretory granules. As these granules mature, they are poised beneath the plasma membrane for imminent release into the circulation. In most instances, the stimulus for hormone secretion is a releasing factor or neural signal that induces rapid changes in intracellular calcium concentrations, leading to secretory granule fusion with the plasma membrane and release of its contents into the extracellular environment and bloodstream. Steroid hormones, in contrast, diffuse into the circulation as they are synthesized. Thus, their secretory rates are closely aligned with rates of synthesis. For example, ACTH and LH induce steroidogenesis by stimulating the activity of the steroidogenic acute regulatory (StAR) protein (transports cholesterol into the mitochondrion) along with other rate-limiting steps (e.g., cholesterol side-chain cleavage enzyme, CYP11A1) in the steroidogenic pathway. Hormone transport and degradation dictate the rapidity with which a hormonal signal decays. Some hormone signals are evanescent (e.g., somatostatin), whereas others are longer-lived (e.g., TSH). Because somatostatin exerts effects in virtually every tissue, a short half-life allows its concentrations and actions to be controlled locally. Structural modifications that impair somatostatin degradation have been useful for generating long-acting therapeutic analogues such as octreotide (Chap. 373). In contrast, the actions of TSH are highly specific for the thyroid gland. Its prolonged half-life accounts for relatively constant serum levels even though TSH is secreted in discrete pulses. An understanding of circulating hormone half-life is important for achieving physiologic hormone replacement, as the frequency of dosing and the time required to reach steady state are intimately linked to rates of hormone decay. T4, for example, has a circulating half-life of 7 days. Consequently, >1 month is required to reach a new steady state, and single daily doses are sufficient to achieve constant hormone levels. T3, in contrast, has a half-life of 1 day. Its administration is associated with more dynamic serum levels, and it must be administered two to three times per day. Similarly, synthetic glucocorticoids vary widely in their half-lives; those with longer half-lives (e.g., dexamethasone) are associated with greater suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Most protein hormones (e.g., ACTH, GH, prolactin [PRL], PTH, LH) have relatively short half-lives (3 μg/L Normal response is GH >3 μg/L Normal response is GH >3 μg/L Normal prolactin is >2 μg/L and increase >200% of baseline –30, 0, 30, 60, 90 min for glucose and Glucose 7 μg/dL or to >20 μg/dL 0, 15, 30, 60, 90, 120 min for ACTH Basal ACTH increases 2- to 4-fold and peaks at and cortisol 20–100 pg/mL Cortisol levels >20–25 μg/dL Plasma 11-deoxycortisol and cortisol Plasma cortisol should be 7.5 μg/dL or ACTH >75 pg/mL 0, 30, 60 min for cortisol and Normal response is cortisol >21 g/dL and aldosterone aldosterone response of >4 ng/dL above baseline 0, 30, 60 min for cortisol Cortisol should be >21 g/dL Cortisol >21 g/dL

Basal measurements

TRH test: 200–500 μg IV

0, 20, 60 min for TSH and PRLa

LH, FSH, testosterone, estrogen

Basal measurements

GnRH test: GnRH (100 μg) IV

0, 30, 60 min for LH and FSH

Combined anterior pituitary test: GHRH (1 g/kg), CRH (1 μg/kg), GnRH (100 g), TRH (200 μg) are given IV

–30, 0, 15, 30, 60, 90, 120 min for GH, ACTH, cortisol, LH, FSH, and TSH

Low free thyroid hormone levels in the setting of TSH levels that are not appropriately increased indicate pituitary insufficiency TSH should increase by >5 mU/L unless thyroid hormone levels are increased Basal LH and FSH should be increased in postmenopausal women Low testosterone levels in the setting of low LH and FSH indicate pituitary insufficiency In most adults, LH should increase by 10 IU/L and FSH by 2 IU/L Normal responses are variable Combined or individual releasing hormone responses must be elevated in the context of basal target gland hormone values and may not be uniformly diagnostic (see text)

Evoked PRL response indicates lactotrope integrity.

a

Abbreviations: T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone. For other abbreviations, see text.

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TABLE 372-3  Hormone Replacement Therapy for Adult Hypopituitarisma TROPHIC HORMONE DEFICIT ACTH

TSH FSH/LH

Vasopressin

a All doses shown should be individualized for specific patients and should be reassessed during stress, surgery, or pregnancy. Male and female fertility requirements should be managed as discussed in Chaps. 384 and 385.

Note: For abbreviations, see text.

■■DISORDERS OF GROWTH AND DEVELOPMENT Skeletal Maturation and Somatic Growth  The growth plate

is dependent on a variety of hormonal stimuli, including GH, insulinlike growth factor (IGF)-I, sex steroids, thyroid hormones, paracrine growth factors, and cytokines. The growth-promoting process also requires caloric energy, amino acids, vitamins, and trace metals and consumes about 10% of normal energy production. Malnutrition impairs chondrocyte activity, increases GH resistance, and reduces circulating IGF-I and IGF binding protein (IGBP)-3 levels. Linear bone growth rates are very high in infancy and are pituitary-dependent. Mean growth velocity is ~6 cm/year in later childhood and usually is maintained within a given range on a standardized percentile chart. Peak growth rates occur during midpuberty when bone age is 12 (girls) or 13 (boys). Secondary sexual development is associated with elevated sex steroids that cause progressive epiphyseal growth plate closure. Bone age is delayed in patients with all forms of true GH deficiency or GH receptor defects that result in attenuated GH action. Short stature may occur as a result of constitutive intrinsic growth defects or because of acquired extrinsic factors that impair growth. In general, delayed bone age in a child with short stature is suggestive of a hormonal or systemic disorder, whereas normal bone age in a short child is more likely to be caused by a genetic cartilage dysplasia or growth plate disorder (Chap. 406).

GH Deficiency in Children  • 

GH DEFICIENCY  Isolated GH deficiency is characterized by short stature, micropenis, increased fat, high-pitched voice, and a propensity to hypoglycemia due to relatively unopposed insulin action. Familial modes of inheritance are seen in at least one-third of these individuals and may be autosomal dominant, recessive, or X-linked. About 10% of children with GH deficiency have mutations in the GH-N gene, including gene deletions and a wide range of point mutations. Mutations in transcription factors Pit-1 and Prop-1, which control somatotrope development, result in GH deficiency in combination with other pituitary hormone deficiencies, which may become manifest only in adulthood. The diagnosis of idiopathic GH deficiency (IGHD) should be made only after known molecular defects have been rigorously excluded.

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This is caused by defects of GH receptor structure or signaling. Homozygous or heterozygous mutations of the GH receptor are associated with partial or complete GH insensitivity and growth failure (Laron syndrome). The diagnosis is based on normal or high GH levels, with decreased circulating GH-binding protein (GHBP), and low IGF-I levels. Very rarely, defective IGF-I, IGF-I receptor, or IGF-I signaling defects are also encountered. STAT5B mutations result in both immunodeficiency as well as abrogated GH signaling, leading to short stature with normal or elevated GH levels and low IGF-I levels. Circulating GH receptor antibodies may rarely cause peripheral GH insensitivity.

GH INSENSITIVITY 

NUTRITIONAL SHORT STATURE  Caloric deprivation and malnutrition, uncontrolled diabetes, and chronic renal failure represent secondary causes of abrogated GH receptor function. These conditions also stimulate production of proinflammatory cytokines, which act to exacerbate the block of GH-mediated signal transduction. Children with these conditions typically exhibit features of acquired short stature with normal or elevated GH and low IGF-I levels.

CHAPTER 372 Hypopituitarism

GH

HORMONE REPLACEMENT Hydrocortisone (10–20 mg/d in divided doses) Cortisone acetate (15–25 mg/d in divided doses) Prednisone (5 mg a.m.) l-Thyroxine (0.075–0.15 mg daily) Males   Testosterone gel (5–10 g/d)   Testosterone skin patch (5 mg/d)   Testosterone enanthate (200 mg IM every 2 weeks) Females  Conjugated estrogen (0.65–1.25 mg qd for 25 days)   Progesterone (5–10 mg qd) on days 16–25  Estradiol skin patch (0.025–0.1 mg every week), adding progesterone on days 16–25 if uterus intact  For fertility: menopausal gonadotropins, human chorionic gonadotropins Adults: Somatotropin (0.1–1.25 mg SC qd) Children: Somatotropin (0.02–0.05 mg/kg per day) Intranasal desmopressin (5–20 g twice daily) Oral 300–600 μg qd

Recessive mutations of the GHRH recep- 2667 tor gene in subjects with severe proportionate dwarfism are associated with low basal GH levels that cannot be stimulated by exogenous GHRH, GHRP, or insulin-induced hypoglycemia, as well as anterior pituitary hypoplasia. The syndrome exemplifies the importance of the GHRH receptor for somatotrope cell proliferation and hormonal responsiveness.

GHRH RECEPTOR MUTATIONS 

PSYCHOSOCIAL SHORT STATURE  Emotional and social deprivation lead to growth retardation accompanied by delayed speech, discordant hyperphagia, and an attenuated response to administered GH. A nurturing environment restores growth rates.

■■PRESENTATION AND DIAGNOSIS

Short stature is commonly encountered in clinical practice, and the decision to evaluate these children requires clinical judgment in association with auxologic data and family history. Short stature should be evaluated comprehensively if a patient’s height is >3 standard deviations (SD) below the mean for age or if the growth rate has decelerated. Skeletal maturation is best evaluated by measuring a radiologic bone age, which is based mainly on the degree of wrist bone growth plate fusion. Final height can be predicted using standardized scales (Bayley-Pinneau or Tanner-Whitehouse) or estimated by adding 6.5 cm (boys) or subtracting 6.5 cm (girls) from the midparental height.

■■LABORATORY INVESTIGATION

Because GH secretion is pulsatile, GH deficiency is best assessed by examining the response to provocative stimuli, including exercise, insulin-induced hypoglycemia, and other pharmacologic tests that normally increase GH to >7 μg/L in children. Random GH measurements do not distinguish normal children from those with true GH deficiency. Adequate adrenal and thyroid hormone replacement should be assured before testing. Age- and sex-matched IGF-I levels are not sufficiently sensitive or specific to make the diagnosis but can be useful to confirm GH deficiency. Pituitary MRI may reveal pituitary mass lesions or structural defects. Molecular analyses for known mutations should be undertaken when the cause of short stature remains cryptic, or when additional clinical features suggest a genetic cause.

TREATMENT

Disorders of Growth and Development Replacement therapy with recombinant GH (0.02–0.05 mg/kg per day SC) restores growth velocity in GH-deficient children to ~10 cm/year. If pituitary insufficiency is documented, other associated hormone deficits should be corrected, especially adrenal steroids. GH treatment is also moderately effective for accelerating growth rates in children with Turner syndrome and chronic renal failure. In patients with GH insensitivity and growth retardation due to mutations of the GH receptor, treatment with IGF-I bypasses the dysfunctional GH receptor.

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2668

ADULT GH DEFICIENCY (AGHD)

This disorder usually is caused by acquired hypothalamic or pituitary somatotrope damage. Acquired pituitary hormone deficiency follows a typical pattern in which loss of adequate GH reserve foreshadows subsequent hormone deficits. The sequential order of hormone loss is usually GH → FSH/LH → TSH → ACTH. Patients previously diagnosed with childhood-onset GH deficiency should be retested as adults to affirm the diagnosis.

■■PRESENTATION AND DIAGNOSIS PART 12 Endocrinology and Metabolism

The clinical features of AGHD include changes in body composition, lipid metabolism, and quality of life and cardiovascular dysfunction (Table 372-4). Body composition changes are common and include reduced lean body mass, increased fat mass with selective deposition of intraabdominal visceral fat, and increased waist-to-hip ratio. Hyperlipidemia, left ventricular dysfunction, hypertension, and increased plasma fibrinogen levels also may be present. Bone mineral content is reduced, with resultant increased fracture rates. Patients may experience social isolation, depression, and difficulty maintaining gainful employment. Adult hypopituitarism is associated with a threefold increase in cardiovascular mortality rates in comparison to age- and sex-matched controls, and this may be due to GH deficiency, as patients in these studies were replaced with other deficient pituitary hormones.

■■LABORATORY INVESTIGATION

AGHD is rare, and in light of the nonspecific nature of associated clinical symptoms, patients appropriate for testing should be selected carefully on the basis of well-defined criteria. With few exceptions, testing should be restricted to patients with the following predisposing factors: (1) pituitary surgery, (2) pituitary or hypothalamic tumor or granulomas, (3) history of cranial irradiation, (4) radiologic evidence of a pituitary lesion, and (5) childhood requirement for GH replacement TABLE 372-4  Features of Adult Growth Hormone Deficiency Clinical Impaired quality of life   Decreased energy and drive   Poor concentration   Low self-esteem   Social isolation Body composition changes   Increased body fat mass   Central fat deposition   Increased waist-to-hip ratio   Decreased lean body mass Reduced exercise capacity   Reduced maximum O2 uptake   Impaired cardiac function   Reduced muscle mass Cardiovascular risk factors   Impaired cardiac structure and function   Abnormal lipid profile   Decreased fibrinolytic activity  Atherosclerosis   Omental obesity

therapy. The transition of a GH-deficient adolescent to adulthood requires retesting to document subsequent AGHD. Up to 20% of patients previously treated for childhood-onset GH deficiency are found to be GH-sufficient on repeat testing as adults. A significant proportion (~25%) of truly GH-deficient adults have low-normal IGF-I levels. Thus, as in the evaluation of GH deficiency in children, valid age- and sex-matched IGF-I measurements provide a useful index of therapeutic responses but are not sufficiently sensitive for diagnostic purposes. The most validated test to distinguish pituitary-sufficient patients from those with AGHD is insulin-induced (0.05–0.1 U/kg) hypoglycemia. After glucose reduction to ~40 mg/dL, most individuals experience neuroglycopenic symptoms (Chap. 399), and peak GH release occurs at 60 min and remains elevated for up to 2 h. About 90% of healthy adults exhibit GH responses >5 μg/L; AGHD is defined by a peak GH response to hypoglycemia of 1 year). Many patients note significant improvement in quality of life when evaluated by standardized questionnaires. The effect of GH replacement on mortality rates in GH-deficient patients is currently the subject of long-term prospective investigation.

MANAGEMENT OF ADULT GH DEFICIENCY History of pituitary pathology Clinical features present Evoked GH < 3 µg/L Exclude contraindications Treat with GH 0.1–0.3 mg/d Check IGF-I after 1 mo Titrate GH dose up to 1.25 mg/d

Imaging Pituitary: mass or structural damage Bone: reduced bone mineral density Abdomen: excess omental adiposity Laboratory Evoked GH 1 cm) are encountered, they should also be distinguished from nonadenomatous lesions. Meningiomas often are associated with bony hyperostosis; craniopharyngiomas may be calcified and are usually hypodense, whereas gliomas are hyperdense on T2-weighted images.

Ophthalmologic Evaluation  Because optic tracts may be con-

tiguous to an expanding pituitary mass, reproducible visual field assessment using perimetry techniques should be performed on all patients with sellar mass lesions that impinge the optic chiasm (Chap. 28). Bitemporal hemianopia, often more pronounced superiorly, is observed classically. It occurs because nasal ganglion cell fibers, which cross in the optic chiasm, are especially vulnerable to compression of the ventral optic chiasm. Occasionally, homonymous hemianopia occurs from postchiasmal compression or monocular temporal field loss from prechiasmal compression. Invasion of the cavernous sinus can produce diplopia from ocular motor nerve palsy. Early diagnosis reduces the risk of optic atrophy, vision loss, or eye misalignment.

Laboratory Investigation  The presenting clinical features of

functional pituitary adenomas (e.g., acromegaly, prolactinomas, or Cushing syndrome) should guide the laboratory studies (Table 373-2). However, for a sellar mass with no obvious clinical features of hormone excess, laboratory studies are geared toward determining the nature of the tumor and assessing the possible presence of hypopituitarism. When a pituitary adenoma is suspected based on MRI, initial hormonal evaluation usually includes (1) basal prolactin (PRL); (2) insulin-like growth factor (IGF)-I; (3) 24-h urinary free cortisol (UFC) and/or overnight oral dexamethasone (1 mg) suppression test; (4) α subunit, follicle-stimulating hormone (FSH), and luteinizing hormone (LH); and (5) thyroid function tests. Additional hormonal evaluation may be indicated based on the results of these tests. Pending more detailed assessment of hypopituitarism, a menstrual history, measurement of testosterone and 8 a.m. cortisol levels, and thyroid function tests usually identify patients with pituitary hormone deficiencies that require hormone replacement before further testing or surgery.

Histologic Evaluation  Immunohistochemical staining of pitu-

itary tumor specimens obtained at transsphenoidal surgery confirms clinical and laboratory studies and provides a histologic diagnosis when hormone studies are equivocal and in cases of clinically nonfunctioning tumors.

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TREATMENT

Hypothalamic, Pituitary, and Other Sellar Masses

CHAPTER 373 Pituitary Tumor Syndromes

Cushing’s disease

COMMENTS Interpret IGF-I relative to ageand sex-matched controls Normal subjects should suppress growth hormone to 20% at 45–60 min after CRH 100 µg IV) • High dose DEX test (Cortisol suppression >50% after q6h 2 mg DEX for 2 days)

Unenhanced CT adrenals

CRH test and high dose DEX positive Cushing’s disease

Transsphenoidal pituitary surgery

ACTH suppressed to 2 at baseline, >3 at 2–5 min after CRH 100 µg i.v.)

Bilateral micronodular or macronodular adrenal hyperplasia

Bilateral Locate and adrenalremove Neg. ectomy ectopic ACTH source

Unilateral adrenal mass

Adrenal tumor workup

Unilateral adrenalectomy

FIGURE 379-10  Management of the patient with suspected Cushing’s syndrome. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; CT, computed tomography; DEX, dexamethasone; MRI, magnetic resonance imaging.

A diagnosis of Cushing’s can be considered as established if the results of several tests are consistently suggestive of Cushing’s. These tests may include increased 24-h urinary free cortisol excretion in three separate collections, failure to appropriately suppress morning cortisol after overnight exposure to dexamethasone, and evidence of loss of diurnal cortisol secretion with high levels at midnight, the time of the physiologically lowest secretion (Fig. 379-10). Factors potentially affecting the outcome of these diagnostic tests have to be excluded such as incomplete 24-h urine collection or rapid inactivation of dexamethasone due to concurrent intake of CYP3A4-inducing drugs (e.g., antiepileptics, rifampicin). Concurrent intake of oral contraceptives that raise CBG and thus total cortisol can cause failure to suppress after dexamethasone. If in doubt, testing should be repeated after 4–6 weeks off estrogens. Patients with pseudo-Cushing states, i.e., alcohol-related, and those with cyclic Cushing’s may require further testing to safely confirm or exclude the diagnosis of Cushing’s. In addition, the biochemical assays employed can affect the test results,

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with specificity representing a common problem with antibody-based assays for the measurement of urinary free cortisol. These assays have been greatly improved by the introduction of highly specific tandem mass spectrometry.

Differential Diagnosis  The evaluation of patients with con-

firmed Cushing’s should be carried out by an endocrinologist and begins with the differential diagnosis of ACTH-dependent and ACTH-independent cortisol excess (Fig. 379-10). Generally, plasma ACTH levels are suppressed in cases of autonomous adrenal cortisol excess, as a consequence of enhanced negative feedback to the hypothalamus and pituitary. By contrast, patients with ACTH-dependent Cushing’s have normal or increased plasma ACTH, with very high levels being found in some patients with ectopic ACTH syndrome. Importantly, imaging should only be used after it is established whether the cortisol excess is ACTH-dependent or ACTH-independent, because nodules in the pituitary or the adrenal are a common finding in

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2727

C

B

D

CHAPTER 379 Disorders of the Adrenal Cortex

A

FIGURE 379-11  Adrenal imaging in Cushing’s syndrome. A. Adrenal computed tomography (CT) showing normal bilateral adrenal morphology (arrows). B. CT scan depicting a right adrenocortical adenoma (arrow) causing Cushing’s syndrome. C. Magnetic resonance imaging (MRI) showing bilateral adrenal hyperplasia due to excess adrenocorticotropic hormone stimulation in Cushing’s disease. D. MRI showing bilateral macronodular hyperplasia causing Cushing’s syndrome.

the general population. In patients with confirmed ACTH-independent excess, adrenal imaging is indicated (Fig. 379-11), preferably using an unenhanced computed tomography (CT) scan. This allows assessment of adrenal morphology and determination of precontrast tumor density in Hounsfield units (HUs), which helps to distinguish between benign and malignant adrenal lesions. For ACTH-dependent cortisol excess (Chap. 373), a magnetic resonance image (MRI) of the pituitary is the investigation of choice, but it may not show an abnormality in up to 40% of cases because of small tumors below the sensitivity of detection. Characteristically, pituitary corticotrope adenomas fail to enhance following gadolinium administration on T1-weighted MRI images. In all cases of confirmed ACTH-dependent Cushing’s, further tests are required for the differential diagnosis of pituitary Cushing’s disease and ectopic ACTH syndrome. These tests exploit the fact that most pituitary corticotrope adenomas still display regulatory features, including residual ACTH suppression by high-dose glucocorticoids and CRH responsiveness. In contrast, ectopic sources of ACTH are typically resistant to dexamethasone suppression and unresponsive to CRH (Fig. 379-10). However, it should be noted that a small minority of ectopic ACTH-producing tumors exhibit dynamic responses similar to pituitary corticotrope tumors. If the two tests show discordant results, or if there is any other reason for doubt, the differential diagnosis can be further clarified by performing bilateral inferior petrosal sinus sampling (IPSS) with concurrent blood sampling for ACTH in the right and left inferior petrosal sinus and a peripheral vein. An increased central/peripheral plasma ACTH ratio >2 at baseline and >3 at 2–5 min after CRH injection is indicative of Cushing’s disease (Fig. 379-10), with very high sensitivity and specificity. Of note, the results of the IPSS cannot be reliably used for lateralization (i.e., prediction of the location of the tumor within the pituitary), because there is broad interindividual variability in

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the venous drainage of the pituitary region. Importantly, no cortisollowering agents should be used prior to IPSS. If the differential diagnostic testing indicates ectopic ACTH syndrome, then further imaging should include high-resolution, fine-cut CT scanning of the chest and abdomen for scrutiny of the lung, thymus, and pancreas. If no lesions are identified, an MRI of the chest can be considered because carcinoid tumors usually show high signal intensity on T2-weighted images. Furthermore, octreotide scintigraphy can be helpful in some cases because ectopic ACTH-producing tumors often express somatostatin receptors. Depending on the suspected cause, patients with ectopic ACTH syndrome should also undergo blood sampling for fasting gut hormones, chromogranin A, calcitonin, and biochemical exclusion of pheochromocytoma.

TREATMENT

Cushing’s Syndrome Overt Cushing’s is associated with a poor prognosis if left untreated. In ACTH-independent disease, treatment consists of surgical removal of the adrenal tumor. For smaller tumors, a minimally invasive approach can be used, whereas for larger tumors and those suspected of malignancy, an open approach is preferred. In Cushing’s disease, the treatment of choice is selective removal of the pituitary corticotrope tumor, usually via an endoscopic transsphenoidal approach. This results in an initial cure rate of 70–80% when performed by a highly experienced surgeon. However, even after initial remission following surgery, long-term follow-up is important because late relapse occurs in a significant number of patients. If pituitary disease recurs, there are several options, including second surgery, radiotherapy, stereotactic radiosurgery, and

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PART 12 Endocrinology and Metabolism

bilateral adrenalectomy. These options need to be applied in a highly individualized fashion. In some patients with very severe, overt Cushing’s (e.g., difficult to control hypokalemic hypertension or acute psychosis), it may be necessary to introduce medical therapy to rapidly control the cortisol excess during the period leading up to surgery. Similarly, patients with metastasized, glucocorticoid-producing carcinomas may require long-term antiglucocorticoid drug treatment. In case of ectopic ACTH syndrome, in which the tumor cannot be located, one must carefully weigh whether drug treatment or bilateral adrenalectomy is the most appropriate choice, with the latter facilitating immediate cure but requiring life-long corticosteroid replacement. In this instance, it is paramount to ensure regular imaging follow-up for identification of the ectopic ACTH source. Oral agents with established efficacy in Cushing’s syndrome are metyrapone and ketoconazole. Metyrapone inhibits cortisol synthesis at the level of 11β-hydroxylase (Fig. 379-1), whereas the antimycotic drug ketoconazole inhibits the early steps of steroidogenesis. Typical starting doses are 500 mg tid for metyrapone (maximum dose, 6 g) and 200 mg tid for ketoconazole (maximum dose, 1200 mg). Mitotane, a derivative of the insecticide o,p’DDD, is an adrenolytic agent that is also effective for reducing cortisol. Because of its side effect profile, it is most commonly used in the context of ACC, but low-dose treatment (500–1000 mg/d) has also been used in benign Cushing’s. In severe cases of cortisol excess, etomidate, an agent that potently blocks 11β-hydroxylase and aldosterone synthase, can be used to lower cortisol. It is administered by continuous IV infusion in low, nonanesthetic doses. After the successful removal of an ACTH- or cortisol-producing tumor, the HPA axis will remain suppressed. Thus, hydrocortisone replacement needs to be initiated at the time of surgery and slowly tapered following recovery, to allow physiologic adaptation to normal cortisol levels. Depending on degree and duration of cortisol excess, the HPA axis may require many months or even years to resume normal function and sometimes does not recover. Generally, ectopic ACTH syndrome shows the best recovery rate (80%) and adrenal Cushing’s has the lowest (40%), with Cushing’s disease intermediate (60%).

■■MINERALOCORTICOID EXCESS Epidemiology  Following the first description of a patient with an

aldosterone-producing adrenal adenoma (Conn’s syndrome), mineralocorticoid excess was thought to represent a rare cause of hypertension. However, in studies systematically screening all patients with hypertension, a much higher prevalence is now recognized, ranging from 5 to 12%. The prevalence is higher when patients are preselected for hypokalemic hypertension.

Etiology  The most common cause of mineralocorticoid excess is primary aldosteronism, reflecting excess production of aldosterone by the adrenal zona glomerulosa. Bilateral micronodular hyperplasia is somewhat more common than unilateral adrenal adenomas (Table 379-3). Somatic mutations in channels and enzymes responsible for increasing sodium and calcium influx in adrenal zona glomerulosa cells have been identified as prevalent causes of aldosterone-producing adrenal adenomas (Table 379-3) and, in the case of germline mutations, also of primary aldosteronism due to bilateral macronodular adrenal hyperplasia. However, bilateral adrenal hyperplasia as a cause of mineralocorticoid excess is usually micronodular, but can also contain larger nodules that might be mistaken for a unilateral adenoma. In rare instances, primary aldosteronism is caused by an ACC. Carcinomas should be considered in younger patients and in those with larger tumors, because benign aldosterone-producing adenomas usually measure 3 BP drugs, drug-resistant) or • Hypokalemia (spontaneous or diuretic-induced) or • Adrenal mass or • Family history of early-onset hypertension or cerebrovascular events at 750 pmol/L: ng/mL/h and aldosterone >450 pmol/L) (consider repeat off β-blockers for 2 weeks if results are equivocal) Negative Confirmation of diagnosis E.g., saline infusion test (2 liters physiologic saline over 4 h IV), oral sodium loading, fludrocortisone suppression

Rare: Both renin and Aldo suppressed

Negative 24-h urinary steroid profile (GC/MS)

Unenhanced CT adrenals

Unilateral adrenal mass*

Age 40 years (if surgery practical and desired)

Family history of early onset hypertension? Screen for glucocorticoidremediable aldosteronism

Adrenal vein sampling Pos.

Pos.

Neg. Drug treatment

Unilateral adrenalectomy

Normal adrenal morphology

Neg.

(MR antagonists, amiloride)

Dexamethasone 0.125-0.5 mg/d

Diagnostic for • Apparent mineralocorticoid excess (HSD11B2 def.) • CAH (CYP11B1 or CYP17A1 def.) • Adrenal tumor-related desoxycorticosterone excess If negative, consider • Liddle’s syndrome (ENaC mutations) (responsive to amiloride trial)

FIGURE 379-12  Management of patients with suspected mineralocorticoid excess. *Perform adrenal tumor workup (see Fig. 379-13). BP, blood pressure; CAH, congenital adrenal hyperplasia; CT, computed tomography; GC/MS, gas chromatography/mass spectrometry; PRA, plasma renin activity.

TABLE 379-4  Effects of Antihypertensive Drugs on the AldosteroneRenin Ratio (ARR)

chromatography/mass spectrometry (GC/MS). An increased free cortisol over free cortisone ratio is suggestive of SAME and can be treated with dexamethasone. Steroid profiling by GC/MS also detects the steroids associated with CYP11B1 and CYP17A1 deficiency or the irregular steroid secretion pattern in a DOC-producing ACC (Fig. 379-12). If the GC/MS profile is normal, then Liddle’s syndrome should be considered. It is very sensitive to amiloride treatment but will not respond to MR antagonist treatment, because the defect is due to a constitutively active ENaC.

DRUG

EFFECT ON RENIN

EFFECT ON ALDOSTERONE

NET EFFECT ON ARR

β Blockers

↓

↑

↑

α1 Blockers

→

→

→

α2 Sympathomimetics ACE inhibitors

→

→

→

↑

↓

↓

AT1R blockers

↑

↓

↓

Calcium antagonists

→

→

→

■■APPROACH TO THE PATIENT: INCIDENTALLY DISCOVERED ADRENAL MASS

Diuretics

(↑)

(↑)

→/(↓)

Epidemiology  Incidentally discovered adrenal masses, commonly

Abbreviations: ACE, angiotensin-converting enzyme; AT1R, angiotensin II receptor type 1.

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termed adrenal “incidentalomas,” are common, with a prevalence of 2–5% in the general population as documented in CT and autopsy

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series. The prevalence increases with age, with 1% of 40-year-olds and 7% of 70-year-olds harboring an adrenal mass. The widespread use of cross-sectional imaging has also increased the recognized prevalence.

Differential Diagnosis and Treatment  Patients with an adrenal mass >1 cm require a diagnostic evaluation. Two key questions need to be addressed: (1) Does the tumor autonomously secrete hormones that could have a detrimental effect on health? (2) Is the adrenal mass benign or malignant? Hormone secretion by an adrenal mass occurs along a continuum, with a gradual increase in clinical manifestations in parallel with hormone levels. Exclusion of catecholamine excess from a pheochromocytoma arising from the adrenal medulla is a mandatory part of the diagnostic workup (Fig. 379-13). Furthermore, autonomous cortisol resulting in Cushing’s syndrome requires exclusion and, in patients with hypertension or low serum potassium, also primary aldosteronism. Adrenal incidentalomas can be associated with MACE, and patients usually lack overt clinical features of Cushing’s syndrome. TABLE 379-5  Classification of Unilateral Adrenal Masses MASS

APPROXIMATE PREVALENCE (%)

Benign Adrenocortical adenoma  Endocrine-inactive  Cortisol-producing  Aldosterone-producing Pheochromocytoma Adrenal myelolipoma Adrenal ganglioneuroma Adrenal hemangioma Adrenal cyst Adrenal hematoma/hemorrhagic infarction

60–85 5–10 2–5 5–10 1.4 ng/mL in any one year after starting testosterone therapy, if confirmed, should lead

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to urologic evaluation. PSA velocity criterion can be used for patients who have sequential PSA measurements for >2 years; a change of >0.40 ng/mL per year merits closer urologic follow-up. Cardiovascular Risk  As discussed above, there is insufficient evidence to determine whether testosterone replacement therapy increases the risk of major adverse cardiovascular events in hypogonadal men. A large prospective randomized trial is being planned to determine the effects of testosterone replacement therapy on major adverse cardiovascular events in middle-aged and older men with low testosterone levels and symptoms of androgen deficiency. Androgen Abuse by Athletes and Recreational Bodybuilders  The illicit use of androgenic-anabolic steroids (AAS) to enhance athletic performance first surfaced in the 1950s among powerlifters and spread rapidly to other sports, professional as well as high school athletes, and recreational bodybuilders. In the early 1980s, the use of AAS spread beyond the athletic community into the general population, and now, as many as 3 million Americans—most of them men—have likely used these compounds. Most AAS users are not athletes, but rather recreational weightlifters, who use these drugs to look lean and more muscular. The most commonly used AAS include testosterone esters, nandrolone, stanozolol, methandienone, and methenolol. AAS users generally use increasing doses of multiple steroids in a practice known as stacking. The adverse effects of long-term AAS abuse remain poorly understood. Most of the information about the adverse effects of AAS has emerged from case reports, uncontrolled studies, or from clinical trials that used replacement doses of testosterone. The adverse event data from clinical trials using physiologic replacement doses of testosterone have been extrapolated unjustifiably to AAS users who may administer 10–100 times the replacement doses of testosterone over many years, to support the claim that AAS use is safe. A substantial fraction of androgenic steroid users also use other drugs that are perceived to be muscle-building or performance-enhancing, such as growth hormone; erythropoiesis stimulating agents; insulin; stimulants such as amphetamine, clenbuterol, cocaine, ephedrine, and thyroxine; and drugs perceived to reduce adverse effects such as hCG, aromatase inhibitors, or estrogen antagonists. The adverse events associated with AAS use may be due to AAS themselves, concomitant use of other drugs, high-risk behaviors, and host characteristics that may render these individuals more susceptible to AAS use or to other high risk behaviors. The high rates of premature mortality and morbidities observed in AAS users are alarming. One Finnish study reported 4.6 times the risk of death among elite power lifters than in age-matched men from the general population. The causes of death among power lifters included suicides, myocardial infarction, and hepatic coma. A retrospective review of patient records in Sweden also reported higher standardized mortality ratios for AAS users than for nonusers. Increased death rates among AAS users include suicide, homicide, and accidents. The median age of death among AAS users— 24 years—is even lower than that for heroin or amphetamine users. Four categories of adverse events associated with AAS abuse are of particular concern: cardiovascular events, psychiatric, prolonged suppression of the hypothalamic-pituitary-testicular axis, and potential neurotoxicity. Numerous reports of premature cardiac death among young AAS users raise concerns about the adverse cardiovascular effects of AAS. High doses of AAS may induce proatherogenic dyslipidemia, accelerate atherogenesis, increase thrombosis risk via effects on clotting factors and platelets, and induce vasospasm through their effects on vascular nitric oxide. Recent studies of AAS users using tissue Doppler and strain imaging, and magnetic resonance imaging have reported diastolic and systolic dysfunction, including significantly lower early and late diastolic tissue velocities, reduced E/A ratio, and reduced peak systolic strain in AAS users than in nonusers. Power athletes using AAS often have short QT intervals but increased QT dispersion, which may predispose them to ventricular arrhythmias. Long-term AAS use may be associated with myocardial hypertrophy and fibrosis.

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consequently the testosterone to epitestosterone ratio. Ratios above 4 suggest exogenous testosterone use but can also reflect genetic variation. Genetic variations in the uridine diphospho-glucuronyl transferase 2B17 (UGT2B17), the major enzyme for testosterone glucuronidation, affect testosterone to epitestosterone ratio. Synthetic testosterone has a lower 13C:12C ratio than endogenously produced testosterone and these differences in 13C:12C ratio can be detected by isotope ratio combustion mass spectrometry, which is used to confirm exogenous testosterone use in individuals with a high testosterone to epitestosterone ratio.

■■FURTHER READING

Abreu AP et al: Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med 368:26, 2013. Balasubramanian R et al: Human GnRH deficiency: A unique disease model to unravel the ontogeny of GnRH neurons. Neuroendocrinology 92:81, 2010. Basaria S et al: Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: A randomized clinical trial. JAMA 314:570, 2015. Bhasin S et al: Testosterone therapy in men with androgen deficiency syndromes: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 95:2536, 2010. Bhasin S et al: Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial. JAMA 307:931, 2012. Budoff MJ et al: Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA 317:708, 2017. Finkelstein JS et al: Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 369:1011, 2013. Forni PE, Wray S: GnRH, anosmia and hypogonadotropic hypogonadism—Where are we? Front Neuroendocrinol 36:165, 2015. Pope HG Jr et al: Adverse health consequences of performanceenhancing drugs: An Endocrine Society scientific statement. Endocr Rev 35:341, 2014. Snyder PJ et al: Effects of testosterone treatment in older men. N Engl J Med 74:611, 2016. Spitzer M et al: Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol 9:414, 2013. Travison TG et al: Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the USA and Europe. J Clin Endocrinol Metab 2017 in press. Zakharov MN et al: A multi-step, dynamic allosteric model of testosterone’s binding to sex hormone binding globulin. Mol Cell Endocrinol 399:190, 2015.

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CHAPTER 385 Disorders of the Female Reproductive System

Myocardial tissue of power lifters using AAS has been shown to be infiltrated with fibrous tissue and fat droplets. The finding of AR on myocardial cells suggests that AAS might be directly toxic to myocardial cells. Studies of long-term AAS users using computerized tomography angiography have revealed accelerated atherogenesis. Unlike replacement doses of testosterone, which are associated with only a small decrease in HDL cholesterol and little or no effect on total cholesterol, LDL cholesterol and triglyceride levels, supraphysiologic doses of testosterone and orally administered, 17-αalylated, nonaromatizable AAS are associated with marked reductions in HDL cholesterol and increases in LDL cholesterol. Some AAS users develop hypomanic and manic symptoms (irritability, aggressiveness, reckless behavior, and occasional psychotic symptoms, sometimes associated with violence) during AAS exposure, and major depression (sometimes associated with suicidality) during AAS withdrawal. Users may also be susceptible to other forms of illicit drug use, which may be potentiated or exacerbated by AAS. Long-term AAS use suppresses LH and FSH secretion and inhibits endogenous testosterone production and spermatogenesis. Men, who have used AAS for more than a few months, experience marked suppression of the hypothalamic-pituitary-testicular (HPT) axis after stopping AAS that may be associated with sexual dysfunction, fatigue, infertility, depressed mood, and even suicidality. In some long-term AAS users, HPT suppression may last more than a year, and in a few individuals, recovery of the HPT axis may be incomplete or may never occur. The symptoms of androgen deficiency caused by androgen withdrawal may cause some men to revert back to using AAS, leading to continued use and AAS dependence. As many as 30% of AAS users develop a syndrome of AAS dependence, characterized by long-term AAS use despite adverse medical and psychiatric effects. AAS withdrawal hypogonadism has emerged as an important cause of androgen deficiency accounting for a substantial fraction of testosterone prescriptions in many men’s health clinics. Supraphysiologic doses of testosterone may also impair insulin sensitivity. Orally administered androgens also have been associated with insulin resistance and diabetes. Unsafe injection practices, high-risk behaviors, and increased rates of incarceration render AAS users at increased risk of HIV, and hepatitis B and C. In one survey, nearly 1 in 10 gay men had injected AAS or other substances, and AAS users were more likely to report high-risk unprotected anal sex than other men. Elevated liver enzymes, cholestatic jaundice, hepatic neoplasms, and peliosis hepatis have been reported with oral, 17-α-alkylated AAS. AAS use may cause muscle hypertrophy without compensatory adaptations in tendons, ligaments, and joints, thus increasing the risk of tendon and joint injuries. Upper extremity tendon ruptures are observed almost exclusively among weightlifters who use AAS. AAS use is associated with acne, baldness, as well as increased body hair. The suspicion of AAS use should be raised by the increased hemoglobin and hematocrit, suppressed LH and FSH and testosterone levels, low high-density lipoproteins cholesterol, and low testicular volume and sperm density in a person who looks highly muscular. In most AAS users seeking medical attention, direct nonjudgmental questioning is sufficient to uncover AAS use and formal testing for AAS usually is not needed. However, if needed, accredited laboratories use gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry to detect anabolic steroid abuse. In recent years, the availability of high-resolution mass spectrometry and tandem mass spectrometry has further improved the sensitivity of detecting androgen abuse. Illicit testosterone use is detected generally by the application of the measurement of urinary testosterone to epitestosterone ratio and further confirmed by the use of the 13C:12C ratio in testosterone by the use of isotope ratio combustion mass spectrometry. Exogenous testosterone administration increases urinary testosterone glucuronide excretion and

of the Female 385 Disorders Reproductive System Janet E. Hall

The female reproductive system regulates the hormonal changes responsible for puberty and adult reproductive function. Normal reproductive function in women requires the dynamic integration of hormonal signals from the hypothalamus, pituitary, and ovary, resulting in repetitive cycles of follicle development, ovulation, and preparation of the endometrial lining of the uterus for implantation should conception occur. It is critical to understand pubertal development in normal girls (and boys) as a yardstick for identifying precocious and delayed puberty.

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2788

For further discussion of related topics, see the following chapters: amenorrhea and pelvic pain (Chap. 386), infertility and contraception (Chap. 389), menopause (Chap. 388), disorders of sex development (Chap. 383), and disorders of the male reproductive system (Chap. 384).

7 × 106

Migratory germ cells Oogonia Primary oocytes

DEVELOPMENT OF THE OVARY AND EARLY FOLLICULAR GROWTH PART 12 Endocrinology and Metabolism

The ovary orchestrates the development and release of a mature oocyte and secretes hormones (e.g., estrogen, progesterone, inhibins A and B, relaxin) that play critical roles in a variety of target tissues, including breast, bone, and uterus, in addition to the hypothalamus and pituitary. To achieve these functions in repeated monthly cycles, the ovary undergoes some of the most dynamic changes of any organ in the body. Primordial germ cells can be identified by the third week of gestation, and their migration to the genital ridge is complete by 6 weeks of gestation. Germ cells persist within the genital ridge, are then referred to as oogonia, and are essential for induction of ovarian development. In patients with 45,X Turner syndrome, primordial germ cells proliferate and migrate to the genital ridge, but do not persist as their survival requires the presence of pregranulosa cells that are dependent on the presence of both X chromosomes. (Chap. 383). The germ cell population expands, and starting at ~8 weeks of gestation, oogonia begin to enter prophase of the first meiotic division and become primary oocytes. This allows the oocyte to be surrounded by a single layer of flattened granulosa cells to form a primordial follicle (Fig. 385-1). Granulosa cells are derived from mesonephric cells that invade the ovary early in its development, pushing the germ cells to the periphery. Although there is evidence that both oocyte-like cells and follicle-like structures can form from embryonic stem cells in culture, there is, as yet, no clear evidence that this occurs in vivo and thus, the ovary appears to contain a nonrenewable pool of germ cells. Through the combined processes of mitosis, meiosis, and atresia, the population of oogonia reaches its maximum of 6–7 million by 20 weeks of gestation, after which there is a progressive loss of both oogonia and primordial follicles through the process of atresia. It appears that entry into meiosis provides some degree of protection from programmed cell death. At birth, oogonia are no longer present in the ovary, and only 1–2 million germ cells remain in the form of primordial follicles (Fig. 385-2). The oocyte persists in prophase of the first meiotic division until just before ovulation, when meiosis resumes. Migratory germ cells Genital ridge

Mature oocyte

Corpus luteum

2 × 106 4 × 105

2m

5m

Granulosa cells

LH Gonadotropin dependent

Primordial follicles Theca cells

Ovulation Secondary follicles

LH FSH

Preovulatory follicles

LH FSH

Antral follicles

FIGURE 385-1  Stages of ovarian development from the arrival of the migratory germ cells at the genital ridge through gonadotropin-independent and gonadotropin-dependent phases that ultimately result in ovulation of a mature oocyte. FSH, follicle-stimulating hormone; LH, luteinizing hormone.

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Menarche

Menopause

The quiescent primordial follicles are recruited to further growth and differentiation through a highly regulated process that limits the size of the developing cohort to ensure that folliculogenesis can continue throughout the reproductive life span. This initial recruitment of primordial follicles to form primary follicles (Fig. 385-1) is characterized by growth of the oocyte and the transition from squamous to cuboidal granulosa cells. The theca interna cells that surround the developing follicle begin to form as the primary follicle grows. Acquisition of a zona pellucida by the oocyte and the presence of several layers of surrounding cuboidal granulosa cells mark the development of secondary follicles. It is at this stage that granulosa cells develop follicle-stimulating hormone (FSH), estradiol, and androgen receptors and communicate with one another through the development of gap junctions. Bidirectional signaling between the germ cells and the somatic cells in the ovary is a necessary component underlying the maturation of the oocyte and the capacity for hormone secretion. For example, oocyte-derived growth differentiation factor 9 (GDF-9) and bone morphogenic protein-15 (BMP-15), also known as GDF-9b, are required for migration of pregranulosa and pretheca cells to the outer surface of the developing follicle and, hence, initial follicle formation. GDF-9 is also required for formation of secondary follicles, as are granulosa cell–derived KIT ligand (KITL) and the forkhead transcription factor (FOXL2). A significant number of genes have been identified that are required for development of the normal complement of oogonia in the ovary, initial follicle development and resistance to follicle loss; all are candidates for premature ovarian insufficiency (POI) and mutations in >50 genes have Prophase of first been identified in patients with POI with meiotic division Oogonia even more that have been associated with 1° Oocytes an earlier age at natural menopause.

Gonadotropin independent

Resumption of meiosis

Birth

FIGURE 385-2  Ovarian germ cell number is maximal at mid-gestation and decreases precipitously thereafter.

DEVELOPMENT OF A MATURE FOLLICLE

The early stages of follicle growth are primarily driven by intraovarian factors; after initial recruitment, development to the secondary follicle stage may take close to a year. Further maturation to the preovulatory stage, including the resumption of meiosis in the oocyte, requires the combined stimulus of FSH and luteinizing hormone (LH) (Fig. 385-1). Recruitment of secondary follicles from the resting follicle pool requires the direct action of FSH, whereas anti-müllerian hormone (AMH) produced from small growing follicles, restrains this effect of FSH controlling the number of follicles entering the actively growing pool. Accumulation of follicular fluid between

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REGULATION OF OVARIAN FUNCTION

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■■HYPOTHALAMIC AND PITUITARY SECRETION

the layers of granulosa cells creates an antrum that divides the granulosa cells into two functionally distinct groups: mural cells that line the follicle wall and cumulus cells that surround the oocyte (Fig. 385-3). In addition to its role in normal development of the müllerian system, the WNT signaling pathway is required for normal antral follicle development and may also play a role in ovarian steroidogenesis. Recruitment to the small antral stage generally occurs over several cycles with further growth to follicle sizes of >4–7 mm in several waves during a single cycle. A single dominant follicle emerges from the growing follicle pool within the first 5–7 days after the onset of menses while the majority of follicles fall off their growth trajectory and become atretic. Autocrine actions of activin and BMP-6, derived from the granulosa cells, and paracrine actions of GDF-9, BMP-15, BMP-6, and Gpr149, derived from the oocyte, are involved in granulosa cell proliferation and modulation of FSH responsiveness. Differential exposure to these factors, and to vascular endothelial growth factor (VEGF), can attenuate vascular density and permeability, likely explaining the mechanism whereby a given follicle is selected for continued growth to the preovulatory stage. The dominant follicle can be distinguished by its size, evidence of granulosa cell proliferation, large number of FSH receptors, high aromatase activity, and elevated concentrations of estradiol and inhibin A in follicular fluid. In addition, secretion of estradiol and inhibin from the dominant follicle inhibits FSH and the growth of other follicles. The dominant follicle undergoes rapid expansion during the 5–6 days prior to ovulation, reflecting granulosa cell proliferation and accumulation of follicular fluid. FSH induces LH receptors on the granulosa cells, and the preovulatory, or Graafian, follicle moves to the outer ovarian surface in preparation for ovulation. The LH surge triggers the resumption of meiosis, the suppression of granulosa cell proliferation, and the induction of cyclooxygenase 2 (COX-2), prostaglandins, the progesterone receptor (PR), and the epidermal growth factor (EGF)-like growth factors amphiregulin, epiregulin, betacellulin, and neuroregulin 1, all of which are required for ovulation. Ovulation requires production of extracellular matrix leading to expansion of the cumulus cell population that surrounds the oocyte and the controlled expulsion of the egg and follicular fluid. Both progesterone and prostaglandins (induced by the ovulatory stimulus) are essential for this process as are members of the matrix metalloproteinase family. After ovulation, luteinization of theca and granulosa cells is induced by LH in conjunction with the acquisition of a rich vascular network in response to VEGF and basic fibroblast growth factor (FGF). Traditional regulators of central reproductive control, gonadotropin-releasing hormone (GnRH) and its receptor (GnRHR), as well as kisspeptin, are also produced in the ovary and may be involved in corpus luteum function.

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CHAPTER 385 Disorders of the Female Reproductive System

FIGURE 385-3  Development of ovarian follicles. The Graafian follicle is also known as a tertiary or preovulatory follicle. (Courtesy of J.H. Eichhorn and D. Roberts, Massachusetts General Hospital; with permission.)

GnRH neurons derive from cells in the olfactory placode and to a lesser extent, the neural crest. They migrate along the scaffold of the olfactory neurons across the cribiform plate to the hypothalamus where they separate from the olfactory neurons. Studies in GnRH-deficient patients who fail to undergo puberty have provided insights into genes that control the ontogeny and function of GnRH neurons (Fig. 385-4). KAL1, FGF8/FGFR1, PROK2/PROKR2, NSMF, HS6SD1, and CDH7, among others (Chap. 384), have been implicated in the migration of GnRH neurons to the hypothalamus. Approximately 7000 GnRH neurons, scattered throughout the medial basal hypothalamus, establish contacts with capillaries of the pituitary portal system in the median eminence. GnRH is secreted into the pituitary portal system in discrete pulses to stimulate synthesis and secretion of LH and FSH from pituitary gonadotropes, which comprise ~10% of cells in the pituitary (Chap. 371). Functional connections of GnRH neurons with the portal system are established by the end of the first trimester, coinciding with the production of pituitary gonadotropins. Thus, like the ovary, the hypothalamic and pituitary components of the reproductive system are present before birth. However, the high levels of estradiol and progesterone produced by the placenta suppress hypothalamic-pituitary stimulation of ovarian hormonal secretion in the fetus. After birth and the loss of placenta-derived steroids, gonadotropin levels rise. FSH levels are much higher in girls than in boys. This rise in FSH results in circulating estradiol and increased inhibin B, but without terminal follicle maturation or ovulation . Studies that have identified mutations in TAC3, which encodes neurokinin B, and its receptor, TAC3R, in patients with GnRH deficiency indicate that both are involved in control of GnRH secretion and may be particularly important at this early stage of development. By 12–20 months of age, the reproductive axis is again suppressed, and a period of relative quiescence persists until puberty (Fig. 385-5). At the onset of puberty, pulsatile GnRH secretion induces pituitary gonadotropin production. In the early stages of puberty, LH and FSH secretion are apparent only during sleep, but as puberty develops, pulsatile gonadotropin secretion occurs throughout the day and night. The mechanisms responsible for the childhood quiescence and pubertal reactivation of the reproductive axis remain incompletely Function

Migration

Hypothalamus KNDY Neural crest

KISS1R

Olfactory placode KISS1R GnRH1

Pituitary GnRHR

FIGURE 385-4  Genetic studies in patients with congenital forms of hypogonadotropic hypogonadism have expanded our understanding of the development and migration of gonadotropin-releasing hormone (GnRH) neurons from the olfactory placode and neural crest to the hypothalamus as well as the upstream regulation of GnRH secretion.

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Plasma gonadotropins

2790

Birth−20 mo. Infancy

LH

Theca cell Cholesterol

FSH

Childhood

LH

progesterone 17 hydroxylase 17-OHP 17,20 lyase

50 yr 10–14 yr Puberty reproductive years Menopause

Androstenedione 17βHSD

PART 12

FIGURE 385-5  Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are increased during the neonatal years but go through a period of childhood quiescence before increasing again during puberty. Gonadotropin levels are cyclic during the reproductive years and increase dramatically with the loss of negative feedback that accompanies menopause.

Endocrinology and Metabolism

understood. GnRH neurons in the hypothalamus respond to both excitatory and inhibitory factors. Increased sensitivity to the inhibitory influence of gonadal steroids has long been implicated in the inhibition of GnRH secretion during childhood but has not been definitively established in the human. Metabolic signals, including adipocyte-derived leptin, play a permissive role in reproductive function (Chap. 394). Studies of patients with isolated GnRH deficiency reveal that mutations in the G protein–coupled receptor 54 (GPR54) gene (now known as KISS1R) preclude the onset of puberty. The ligand for this receptor is derived from the parent peptide, kisspeptin-1 (KISS1), and is a powerful stimulant for GnRH release. A potential role for kisspeptin in the onset of puberty has been suggested by upregulation of KISS1 and KISS1R transcripts in the hypothalamus at the time of puberty. TAC3, which stimulates GnRH secretion through kisspeptin signaling, and dynorphin (Dyn), which plays an inhibitory role in GnRH control, are frequently co-expressed with KISS1 in KNDy neurons of the median eminence that project to GnRH neurons. This system is intimately involved in both estrogen and progesterone negative feedback regulation of GnRH secretion. RFamide-Related peptides (RFRPs) are the mammalian orthologues of gonadotropin inhibitory hormone (GnIH) which was initially discovered in the quail. While RFRP-1 and RFRP-3 neurons send axonal projections to GnRH neurons in humans, and RFRPs are secreted into the pituitary portal system, further studies are required to determine their potential physiologic role in the human.

■■OVARIAN STEROIDS

Ovarian steroid-producing cells do not store hormones but produce them in response to LH and FSH during the normal menstrual cycle. The sequence of steps and the enzymes involved in the synthesis of steroid hormones are similar in the ovary, adrenal, and testis. However, the enzymes required to catalyze specific steps are compartmentalized and may not be abundant or even present in all cell types. Within the developing ovarian follicle, estrogen synthesis from cholesterol requires close integration between theca and granulosa cells—sometimes called the two-cell model for steroidogenesis (Fig. 385-6). FSH receptors are confined to the granulosa cells, whereas LH receptors are restricted to the theca cells until the late stages of follicular development, when they are also found on granulosa cells. The theca cells surrounding the follicle are highly vascularized and use cholesterol, derived primarily from circulating lipoproteins, as the starting point for the synthesis of androstenedione and testosterone under the control of LH. These steroid precursors cross the basal lamina to the granulosa cells, which receive no direct blood supply. The mural granulosa cells are particularly rich in aromatase and, under the control of FSH, produce estradiol, the primary steroid secreted from the follicular phase ovary and the most potent estrogen. Theca cell–produced androstenedione and, to a lesser extent, testosterone are also secreted into peripheral blood, where they can be converted to dihydrotestosterone in skin and to estrogens in adipose tissue. The hilar interstitial cells of the ovary are functionally similar to Leydig cells and are also capable of secreting androgens.

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pregnenolone 3βHSD

Testosterone

Androstenedione Testosterone

aromatase

Estrone Estradiol

FSH

Granulosa cell

FIGURE 385-6  Estrogen production in the ovary requires the cooperative function of the theca and granulosa cells under the control of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). HSD, hydroxysteroid dehydrogenase; OHP, hydroxyprogesterone.

Stromal cells proliferate in response to androgens (as in polycystic ovarian syndrome [PCOS]), but do not secrete androgens. However, high levels of androgens may be produced by luteinized theca cells in women with hyperthecosis. Development of the rich capillary network following rupture of the follicle at the time of ovulation makes it possible for large molecules such as low-density lipoprotein (LDL) to reach the luteinized granulosa and theca lutein cells. As in the follicle, both cell types are required for steroidogenesis in the corpus luteum. The luteinized granulosa cells are the main source of progesterone production, whereas the smaller theca lutein cells produce 17-hydroxyprogesterone and androgenic substrates for aromatization to estradiol by the luteinized granulosa cells. Production of estrogen metabolites by the corpus luteum plays a significant role in maintenance of the vascularization required for its function. LH is critical for formation and maintenance of corpus luteum structure and function. LH and human chorionic gonadotropin (hCG) bind to a common receptor; thus, in conception cycles, hCG rescues the declining function of the corpus luteum, maintaining steroid and peptide secretion for the first 10 weeks of pregnancy. HCG is commonly used for luteal phase support in the treatment of infertility.

Steroid Hormone Actions  Both estrogen and progesterone

play critical roles in the expression of secondary sexual characteristics in women (Chap. 370). Estrogen promotes development of the ductule system in the breast, whereas progesterone is responsible for glandular development. In the reproductive tract, estrogens create a receptive environment for fertilization and support pregnancy and parturition through carefully coordinated changes in the endometrium, thickening of the vaginal mucosa, thinning of the cervical mucus, and uterine growth and contractions. Progesterone induces secretory activity in the estrogen-primed endometrium, increases the viscosity of cervical mucus, and inhibits uterine contractions. Both gonadal steroids play critical roles in negative and positive feedback of gonadotropin secretion. Progesterone also increases basal body temperature and has therefore been used clinically as a marker of ovulation. The vast majority of circulating estrogens and androgens are carried in the blood bound to carrier proteins, which restrain their free diffusion into cells and prolong their clearance, serving as a reservoir. High-affinity binding proteins include sex hormone–binding globulin (SHBG), which binds androgens with somewhat greater affinity than

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■■OVARIAN PEPTIDES

Inhibin was initially isolated from gonadal fluids based on its ability to selectively inhibit FSH secretion from pituitary cells. Inhibin is a heterodimer composed of an α subunit and a βA or βB subunit to form inhibin A or inhibin B, both of which are secreted from the ovary. Activin is a homodimer of inhibin β subunits with the capacity to stimulate the synthesis and secretion of FSH. Inhibins and activins are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation factors. During the purification of inhibin, follistatin, an unrelated monomeric protein that inhibits FSH secretion, was discovered. Within the pituitary, follistatin inhibits FSH secretion indirectly by binding and neutralizing activin. Inhibin B is constitutively secreted from the granulosa cells of small antral follicles and its serum levels increase in conjunction with granulosa cell proliferation during recruitment of secondary follicles under the control of FSH. In addition to its role as a marker of decreasing ovarian reserve during reproductive aging, inhibin B is an important inhibitor of FSH, independent of estradiol, during the menstrual cycle. Inhibin A is present in both granulosa and theca cells and is secreted by the dominant follicle. Inhibin A is also present in luteinized granulosa cells and is a major secretory product of the corpus luteum. Synthesis and secretion of inhibin A are directly controlled by FSH and LH. Although activin is also secreted from the ovary, the excess of follistatin in serum, combined with its nearly irreversible binding of activin, make it unlikely that ovarian activin plays an endocrine role in FSH regulation. However, there is evidence that activin plays an autocrine/ paracrine role in the ovary, in addition to its intra-pituitary role in modulation of FSH production. AMH (also known as müllerian-inhibiting substance) is important in ovarian biology in addition to the function from which it derived its name (i.e., promotion of the degeneration of the müllerian system during embryogenesis in the male). AMH is produced by granulosa cells from small follicles and is a marker of ovarian reserve with advantages over inhibin B because of its relative stability across the menstrual cycle. AMH inhibits the recruitment of primordial follicles into the follicle pool and counters FSH stimulation of aromatase expression. AMH is increased in polycystic ovarian syndrome in conjunction with the abundance of small follicles in this disorder. Gonadotropin Surge Attenuating Factor (GnSAF) is an ovarian factor that attenuates GnRH-induced gonadotropin secretion. Its role is not yet fully understood, but there is an inverse relationship between GnSAF and follicle size suggesting that its primary role involves the early stages of follicle development rather than curtailing the gonadotropin surge as its name implies. Relaxin is produced primarily by the theca lutein cells of the corpus luteum. Both relaxin and its receptor, RXFP1, are highly expressed in the uterus during the peri-implantation period in the marmoset and its primary role appears to be in promoting decidualization and vascularization of the endometrium prior to implantation. Relaxin was named

Harrisons_20e_Part12_p2649-p3024.indd 2791

for its ability to suppress myometrial contractility in pigs and rodents, 2791 but it does not appear to exert this activity in women.

HORMONAL INTEGRATION OF THE NORMAL MENSTRUAL CYCLE

The sequence of changes responsible for mature reproductive function is coordinated through a series of negative and positive feedback loops that alter pulsatile GnRH secretion, the pituitary response to GnRH, and the relative secretion of LH and FSH from the gonadotrope. The frequency and amplitude of pulsatile GnRH secretion differentially modulate the synthesis and secretion of LH and FSH. Slow GnRH pulse frequencies favor FSH synthesis whereas increased GnRH pulse frequency and amplitude favor LH synthesis. Activin is produced in both pituitary gonadotropes and folliculostellate cells and stimulates the synthesis and secretion of FSH through autocrine-paracrine mechanisms that are modulated by follistatin. Inhibins function as potent antagonists of activins through sequestration of the activin receptors. Although inhibin is expressed in the pituitary, gonadal inhibin is the principal source of feedback inhibition of FSH. For the majority of the cycle, the reproductive system functions in a classic endocrine negative feedback mode. Estradiol and progesterone inhibit GnRH secretion, acting through kisspeptin and dynorphin in the KNDy neurons, and the inhibins act at the pituitary to selectively inhibit FSH synthesis and secretion (Fig. 385-7). Estradiol also contributes to negative feedback at the pituitary with an effect that is greater for FSH than LH. This tightly regulated negative feedback control of FSH is critical for development of the single mature oocyte that characterizes normal reproductive function in women. In addition to these negative feedback controls, the menstrual cycle is uniquely dependent on estrogen-induced positive feedback to produce an LH surge that is essential for ovulation of a mature follicle. Estrogen negative feedback in women occurs primarily at the hypothalamus with a small pituitary contribution, whereas estrogen positive feedback occurs at the pituitary in women with upregulation of GnRH signaling. In women, hypothalamic GnRH secretion plays a permissive role in generating the preovulatory gonadotropin surge, a mechanism that differs significantly from that in rodents and other species that rely on seasonal and circadian cues, in which a surge of GnRH also occurs.

CHAPTER 385 Disorders of the Female Reproductive System

estrogens, and corticosteroid-binding globulin (CBG), which also binds progesterone. Modulations in binding protein levels by insulin, androgens, and estrogens contribute to high bioavailable testosterone levels in PCOS and to high circulating total estrogen and progesterone levels during pregnancy. Estrogens act primarily through binding to the nuclear receptors, estrogen receptor (ER) α and β. Transcriptional coactivators and co-repressors modulate ER action (Chap. 370). Both ER subtypes are present in the hypothalamus, pituitary, ovary, and reproductive tract. Although ERα and β exhibit some functional redundancy, there is also a high degree of specificity, particularly in expression within cell types. For example, ERα functions in ovarian theca cells, whereas ERβ is critical for granulosa cell function. There is also evidence for membrane-initiated signaling by estrogen. Similar signaling mechanisms pertain for progesterone with evidence of transcriptional regulation through PR A and B protein isoforms, as well as rapid membrane signaling.

■■THE FOLLICULAR PHASE

The follicular phase is characterized by recruitment of a cohort of secondary follicles and the ultimate selection of a dominant preovulatory follicle (Fig. 385-8). The follicular phase begins, by convention, on the first day of menses. However, follicle recruitment is initiated Negative Feedback

Positive Feedback

– GnRH

++

–

Inhibin B Inhibin A Estradiol

+

Estradiol

LH FSH

++

Estradiol Progesterone

FIGURE 385-7  The reproductive system in women is critically dependent on both negative feedback of gonadal steroids and inhibin to modulate follicle-stimulating hormone (FSH) secretion and on estrogen positive feedback to generate the preovulatory luteinizing hormone (LH) surge. GnRH, gonadotropin-releasing hormone.

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2792 FSH LH

Follicular phase

Secondary Antral Dominant Ovarian follicles

Luteal phase

Ovulation

Corpus luteum

Corpus albicans

Inhibin B Inhibin A

PART 12

E2 Prog Endo

Endocrinology and Metabolism

Proliferative

Secretory

FIGURE 385-8  Relationship between gonadotropins, follicle development, gonadal secretion, and endometrial changes during the normal menstrual cycle. E2, estradiol; Endo, endometrium; FSH, follicle-stimulating hormone; LH, luteinizing hormone; Prog, progesterone.

by the rise in FSH that begins in the late luteal phase of the previous cycle in conjunction with the loss of negative feedback of gonadal steroids and likely inhibin A. The fact that a 20–30% increase in FSH is adequate for follicular recruitment speaks to the marked sensitivity of the resting follicle pool to FSH. The resultant granulosa cell proliferation is responsible for increasing early follicular phase levels of inhibin B. Inhibin B in conjunction with rising levels of estradiol and inhibin A, restrain FSH secretion during this critical period such that only a single follicle matures in the vast majority of cycles. The increased risk of multiple gestation associated with the increased levels of FSH characteristic of advanced maternal age, or with exogenous gonadotropin administration in the treatment of infertility, attests to the importance of negative feedback regulation of FSH. With further growth of the dominant follicle, estradiol and inhibin A increase and the follicle acquires LH receptors. Increasing levels of estradiol are responsible for proliferative changes in the endometrium. The exponential rise in estradiol results in positive feedback on the pituitary, leading to the generation of an LH surge (and a smaller FSH surge), thereby triggering ovulation and luteinization of granulosa and theca cells.

■■THE LUTEAL PHASE

The luteal phase begins with the formation of the corpus luteum from the ruptured follicle (Fig. 385-8). Progesterone and inhibin A are produced from the luteinized granulosa cells, which continue to aromatize theca-derived androgen precursors, producing estradiol. The combined actions of estrogen and progesterone are responsible for the secretory changes in the endometrium that are necessary for implantation. The corpus luteum is supported by LH but has a finite life span because of diminished sensitivity to LH. The demise of the corpus luteum results in a progressive decline in hormonal support of the endometrium. Inflammation or local hypoxia and ischemia result in vascular changes in the endometrium, leading to the release of cytokines, cell death, and shedding of the endometrium. If conception occurs, hCG produced by the trophoblast binds to LH receptors on the corpus luteum, maintaining steroid hormone production and preventing involution of the corpus luteum until its hormonal function is taken over by the placenta 6–10 weeks after conception.

CLINICAL ASSESSMENT OF OVARIAN FUNCTION

Menstrual bleeding should become regular within 2–4 years of menarche, although anovulatory and irregular cycles are common before that. For the remainder of adult reproductive life, the cycle length counted from the first day of menses to the day preceding subsequent menses

Harrisons_20e_Part12_p2649-p3024.indd 2792

is ~28 days, with a range of 25–35 days. However, cycle-to-cycle variability for an individual woman is ±2 days. Luteal phase length is relatively constant between 12 and 14 days in normal cycles; thus, the major variability in cycle length is due to variations in follicular phase length. The duration of menstrual bleeding in ovulatory cycles varies between 4 and 6 days. There is a gradual shortening of cycle length with age such that women aged >35 years have cycles that are shorter than during their younger reproductive years. Anovulatory cycles increase as women approach menopause, and bleeding patterns may be erratic. Women who report regular monthly bleeding with cycles that do not vary by >4 days generally have ovulatory cycles, but several other clinical signs can be used to assess the likelihood of ovulation. Some women experience mittelschmerz, described as midcycle pelvic discomfort that is thought to be caused by the rapid expansion of the dominant follicle at the time of ovulation. A constellation of premenstrual moliminal symptoms such as bloating, breast tenderness, and food cravings often occur several days before menses in ovulatory cycles, but their absence cannot be used as evidence of anovulation. Methods that can be used to determine whether ovulation is likely include a serum progesterone level >5 ng/mL ~7 days before expected menses, an increase in basal body temperature of 0.24°C (>0.5°F) in the second half of the cycle due to the thermoregulatory effect of progesterone, or the detection of the urinary LH surge using ovulation predictor kits. Because ovulation occurs ~36 h after the LH surge, urinary LH can be helpful in timing intercourse to coincide with ovulation. Ultrasound can be used to detect the growth of the fluid-filled antrum of the developing follicle and to assess endometrial proliferation in response to increasing estradiol levels in the follicular phase. It can also be used to provide evidence of ovulation by documenting collapse of the dominant follicle and/or the presence of a corpus luteum as well as the characteristic echogenicity of the secretory endometrium of the luteal phase.

PUBERTY ■■NORMAL PUBERTAL DEVELOPMENT IN GIRLS

The first menstrual period (menarche) occurs relatively late in the series of developmental milestones that characterize normal pubertal development (Table 385-1). Menarche is preceded by the appearance of pubic and then axillary hair (adrenarche) as a result of maturation of the zona reticularis in the adrenal gland and increased adrenal androgen secretion, particularly dehydroepiandrosterone (DHEA). The triggers for adrenarche remain unknown but may involve increases in body mass index, as well as in utero and neonatal factors. Menarche is also preceded by breast development (thelarche). The breast is exquisitely sensitive to the very low levels of estrogen that result from peripheral conversion of adrenal androgens and the low levels of estrogen secreted from the ovary early in pubertal maturation. Breast development precedes the appearance of pubic and axillary hair in ~60% of girls. The interval between the onset of breast development and menarche is ~2 years. There has been a gradual decline in the age of menarche over the past century, attributed in large part to improvement in nutrition, and there is a relationship between adiposity and earlier sexual maturation in girls. In the United States, menarche occurs at an average age of 12.5 years (Table 385-1). TABLE 385-1  Mean Age (Years) of Pubertal Milestones in Girls

  White Black

ONSET OF BREAST/ PUBIC HAIR DEVELOPMENT 10.2 9.6

AGE OF FINAL PEAK BREAST/ HEIGHT PUBIC HAIR VELOCITY MENARCHE DEVELOPMENT 11.9 12.6 14.3 11.5 12 13.6

ADULT HEIGHT 17.1 16.5

Source: From FM Biro et al: J Pediatr 148:234, 2006.

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■■DISORDERS OF PUBERTY

The differential diagnosis of precocious and delayed puberty is similar in boys (Chap. 384) and girls. However, there are differences in the timing of normal puberty and differences in the relative frequency of specific disorders in girls compared with boys.

Precocious Puberty  Traditionally, precocious puberty has been

defined as the development of secondary sexual characteristics before the age of 8 in girls based on data from Marshall and Tanner in British girls studied in the 1960s. More recent studies led to recommendations that girls be evaluated for precocious puberty if breast development or pubic hair is present at 30 kg/m2 are often seen in association with hirsutism, probably the result of increased conversion of androgen precursors to testosterone. Notation should be made of blood pressure, as adrenal causes may be associated with hypertension. Cutaneous signs sometimes associated with androgen excess and insulin resistance include acanthosis nigricans and skin tags. An objective clinical assessment of hair distribution and quantity is central to the evaluation in any woman presenting with concerns about excessive hair growth. This assessment permits the distinction between hirsutism and hypertrichosis and provides a baseline reference point to gauge the response to treatment. A simple and commonly used method to grade hair growth is the modified scale of Ferriman and Gallwey (Fig. 387-1), in which each of nine androgen-sensitive sites is graded from 0 to 4. Approximately 95% of white women have a score 8 suggest excess androgen-mediated hair growth, a finding that should be assessed further by means of hormonal evaluation (see below). In racial/ethnic groups that are less likely to manifest hirsutism (e.g., Asian women), additional cutaneous evidence of androgen excess should be sought, including pustular acne and thinning scalp hair.

■■HORMONAL EVALUATION

Androgens are secreted by the ovaries and adrenal glands in response to their respective tropic hormones: luteinizing hormone (LH) and adrenocorticotropic hormone (ACTH). Testosterone is the principal circulating steroid involved in the etiology of hirsutism; other steroids that may contribute to the development of hirsutism include androstenedione, dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS). The ovaries and adrenal glands normally contribute about equally to testosterone production. Approximately half of the total testosterone originates from direct glandular secretion, and the remainder is derived from the peripheral conversion of androstenedione and DHEA (Chap. 384). Although it is the most important circulating androgen, testosterone is in effect the penultimate androgen in mediating hirsutism; it is converted to the more potent dihydrotestosterone (DHT) by the enzyme 5α-reductase, which is located in the PSU. DHT has a higher affinity for, and slower dissociation from, the androgen receptor. The local production of DHT allows it to serve as the primary mediator of androgen action at the level of the pilosebaceous unit. There are two isoenzymes of 5α-reductase: type 2 is found in the prostate gland and in hair follicles, and type 1 is found primarily in sebaceous glands. One approach to testing for hyperandrogenemia is depicted in Fig. 387-2. In addition to measuring blood levels of testosterone and DHEAS, it is important to measure the level of free (or unbound) testosterone. The fraction of testosterone that is not bound to its carrier protein, sex hormone–binding globulin (SHBG), is biologically available for conversion to DHT and binding to androgen receptors. Hyperinsulinemia and/or androgen excess decrease hepatic production of SHBG, resulting in levels of total testosterone within the high-normal range, whereas the unbound hormone is elevated more substantially. Although there is a decline in ovarian testosterone production after menopause, ovarian estrogen production decreases to an even greater extent, and the concentration of SHBG is reduced. Consequently, there is an increase in the relative proportion of unbound testosterone, and it may exacerbate hirsutism after menopause.

Harrisons_20e_Part12_p2649-p3024.indd 2800

A baseline plasma total testosterone level >12 nmol/L (>3.5 ng/mL) usually indicates a virilizing tumor, whereas a level >7 nmol/L (>2 ng/mL) is suggestive of tumor but may also be observed in women with hyperthecosis. A basal DHEAS level >18.5 μmol/L (>7000 μg/L) suggests an adrenal tumor. Although DHEAS has been proposed as a “marker” of predominant adrenal androgen excess, it is not unusual to find modest elevations in DHEAS among women with PCOS. Computed tomography (CT) or magnetic resonance imaging (MRI) should be used to localize an adrenal mass, and ultrasound usually suffices to identify an ovarian mass if clinical evaluation and hormonal levels suggest these possibilities. PCOS is the most common cause of ovarian androgen excess (Chap. 385). An increased ratio of LH to follicle-stimulating hormone is characteristic in carefully studied patients with PCOS. However, because of the pulsatile nature of gonadotropin secretion, this finding may be absent in up to half of women with PCOS. Transvaginal ultrasound classically shows enlarged ovaries and increased stroma in women with PCOS. However, cystic ovaries also may be found in women without clinical or laboratory features of PCOS. Although usually limited to a research setting, a gonadotropin-releasing hormone agonist test can be used to make a specific diagnosis of ovarian hyperandrogenism. A peak 17-hydroxyprogesterone level ≥7.8 nmol/L (≥2.6 μg/L) after the administration of 100 μg nafarelin (or 10 μg/kg leuprolide) subcutaneously is virtually diagnostic of ovarian hyperandrogenism. Because adrenal androgens are readily suppressed by low doses of glucocorticoids, the dexamethasone androgen-suppression test may broadly distinguish ovarian from adrenal androgen overproduction. A blood sample is obtained before and after the administration of dexamethasone (0.5 mg orally every 6 h for 4 days). An adrenal source is suggested by suppression of unbound testosterone into the normal range; incomplete suppression suggests ovarian androgen excess. An overnight 1-mg dexamethasone suppression test, with measurement of 8:00 a.m. serum cortisol, is useful when there is clinical suspicion of Cushing’s syndrome (Chap. 379). Nonclassic CAH is most commonly due to 21-hydroxylase deficiency but also can be caused by autosomal recessive defects in other steroidogenic enzymes necessary for adrenal corticosteroid synthesis (Chap. 379). Because of the enzyme defect, the adrenal gland cannot secrete glucocorticoids (especially cortisol) efficiently. This results in diminished negative feedback inhibition of ACTH, leading to compensatory adrenal hyperplasia and the accumulation of steroid precursors that subsequently are converted to androgen. Deficiency of 21-hydroxylase can be reliably excluded by determining a morning 17-hydroxyprogesterone level 18.5 µmol/L (>7000 µg/L)

Endocrinology and Metabolism

Treat empirically or Consider further testing • Dexamethasone suppression → adrenal vs ovarian causes; R/O Cushing’s • ACTH stimulation → assess nonclassic CAH Final diagnosis Idiopathic Other causes see Table 387-1

• Nonclassic CAH • Functional adrenal hyperandrogenism

• PCOS • Functional ovarian hyperandrogenism

FIGURE 387-2  Algorithm for the evaluation and differential diagnosis of hirsutism. ACTH, adrenocorticotropic hormone; CAH, congenital adrenal hyperplasia; DHEAS, sulfated form of dehydroepiandrosterone; PCOS, polycystic ovarian syndrome.

Combination estrogen-progestin therapy in the form of an oral contraceptive is usually the first-line endocrine treatment for hirsutism and acne, after cosmetic and dermatologic management. The estrogenic component of most oral contraceptives currently in use is either ethinyl estradiol or mestranol. The suppression of LH leads to reduced production of ovarian androgens. The reduced androgen levels also result in a dose-related increase in SHBG, thus lowering the fraction of unbound plasma testosterone. Estrogens also have a direct, dose-dependent suppressive effect on sebaceous cell function. The choice of a specific oral contraceptive should be predicated on the progestational component, as progestins vary in their suppressive effect on SHBG levels and in their androgenic potential. Ethynodiol diacetate has relatively low androgenic potential, whereas progestins such as norgestrel and levonorgestrel are particularly androgenic, as judged from their attenuation of the estrogen-induced increase in SHBG. Norgestimate exemplifies the newer generation of progestins that are virtually nonandrogenic. Drospirenone, an analogue of spironolactone that has both antimineralocorticoid and antiandrogenic activities, has been approved for use as a progestational agent in combination with ethinyl estradiol. Oral contraceptives are contraindicated in women with a history of thromboembolic disease and women with increased risk of breast or other estrogen-dependent cancers (Chap. 388). There is a relative contraindication to the use of oral contraceptives in smokers and those with hypertension or a history of migraine headaches. In most trials, estrogen-progestin therapy alone improves the extent of acne by a maximum of 50–70%. The effect on hair growth may not be evident for 6 months, and the maximum effect may require 9–12 months owing to the length of the hair growth cycle. Improvements in hirsutism are typically in the range of 20%, but there may be an arrest of further progression of hair growth. Because oral contraceptives are efficacious and have fewer side effects, they are recommended over glucocorticoids as first-line treatment of hirsutism in CAH. If the response to oral contraceptives is inadequate, glucocorticoids may be used. The lowest effective dose of glucocorticoid should be used (e.g., dexamethasone [0.2–0.5 mg]

Harrisons_20e_Part12_p2649-p3024.indd 2802

or prednisone [5–10 mg]) taken at bedtime to achieve maximal suppression by inhibiting the nocturnal surge of ACTH. Cyproterone acetate is the prototypic antiandrogen. It acts mainly by competitive inhibition of the binding of testosterone and DHT to the androgen receptor. In addition, it may enhance the metabolic clearance of testosterone by inducing hepatic enzymes. Although not available for use in the United States, cyproterone acetate is widely used in Canada, Mexico, and Europe. Cyproterone (50–100 mg) is given on days 1–15 and ethinyl estradiol (50 μg) is given on days 5–26 of the menstrual cycle. Side effects include irregular uterine bleeding, nausea, headache, fatigue, weight gain, and decreased libido. Spironolactone, which usually is used as a mineralocorticoid antagonist, is also a weak antiandrogen. It is almost as effective as cyproterone acetate when used at high enough doses (100–200 mg daily). Patients should be monitored intermittently for hyperkalemia or hypotension, though these side effects are uncommon. Pregnancy should be avoided because of the risk of feminization of a male fetus. Spironolactone can also cause menstrual irregularity. It often is used in combination with an oral contraceptive, which suppresses ovarian androgen production and helps prevent pregnancy. Flutamide is a potent nonsteroidal antiandrogen that is effective in treating hirsutism, but concerns about the induction of hepatocellular dysfunction preclude its use. Finasteride is a competitive inhibitor of 5α-reductase type 2. Beneficial effects on hirsutism have been reported, but the predominance of 5α-reductase type 1 in the PSU appears to account for its limited efficacy. Finasteride would also be expected to impair sexual differentiation in a male fetus, and it should not be used in women who may become pregnant. Eflornithine cream (Vaniqa) has been approved as a novel treatment for unwanted facial hair in women, but long-term efficacy remains to be established. It can cause skin irritation under exaggerated conditions of use. Ultimately, the choice of any specific agent(s) must be tailored to the unique needs of the patient being treated. As noted previously, pharmacologic treatments for hirsutism should be used in conjunction with nonpharmacologic approaches. It is also helpful to review the pattern of female hair distribution in the normal population to dispel unrealistic expectations.

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80

LH or FSH, IU/L

70

FSH (IU/L)

60

LH (IU/L)

50 40 30

Estrone (pg/mL)

20 10

Estradiol (pg/mL)

0 –6

–4

–2

0 2 Menopause, years

4

6

200 180 160 140 120 100 80 60 40 20 0

2803

8

FIGURE 388-1  Mean serum levels of ovarian and pituitary hormones during the menopausal transition. FSH, follicle-stimulating hormone; LH, luteinizing hormone. (From JL Shifren, I Schiff: J Womens Health Gend Based Med 9 Suppl 1: S3, 2000. Reproduced with permission.)

■■DIAGNOSTIC TESTS

and 388 Menopause Postmenopausal Hormone Therapy

JoAnn E. Manson, Shari S. Bassuk

Menopause is the permanent cessation of menstruation due to loss of ovarian follicular function. It is diagnosed retrospectively after 12 months of amenorrhea. The average age at menopause is 51 years among U.S. women. Perimenopause refers to the time period preceding menopause, when fertility wanes and menstrual cycle irregularity increases, until the first year after cessation of menses. The onset of perimenopause precedes the final menses by 2–8 years, with a mean duration of 4 years. Smoking accelerates the menopausal transition by 2 years. Although the peri- and postmenopausal transitions share many symptoms, the physiology and clinical management of the two differ. Low-dose oral contraceptives have become a therapeutic mainstay in perimenopause, whereas postmenopausal hormone therapy (HT) has been a common method of symptom alleviation after menstruation ceases.

PERIMENOPAUSE ■■PHYSIOLOGY

Ovarian mass and fertility decline sharply after age 35 and even more precipitously during perimenopause; depletion of primary follicles, a process that begins before birth, occurs steadily until menopause (Chap. 385). In perimenopause, intermenstrual intervals shorten significantly (typically by 3 days) as a result of an accelerated follicular phase. Follicle-stimulating hormone (FSH) levels rise because of altered folliculogenesis and reduced inhibin secretion. In contrast to the consistently high FSH and low estradiol levels seen in menopause, perimenopause is characterized by “irregularly irregular” hormone levels. The propensity for anovulatory cycles can produce a hyperestrogenic, hypoprogestagenic environment that may account for the increased incidence of endometrial hyperplasia or carcinoma, uterine polyps, and leiomyoma observed among women of perimenopausal age. Mean serum levels of selected ovarian and pituitary hormones during the menopausal transition are shown in Fig. 388-1. With transition into menopause, estradiol levels fall markedly, whereas estrone levels are relatively preserved, a pattern reflecting peripheral aromatization of adrenal and ovarian androgens. Levels of FSH increase more than those of luteinizing hormone, presumably because of the loss of inhibin as well as estrogen feedback.

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The Stages of Reproductive Aging Workshop +10 (STRAW+10) classification provides a comprehensive framework for the clinical assessment of ovarian aging. As shown in Fig. 388-2, menstrual cycle characteristics are the principal criteria for characterizing the menopausal transition, with biomarker measures as supportive criteria. Because of their extreme intraindividual variability, FSH and estradiol levels are imperfect diagnostic indicators of perimenopause in menstruating women. However, a consistently low FSH level in the early follicular phase (days 2–5) of the menstrual cycle does not support a diagnosis of perimenopause, while levels >25 IU/L in a random blood sample are characteristic of the late menopause transition. FSH measurement can also aid in assessing fertility; levels of 1.0 in men being abnormal. Many of the most important complications of obesity, such as insulin resistance, diabetes, hypertension, hyperlipidemia, and hyperandrogenism in women, are linked more strongly to intraabdominal and/or

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2838

Weight kg lb 150 140 130 120

Height cm in.

340 320 300 280

125

Body Mass Index [kg/m2]

50 130

70

260

PART 12

110

240

WOMEN

60

MEN

135

100 95

220

RELATIVE RISK

50

RELATIVE RISK

140

90

200 190 180

VERY HIGH

145

85

Endocrinology and Metabolism

80 75 70 65

VERY HIGH

40

HIGH

HIGH

MODERATE

MODERATE

170 160 150 140

150

30

LOW

60 155

LOW 160

60

130

55

120

50

110

170

45

100

175

95 90

180

40

35

VERY LOW

20

85 80 75 70

30

55

VERY LOW

165

65

70

185

10

190 195

75

■■GLOBAL CONSIDERATIONS

According to the World Health Organization, global obesity almost doubled between 1980 and 2008. There were >200 million obese men and almost 300 million obese women, 11% of adults worldwide, in 2008. A majority (65%) of the world’s population lives in countries where being overweight or obese kills more people than being underweight. In 2014, the U.S. led the Organization for Economic Cooperation and Development (OECD) countries in obesity prevalence (34%), with New Zealand, Australia, the UK, Mexico, and Canada close behind in the high 20% range. Worldwide, the highest prevalence of obesity is in several Pacific Island states including the Cook Islands (50%), Nauru (45.6%), and Tonga (43.3%) and Gulf States including Qatar (42%) and Kuwait (38%). In developing countries, such as India, obesity prevalence is rising (5%) with a greater tendency to harmful intraabdominal obesity at lower BMIs in this population, and the consequences for metabolic and cardiovascular health are disproportionate to obesity prevalence. The causes of increased obesity globally are complicated, and may vary from country to country, but contributory factors include rising incomes, changing food supplies, and reduced activity.

■■PHYSIOLOGIC REGULATION OF ENERGY BALANCE

Substantial evidence suggests that body weight is regulated by both endocrine and 60 80 neural components that ultimately influ205 ence the effector arms of energy intake 25 55 210 and expenditure. This complex regulatory 85 50 system is necessary because even small FIGURE 394-1  Nomogram for determining body mass index. To use this nomogram, place a ruler or other imbalances between energy intake and straight edge between the body weight (without clothes) in kilograms or pounds located on the left-hand line and expenditure will ultimately have large the height (without shoes) in centimeters or inches located on the right-hand line. The body mass index is read effects on body weight. For example, a 0.3% from the middle of the scale and is in metric units. (Copyright 1979, George A. Bray, MD; used with permission.) positive imbalance over 30 years would result in a 9-kg (20-lb) weight gain. This upper body fat than to overall adiposity (Chap. 401). The mechanism exquisite regulation of energy balance cannot be monitored easily by underlying this association is unknown but may relate to the fact that calorie-counting in relation to physical activity. Rather, body weight intraabdominal adipocytes are more lipolytically active than those regulation or dysregulation depends on a complex interplay of horfrom other depots. Release of free fatty acids into the portal circulation monal and neural signals. Alterations in stable weight by forced has adverse metabolic actions, especially on the liver. Adipokines and overfeeding or food deprivation induce physiologic changes that cytokines that are differentially secreted by adipocyte depots may play resist these perturbations: with weight loss, appetite increases and a role in the systemic complications of obesity. energy expenditure falls; with overfeeding, appetite falls and energy expenditure increases. This latter compensatory mechanism frequently fails, however, permitting obesity to develop when food is abundant ■■PREVALENCE Data from the National Health and Nutrition Examination Surveys and physical activity is limited. A major regulator of these adaptive (NHANES) show that the percentage of the American adult population responses is the adipocyte-derived hormone leptin, which acts through with obesity (BMI >30) has increased from 14.5% (between 1976 and brain circuits (predominantly in the hypothalamus) to influence appe1980) to 36.5% (between 2011 and 2014). As many as 70% of U.S. adults tite, energy expenditure, and neuroendocrine function (see below). Appetite is influenced by many factors that are integrated by the aged ≥20 years were either overweight (defined as BMI >25) or obese (BMI >30) between the years of 2013 and 2014. Extreme obesity (BMI brain, most importantly within the hypothalamus (Fig. 394-2). Signals ≥40) has also increased and affects 5.7% of the population. The increas- that impinge on the hypothalamic center include neural afferents, ing prevalence of medically significant obesity raises great concern. hormones, and metabolites. Vagal inputs are particularly important, Overall, the prevalence of obesity is higher in women (38%) than in bringing information from viscera, such as gut distention. Hormonal men (34%). In women, poverty is associated with increased prevalence. signals include leptin, insulin, cortisol, and gut peptides. Among the Obesity is more common among blacks and Hispanics, and less com- latter is ghrelin, which is made in the stomach and stimulates feeding, mon in Asians. Among some Asian subgroups, health and mortality and peptide YY (PYY) and cholecystokinin, which is made in the small risks may begin at lower BMIs, associated with greater intraabdomnal intestine and signals to the brain through direct action on hypothalamic obesity. The prevalence in children and adolescents has been rising at a control centers and/or via the vagus nerve. Metabolites, including glucose, can influence appetite, as seen by the effect of hypoglycemia worrisome rate, reaching 17.0% in 2011–2014, but may be leveling off. 65

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200

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Psychological factors

Complement factors Factor D/adipsin

Central controllers of appetite Increase

Decrease appetite

NPY MCH AgRP Orexin Endocannabinoid

α-MSH CART GLP-1 Serotonin

Gut peptides CCK Ghrelin PYY

Hormones Leptin Insulin Cortisol

Metabolites Glucose Ketones

FIGURE 394-2  The factors that regulate appetite through effects on central neural circuits. Some factors that increase or decrease appetite are listed. AgRP, Agouti-related peptide; CART, cocaine- and amphetamine-related transcript; CCK, cholecystokinin; GLP-1, glucagon--related peptide-1; MCH, melanin-concentrating hormone; α-MSH, α-melanocyte-stimulating hormone; NPY, neuropeptide Y.

to induce hunger; however, glucose is not normally a major regulator of appetite. These diverse hormonal, metabolic, and neural signals act by influencing the expression and release of various hypothalamic peptides (e.g., neuropeptide Y [NPY], Agouti-related peptide [AgRP], α-melanocyte-stimulating hormone [α-MSH], and melanin-concentrating hormone [MCH]) that are integrated with serotonergic, catecholaminergic, endocannabinoid, and opioid-signaling pathways (see below). Psychological and cultural factors also play a role in the final expression of appetite. Apart from rare genetic syndromes involving leptin, its receptor, and the melanocortin system, specific defects in this complex appetite control network that influence common cases of obesity are not well defined. Energy expenditure includes the following components: (1) resting or basal metabolic rate; (2) the energy cost of metabolizing and storing food; (3) the thermic effect of exercise; and (4) adaptive thermogenesis, which varies in response to long-term caloric intake (rising with increased intake). Basal metabolic rate accounts for ~70% of daily energy expenditure, whereas active physical activity contributes 5–10%. Thus, a significant component of daily energy consumption is fixed. Genetic models in mice indicate that mutations in certain genes (e.g., targeted deletion of the insulin receptor in adipose tissue) protect against obesity, apparently by increasing energy expenditure. Adaptive thermogenesis occurs in brown adipose tissue (BAT), which plays an important role in energy metabolism in many mammals. In contrast to white adipose tissue, which is used to store energy in the form of lipids, BAT expends stored energy as heat. A mitochondrial uncoupling protein (UCP-1) in BAT dissipates the hydrogen ion gradient in the oxidative respiration chain and releases energy as heat. The metabolic activity of BAT is increased by a central action of leptin, acting through the sympathetic nervous system that heavily innervates this tissue. In rodents, BAT deficiency causes obesity and diabetes; stimulation of BAT with a specific adrenergic agonist (β3 agonist) protects against diabetes and obesity. BAT exists in humans (especially neonates), and although its physiologic role is not yet established, identification of functional BAT in many adults using positron emission tomography (PET) imaging has increased interest in the implications of the tissue for pathogenesis and therapy of obesity. Beige fat cells, recently described, resemble BAT cells in expressing UCP-1. They are scattered through white adipose tissue, and their thermogenic potential is uncertain.

■■THE ADIPOCYTE AND ADIPOSE TISSUE

Adipose tissue is composed of the lipid-storing adipose cell and a stromal/vascular compartment in which cells including preadipocytes and macrophages reside. Adipose mass increases by enlargement of adipose cells through lipid deposition, as well as by an increase in the

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Adipocyte Others PAI-1 Angiotensinogen RBP4 Enzymes Aromatase 11β-HSD-1

Cytokines TNF-α IL-6 Substrates Free fatty acids Glycerol

FIGURE 394-3  Factors released by the adipocyte that can affect peripheral tissues. IL-6, interleukin 6; PAI, plasminogen activator inhibitor; RBP4, retinal binding protein 4; TNF, tumor necrosis factor.

number of adipocytes. Obese adipose tissue is also characterized by increased numbers of infiltrating macrophages. The process by which adipose cells are derived from a mesenchymal preadipocyte involves an orchestrated series of differentiation steps mediated by a cascade of specific transcription factors. One of the key transcription factors is peroxisome proliferator-activated receptor g (PPARγ), a nuclear receptor that binds the thiazolidinedione class of insulin-sensitizing drugs used in the treatment of type 2 diabetes (Chap. 397). Although the adipocyte has generally been regarded as a storage depot for fat, it is also an endocrine cell that releases numerous molecules in a regulated fashion (Fig. 394-3). These include the energy balance–regulating hormone leptin, cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, complement factors such as factor D (also known as adipsin), prothrombotic agents such as plasminogen activator inhibitor I, and a component of the blood pressure–regulating system, angiotensinogen. Adiponectin, an abundant adipose-derived protein whose levels are reduced in obesity, enhances insulin sensitivity and lipid oxidation and has vascular-protective effects, whereas RBP4, whose levels are increased in obesity, may induce insulin resistance. Obesity is accompanied by increased fat storage in tissues such as muscle and liver, and this ectopic lipid has been linked to metabolic disturbances. These factors, and others not yet identified, play a role in the physiology of lipid homeostasis, insulin sensitivity, blood pressure control, coagulation, and vascular health, and are likely to contribute to obesity-related pathologies.

CHAPTER 394 Pathobiology of Obesity

Neural afferents (vagal)

Cultural factors

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Hormones Leptin Adiponectin Resistin

■■ETIOLOGY OF OBESITY

Although the molecular pathways regulating energy balance are beginning to be illuminated, the causes of obesity remain elusive. In part, this reflects the fact that obesity is a heterogeneous group of disorders. At one level, the pathophysiology of obesity seems simple: a chronic excess of nutrient intake relative to the level of energy expenditure. However, due to the complexity of the neuroendocrine and metabolic systems that regulate energy intake, storage, and expenditure, it has been difficult to quantitate all the relevant parameters (e.g., food intake and energy expenditure) over time in human subjects.

Role of Genes Versus Environment  Obesity is commonly seen

in families, and the heritability of body weight is similar to that for height. Inheritance is usually not Mendelian, however, and it is difficult to distinguish the role of genes and environmental factors. Adoptees more closely resemble their biologic than adoptive parents with respect to obesity, providing strong support for genetic influences. Likewise, identical twins have very similar BMIs whether reared together or apart, and their BMIs are much more strongly correlated than those of dizygotic twins. These genetic effects appear to relate to both energy intake and expenditure. Currently, identified genetic variants, both common and rare, account for 160% ideal body weight (IBW), plasma testosterone and sex hormone– binding globulin (SHBG) are often reduced, and estrogen levels (derived from conversion of adrenal androgens in adipose tissue) are increased (Chap. 384). Gynecomastia may be seen. However, masculinization, libido, potency, and spermatogenesis are preserved in most of these individuals. Free testosterone may be decreased in morbidly obese men whose weight is >200% IBW.

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Cardiovascular Disease  The Framingham Study revealed that

obesity was an independent risk factor for the 26-year incidence of cardiovascular disease in men and women (including coronary disease, stroke, and congestive heart failure). The waist-to-hip ratio may be the best predictor of these risks. When the additional effects of hypertension and glucose intolerance associated with obesity are included, the adverse impact of obesity is even more evident. The effect of obesity on cardiovascular mortality in women may be seen at BMIs as low as 25. Obesity, especially abdominal obesity, is associated with an atherogenic lipid profile; with increased low-density lipoprotein cholesterol, very-low-density lipoprotein, and triglyceride; and with decreased high-density lipoprotein cholesterol and decreased levels of the vascular protective adipokine adiponectin (Chap. 400). Obesity is also associated with hypertension. Measurement of blood pressure in the obese requires use of a larger cuff size to avoid artifactual increases. Obesity-induced hypertension is associated with increased peripheral resistance and cardiac output, increased sympathetic nervous system tone, increased salt sensitivity, and insulin-mediated salt retention; it is often responsive to modest weight loss.

Pulmonary Disease  Obesity may be associated with a number of pulmonary abnormalities. These include reduced chest wall compliance, increased work of breathing, increased minute ventilation due to increased metabolic rate, and decreased functional residual capacity and expiratory reserve volume. Severe obesity may be associated with obstructive sleep apnea and the “obesity hypoventilation syndrome” with attenuated hypoxic and hypercapnic ventilatory responses. Sleep apnea can be obstructive (most common), central, or mixed and is associated with hypertension. Weight loss (10–20 kg) can bring substantial improvement, as can major weight loss following gastric bypass or restrictive surgery. Continuous positive airway pressure has been used with some success. Hepatobiliary Disease  Obesity is frequently associated with nonalcoholic fatty liver disease (NAFLD), and this association represents one of the most common causes of liver disease in industrialized countries. The hepatic fatty infiltration of NAFLD progresses in a subset to inflammatory nonalcoholic steatohepatitis (NASH) and more rarely to cirrhosis and hepatocellular carcinoma. Steatosis typically improves following weight loss, secondary to diet or bariatric surgery. The mechanism for the association remains unclear. Obesity is associated with enhanced biliary secretion of cholesterol, supersaturation of bile, and a higher incidence of gallstones, particularly cholesterol gallstones (Chap. 339). A person 50% above IBW has about a sixfold increased incidence of symptomatic gallstones. Paradoxically, fasting increases supersaturation of bile by decreasing the phospholipid component. Fasting-induced cholecystitis is a complication of extreme diets. Cancer  Obesity is associated with increased risk of several cancer types, and in addition can lead to poorer treatment outcomes and increased cancer mortality. Obesity in males is associated with higher mortality from cancer of the esophagus, colon, rectum, pancreas, liver, and prostate; obesity in females is associated with higher mortality

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from cancer of the gallbladder, bile ducts, breasts, endometrium, cer- 2843 vix, and ovaries. Some of the latter may be due to increased rates of conversion of androstenedione to estrone in adipose tissue of obese individuals. Other possible mechanistic links may involve hormones, growth factors, and cytokines whose levels are linked to nutritional state, including insulin, leptin, adiponectin, and IGF-I, as well as activation of signaling pathways linked to both obesity and cancer. It has been estimated that obesity accounts for 14% of cancer deaths in men and 20% in women in the United States.

Bone, Joint, and Cutaneous Disease  Obesity is associated with an increased risk of osteoarthritis, no doubt partly due to the trauma of added weight bearing, but potentially linked as well to activation of inflammatory pathways that could promote synovial pathology. The prevalence of gout may also be increased (Chap. 365). One of the skin problems associated with obesity is acanthosis nigricans, manifested by darkening and thickening of the skinfolds on the neck, elbows, and dorsal interphalangeal spaces. Acanthosis reflects the severity of underlying insulin resistance and diminishes with weight loss. Friability of skin may be increased, especially in skinfolds, enhancing the risk of fungal and yeast infections. Finally, venous stasis is increased in the obese. ■■FURTHER READING

Allison MB, Myers MG: 20 years of leptin: Connecting leptin signaling to biological function. J Endocrinol 223:T25, 2014. Farooqi IS, O’Rahilly S: 20 years of leptin: Human disorders of leptin action. J Endocrinol 223:T63, 2014. Heymsfield SB, Wadden TA: Mechanisms, pathophysiology and management of obesity. N Engl J Med 376:254, 2017. Ogden CL et al: Prevalence of obesity in the United States. JAMA 312:189, 2014.

CHAPTER 395 Evaluation and Management of Obesity

Obesity has long been associated with menstrual abnormalities in women, particularly in women with upper body obesity (Chap. 385). Common findings are increased androgen production, decreased SHBG, and increased peripheral conversion of androgen to estrogen. Most obese women with oligomenorrhea have polycystic ovarian syndrome (PCOS), with its associated anovulation and ovarian hyperandrogenism; 40% of women with PCOS are obese. Most nonobese women with PCOS are also insulin-resistant, suggesting that insulin resistance, hyperinsulinemia, or the combination of the two are causative or contribute to the ovarian pathophysiology in PCOS in both obese and lean individuals. In obese women with PCOS, weight loss often restores normal menses. The increased conversion of androstenedione to estrogen, which occurs to a greater degree in women with lower body obesity, may contribute to the increased incidence of uterine cancer in postmenopausal women with obesity.

and Management 395 Evaluation of Obesity Robert F. Kushner

More than 66% of U.S. adults are categorized as overweight or obese, and the prevalence of obesity is increasing rapidly in most of the industrialized world. Children and adolescents also are becoming more obese, indicating that the current trends will accelerate over time. Obesity is associated with an increased risk of multiple health problems, including hypertension, type 2 diabetes, dyslipidemia, obstructive sleep apnea, nonalcoholic fatty liver disease, degenerative joint disease, and some malignancies. Thus, it is important for physicians to identify, evaluate, and treat patients for obesity and associated comorbid conditions.

■■EVALUATION

Physicians should screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss. The five main steps in the evaluation of obesity, as described below, are (1) a focused obesity-related history, (2) a physical examination to determine the degree and type of obesity, (3) assessment of comorbid conditions, (4) determination of fitness level, and (5) assessment of the patient’s readiness to adopt lifestyle changes.

The Obesity-Focused History  Information from the history should address the following seven questions:

• • • •

What factors contribute to the patient’s obesity? How is the obesity affecting the patient’s health? What is the patient’s level of risk from obesity? What does the patient find difficult about managing weight?

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2844 • What are the patient’s goals and expectations?

• Is the patient motivated to begin a weight management program? • What kind of help does the patient need?

PART 12 Endocrinology and Metabolism

Although the vast majority of cases of obesity can be attributed to behavioral factors that affect diet and physical activity patterns, the history may suggest secondary causes that merit further evaluation. Disorders to consider include polycystic ovarian syndrome, hypothyroidism, Cushing’s syndrome, and hypothalamic disease. Drug-induced weight gain also should be considered. Common causes include medications for diabetes (insulin, sulfonylureas, thiazolidinediones); steroid hormones; antipsychotic agents (clozapine, olanzapine, risperidone); mood stabilizers (lithium); antidepressants (tricyclics, monoamine oxidase inhibitors, paroxetine, mirtazapine); and antiepileptic drugs (valproate, gabapentin, carbamazepine). Other medications, such as nonsteroidal anti-inflammatory drugs and calcium channel blockers, may cause peripheral edema but do not increase body fat. The patient’s current diet and physical activity patterns may reveal factors that contribute to the development of obesity and may identify behaviors to target for treatment. This type of historic information is best obtained by the combination of a questionnaire and an interview.

Body Mass Index (BMI) and Waist Circumference  Three

key anthropometric measurements are important in evaluating the degree of obesity: weight, height, and waist circumference. The BMI, calculated as weight (kg)/height (m)2 or as weight (lb)/height (in)2 × 703, is used to classify weight status and risk of disease (Table 395-1). BMI provides an estimate of body fat and is related to disease risk. Lower BMI thresholds for overweight and obesity have been proposed for the Asia-Pacific region since this population appears to be at risk for glucose and lipid abnormalities at lower body weights. Excess abdominal fat, assessed by measurement of waist circumference or waist-to-hip ratio, is independently associated with a higher risk for diabetes mellitus and cardiovascular disease. Measurement of the waist circumference is a surrogate for visceral adipose tissue and should be performed in the horizontal plane above the iliac crest (Table 395-2).

Physical Fitness  Several prospective studies have demonstrated

that physical fitness, reported by questionnaire or measured by a maximal treadmill exercise test, is an important predictor of all-cause mortality rate independent of BMI and body composition. These observations highlight the importance of taking a physical activity and exercise history during examination as well as emphasizing physical activity as a treatment approach.

Obesity-Associated Comorbid Conditions  The evaluation of comorbid conditions should be based on presentation of symptoms, risk factors, and index of suspicion. For all patients, a fasting lipid panel should be performed (total, low-density lipoprotein, and high-density lipoprotein cholesterol and triglyceride levels) and a fasting blood glucose level and blood pressure determined. Symptoms and diseases that are directly or indirectly related to obesity are listed in Table 395-3. Although individuals vary, the number and severity of TABLE 395-1  Classification of Weight Status and Disease Risk CLASSIFICATION Underweight Healthy weight Overweight Obesity Obesity Extreme obesity

BODY MASS INDEX (kg/m2) 94 cm (>37 in) >80 cm (>31.5 in) >90 cm (>35 in) >80 cm (>31.5 in) >85 cm (>33.5 in) >90 cm (>35 in) Use South Asian recommendations until more specific data are available. Use European data until more specific data are available. Use European data until more specific data are available.

Source: From KGMM Alberti et al for the IDF Epidemiology Task Force Consensus Group: Lancet 366:1059, 2005.

organ-specific comorbid conditions usually rise with increasing levels of obesity. Patients at very high absolute risk include those with the following: established coronary heart disease; presence of other atherosclerotic diseases, such as peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease; type 2 diabetes; and sleep apnea.

Identifying the High-Risk Patient  Efforts are under way to

develop more practical and useful assessments to identify patients TABLE 395-3  Obesity-Related Organ Systems Review Cardiovascular  Hypertension   Congestive heart failure   Cor pulmonale   Varicose veins   Pulmonary embolism   Coronary artery disease Endocrine   Metabolic syndrome   Type 2 diabetes  Dyslipidemia   Polycystic ovarian syndrome Musculoskeletal   Hyperuricemia and gout  Immobility   Osteoarthritis (knees and hips)   Low back pain   Carpal tunnel syndrome Psychological   Depression/low self-esteem   Body image disturbance   Social stigmatization Integument   Striae distensae   Stasis pigmentation of legs  Lymphedema  Cellulitis   Intertrigo, carbuncles   Acanthosis nigricans   Acrochordons (skin tags)   Hidradenitis suppurativa

Respiratory  Dyspnea   Obstructive sleep apnea   Hypoventilation syndrome   Pickwickian syndrome  Asthma Gastrointestinal   Gastroesophageal reflux disease   Nonalcoholic fatty-liver disease  Cholelithiasis  Hernias   Colon cancer Genitourinary   Urinary stress incontinence   Obesity-related glomerulopathy   Hypogonadism (male)   Breast and uterine cancer   Pregnancy complications Neurologic  Stroke   Idiopathic intracranial hypertension   Meralgia paresthetica  Dementia

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Assessing the Patient’s Readiness to Change  An attempt to initiate lifestyle changes when the patient is not ready usually leads to frustration and may hamper future weight-loss efforts. Assessment includes patient motivation and support, stressful life events, psychiatric status, time availability and constraints, and appropriateness of goals and expectations. Readiness can be viewed as the balance of two opposing forces: (1) motivation, or the patient’s desire to change; and (2) resistance, or the patient’s resistance to change. A helpful method to begin a readiness assessment is to use the motivational interviewing technique of “anchoring” the patient’s interest and confidence to change on a numerical scale. With this technique, the patient is asked to rate—on a scale from 0 to 10, with 0 being not so important (or confident) and 10 being very important (or confident)— his or her level of interest in and confidence about losing weight at this time. This exercise helps establish readiness to change and also serves as a basis for further dialogue.

TREATMENT

Obesity THE GOAL OF THERAPY The primary goals of treatment are to improve obesity-related comorbid conditions and reduce the risk of developing future comorbidities. Information obtained from the history, physical examination, and diagnostic tests is used to determine risk and develop a treatment plan (Fig. 395-1). The decision of how aggressively to treat the patient and which modalities to use is determined by the patient’s risk status, expectations, and available resources. Not all patients who are deemed obese by BMI alone need to be treated, as exemplified by the concepts of obesity paradox or the metabolically healthy obese. However, patients who present with obesity-related comorbidities and who would benefit from weight-loss intervention should be managed proactively. Therapy for obesity always begins with lifestyle management and may include pharmacotherapy or surgery, depending on BMI risk category (Table 395-4). Setting an initial weight-loss goal of 8–10% over 6 months is a realistic target. LIFESTYLE MANAGEMENT Obesity care involves attention to three essential elements of lifestyle: dietary habits, physical activity, and behavior modification. Because obesity is fundamentally a disease of energy imbalance, all patients must learn how and when energy is consumed (diet), how and when energy is expended (physical activity), and how to incorporate this information into their daily lives (behavioral therapy). Lifestyle management has been shown to result in a modest (typically 3–5 kg) weight loss when compared with no treatment or usual care. Diet Therapy  The primary focus of diet therapy is to reduce overall calorie consumption. Guidelines from the American Heart Association/American College of Cardiology/The Obesity Society (AHA/ACC/TOS) recommend initiating treatment with a calorie

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deficit of 500–750 kcal/d compared with the patient’s habitual diet. Alternatively, a diet of 1200–1500 kcal/d for women and 1500–1800 kcal/d for men (adjusted for the individual’s body weight) can be prescribed. This reduction is consistent with a goal of losing ~1–2 lb/week. The calorie deficit can be instituted through dietary substitutions or alternatives. Examples include choosing smaller portion sizes, eating more fruits and vegetables, consuming more whole-grain cereals, selecting leaner cuts of meat and skimmed dairy products, reducing consumption of fried foods and other foods with added fats and oils, and drinking water instead of sugar-sweetened beverages. It is important that dietary counseling remains patient centered and that the selected goals are SMART (specific, measurable, agreed upon, realistic, timely). The macronutrient composition of the diet will vary with the patient’s preference and medical condition. The 2015 U.S. Department of Agriculture Dietary Guidelines for Americans (Chap. 325), which focus on health promotion and risk reduction, can be applied to treatment of patients who are overweight or obese. The recommendations include maintaining a diet rich in whole grains, fruits, vegetables, and dietary fiber; decreasing sodium intake to 1.5 kg/week (3.3 lb/week). Prophylaxis against gallstone formation with ursodeoxycholic acid (600 mg/d) is effective in reducing this risk. VLCDs should be used only in limited circumstances and only when provided by trained practitioners in a medical care setting where medical monitoring and high intensity lifestyle intervention can be provided. Medical supervision is required because of the rapid rate of weight loss and potential for health complications.

Behavioral Therapy  Cognitive behavioral therapy is used to help change and reinforce new dietary and physical activity behaviors. Strategies include self-monitoring techniques (e.g., journaling, weighing, and measuring food and activity); stress management; stimulus control (e.g., using smaller plates, not eating in front of the television or in the car); social support; problem solving; and cognitive restructuring to help patients develop more positive and realistic thoughts about themselves. When recommending any behavioral lifestyle change, the patient should be asked to identify what, when, where, and how the behavioral change will be performed. The patient should keep a record of the anticipated behavioral change so that progress can be reviewed at the next office visit. Because these techniques are time consuming to implement, their supervision is often undertaken by ancillary office staff, such as a nurse-clinician or registered dietitian. PHARMACOTHERAPY Adjuvant pharmacologic treatments should be considered for patients with a BMI ≥30 kg/m2 or for patients with a BMI ≥27 kg/m2 who have concomitant obesity-related diseases and for whom dietary and physical activity therapy has not been successful. When an antiobesity medication is prescribed, patients should be actively engaged in a lifestyle program that provides the strategies and skills needed to use the drug effectively, since such support increases total weight loss. Medications for obesity have traditionally fallen into two major categories: appetite suppressants (anorexiants) and gastrointestinal fat blockers.. Four new antiobesity medications have been approved by the U.S. Food and Drug Administration (FDA) since 2012: lorcaserin, phentermine/topiramate (PHEN/TPM) extended release, naltrexone sustained release (SR)/bupropion SR, and liraglutide. Gastrointestinal fat blockers reduce the absorption of selective macronutrients, such as fat, from the gastrointestinal tract. Centrally Acting Anorexiant Medications  Anorexiants affect satiety (the absence of hunger after eating) and hunger (the biologic

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CHAPTER 395 Evaluation and Management of Obesity

Physical Activity Therapy  Although exercise alone is only moderately effective for weight loss, the combination of dietary modification and exercise is the most effective behavioral approach for the treatment of obesity. The most important role of exercise appears to be in the maintenance of the weight loss. The 2008 Physical Activity Guidelines for Americans (www.health.gov/paguidelines) recommend that adults should engage in 150 min of moderate-intensity or 75 min a week of vigorous-intensity aerobic physical activity per week, performed in episodes of at least 10 min and preferably spread throughout the week. Focusing on simple ways to add physical activity into the normal daily routine through leisure activities, travel, and domestic work should be suggested. Examples include brisk walking, using the stairs, doing housework and yard work, and engaging in sports. Asking the patient to wear a pedometer or accelerometer to monitor total accumulation of steps or kcal expended as part of the activities of daily living is a useful strategy. Step counts are highly correlated with activity level. Studies have demonstrated that lifestyle activities are as effective as structured exercise programs for improving cardiorespiratory fitness and weight loss. A high level of physical activity (>300 min of moderate-intensity activity per week) is often needed to lose weight and sustain weight loss. These exercise recommendations are daunting to most patients and need to be implemented gradually. Consultation with an exercise physiologist or personal trainer may be helpful.

sensation that prompts eating). By increasing satiety and decreasing hunger, these agents help patients reduce caloric intake without a sense of deprivation. The target site for the actions of anorexiants is the ventromedial and lateral hypothalamic regions in the central nervous system (Chap. 394). The biologic effect of these agents on appetite regulation is produced by augmentation of the neurotransmission of three monoamines: norepinephrine; serotonin (5-hydroxytryptamine [5-HT]); and, to a lesser degree, dopamine. The classic sympathomimetic adrenergic agents (benzphetamine, phendimetrazine, diethylpropion, mazindol, and phentermine) function by stimulating norepinephrine release or by blocking its reuptake. Among the anorexiants, phentermine is the most commonly prescribed; there are limited long-term data on its effectiveness. A 2002 review of six randomized, placebo-controlled trials of phentermine for weight control found that patients lost 0.6–6.0 additional kg of weight over 2–24 weeks of treatment. The most common side effects of the amphetamine-derived anorexiants are restlessness, insomnia, dry mouth, constipation, and increased blood pressure and heart rate. PHEN/TPM is a combination drug that contains a catecholamine releaser (phentermine) and an anticonvulsant (topiramate). Topiramate is approved by the FDA as an anticonvulsant for the treatment of epilepsy and for the prophylaxis of migraine headaches. Weight loss was identified as an unintended side effect of topiramate during clinical trials for epilepsy. The mechanism responsible for weight loss is uncertain but is thought to be mediated through the drug’s modulation of γ-aminobutyric acid receptors, inhibition of carbonic anhydrase, and antagonism of glutamate. PHEN/TPM has undergone two 1-year pivotal randomized, placebo-controlled, double-blind trials of efficacy and safety: EQUIP and CONQUER. In a third study, SEQUEL, 78% of CONQUER participants continued to receive their blinded treatment for an additional year. All participants received diet and exercise counseling. Participant numbers, eligibility, characteristics, and weight-loss outcomes are displayed in Table 395-5. Intention-to-treat 1-year placebosubtracted weight loss for PHEN/TPM was 9.3% (15-mg/92-mg dose) and 6.6% (7.5-mg/46-mg dose), respectively, in the EQUIP and CONQUER trials. Clinical and statistical dose-dependent improvements were seen in selected cardiovascular and metabolic outcome measurements that were related to the weight loss. The most common adverse events experienced by the drug-randomized group were paresthesias, dry mouth, constipation, dysgeusia, and insomnia. Because of an increased risk of congenital fetal oral-cleft formation from topiramate, women of childbearing age should have a negative pregnancy test before treatment and monthly thereafter, and use effective contraception consistently during medication therapy. Lorcaserin is a selective 5-HT2C receptor agonist with a functional selectivity ~15 times that of 5-HT2A receptors and 100 times that of 5-HT2B receptors. This selectivity is important, since the drug-induced valvulopathy documented with two other serotonergic agents that were removed from the market—fenfluramine and dexfenfluramine—was due to activation of the 5-HT2B receptors expressed on cardiac valvular interstitial cells. By activating the 5-HT2C receptor, lorcaserin is thought to decrease food intake through the pro-opiomelanocortin (POMC) system of neurons. Lorcaserin has undergone two randomized, placebo-controlled, double-blind trials for efficacy and safety. Participants were randomized to receive lorcaserin (10 mg bid) or placebo in the BLOOM study and lorcaserin (10 mg bid or qd) or placebo in the BLOSSOM study. All participants received diet and exercise counseling. Participant numbers, eligibility, characteristics, and weight-loss outcomes are displayed in Table 395-5. Patients who were overweight or obese had at least one coexisting condition (hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea)—medical conditions that are commonly seen in the office setting. Intention-to-treat 1-year placebo-subtracted weight loss was 3.6% and 3.0%, respectively, in the BLOOM and BLOSSOM trials. Echocardiography was performed at the screening visit and

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2848

TABLE 395-5  Clinical Trials for Antiobesity Medications PHEN/TPM

PART 12 Endocrinology and Metabolism

No. of participants (ITT-LOCF) BMI (kg/m2) Age (y) Comorbid conditions (cardiovascular and metabolic) Mean weight loss (%) with treatment vs placebo Placebo-subtracted weight loss (%) Categorical change in 5% weight loss with treatment vs placebo Study completion rate, treatment vs placebo (%)

LORCASERIN

NALTREXONE SR/BUPROPION SR

LIRAGLUTIDE

EQUIP 1230

CONQUER 2487

BLOOM 3182

BLOSSOM 4008

COR-I 1742

COR-II 1496

COR-BMOD 793

SCALE 3731

SCALE MAINTENANCE 422

≥35 18–70 ≥1

27–45 18–70 ≥2

27–45 18–65 ≥1

30–45 18–65 ≥1

30–45 18–65 ≥1

30–45 18–65 ≥1

30–45 18–65 ≥1

≥27 ≥18 ≥1

≥27 ≥18 ≥1

10.9 vs 1.6

7.8 vs 1.2

5.8 vs 2.2

4.8 vs 2.8

6.1 vs 1.3

6.5 vs 1.9

9.3 vs 5.1

8.0 vs 2.6

6.2 vs 0.2

9.3

6.6

3.6

3.0

4.8

4.6

4.2

5.4

6.0

66.7 vs 17.3

62 vs 21

47.5 vs 20.3

47.2 vs 25

48 vs 16

50.5 vs 17.1

66.4 vs 42.5

63.2 vs 27.1

81.4 vs 48.9

66.4 vs 52.9

69 vs 57

55.4 vs 45.1

57.2 vs 52

50

54

57.9 vs 58.4

71.9 vs 64.4

75 vs 69.5

Note: EQUIP (PHEN/TPM = 15/92 mg dose; CONQUER (PHEN/TPM = 7.5/46 mg dose). Abbreviations: BMI, body mass index; ITT-LOCF, intention to treat, last observation carried forward; PHEN-TPM, phentermine-topiramate extended release.

at scheduled time points over the course of the studies. There was no difference in the development of FDA-defined valvulopathy between drug-treated and placebo-treated participants at 1 or 2 years. Modest statistical improvements consistent with the weight loss were seen in selected cardiovascular and metabolic outcome measurements. The most common adverse events experienced by the drug group were headache, dizziness, and nausea. Naltrexone SR/bupropion SR (NB) is a combination of an opioid antagonist and a mild reuptake inhibitor of dopamine and norepinephrine, respectively. Individually, naltrexone is approved by the FDA for the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids, whereas bupropion is approved as an antidepressant and smoking cessation aid. As a combination drug, each component works in consort: bupropion stimulates secretion of α-melanocyte stimulating hormone (MSH) from POMC whereas naltrexone blocks the feedback inhibitory effects of opioid receptors activated by the β-endorphin released in the hypothalamus, thus allowing the inhibitory effects of MSH to reduce food intake. The medication has undergone three randomized, placebocontrolled, double-blind trials for efficacy and safety. Participants were randomized to receive NB (8 mg/90 mg two tablets bid) or placebo in the three COR studies. Whereas participants received standardized nutritional and exercise counseling in COR-I and COR-II, a more intensive behavior modification program was provided in COR-BMOD (Table 395-5). Intention-to-treat 1-year placebosubtracted weight loss was 4.8%, 5.1%, and 4.2%, respectively, in the COR-I, COR-II, and COR-BMOD trials. Clinical and statistical dose-dependent improvements were seen in selected cardiovascular and metabolic outcome measurements that were related to the weight loss. However, the medication led to slight increased or smaller decreases in blood pressure and pulse than placebo. The most common adverse events experienced by the drug-randomized groups were nausea, constipation, headache, vomiting, dizziness, diarrhea, insomnia, and dry mouth. Liraglutide, the fourth new medication, is a glucagon-like peptide-1 (GLP-1) analogue with 97% homology to human GLP-1 that was previously approved for the treatment of type 2 diabetes at doses up to 1.8 mg once daily. In addition to its effect as an incretin hormone (glucose-induced insulin secretion), liraglutide inhibits both gastric emptying and glucagon secretion and stimulates GLP-1

Harrisons_20e_Part12_p2649-p3024.indd 2848

receptors in the arcuate nucleus of the hypothalamus to reduce feeding. Liraglutide has undergone three randomized, placebo-controlled, double-blind trials for efficacy and safety. Participants were randomized to receive liraglutide (3.0 mg sc daily) or placebo for initial weight loss—SCALE (patients without diabetes) and SCALE Diabetes (patients with diabetes), or for weight maintenance after initial weight loss (SCALE Maintenance) (Table 395-5). All participants received diet and exercise counseling. For SCALE and SCALE Maintenance, patients were overweight or obese and had treated or untreated hypertension or dyslipidemia. Intention-to-treat 1-year placebo-subtracted weight loss was 5.4%, and 6.1%, respectively, in the SCALE and SCALE Maintenance trials. Clinical and statistical dose-dependent improvements were seen in selected cardiovascular and metabolic outcome measurements; however, there is a small increase in heart rate. The most common adverse effects include nausea, diarrhea, constipation, and vomiting. GLP-1 agonists should not be prescribed in patients with a family or personal history of medullary thyroid cancer or multiple endocrine neoplasia. In approving the four new antiobesity medications, the FDA introduced a new provision with important clinical relevance: a prescription trial period to assess effectiveness. Response to these medications should be assessed after 12 weeks of treatment for PHEN/TPM and lorcaserin (or 16 weeks for naltrexone SR/bupropion SR and liraglutide since these medications are uptitrated during the first month). Determining responsiveness at 3 or 4 months is based on the post hoc observed trial data that patients who did not lose a prespecified amount of weight early in treatment were less successful at 1 year. For PHEN/TPM, if the patient has not lost at least 3% of body weight at 3 months, the clinician can either escalate the dose and reassess progress at 6 months or discontinue treatment entirely. For lorcaserin and naltrexone SR/bupropion SR, the medication should be discontinued if the patient has not lost at least 5% of body weight. The corresponding responsive target for liraglutide is a 4% weight loss. Peripherally Acting Medications  Orlistat (XenicalTM) is a synthetic hydrogenated derivative of a naturally occurring lipase inhibitor, lipostatin, that is produced by the mold Streptomyces toxytricini. This drug is a potent, slowly reversible inhibitor of pancreatic, gastric, and carboxylester lipases and phospholipase A2, which are required for the hydrolysis of dietary fat into fatty acids and

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SURGERY Bariatric surgery (Fig. 395-2) can be considered for patients with severe obesity (BMI, ≥40 kg/m2) or for those with moderate obesity (BMI, ≥35 kg/m2) associated with a serious medical condition. Weight-loss surgeries have traditionally been classified into three categories on the basis of anatomic changes: restrictive, restrictive malabsorptive, and malabsorptive. More recently, however, the clinical benefits of bariatric surgery in achieving weight loss and alleviating metabolic comorbidities have been attributed largely to changes

A

in the physiologic responses of gut hormones, bile acid metabolism, the microbiota, and in adipose tissue metabolism. Metabolic effects resulting from bypassing the foregut include altered responses of ghrelin, glucagon-like peptide 1, peptide YY3-36, and oxyntomodulin. Additional effects on food intake and body weight control may be attributed to changes in vagal signaling. The loss of fat mass, particularly visceral fat, is associated with multiple metabolic, adipokine, and inflammatory changes that include improved insulin sensitivity and glucose disposal; reduced free fatty acid flux; increased adiponectin levels; and decreased interleukin 6, tumor necrosis factor α, and high-sensitivity C-reactive protein levels. Restrictive surgeries limit the amount of food the stomach can hold and slow the rate of gastric emptying. Laparoscopic adjustable gastric banding is the prototype of this category. The first banding device, the LAP-BAND, was approved for use in the United States in 2001 and the second, the REALIZE band, in 2007. In contrast to previous devices, these bands have diameters that are adjustable by way of their connection to a reservoir that is implanted under the skin. Injection of saline into the reservoir and removal of saline from the reservoir tighten and loosen the band’s internal diameter, respectively, thus changing the size of the gastric opening. Although the mean percentage of total body weight lost at 5 years is estimated at 20–25%, longer-term follow-up has been more disappointing leading to near abandonment of the procedure. In the laparoscopic sleeve gastrectomy, the stomach is restricted by stapling and dividing it vertically, removing ~80% of the greater curvature and leaving a slim banana-shaped remnant stomach along the lesser curvature. Weight loss after this procedure is superior to that after laparoscopic adjustable gastric banding. The three restrictive-malabsorptive bypass procedures combine the elements of gastric restriction and selective malabsorption: Roux-en-Y gastric bypass, biliopancreatic diversion, and biliopancreatic diversion with duodenal switch (Fig. 395-2). Roux-en-Y is the

2849

CHAPTER 395 Evaluation and Management of Obesity

monoacylglycerols. Orlistat acts in the lumen of the stomach and small intestine by forming a covalent bond with the active site of these lipases. Taken at a therapeutic dose of 120 mg tid, orlistat blocks the digestion and absorption of ~30% of dietary fat. After discontinuation of the drug, fecal fat content usually returns to normal within 48–72 h. Multiple randomized, double-blind, placebo-controlled studies have shown that, after 1 year, orlistat produces a weight loss of ~9–10%, whereas placebo recipients have a 4–6% weight loss. Because orlistat is minimally (4000 adults with diabetes found that overall 68.2% of patients experienced an initial complete type 2 diabetes remission within 5 years after surgery. However, among these patients, one-third redeveloped type 2 diabetes within 5 years. The rapid improvement seen in diabetes after restrictive-malabsorptive procedures is thought to be due to caloric restriction, reduced insulin resistance, and surgery-specific effects on glucose homeostasis brought about by alteration of gut hormones. The mortality rate from bariatric surgery is generally 70 genes, each with a relative risk of 1.06–1.5). Most prominent is a variant of the transcription factor 7–like 2 gene that has been associated with type 2 DM in several populations and with IGT. Genetic polymorphisms associated with type 2 DM have also been found in the genes encoding the peroxisome proliferator–activated receptor γ, inward rectifying potassium channel, zinc transporter, IRS, and calpain 10. The mechanisms by which these genetic loci increase the susceptibility to type 2 DM are not clear, but most are predicted to alter islet function or development or insulin secretion. Although the genetic susceptibility to type 2 DM is under active investigation (it is estimated that 1–1.5 in.) is an indication for VFA by DXA or radiography to rule out asymptomatic vertebral fractures, as is the presence of significant kyphosis or back pain, particularly if it began after menopause. For patients who present with fractures, it is important to ensure that the fractures are not caused by an underlying malignancy. Usually this is clear on routine radiography, but on occasion, CT, MRI, or radionuclide scans may be necessary. In this regard it is important not to dismiss fractures simply because they happened on significant trauma. Persons with osteoporosis fracture more readily with any level of injury, a concept that needs continual emphasis. ROUTINE LABORATORY EVALUATION There is no established algorithm for the evaluation of women who present with osteoporosis. A general evaluation that includes complete blood count, serum and 24-h urine calcium, and renal and hepatic function tests is useful for identifying selected secondary causes of low bone mass, particularly for women with fractures or unexpectedly low Z-scores. An elevated serum calcium level suggests hyperparathyroidism or malignancy, whereas a reduced serum calcium level may reflect malnutrition or a malabsorption disease such as celiac disease. In the presence of hypercalcemia, a serum PTH level differentiates between hyperparathyroidism (PTH↑) and malignancy (PTH↓), and a high PTHrP level can help document the presence of humoral hypercalcemia of malignancy (Chap. 403). A low urine calcium (300 mg/24 h) during normal calcium intake (excluding calcium supplements for at least a week before the urine collection) is indicative of hypercalciuria. Hypercalciuria occurs primarily in three situations: (1) a renal calcium leak, which is more common in males with osteoporosis; (2) absorptive hypercalciuria, which can be idiopathic or associated with increased 1,25(OH)2D in granulomatous disease; or (3) hematologic malignancies or conditions associated with excessive bone turnover such as Paget’s disease, hyperparathyroidism, and hyperthyroidism. Renal hypercalciuria is treated with thiazide diuretics, which lower urine

6/1/18 3:30 PM

2949

CHAPTER 404 Osteoporosis FIGURE 404-7  FRAX calculation tool. When the answers to the indicated questions are filled in, the calculator can be used to assess the 10-year probability of fracture. The calculator (available online at http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9) also can risk adjust for various ethnic groups.

calcium and help improve calcium economy. In this setting, thiazides alone can improve bone mass and possibly reduce risk of fracture. They might also reduce renal stone risk. Individuals who have osteoporosis-related fractures or bone density in the osteoporotic range should have a measurement of serum 25(OH)D level, since the intake of vitamin D required to achieve a target level >30 ng/mL is highly variable. Hyperthyroidism should be evaluated by measuring thyroid-stimulating hormone (TSH). When there is clinical suspicion of Cushing’s syndrome, urinary free cortisol levels or a fasting serum cortisol should be measured after overnight dexamethasone. When bowel disease, malabsorption, or malnutrition is suspected, serum albumin, cholesterol, and a complete blood count should be checked. Asymptomatic malabsorption TABLE 404-5  Indications for Vertebral Testing Consider vertebral imaging tests for the following individualsa •  All women aged ≥70 and all men aged ≥80 if BMD T-score at the spine, total hip, or femoral neck is 20% for 10-year major fracture probability and >3% 10-year hip fracture probability. It must be emphasized, however, that as with other diseases, risk assessment is an inexact science when applied to individual patients. Fractures are chance occurrences that can happen to anyone and do! Patients often accept risks that are higher than the physician might like out of concern for the (usually considerably lower) risks of adverse events of drugs. Pharmacologic therapies for osteoporosis are either antiresorptive or anabolic. The antiresorptive agents include medications that have broad effects such as hormone/estrogen therapy and selective estrogen receptor modulators (SERMS) as well as those agents that are specific for the treatment of osteoporosis (bisphosphonates, denosumab, and calcitonin). The only currently approved anabolic agent is teriparatide, but two additional anabolic agents are currently

Harrisons_20e_Part12_p2649-p3024.indd 2952

under FDA review for treatment of osteoporosis (abaloparatide and romosozumab). Antiresorptive Agents  •  Estrogens  A large body of clinical trial data indicates that various types of estrogens (conjugated equine estrogens, estradiol, estrone, esterified estrogens, ethinyl estradiol, and mestranol) reduce bone turnover, prevent bone loss, and induce small increases in bone mass of the spine, hip, and total body. The effects of estrogen are seen in women with natural or surgical menopause and in late postmenopausal women with or without established osteoporosis. Estrogens are efficacious when administered orally or transdermally. For both oral and transdermal routes of administration, combined estrogen/progestin preparations are now available in many countries, obviating the problem of taking two tablets or using a patch and oral progestin. For oral estrogens, the standard recommended doses have been 0.3 mg/d for esterified estrogens, 0.625 mg/d for conjugated equine estrogens, and 5 μg/d for ethinyl estradiol. For transdermal estrogen, the commonly used dose supplies 50 μg estradiol per day, but a lower dose may be appropriate for some individuals. Dose-response data for conjugated equine estrogens indicate that lower doses (0.3 and 0.45 mg/d) are effective. Doses even lower have also been shown to slow bone loss. Fracture Data  Epidemiologic databases indicate that women who take estrogen replacement have a 50% reduction, on average, of osteoporosis related fractures, including hip fractures. The beneficial effect of estrogen is greatest among those who start replacement early and continue the treatment; the benefit declines after discontinuation to the extent that there is no residual protective effect against fracture by 10 years after discontinuation. The first clinical trial evaluating fractures as secondary outcomes, the Heart and Estrogen-progestin Replacement Study (HERS) trial, showed no effect of hormone therapy on hip or other clinical fractures in women with established coronary artery disease. These data made the results of the Women’s Health Initiative (WHI) exceedingly important (Chap. 388). The estrogen-progestin arm of the WHI in >16,000 postmenopausal healthy women indicated that hormone therapy reduces the risk of hip and clinical spine fracture by 34% and that of all clinical fractures by 24%. A few smaller clinical trials have evaluated spine fracture occurrence as an outcome with estrogen therapy. They have consistently shown that estrogen treatment reduces the incidence of vertebral compression fracture. The WHI has provided a vast amount of data on the multisystemic effects of hormone therapy. Although earlier observational studies suggested that estrogen replacement might reduce heart disease, the WHI showed that combined estrogen-progestin treatment increased risk of fatal and nonfatal myocardial infarction by ~29%, confirming data from the HERS study. Other important relative risks included a 40% increase in stroke, a 100% increase in venous thromboembolic disease, and a 26% increase in risk of breast cancer. Subsequent analyses have confirmed the increased risk of stroke and in a substudy showed a twofold increase in dementia. Benefits other than the fracture reductions noted above included a 37% reduction in the risk of colon cancer. These relative risks have to be interpreted in light of absolute risk (Fig. 404-8). For example, out of 10,000 women treated with estrogen-progestin for 1 year, there will be 8 excess heart attacks, 8 excess breast cancers, 18 excess venous thromboembolic events, 5 fewer hip fractures, 44 fewer clinical fractures, and 6 fewer colorectal cancers. These numbers must be multiplied by years of hormone treatment. There was no effect of hormone treatment on the risk of uterine cancer or total mortality. It is important to note that these WHI findings apply specifically to hormone treatment in the form of conjugated equine estrogen plus medroxyprogesterone acetate. The relative benefits and risks of unopposed estrogen in women who had hysterectomies vary somewhat. They still show benefits against fracture occurrence and increased risk of venous thrombosis and stroke, similar in magnitude to the risks for combined hormone therapy. In contrast, though,

6/1/18 3:30 PM

Risks

Benefits

Neutral

Additional events

50 40

7

8

8

18 Reduced events

30

6

20

5

10 0

CHD

Stroke Breast cancer

VTE Colorectal cancer

Hip Endometrial fracture cancer

Deaths

FIGURE 404-8  Effects of hormone therapy on event rates: green, placebo; purple, estrogen and progestin. CHD, coronary heart disease; VTE, venous thromboembolic events. (Adapted from Women’s Health Initiative. WHI HRT Update. Available at http://www.nhlbi.nih.gov/health/women/upd2002.htm.)

the estrogen-only arm of WHI indicated no increased risk of heart attack or breast cancer. The data suggest that at least some of the detrimental effects of combined therapy are related to the progestin component. In addition, there is the possibility, suggested by primate data that the risk accrues mainly to women who have some years of estrogen deficiency before initiating treatment. Nonetheless there is marked reluctance among women for ET/HT and the US preventive services task force has specifically suggested that ET/HT not be used for disease prevention. Mode of Action  Two subtypes of ERs, α and β, have been identified in bone and other tissues. Cells of monocyte lineage express both ERα and ERβ, as do osteoblasts. Estrogen-mediated effects vary with the receptor type. Using ER knockout mouse models, elimination of ERα produces a modest reduction in bone mass, whereas mutation of ERβ has less of an effect on bone. A male patient with a homozygous mutation of ERα had markedly decreased bone density as well as abnormalities in epiphyseal closure, confirming the important role of ERα in bone biology. The mechanism of estrogen action in bone is an area of active investigation (Fig. 404-5). Although data are conflicting, estrogens may inhibit osteoclasts directly. However, the majority of estrogen (and androgen) effects on bone resorption are mediated indirectly through paracrine factors produced by osteoblasts. These actions include (1) increasing OPG production by osteoblasts (2) Increasing IGF-I and TGF-β and (3) suppressing IL-1 (α and β), IL-6, TNF-α, and osteocalcin synthesis. The indirect estrogen actions primarily decrease bone resorption. Progestins  In women with a uterus, daily progestin or cyclical progestins at least 12 days per month are prescribed in combination with estrogens to reduce the risk of uterine cancer. Medroxyprogesterone acetate and norethindrone acetate blunt the high-density lipoprotein response to estrogen, but micronized progesterone does not. Neither medroxyprogesterone acetate nor micronized progesterone appears to have an independent effect on bone; at lower doses of estrogen, norethindrone acetate may have an additive benefit. On breast tissue, progestins may account for the increase the risk of breast cancer with combination treatment. SERMs  Two SERMs are used currently in postmenopausal women: raloxifene, which is FDA-approved for the prevention and treatment of osteoporosis as well as the prevention of breast cancer, and tamoxifen, which is approved for the prevention and treatment of breast cancer. A third SERM, bazodoxiphene, is marketed in combination with conjugated estrogen for treatment of menopausal symptoms and prevention of bone loss. Bazedoxifene protects the uterus and breast from effects of estrogen and makes the use of progestin unnecessary. Tamoxifen reduces bone turnover and bone loss in postmenopausal women compared with placebo groups. These findings

Harrisons_20e_Part12_p2649-p3024.indd 2953

support the concept that tamoxifen acts as an estrogenic agent in bone. There are limited data on the effect of tamoxifen on fracture risk, but the Breast Cancer Prevention study indicated a possible reduction in clinical vertebral, hip, and Colles’ fractures. Tamoxifen is not FDA approved for prevention or treatment of osteoporosis. The major benefit of tamoxifen is on breast cancer occurrence. The breast cancer prevention trial indicated that tamoxifen administration over 4–5 years reduced the incidence of new invasive and noninvasive breast cancer by ~45% in women at increased risk of breast cancer. The incidence of ER-positive breast cancers was reduced by 65%. Tamoxifen increases the risk of uterine cancer in postmenopausal women, limiting its use for breast cancer prevention in women at low or moderate risk. Raloxifene (60 mg/d) has effects on bone turnover and bone mass that are very similar to those of tamoxifen, indicating that this agent is also estrogenic on the skeleton. The effect of raloxifene on bone density (+1.4–2.8% versus placebo in the spine, hip, and total body) is somewhat less than that seen with standard doses of estrogens. Raloxifene reduces the occurrence of vertebral fracture by 30–50%, depending on the population; however, there are no data confirming that raloxifene can reduce the risk of nonvertebral fractures >8 years of observation. Raloxifene, like tamoxifen and estrogen, has effects in other organ systems. The most beneficial effect appears to be a reduction in invasive breast cancer (mainly decreased ER-positive) occurrence of ~65% in women who take raloxifene compared to placebo. In a head-to-head study raloxifene was as effective as tamoxifen in preventing breast cancer in high-risk women and raloxifene is FDA approved for this indication. In a further study raloxifene had no effect on heart disease in women with increased risk for this outcome. In contrast to tamoxifen, raloxifene is not associated with an increase in the risk of uterine cancer or benign uterine disease. Raloxifene increases the occurrence of hot flashes but reduces serum total and low-density lipoprotein cholesterol, lipoprotein(a), and fibrinogen. Raloxifene with positive effects on breast cancer and vertebral fractures has become a useful agent for the treatment of the younger asymptomatic postmenopausal woman. In some women, a recurrence of menopausal symptoms may occur. Usually this is evanescent but occasionally is sufficiently impactful on daily life and sleep, that the drug must be withdrawn. Raloxifene increases the risk of deep vein thrombosis and may increase the risk of death from stroke among older women. Consequently it is not usually recommended for women aged >70 years.

2953

CHAPTER 404 Osteoporosis

Number of cases in 10,000 women/year

60

Mode of Action of SERMs  All SERMs bind to the ER, but each agent produces a unique receptor-drug conformation. As a result, specific coactivator or co-repressor proteins are bound to the receptor (Chap. 370), resulting in differential effects on gene transcription that vary depending on other transcription factors present in the cell. Another aspect of selectivity is the affinity of each SERM for the different ERα and ERβ subtypes, which are expressed differentially in various tissues. These tissue-selective effects of SERMs offer the possibility of tailoring estrogen therapy to best meet the needs and risk factor profile of an individual patient. Bisphosphonates  Alendronate, risedronate, ibandronate, and zoledronic acid are approved for the prevention and treatment of postmenopausal osteoporosis. Alendronate, risedronate, and zoledronic acid are also approved for the treatment of steroid-induced osteoporosis, and risedronate and zoledronic acid are approved for prevention of steroid-induced osteoporosis. Alendronate, risedronate, and zoledronic acid are also approved for treatment of osteoporosis in men. Alendronate decreases bone turnover and increases bone mass in the spine by up to 8% versus placebo and by 6% versus placebo in the hip. Multiple trials have evaluated its effect on fracture occurrence. The Fracture Intervention Trial provided evidence in >2000 women with prevalent vertebral fractures that daily alendronate treatment (5 mg/d for 2 years and 10 mg/d for 9 months afterward) reduces

6/1/18 3:30 PM

2954

Vertebral fractures Alendronate pooled, post hoc

4

Risedronate pooled, post hoc

4

3

PLB RIS

3

Zoledronate preplanned

6

PLB ALN

PART 12

Percent of patients

Ibandronate preplanned PLB IBAN

PLB ZOL

3 4

45%↓* 2

2 49↓*

2 *

1

* 1

*

*

69%↓*

12

A

24

36

0

? 0

6

Months

77%↓*

1

*

*

0 0

12

0 0

12

Months

24

36

0

12

Months

24

36

Months

Nonvertebral fractures Alendronate pooled, post hoc

Risedronate pooled, post hoc

15

15 PLB

PLB

ALN

RIS

Zoledronate preplanned

15

PLB ZOL

27%↓* Percent of patients

Endocrinology and Metabolism

0

2

*

25%↓*

*

59%↓* 5

5

*

0

0 0 B

10

10

10

12

24

36

0

* * *

*

* *

* *

?

5

*

0 12

Months

24 Months

0

36

12

24

36

Months

Hip fractures

Cumulative incidence of hip fractures over 3 years

Cumulative incidence (%)

3

2

RRR 41%

Placebo (n = 3861) Zolendronate (n = 3875)

1

0 0

C

3

6

12 15 18 21 24 27 9 Time to first hip fracture (months)

30

33

36

FIGURE 404-9  Effects of various bisphosphonates on clinical vertebral fractures A. nonvertebral fractures B., and hip fractures C. Plb, placebo; RRR, relative risk reduction. (After DM Black et al: J Clin Endocrinol Metab 85:4118, 2000; C Roux et al: Curr Med Res Opin 4:433, 2004; CH Chesnut et al: J Bone Miner Res 19: 1241, 2004; DM Black et al: N Engl J Med 356:1809, 2007; JT Harrington et al: Calcif Tissue Int 74:129, 2003.)

vertebral fracture risk by about 50%, multiple vertebral fractures by up to 90%, and hip fractures by up to 50%. Several subsequent trials have confirmed these findings (Figs. 404-9 and 404-10). For example, in a study of >1900 women with low bone mass treated with

Harrisons_20e_Part12_p2649-p3024.indd 2954

alendronate (10 mg/d) versus placebo, the incidence of all nonvertebral fractures was reduced by ~47% after only 1 year. In the United States the 10mg dose is approved for treatment of osteoporosis and 5 mg/d for prevention.

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Placebo 60 mg/d of raloxifene

20

RR, 0.5 (95% CI, 0.4-0.6) RR, 0.7 (95% CI, 0.6-0.9)

120 mg/d of raloxifene

15

10

RR, 0.6 (95% CI, 0.4-0.9) RR, 0.5 (95% CI, 0.3-0.7)

5

0

No preexisting fractures

Preexisting fractures

FIGURE 404-10  Effects of two doses of raloxifene on incident vertebral fractures in the MORE trial. (After B Ettinger et al: JAMA:282:637, 1999.)

Trials comparing once-weekly alendronate, 70 mg, with daily 10-mg dosing have shown equivalence with regard to bone mass and bone turnover responses. Consequently, once-weekly therapy generally is preferred because of the low incidence of gastrointestinal side effects and ease of administration. Alendronate should be taken with a full glass of water before breakfast after an overnight fast, as bisphosphonates are poorly absorbed. Because of the potential for esophageal irritation, alendronate is contraindicated in patients who have stricture or inadequate emptying of the esophagus. It is recommended that patients remain upright (standing or sitting)t for at least 30 min after taking the medication to avoid esophageal irritation, and that food and fluids (other than water) be avoided for the same duration. In clinical trials, overall gastrointestinal symptomatology was no different with alendronate than with placebo, but all oral bisphosphonates have been associated with esophageal irritation and inflammation. Risedronate also reduces bone turnover and increases bone mass. Controlled clinical trials have demonstrated 40–50% reduction in vertebral fracture risk over 3 years, accompanied by a 40% reduction in clinical non-spine fractures. The only clinical trial specifically designed to evaluate hip fracture outcome (HIP) indicated that risedronate reduced hip fracture risk in women in their seventies with confirmed osteoporosis by 40%. In contrast, risedronate was not effective at reducing hip fracture occurrence in older women (80+ years) without proven osteoporosis. Studies have shown that 35 mg of risedronate administered once weekly is therapeutically equivalent to 5 mg/d. Patients should take risedronate with a full glass of plain water to facilitate delivery to the stomach and should not lie down for 30 min after taking the drug. (There is also a preparation of risedronate that can be taken with food; it is the only bisphosphonate that has this dosing flexibility.) The incidence of gastrointestinal side effects in trials with risedronate was similar to that of placebo. Ibandronate is the third amino-bisphosphonate approved in the United States. Ibandronate (2.5 mg/d) has been shown in clinical trials to reduce vertebral fracture risk by ~40% but with no overall effect on non-vertebral fractures. In a post hoc analysis of subjects with a femoral neck T-score of ≤–3, ibandronate reduced the risk of nonvertebral fractures by ~60%. In clinical trials, ibandronate doses of 150 mg/month PO or 3 mg every 3 months IV had greater effects on turnover and bone mass than did 2.5 mg/d. Patients should take oral ibandronate in the same way as other bisphosphonates, but with 1 h elapsing before other food or drink (other than plain water). Zoledronic acid is a potent bisphosphonate with a unique administration regimen (5 mg by 15 min IV infusion annually). Zoledronic acid data confirm that it is highly effective in fracture risk reduction. In a study of >7000 women followed for 3 years, zoledronic acid 5 mg IV annually) reduced the risk of vertebral fractures by 70%, nonvertebral fractures by 25%, and hip fractures by 40%. These results

Harrisons_20e_Part12_p2649-p3024.indd 2955

were associated with less height loss and disability. In the treated population, there was an increased risk of almost 25% of an acute phase reaction in patients with no prior bisphosphonate exposure (fever, myalgias, headache, malaise), but effects were short-lived (2–3 days). Detailed evaluation of all bisphosphonates failed to confirm a risk of atrial fibrillation. Zoledronic acid has also been studied in a placebo controlled trial of women and men within 3 months of an acute hip fracture. The risk of recurrent fracture was reduced by 35% and there was a 28% reduction in mortality. Common Bisphosphonate Adverse Events  All bisphosphonates have been associated with some musculoskeletal and joint pains of unclear etiology, which are occasionally severe. There is potential for renal toxicity and bisphosphonates are contraindicated in those with estimated GFR 5 years past menopause.

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A

RR, 0.32 8 P /=40 years: results from the National Health and Nutrition Examination Survey (NHANES) 2013–2014. Osteoporos Int 28:2319, 2017. Panday K et al: Medication-induced osteoporosis: Screening and treatment strategies. Ther Adv Musculoskel Dis 6:185, 2014. Roux C, Briot K: Imminent fracture risk. Osteoporos Int. 28:1765, 2017. Sapir-Koren R, Livshits G: Osteocyte control of bone remodeling: Is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles? Osteoporos Int 25:2685, 2014. Wright NC et al: The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res 29:2520, 2014.

CHAPTER 405 Paget’s Disease and Other Dysplasias of Bone

glucocorticoid-induced osteoporosis (GCIO). Glucocorticoids are used widely in the treatment of a variety of disorders, including chronic lung disorders, rheumatoid arthritis, and other connective tissue diseases, inflammatory bowel disease, and after transplantation. Osteoporosis and related fractures are serious side effects of chronic glucocorticoid therapy. Because the effects of glucocorticoids on the skeleton are often superimposed on the consequences of aging and menopause, it is not surprising that women and the elderly are most frequently affected. The skeletal response to steroids is remarkably heterogeneous, however, and even young, growing individuals treated with glucocorticoids can present with fractures. The risk of fractures depends on the dose and duration of glucocorticoid therapy, although recent data suggest that there may be no completely safe dose. Bone loss is more rapid during the early months of treatment, and trabecular bone is affected more severely than cortical bone. As a result, fractures have been shown to increase within 3 months of steroid treatment. There is an increase in fracture risk in both the axial skeleton and the appendicular skeleton, including risk of hip fracture. Bone loss can occur with any route of steroid administration, including high-dose inhaled glucocorticoids and intraarticular injections. Alternate-day delivery does not appear to ameliorate the skeletal effects of glucocorticoids.

Disease and Other 405 Paget’s Dysplasias of Bone Murray J. Favus, Tamara J. Vokes

PAGET’S DISEASE OF BONE

Paget’s disease is a localized bone-remodeling disorder that affects widespread, noncontiguous areas of the skeleton. The pathologic process is initiated by overactive osteoclastic bone resorption followed by a compensatory increase in osteoblastic new bone formation, resulting in a structurally disorganized mosaic of woven and lamellar bone. Pagetic bone is expanded, less compact, and more vascular; thus, it is more susceptible to deformities and fractures. Although most patients are asymptomatic, symptoms resulting directly from bony involvement (bone pain, secondary arthritis, fractures) or secondarily from the expansion of bone causing compression of surrounding neural tissue are not uncommon.

Epidemiology  There is a marked geographic variation in

the frequency of Paget’s disease, with high prevalence in Western Europe (Great Britain, France, and Germany, but not Switzerland or Scandinavia) and among those who have immigrated to Australia, New Zealand, South Africa, and North and South America. The disease is rare in native populations of the Americas, Africa, Asia, and the Middle East; when it does occur, the affected subjects usually have evidence of European ancestry, supporting the migration theory. For unclear reasons, the prevalence and severity of Paget’s disease are decreasing, and the age of diagnosis is increasing. The prevalence is greater in males and increases with age. Autopsy series reveal Paget’s disease in about 3% of those over age 40. Prevalence of positive skeletal radiographs in patients aged >55 years is 2.5% for men and 1.6% for women. Elevated alkaline phosphatase (ALP) levels in asymptomatic patients have an age-adjusted incidence of 12.7 and 7 per 100,000 person-years in men and women, respectively.

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2960

Mesenchymal cell M-CSF c-fms OPG + RANK L

Osteoclast precursor IL-1, IL-6

PART 12

IGF-1 IGF-2

RANK

Endocrinology and Metabolism

Osteoblasts

Osteoblasts

Osteoclast

Collagen osteocalcin

FIGURE 405-1  Diagram illustrating factors that promote differentiation and function of osteoclasts and osteoblasts and the role of the RANK pathway. Stromal bone marrow (mesenchymal) cells and differentiated osteoblasts produce multiple growth factors and cytokines, including macrophage colonystimulating factor (M-CSF), to modulate osteoclastogenesis. RANKL (receptor activator of nuclear factor-κB ligand) is produced by osteoblast progenitors and mature osteoblasts and can bind to a soluble decoy receptor known as osteoprotegerin (OPG) to inhibit RANKL action. Alternatively, a cell-cell interaction between osteoblast and osteoclast progenitors allows RANKL to bind to its membrane-bound receptor, RANK, thereby stimulating osteoclast differentiation and function. RANK binds intracellular proteins called tumor necrosis factor receptor–associated factors (TRAFs) that mediate receptor signaling through transcription factors such as NF-κB. M-CSF binds to its receptor, c-fms, which is the cellular homologue of the fms oncogene. See text for the potential role of these pathways in disorders of osteoclast function such as Paget’s disease and osteopetrosis. IL, interleukin; IGF, insulin-like growth factor.

Etiology  The etiology of Paget’s disease of bone remains unknown, but evidence supports both genetic and viral etiologies. A positive family history is found in 15–25% of patients and, when present, raises the prevalence of the disease seven- to tenfold among first-degree relatives. A clear genetic basis has been established for several rare familial bone disorders that clinically and radiographically resemble Paget’s disease but have more severe presentation and earlier onset. A homozygous deletion of the TNFRSF11B gene, which encodes osteoprotegrin (Fig. 405-1), causes juvenile Paget’s disease, also known as familial idiopathic hyperphosphatasia, a disorder characterized by uncontrolled osteoclastic differentiation and resorption. Familial patterns of disease in several large kindred are consistent with an autosomal dominant pattern of inheritance with variable penetrance. Familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset Paget’s disease are associated with mutations in TNFRSF11A gene, which encodes RANK (receptor activator of nuclear factor-κB), a member of the tumor necrosis factor superfamily critical for osteoclast differentiation (Fig. 405-1). Finally, mutations in the gene for valosin-containing protein cause a rare syndrome with autosomal dominant inheritance and variable penetrance known as inclusion body myopathy with Paget’s disease and frontotemporal dementia (IBMPFD). The role of genetic factors is less clear in the more common form of late-onset Paget’s disease. The most common mutations identified in familial and sporadic cases of Paget’s disease have been in the SQSTM1 gene (sequestasome-1 or p62 protein) in the C-terminal ubiquitin-binding domain. The other candidate genes include: CSF1 (1p13), which encodes macrophage colony stimulating factor (M-CSF), a cytokine that is required for osteoclast differentiation; RIN3 (14q32), which encodes a guanine exchange factor called Rab and Ras interactor 3; OPTN (10p13), which is involved in regulating NFkB, TNFRSF11A (18q21) which encodes Receptor Activator of Nuclear Factor-kB (RANK), a receptor that is essential for osteoclast differentiation; and TM7SF4, which encodes Dendritic

Harrisons_20e_Part12_p2649-p3024.indd 2960

Cell-Specific Transmembrane Protein (DC-STAMP), a molecule that is essential for fusion of osteoclast. The phenotypic variability in patients with SQSTM1 mutations suggests that additional factors, such as other genetic influences or viral infection, may influence clinical expression of the disease. Several lines of evidence suggest that a viral infection may contribute to the clinical manifestations of Paget’s disease, including (1) the presence of cytoplasmic and nuclear inclusions resembling paramyxoviruses (measles and respiratory syncytial virus) in pagetic osteoclasts and (2) viral mRNA in precursor and mature osteoclasts. The viral etiology is further supported by conversion of osteoclast precursors to pagetic-like osteoclasts by vectors containing the measles virus nucleocapsid or matrix genes. The decline in the incidence of Paget’s disease coincides with the widespread vaccination against measles, also consistent with the potential role of virus in the development of the disease. However, the viral etiology has been questioned by the inability to culture a live virus from pagetic bone and by failure to clone the full-length viral genes from material obtained from patients with Paget’s disease.

Pathophysiology  The principal abnormality in Paget’s disease is

the increased number and activity of osteoclasts. Pagetic osteoclasts are large, increased 10- to 100-fold in number, and have a greater number of nuclei (as many as 100 compared to 3–5 nuclei in the normal osteoclast). The overactive osteoclasts may create a sevenfold increase in resorptive surfaces and an erosion rate of 9 μg/d (normal is 1 μg/d). Several causes for the increased number and activity of pagetic osteoclasts have been identified: (1) osteoclastic precursors are hypersensitive to 1,25(OH)2D3; (2) osteoclasts are hyperresponsive to RANK ligand (RANKL), the osteoclast stimulatory factor that mediates the effects of most osteotropic factors on osteoclast formation; (3) marrow stromal cells from pagetic lesions have increased RANKL expression; (4) osteoclast precursor recruitment is increased by interleukin (IL) 6, which is increased in the blood of patients with active Paget’s disease and is overexpressed in pagetic osteoclasts; (5) expression of the protooncogene c-fos, which increases osteoclastic activity, is increased; and (6) the antiapoptotic oncogene Bcl-2 in pagetic bone is overexpressed. Numerous osteoblasts are recruited to active resorption sites and produce large amounts of new bone matrix. As a result, bone turnover is high, and bone mass is normal or increased, not reduced, unless there is concomitant deficiency of calcium and/or vitamin D. The characteristic feature of Paget’s disease is increased bone resorption accompanied by accelerated bone formation. An initial osteolytic phase involves prominent bone resorption and marked hypervascularization. Radiographically, this manifests as an advancing lytic wedge, or “blade of grass” lesion. The second phase is a period of very active bone formation and resorption that replaces normal lamellar bone with haphazard (woven) bone. Fibrous connective tissue may replace normal bone marrow. In the final sclerotic phase, bone resorption declines progressively and leads to a hard, dense, less vascular pagetic or mosaic bone, which represents the so-called burned-out phase of Paget’s disease. All three phases may be present at the same time at different skeletal sites.

Clinical Manifestations  Diagnosis is often made in asymptom-

atic patients because they have elevated ALP levels on routine blood chemistry testing or an abnormality on a skeletal radiograph obtained for another indication. The skeletal sites most commonly involved are the pelvis, vertebral bodies, skull, femur, and tibia. Familial cases with an early presentation often have numerous active sites of skeletal involvement. The most common presenting symptom is pain, which may result from increased bony vascularity, expanding lytic lesions, fractures, bowing, or other deformities. Bowing of the femur or tibia causes gait abnormalities and abnormal mechanical stresses with secondary osteoarthritis of the hip or knee joints. Long bone bowing also causes extremity pain by stretching the muscles attached to the bone softened by the pagetic process. Back pain results from enlarged pagetic vertebrae, vertebral compression fractures, spinal stenosis, degenerative

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Diagnosis  The diagnosis may be suggested on clinical examination

by the presence of an enlarged skull with frontal bossing, bowing of an extremity, or short stature with simian posturing. An extremity with an area of warmth and tenderness to palpation may suggest an underlying pagetic lesion. Other findings include bony deformity of the pelvis, skull, spine, and extremities; arthritic involvement of the joints adjacent to lesions; and leg-length discrepancy resulting from deformities of the long bones. Paget’s disease is usually diagnosed from radiologic and biochemical abnormalities. Radiographic findings typical of Paget’s disease include enlargement or expansion of an entire bone or area of a long bone, cortical thickening, coarsening of trabecular markings, and typical lytic and sclerotic changes. Skull radiographs (Fig. 405-2) reveal regions of “cotton wool,” or osteoporosis circumscripta, thickening of diploic areas, and enlargement and sclerosis of a portion or all of one or more skull bones. Vertebral cortical thickening of the superior and

2961

FIGURE 405-3  Radiograph of a 73-year-old man with Paget’s disease of the right proximal femur. Note the coarsening of the trabecular pattern with marked cortical thickening and narrowing of the joint space consistent with osteoarthritis secondary to pagetic deformity of the right femur.

inferior end plates creates a “picture frame” vertebra. Diffuse radiodense enlargement of a vertebra is referred to as “ivory vertebra.” Pelvic radiographs may demonstrate disruption or fusion of the sacroiliac joints; porotic and radiodense lesions of the ilium with whorls of coarse trabeculation; thickened and sclerotic iliopectineal line (brim sign); and softening with protrusio acetabuli, with axial migration of the hips and functional flexion contracture. Radiographs of long bones reveal bowing deformity and typical pagetic changes of cortical thickening and expansion and areas of lucency and sclerosis (Fig. 405-3). Radionuclide 99mTc bone scans are less specific but are more sensitive than standard radiographs for identifying sites of active skeletal lesions. Although computed tomography (CT) and magnetic resonance imaging (MRI) studies are not necessary in most cases, CT may be useful for the assessment of possible fracture, and MRI is necessary to assess the possibility of sarcoma, giant cell tumor, or metastatic disease in pagetic bone. Definitive diagnosis of malignancy often requires bone biopsy. Biochemical evaluation is useful in the diagnosis and management of Paget’s disease. The marked increase in bone turnover can be monitored using biochemical markers of bone formation and resorption. The parallel rise in markers of bone formation and resorption confirms the coupling of bone formation and resorption in Paget’s disease. The degree of bone marker elevation reflects the extent and severity of the disease. For most patients, serum total ALP remains the test of choice

CHAPTER 405 Paget’s Disease and Other Dysplasias of Bone

changes of the joints, and altered body mechanics with kyphosis and forward tilt of the upper back. Rarely, spinal cord compression may result from bone enlargement or from the vascular steal syndrome. Skull involvement may cause headaches, symmetric or asymmetric enlargement of the parietal or frontal bones (frontal bossing), and increased head size. Cranial expansion may narrow cranial foramens and cause neurologic complications including hearing loss from cochlear nerve damage from temporal bone involvement, cranial nerve palsies, and softening of the base of the skull (platybasia) with the risk of brainstem compression. Pagetic involvement of the facial bones may cause facial deformity; loss of teeth and other dental conditions; and, rarely, airway compression. Fractures are serious complications of Paget’s disease and usually occur in long bones at areas of active or advancing lytic lesions. Common fracture sites are the femoral shaft and subtrochanteric regions. Neoplasms arising from pagetic bone are rare (3.1 μmol (>200 μg) (Obstructive liver disease can cause false-positive results.) Two mutations 2 matches

Usefulness range: + (somewhat useful) to ++++ (very useful).

a

Fanconi’s syndrome is rare. Sunflower cataracts and Kayser-Fleischer rings (copper deposits in the outer rim of the cornea) may be seen. Electrocardiographic and other cardiac abnormalities have been reported but are not common.

■■DIAGNOSIS

Diagnostic tests for Wilson’s disease are listed in Table 408-1. Serum ceruloplasmin levels should not be used for definitive diagnosis, because they are normal in up to 10% of affected patients and are reduced in 20% of carriers. Kayser-Fleischer rings (Fig. 408-1) can be definitively diagnosed only by an ophthalmologist using a slit lamp. They are present in >99% of patients with neurologic/psychiatric forms of the disease and have been described very rarely in the absence of Wilson’s disease. Kayser-Fleischer rings are present in only ~30–50% of patients diagnosed in the hepatic or presymptomatic state; thus, the absence of rings does not exclude the diagnosis. Urine copper measurement is an important diagnostic tool, but urine must be collected carefully to avoid contamination. Symptomatic patients invariably have urine copper levels >1.6 μmol (>100 μg) per 24 h. Heterozygotes have values 200 μg/g [dry weight] of liver). Copper stains are not reliable. False-positive results can occur with long-standing obstructive liver disease, which can elevate hepatic and urine copper concentrations and rarely causes Kayser-Fleischer rings.

CHAPTER 408 Wilson’s Disease

TEST Serum ceruloplasmin Kayser- Fleischer rings

a

TREATMENT

Wilson’s Disease Recommended anticopper treatments are listed in Table 408-2. Penicillamine was previously the primary anticopper treatment but now plays only a minor role because of its toxicity and because it often worsens existing neurologic disease if used as initial therapy. If penicillamine is given, it should always be accompanied by pyridoxine (25 mg/d). Trientine is a less toxic chelator and is supplanting penicillamine when a chelator is indicated. For patients with hepatitis or cirrhosis but without evidence of hepatic decompensation or neurologic/psychiatric symptoms, zinc is the therapy of choice although some experts advocate therapy with trientine. Zinc has proven efficacy in Wilson’s disease and is essentially nontoxic. It produces a negative copper balance by blocking intestinal absorption of copper, and it induces hepatic metallothionein synthesis, thereby sequestering additional toxic copper. TABLE 408-2  Recommended Anticopper Drugs for Wilson’s Disease DISEASE STATUS Initial hepatic  Hepatitis or cirrhosis without decompensation Hepatic decompensation  Mild  Moderate  Severe Initial neurologic/ psychiatric Maintenance Presymptomatic Pediatric Pregnant

FIRST CHOICE   Zinca

SECOND CHOICE   Trientine

  Trientineb and zinc Trientine and zinc Hepatic transplantation Tetrathiomolybdatec and zinc Zinc Zinc Zinc Zinc

  Penicillamineb and zinc Hepatic transplantation Trientine and zinc Zinc Trientine Trientine Trientine Trientine

a Zinc acetate is supplied as Galzin, manufactured by Gate Pharmaceutical. The recommended adult dose for all the above indications is 50 mg of elemental zinc three times daily, with each dose separated by at least 1 h from consumption of food and beverages other than water as well as from trientine or penicillamine doses. bTrientine is supplied as Syprine and penicillamine as Cuprimine, both manufactured by Merck. The recommended adult dosage for both drugs is 500 mg twice daily, with each dose at least 0.5 h before or 2 h after meals and separated by at least 1 h from zinc administration. cTetrathiomolybdate is being studied in clinical trials.

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2984

TABLE 408-3  Prognostic Index of Nazer   LABORATORY MEASUREMENT Serum bilirubina Serum aspartate aminotransferase Prolongation of prothrombin time (s)

SCORE (IN POINTS)

  NORMAL VALUE 0.2–1.2 mg/dL 10–35 IU/L

0 300

—

20

If hemolysis is present, serum bilirubin cannot be used as a measure of liver function until the hemolysis subsides.

a

PART 12

Source: Modified from H Nazer et al: Gut 27:1377, 1986; with permission from BMJ Publishing Group.

Endocrinology and Metabolism

All presymptomatic patients should be treated prophylactically because the disease is close to 100% penetrant. The first step in evaluating patients presenting with hepatic decompensation is to establish disease severity, which can be estimated with the Nazer prognostic index (Table 408-3). Patients with scores 9 should be considered immediately for liver transplantation. For patients with scores between 7 and 9, clinical judgment is required in deciding whether to recommend transplantation or medical therapy. A combination of trientine and zinc has been used to treat patients with Nazer scores as high as 9, but such patients should be watched carefully for indications of hepatic deterioration, which mandates transplantation. For initial medical treatment of patients with hepatic decompensation, the recommended regimen is a chelator (preferably trientine) plus zinc (Table 408-2). Zinc should not, however, be ingested simultaneously with trientine, which chelates zinc and forms therapeutically ineffective complexes. Administration of the two drugs should be separated by at least 1 h. For initial neurologic therapy, tetrathiomolybdate is emerging as the drug of choice because of its rapid control of free copper, preservation of neurologic function, and low toxicity. Penicillamine and trientine should be avoided because both have a high risk of worsening the neurologic condition. Until tetrathiomolybdate is commercially available, zinc therapy is recommended. Although it is relatively slow-acting, zinc itself does not exacerbate neurologic abnormalities. Although hepatic transplantation may alleviate neurologic symptoms, it does so only by copper removal, which can be done more safely and inexpensively with anticopper drugs. Pregnant patients should be treated with zinc or trientine throughout pregnancy but without tight copper control because copper deficiency can be teratogenic. Anticopper therapy must be lifelong. With treatment, liver function usually recovers after about a year although residual liver damage is usually present. Neurologic and psychiatric symptoms usually improve after 6–24 months of treatment.

■■MONITORING ANTICOPPER THERAPY

When trientine or penicillamine is first used, it is necessary to monitor for drug toxicity, particularly bone marrow suppression and proteinuria. Complete blood counts, standard biochemical profiles, and a urinalysis should be performed at weekly intervals for 1 month, then at twice-weekly intervals for 2 or 3 months, then at monthly intervals for 3 or 4 months, and at 4- to 6-month intervals thereafter. The anticopper effects of trientine and penicillamine can be monitored by following “free” serum copper levels. Changes in urine copper levels are more difficult to interpret because excretion reflects the effect of the drug as well as body loading with copper. Free serum copper is calculated by subtracting the ceruloplasmin copper from the total serum copper. Each 10 mg/L (1 mg/dL) of ceruloplasmin contributes 0.5 μmol/L (3 μg/dL) of serum copper. The normal serumfree copper value is 1.6–2.4 μmol/L (10–15 μg/dL); the level is often as high as 7.9 μmol/L (50 μg/dL) in untreated Wilson’s disease. With treatment, the serum-free copper should be 200 μg) per 24 h. This level should decrease during the first 1–2 years of therapy to 30

—

ALAD

9q32

1149

15.9

330

C

12

Y

 Erythroid-specific ALAD

9q32

1154

15.9

12 (1A + 2 – 12) 12 (1B + 2 – 12)

330

C

—

HMB-synthase  Housekeeping

HMBS

11q23.3

1086

11

361

C

400

 Erythroid-specific HMBS

11q23.3

1035

11

15 (1 + 3 – 15) 15 (2 – 15)

344

C

10

URO-synthase  Housekeeping

UROS

10q26.2

1296

34

265

C

45

 Erythroid-specific UROS

10q26.2

1216

34

265

C

4

URO-decarboxylase COPRO-oxidase PROTO-oxidase Ferrochelatase

1p34.1 3q12.1 1q23.3 18q21.31

1104 1062 1431 1269

3 14 5.5 45

10 (1 + 2B – 10) 10 (2A + 2B – 10) 10 7 13 11

367 354 477 423

C M M M

122 70 181 192

ENZYME ALA-synthase  Housekeeping  Erythroid-specific ALA-dehydratase  Housekeeping

PART 12 Endocrinology and Metabolism

UROD CPOX PPOX FECH

E

H

H H — B

a Number of exons and those encoding separate housekeeping and erythroid-specific forms indicated in parentheses. bNumber of known mutations from the Human Gene Mutation Database (www.hgmd.org). cCrystallized from human (H), murine (M), Escherichia coli (E), Bacillus subtilis (B), or yeast (Y) purified enzyme; references in Protein Data Bank (www.rcsb.org).

Abbreviations: C, cytoplasm; M, mitochondria. Source: From KE Anderson et al: Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias, in The Metabolic and Molecular Bases of Inherited Diseases, CR Scriver et al (eds). New York, McGraw-Hill, 2001, pp 2991–3062.

usually sporadic (Table 409-1). The porphyrias are classified as either hepatic or erythropoietic, depending on the primary site of overproduction and accumulation of their respective porphyrin precursors or porphyrins (Tables 409-1 and 409-2), although some have overlapping features. For example, PCT, the most common porphyria, is hepatic and presents with blistering cutaneous photosensitivity, which is typically characteristic of the erythropoietic porphyrias (EPPs). The major manifestations of the acute hepatic porphyrias are neurologic, including neuropathic abdominal pain, peripheral motor neuropathy, and mental disturbances, with attacks often precipitated by dieting, certain porphyrinogenic drugs, and hormonal changes. While hepatic porphyrias are symptomatic primarily in adults, rare homozygous variants of the autosomal dominant hepatic porphyrias usually manifest clinically prior to puberty. In contrast, the erythropoietic porphyrias usually present at birth or in early childhood with cutaneous photosensitivity, or in the case of congenital erythropoietic porphyria (CEP), even in utero as nonimmune hydrops fetalis. Cutaneous sensitivity to sunlight results from excitation of excess porphyrins in the skin by long-wave ultraviolet light, leading to cell damage, scarring, and disfigurement. Thus, the porphyrias are metabolic disorders in which environmental, physiologic, and genetic factors interact to cause disease. Because many symptoms of the porphyrias are nonspecific, diagnosis is often delayed. Laboratory measurement of porphyrin precursors (5′-aminolevulinic acid [ALA] and porphobilinogen [PBG]) in the urine or porphyrins in the urine, plasma, erythrocytes, or feces is required to confirm or exclude the various types of porphyria (see below). However, a definite diagnosis requires demonstration of the specific gene defect (Table 409-3). The genes encoding all the heme biosynthetic enzymes have been characterized, permitting identification of the mutations causing each porphyria (Table 409-2). Molecular genetic analyses now make it possible to provide precise heterozygote or homozygote identification and prenatal diagnoses in families with known mutations. In addition to recent reviews of the porphyrias, informative and up-to-date websites are sponsored by the American Porphyria Foundation (www.porphyriafoundation.com) and the European Porphyria

Harrisons_20e_Part12_p2649-p3024.indd 2986

Initiative (www.porphyria-europe.org). An extensive list of unsafe and safe drugs for individuals with acute porphyrias is provided at the Drug Database for Acute Porphyrias (www.drugs-porphyria.com).

GLOBAL CONSIDERATIONS

The porphyrias are panethnic metabolic diseases that affect individuals around the globe. The acute hepatic porphyrias— acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP)—are autosomal dominant disorders. The frequency of symptomatic AIP, the most common acute hepatic porphyria, is ~1 in 20,000 among Caucasian individuals of Western European ancestry, and it is particularly frequent in Scandinavians, with a frequency of ~1 in 10,000 in Sweden. However, a recent study using genomic/exomic databases showed an estimated frequency of pathogenic variants in the HMBS gene as ~1 in 1,700. Thus, the penetrance of AIP, and likely the other acute hepatic porphyrias, is low, about 1–10% of those with pathogenic mutations experiencing acute attacks (see below). VP is particularly frequent in South Africa, where its high prevalence (>10,000 affected patients) is in part due to a genetic “founder effect.” The autosomal recessive acute hepatic porphyria, ALAdehydratase-deficient porphyria (ADP), is very rare, and 6.8 mg/dL). The risk of developing gouty arthritis or urolithiasis increases with higher urate levels and escalates in proportion to the degree of elevation. The prevalence of hyperuricemia is increasing among ambulatory adults and even more markedly among hospitalized patients. The prevalence of gout in the United States more than doubled between the 1960s and the 1990s. Based on NHANES data from 2007 to 2008, these trends continue, with an approximate prevalence of gout among men of 5.9% (6.1 million) and among women of 2.0% (2.2 million). Mean serum urate levels rose to 6.14 mg/dL among men and 4.87 mg/dL among women, with consequent hyperuricemia prevalences of 21.2 and 21.6%, respectively (with hyperuricemia defined as a serum urate level of >7.0 mg/dL [415 μmol/L] for men and >5.7 mg/dL [340 μmol/L] for women). These numbers represent a 1.2% increase in the prevalence of gout, a 0.15mg/dL increase in the serum urate level, and a 3.2% increase in the prevalence of hyperuricemia over figures reported in NHANES-III (1988–1994). These rises are thought to be driven by increased obesity and hypertension and perhaps also by better medical care and increased longevity.

■■CAUSES OF HYPERURICEMIA

Hyperuricemia may be classified as primary or secondary, depending on whether the cause is innate or an acquired disorder. However, it is more useful to classify hyperuricemia in relation to the underlying pathophysiology— i.e., whether it results from increased production, decreased excretion, or a combination of the two (Fig. 410-1, Table 410-2).

Increased Urate Production  Diet contributes to the serum urate

concentration in proportion to its purine content. Strict restriction of purine intake reduces the mean serum urate level by ~60 μmol/L (~1 mg/dL) and urinary uric acid excretion by ~1.2 mmol/d (~200 mg/d). TABLE 410-2  Classification of Hyperuricemia by Pathophysiology Urate Overproduction Primary idiopathic HPRT deficiency PRPP synthetase overactivity Hemolytic processes Lymphoproliferative diseases

Myeloproliferative diseases Polycythemia vera Psoriasis Paget’s disease Glycogenosis III, V, and VII

Rhabdomyolysis Exercise Alcohol Obesity Purine-rich diet

Decreased Uric Acid Excretion Primary idiopathic Renal insufficiency Polycystic kidney disease Diabetes insipidus Hypertension Acidosis   Lactic acidosis   Diabetic ketoacidosis

Starvation ketosis Berylliosis Sarcoidosis Lead intoxication Hyperparathyroidism Hypothyroidism Toxemia of pregnancy Bartter’s syndrome Down syndrome

Drug ingestion Salicylates (9.0 mg/dL) as opposed to only 0.5% among those with values between 415 and 535 μmol/L (7.0 and 8.9 mg/dL). The complications of gout correlate with both the duration and the severity of hyperuricemia. For further discussion of gout, see Chap. 365. Hyperuricemia also causes several renal problems: (1) nephrolithiasis; (2) urate nephropathy, a rare cause of renal insufficiency attributed to monosodium urate crystal deposition in the renal interstitium; and (3) uric acid nephropathy, a reversible cause of acute renal failure resulting from deposition of large amounts of uric acid crystals in the renal collecting ducts, pelvis, and ureters.

Nephrolithiasis  Uric acid nephrolithiasis occurs most commonly, but not exclusively, in individuals with gout. In gout, the prevalence of nephrolithiasis correlates with the serum and urinary uric acid levels, reaching ~50% with serum urate levels of 770 μmol/L (13 mg/dL) or urinary uric acid excretion >6.5 mmol/d (1100 mg/d). Uric acid stones can develop in individuals with no evidence of arthritis, only 20% of whom are hyperuricemic. Uric acid can also play a role in other types of kidney stones. Some individuals who do not have gout but have calcium oxalate or calcium phosphate stones have hyperuricemia or hyperuricaciduria. Uric acid may act as a nidus on which calcium oxalate can precipitate or lower the formation product for calcium oxalate crystallization. Urate Nephropathy  Urate nephropathy, sometimes referred to as

urate nephrosis, is a late manifestation of severe gout and is characterized histologically by deposits of monosodium urate crystals surrounded by a giant-cell inflammatory reaction in the medullary interstitium and pyramids. The disorder is now rare and cannot be diagnosed in the absence of gouty arthritis. The lesions may be clinically silent or cause proteinuria, hypertension, and renal insufficiency.

Uric Acid Nephropathy  This reversible cause of acute renal fail-

ure is due to precipitation of uric acid in renal tubules and collecting ducts that obstructs urine flow. Uric acid nephropathy develops following sudden urate overproduction and marked hyperuricaciduria. Factors that favor uric acid crystal formation include dehydration and acidosis. This form of acute renal failure occurs most often during an aggressive “blastic” phase of leukemia or lymphoma prior to or coincident with cytolytic therapy but has also been observed in individuals with other neoplasms, following epileptic seizures, and after vigorous exercise with heat stress. Autopsy studies have demonstrated intraluminal precipitates of uric acid, dilated proximal tubules, and normal glomeruli. The initial pathogenic events are believed to include obstruction of collecting ducts with uric acid and obstruction of the distal renal vasculature. If recognized, uric acid nephropathy is potentially reversible. Appropriate therapy has reduced the mortality rate from ~50% to near zero. Serum levels cannot be relied on for diagnosis because this condition has developed in the presence of urate concentrations varying from 720 to 4800 μmol/L (12–80 mg/dL). The distinctive feature is the urinary uric acid concentration. In most forms of acute renal failure with decreased urine output, urinary uric acid content is either normal or reduced, and the ratio of uric acid to creatinine is 1, and a value that high is essentially diagnostic.

HYPERURICEMIA AND METABOLIC SYNDROME

Metabolic syndrome (Chap. 401) is characterized by abdominal obesity with visceral adiposity, impaired glucose tolerance due to insulin resistance with hyperinsulinemia, hypertriglyceridemia, increased low-density lipoprotein cholesterol, decreased high-density lipoprotein cholesterol, and hyperuricemia. Hyperinsulinemia reduces the renal excretion of uric acid and sodium. Not surprisingly, hyperuricemia resulting from euglycemic hyperinsulinemia may precede the onset

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of type 2 diabetes, hypertension, coronary artery disease, and gout in individuals with metabolic syndrome.

TREATMENT

Hyperuricemia

SYMPTOMATIC HYPERURICEMIA See Chap. 365 for treatment of gout, including urate nephrosis. Nephrolithiasis  Antihyperuricemic therapy is recommended for the individual who has both gouty arthritis and either uric acid– or calcium-containing stones, both of which may occur in association with hyperuricaciduria. Regardless of the nature of the calculi, fluid ingestion should be sufficient to produce a daily urine volume >2 L. Alkalinization of the urine with sodium bicarbonate or acetazolamide may be justified to increase the solubility of uric acid. Specific treatment of uric acid calculi requires reducing the urine uric acid concentration with a xanthine oxidase inhibitor, such as allopurinol or febuxostat. These agents decrease the serum urate concentration and the urinary excretion of uric acid in the first 24 h, with a maximal reduction within 2 weeks. Allopurinol can be given once a day because of the long half-life (18 h) of its active metabolite, oxypurinol. In the febuxostat trials, the generally recommended dose of allopurinol (300 mg/d) was effective at achieving a target serum urate concentration 200 5–30/200–1000 6–34/37–180 6–39/40–88 15–31/34–400 13–36/55–86

XR XR AD, variable penetrance AD AD AD AD

FMR-1 protein FMR-2 protein Myotonin protein kinase Huntingtin Ataxin 1 Ataxin 2 Ataxin 3

19p13.1-13.2

CAG

4–16/20–33

AD

Spinocerebellar ataxia type 7 (SCA7) Spinocerebellar ataxia type 12 (SCA12) Dentatorubral pallidoluysian atrophy (DRPLA) Friedreich’s ataxia (FRDA1)

3p21.1-p12 5q31 12p

CAG CAG CAG

4–19/37 to >300 6–26/66–78 7–23/49–75

AD AD AD

Alpha 1A voltagedependent L-type calcium channel Ataxin 7 Protein phosphatase 2A Atrophin 1

9q13-21

GAA

7–22/200–900

AR

Frataxin

CHAPTER 456 Principles of Human Genetics

DISEASE X-chromosomal spinobulbar muscular atrophy (SBMA) Fragile X syndrome (FRAXA) Fragile X syndrome (FRAXE) Dystrophia myotonica (DM) Huntington’s disease (HD) Spinocerebellar ataxia type 1 (SCA1) Spinocerebellar ataxia type 2 (SCA2) Spinocerebellar ataxia type 3 (SCA3); Machado-Joseph disease (MD) Spinocerebellar ataxia type 6 (SCA6, CACNAIA)

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; XR, X-linked recessive.

dominant manner and the second allele is inactivated by a subsequent somatic mutation. This two-hit model applies to other inherited cancer syndromes such as MEN 1 (Chap. 381) and neurofibromatosis type 2 (Chap. 86). In contrast, in the autosomal dominant MEN2 syndrome, the predisposition for tumor formation in various organs is caused by a gain-of-function mutation in a single allele of the RET gene (Chap. 381). Several diseases are associated with an increase in the number of nucleotide repeats above a certain threshold (Table 456-5). The repeats are sometimes located within the coding region of the genes, as in Huntington’s disease or the X-linked form of spinal and bulbar muscular atrophy (SBMA; Kennedy’s syndrome). In other instances, the repeats probably alter gene regulatory sequences. If an expansion is present, the DNA fragment is unstable and tends to expand further during cell division. The length of the nucleotide repeat often correlates with the severity of the disease. When repeat length increases from one generation to the next, disease manifestations may worsen or be observed at an earlier age; this phenomenon is referred to as anticipation. In Huntington’s disease, for example, there is a correlation between age of onset and length of the triplet codon expansion (Chap. 417). Anticipation has also been documented in other diseases caused by dynamic mutations in trinucleotide repeats (Table 456-5). The repeat number may also vary in a tissue-specific manner. In myotonic dystrophy, the CTG repeat may be tenfold greater in muscle tissue than in lymphocytes (Chap. 441).

NUCLEOTIDE REPEAT EXPANSION DISORDERS 

Complex Genetic Disorders  The expression of many com-

mon diseases such as cardiovascular disease, hypertension, diabetes, asthma, psychiatric disorders, and certain cancers is determined by a combination of genetic background, environmental factors, and lifestyle. A trait is called polygenic if multiple genes contribute to the phenotype or multifactorial if multiple genes are assumed to interact with environmental factors. Genetic models for these complex traits need to account for genetic heterogeneity and interactions with other genes and the environment. Complex genetic traits may be influenced by modifier genes that are not linked to the main gene involved in the pathogenesis of the trait. This type of gene-gene interaction, or epistasis, plays an important role in polygenic traits that require the simultaneous presence of variations in multiple genes to result in a pathologic phenotype. Type 2 diabetes mellitus provides a paradigm for considering a multifactorial disorder, because genetic, nutritional, and lifestyle factors are intimately interrelated in disease pathogenesis (Table 456-6) (Chap. 396). The identification of genetic variations and environmental factors that either predispose to or protect against disease is essential for predicting

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disease risk, designing preventive strategies, and developing novel therapeutic approaches. The study of rare monogenic diseases may provide insight into some of the genetic and molecular mechanisms important in the pathogenesis of complex diseases. For example, the identification of the genes causing monogenic forms of permanent neonatal diabetes mellitus or maturity-onset diabetes defined them as candidate genes in the pathogenesis of diabetes mellitus type 2 (Tables 456-2 and 456-6) (Fig. 456-15). Genome scans have identified numerous genes and loci that may be associated with susceptibility to development of diabetes mellitus in certain populations (Fig. 456-16). Efforts to identify susceptibility genes require very large sample sizes, and positive results may depend on ethnicity, ascertainment criteria, and statistical analysis. Association studies analyzing the potential influence of (biologically functional) SNPs and SNP haplotypes on a particular phenotype have revealed new insights into the genes involved in the pathogenesis of these common disorders. Large variants ([micro]deletions, duplications, and inversions) present in the human population also contribute to the pathogenesis of complex disorders, but their contributions remain poorly understood.

Linkage and Association Studies  There are two primary strat-

egies for mapping genes that cause or increase susceptibility to human disease: (1) classic linkage can be performed based on a known genetic model or, when the model is unknown, by studying pairs of affected relatives; or (2) disease genes can be mapped using allelic association studies (Table 456-7).

Genetic linkage refers to the fact that genes are physically connected, or linked, to one another along the chromosomes. Two fundamental principles are essential for understanding the concept of linkage: (1) when two genes are close together on a chromosome, they are usually transmitted together, unless a recombination event separates them (Figs. 456-6); and (2) the odds of a crossover, or recombination event, between two linked genes is proportional to the distance that separates them. Thus, genes that are farther apart are more likely to undergo a recombination event than genes that are very close together. The detection of chromosomal loci that segregate with a disease by linkage can be used to identify the gene responsible for the disease (positional cloning) and to predict the odds of disease gene transmission in genetic counseling. Polymorphic variants are essential for linkage studies because they provide a means to distinguish the maternal and paternal chromosomes in an individual. On average, 1 out of every 1000 bp varies from one person to the next. Although this degree of variation seems low (99.9% identical), it means that >3 million sequence differences exist

GENETIC LINKAGE 

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TABLE 456-6  Genes and Loci Involved in Mono- and Polygenic Forms of Diabetes

PART 16 Genes, the Environment, and Disease

DISORDER Monogenic permanent neonatal diabetes mellitus    

GENES OR SUSCEPTIBILITY LOCUS KCNJ11 (inwardly rectifying potassium channelKir6.2)

CHROMOSOMAL LOCATION 11p15.1

GCK (glucokinase) INS (insulin)

7p15-p13 11p15.5

   

ABCC8 (ATP-binding cassette, subfamily c, member 8; sulfonylurea receptor) GLIS3 (GLIS family zinc finger protein 3)

11p15.1 9p24.2

Maturity-onset diabetes of the young (MODY): Monogenic forms of diabetes mellitus MODY 1

 

 

AR AR, hyperproinsulinemia AD or AR AR, diabetes, congenital hypothyroidism  

HNF4α (hepatocyte nuclear factor 4α) GCK (glucokinase)

20q12-q13.1

AD inheritance

7p15-p13 12q24.2

   

13q12.1 17cen-q21.3

   

2q32 19p13.13-p13.12 9q34.3 7q32 11p15.5 8p23-p22  

            Heavily influenced by diet, energy expenditure, obesity

MODY 2 MODY 3 MODY 4 MODY 5 (renal cysts, diabetes) MODY 6 MODY 7 MODY 8 MODY 9 MODY 10 MODY 11 Diabetes mellitus type 2; loci and genes linked and/or associated with susceptibility for diabetes mellitus type 2  

HNF1α (hepatocyte nuclear factor 1α) IPF1 (insulin receptor substrate) HNF1β (hepatocyte nuclear factor 1β) NeuroD1 (neurogenic differentiation factor 1) KLF1 (Kruppel-like factor 1) CEL (carboxyl ester lipase) PAX4 (paired box transcription factor 4) INS (insulin) BLK (B-lymphocyte-specific tyrosine kinase) Genes and loci identified by linkage/association studies

PPARG, KCNJ11/ABCC8, TCF7L2, HNF1B, WFS1, SLC30A8, FTO, HHEX, IGF2BP2,   CDKN2A/B, CDKAL1, TSPAN8, ADAMTs9, CDC123/CAMK1D, JAZF1, NOTCH2, THADA, KCNQ1, DUSP8, MTNR1B, IRS1, SPRY2, SRR, ZFAND6, GCK, KLF14, TP53INP1, PROX1, PRC1, BCL11A, ZBED3, RBMS1, HNF1A, DGKB/TMEM195, CCND2, C2CD4A/C2CD4B, PTPRD, ARAP1/CENTD2, HMGA2, TLE4/CHCHD9, ADCY5, UBE2E2, DUSP9, GCKR, COBLL1/GRB14, HMG20A, VPS26A, ST6GAL1, AP3S2, HNF4A, BCL2, LAMA1, GIPR, MC4R, TLE1, KCNK16, ANK1, KLHDC5, ZMIZ1, PSMD6 , FITM2/R3HDML/HNF4A, CILP2, ANKRD55, GLIS3, PEPD, GCC1/PAX4, ZFAND3, MAEA, BCAR1, RBM43/RND3 , MACF1, RASGRP1, GRK5, TMEM163, SGCG, LPP, FAF1, TMEM154, MPHOSPH9, ARL15, POU5F1/TCF19, SSR1/RREB1, HLA-B, INS-IGF2, GPSM1, LEP, SLC16A13, PAM/PPIP5K2, SLC16A11, CCDC63, C12orf51, CCND2, HNF1A, TBC1D4, CCDC85A, INAFM2, ASB3, FAM60A, ATP8B2, MIR4686, MTMR3, DMRTA1, SLC35D3, GLP2R, GIP, MAP3K11, PLEKHA1, HSD17B12, NRXN3, CMIP, ZZEF1, MNX1, ABO, ACSL1, HLA-DQA1

OTHER FACTORS AD

 

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; MODY, maturity onset diabetes of the young.

between any two unrelated individuals and the probability that the sequence at such loci will differ on the two homologous chromosomes is high (often >70–90%). These sequence variations include variable number of tandem repeats (VNTRs), short tandem repeats (STRs), and SNPs. Most STRs, also called polymorphic microsatellite markers, consist of di-, tri-, or tetranucleotide repeats that can be characterized readily using the polymerase chain reaction (PCR). Characterization of SNPs, using DNA chips or beads, permits comprehensive analyses of genetic variation, linkage, and association studies. Although these sequence variations often have no apparent functional consequences, they provide much of the basis for variation in genetic traits. In order to identify a chromosomal locus that segregates with a disease, it is necessary to characterize polymorphic DNA markers from affected and unaffected individuals of one or several pedigrees. One can then assess whether certain marker alleles cosegregate with the disease. Markers that are closest to the disease gene are less likely to undergo recombination events and therefore receive a higher linkage score. Linkage is expressed as a lod (logarithm of odds) score—the ratio of the probability that the disease and marker loci are linked rather than unlinked. Lod scores of +3 (1000:1) are generally accepted as supporting linkage, whereas a score of –2 is consistent with the absence of linkage.

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ALLELIC ASSOCIATION, LINKAGE DISEQUILIBRIUM, AND HAPLOTYPES 

Allelic association refers to a situation in which the frequency of an allele is significantly increased or decreased in individuals affected by a particular disease in comparison to controls. Linkage and association differ in several aspects. Genetic linkage is demonstrable in families or sibships. Association studies, on the other hand, compare a population of affected individuals with a control population. Association studies can be performed as case-control studies that include unrelated affected individuals and matched controls or as family-based studies that compare the frequencies of alleles transmitted or not transmitted to affected children. Allelic association studies are particularly useful for identifying susceptibility genes in complex diseases. When alleles at two loci occur more frequently in combination than would be predicted (based on known allele frequencies and recombination fractions), they are said to be in linkage disequilibrium. Evidence for linkage disequilibrium can be helpful in mapping disease genes because it suggests that the two loci are tightly linked. Detecting the genetic factors contributing to the pathogenesis of common complex disorders is challenging. In many instances, these are low-penetrance alleles (e.g., variations that individually have a subtle effect on disease development, and they can only be identified by unbiased GWAS) (Catalog of published Genome-Wide Association

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3365

50

Effect size

CHAPTER 456 Principles of Human Genetics

Rare: Common variants with high effect on complex disease

Rare alleles Mendelian disease

High

3.0 Low frequency variants with intermediate effect

Intermediate 1.5 Modest 1.1

Typical: Common variants with low effect on complex disease

Rare variants with small effect: difficult to identify

Low 0.001 Very rare

0.005 Rare

0.05 Low frequency

Common

Allele frequency FIGURE 456-15  Relationship between allele frequency and effect size in monogenic and polygenic disorders. In classic Mendelian disorders, the allele frequency is typically low but has a high impact (single gene disorder). This contrasts with polygenic disorders that require the combination of multiple low impact alleles that are frequently quite common in the general population.

Studies; Table 456-1) (Fig. 456-16). Most variants occur in noncoding or regulatory sequences but do not alter protein structure. The analysis of complex disorders is further complicated by ethnic differences in disease prevalence, differences in allele frequencies in known susceptibility genes among different populations, locus and allelic heterogeneity, gene-gene and gene-environment interactions, and the possibility of phenocopies. Catalogues of human variation and genotype data (HapMap, International Genome Sample Resource) are greatly facilitating GWAS for the characterization of complex disorders. Adjacent SNPs are inherited together as blocks, and these blocks can be identified by genotyping selected marker SNPs, so-called Tag SNPs, thereby reducing cost and workload (Fig. 456-4). The availability of this information permits the characterization of a limited number of SNPs to identify the set of haplotypes present in an individual (e.g., in cases and controls). This, in turn, permits performing GWAS by searching for associations of certain haplotypes with a disease phenotype of interest, an essential step for unraveling the genetic factors contributing to complex disorders. POPULATION GENETICS  In population genetics, the focus changes from alterations in an individual’s genome to the distribution pattern of different genotypes in the population. In a case where there are only two alleles, A and a, the frequency of the genotypes will be p2 + 2pq + q2 = 1, with p2 corresponding to the frequency of AA, 2pq to the frequency of Aa, and q2 to aa. When the frequency of an allele is known, the frequency of the genotype can be calculated. Alternatively, one can determine an allele frequency if the genotype frequency has been determined. Allele frequencies vary among ethnic groups and geographic regions. For example, heterozygous mutations in the CFTR gene are relatively common in populations of European origin but are rare in the African population. Allele frequencies may vary because certain allelic variants confer a selective advantage. For example, heterozygotes for the sickle cell mutation, which is particularly common in West Africa, are more resistant to malarial infection because the erythrocytes of heterozygotes provide a less favorable environment for Plasmodium parasites. Although homozygosity for the sickle cell mutation is associated with severe anemia and sickle crises, heterozygotes have a higher probability of survival because of the reduced morbidity and mortality from malaria; this phenomenon has led to an increased frequency of the mutant allele. Recessive conditions are more prevalent in geographically isolated populations because of the more restricted gene pool.

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APPROACH TO THE PATIENT

Inherited Disorders For the practicing clinician, the family history remains an essential step in recognizing the possibility of a hereditary predisposition to disease. When taking the history, it is useful to draw a detailed pedigree of the first-degree relatives (e.g., parents, siblings, and children), because they share 50% of genes with the patient. Standard symbols for pedigrees are depicted in Fig. 456-11. The family history should include information about ethnic background, age, health status, and deaths, including infants. Next, the physician should explore whether there is a family history of the same or related illnesses to the current problem. An inquiry focused on commonly occurring disorders such as cancers, heart disease, and diabetes mellitus should follow. Because of the possibility of age-dependent expressivity and penetrance, the family history will need intermittent updating. If the findings suggest a genetic disorder, the clinician should assess whether some of the patient’s relatives may be at risk of carrying or transmitting the disease. In this circumstance, it is useful to confirm and extend the pedigree based on input from several family members. This information may form the basis for genetic counseling, carrier detection, early intervention, and disease prevention in relatives of the index patient (Chap. 457). In instances where a diagnosis at the molecular level may be relevant, it is important to identify an appropriate laboratory that can perform the appropriate test. Genetic testing is available for a large number of monogenic disorders through commercial laboratories. For uncommon disorders, the test may only be performed in a specialized research laboratory. Approved laboratories offering testing for inherited disorders can be identified in continuously updated online resources (e.g., GeneTests; Table 456-1). If genetic testing is considered, the patient and the family should be counseled about the potential implications of positive results, including psychological distress and the possibility of discrimination. The patient or caretakers should be informed about the meaning of a negative result, technical limitations, and the possibility of false-negative and inconclusive results. For these reasons, genetic testing should only be performed after obtaining informed consent. Published ethical guidelines address the specific aspects that should be considered when testing children and adolescents. Genetic testing should usually be limited

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3366

2.00 10,30 4,96

1.90

PART 16

1.80

Approximate allelic effect size

Genes, the Environment, and Disease

1.70

1.60

1.50

1.40

1.30

1.20

1.10

1.00 2000 PPARG

2003 KCNJ11

2006 TCF7L2

Candidate gene

Linkage GWAS Exome sequencing Genome sequencing Targeted sequencing

2007 HNF1B WFS1 SLC30A8 FTO HHEX IGF2BP2 CDKN2A/B CDKAL1

2008 TSPAN8 ADAMTs9 CDC123 JAZF1 NOTCH2 THADA KCNQ1

2009 DUSP8 MTNR1B IRS1

2010 2011 2013 SPRY2 COBLL1/GRB14 2012 2014 BCL2 MACF1 SRR HMG20A LLPP LAMA1 RASGRP1 ZFAND6 VPS26A FAF1 GIPR GRK5 GCK ST6GAL1 TMEM154 MC4R TMEM163 KLF14 AP3S2 MPHOSPH9 TLE1 SGCG TP53INP1 HNF4A ARL15 KCNK16 PROX1 POU5F1/TCF19 ANK1 PRC1 SSR1/RREB1 KLHDC5 BCL11A HLA-B ZMIZ1 ZBED3 INS-IGF2 PSMD6 RBMS1 GPSM1 FITM2/R3HDML/HNF4A HNF1A LEP CILP2 DGKB/TMEM195 SLC16A13 ANKRD55 CCND2 PAM/PPIP5K2 GLIS3 C2CD4A/C2CD4B SLC16A11 PEPD PTPRD CCDC63 GCC1/PAX4 ARAP1/CENTD2) C12orf51 ZFAND3 HMGA2 CCND2 MAEA TLE4/CHCHD9) HNF1A BCAR1 ADCY5 TBC1D4 RBM43/RND3 UBE2E2 DUSP9 GCKR

2016 CCDC85A INAFM2 ASB3 FAM60A ATP8B2 MIR4686 MTMR3 DMRTA1

2017 SLC35D3 GLP2R GIP MAP3K11 PLEKHA1 HSD17B12 NRXN3 CMIP ZZEF1 MNX1 ABO ACSL1 HLA-DQA1

FIGURE 456-16  Loci and genes associated with diabetes mellitus type 2. Loci are listed by year of identification, and the color indicates discovery method. Gene names indicate the locus and does not necessarily imply that the gene itself is causally involved. Approximate allelic effect sizes were either derived from the discovery cohort or, if available, from the DIAGRAM (Diabetes Genetics Replication and Meta-analysis consortium) European ancestry meta-analysis and the Asian ancestry meta-analysis. Gene names that are underlined denote identification in population isolates. (The data have been graciously provided by Dr. Miriam Udler and Dr. Jose Florez, Harvard Medical School, Boston.)

to situations in which the results may have an impact on medical management. IDENTIFYING THE DISEASE-CAUSING GENE Precision medicine aims to enhance the quality of medical care through the use of genotypic analysis (DNA testing) to identify genetic predisposition to disease, to select more specific pharmacotherapy, and to design individualized medical care based on genotype. Genotype can be deduced by analysis of protein (e.g., hemoglobin, apoprotein E), mRNA, or DNA. However, technologic advances have made DNA analysis particularly useful because it can be readily applied. DNA testing is performed by mutational analysis or linkage studies in individuals at risk for a genetic disorder known to be present in a family. Mass screening programs require tests of high

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sensitivity and specificity to be cost-effective. Prerequisites for the success of genetic screening programs include the following: that the disorder is potentially serious; that it can be influenced at a presymptomatic stage by changes in behavior, diet, and/or pharmaceutical manipulations; and that the screening does not result in any harm or discrimination. Screening in Jewish populations for the autosomal recessive neurodegenerative storage disease TaySachs has reduced the number of affected individuals. In contrast, screening for sickle cell trait/disease in African Americans has led to unanticipated problems of discrimination by health insurers and employers. Mass screening programs harbor additional potential problems. For example, screening for the most common genetic alteration in cystic fibrosis, the ΔF508 mutation with a frequency of ~70% in northern Europe, is feasible and seems to be effective.

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TABLE 456-7  Genetic Approaches for Identifying Disease Genes INDICATIONS AND ADVANTAGES

Linkage Studies

 

 

Classical linkage analysis (parametric methods)  

Analysis of monogenic traits

Difficult to collect large informative pedigrees

Suitable for genome scan

 

Control population not required Useful for multifactorial disorders in isolated populations Suitable for identification of susceptibility genes in polygenic and multifactorial disorders Suitable for genome scan

Difficult to obtain sufficient statistical power for complex traits  

 

Allele-sharing methods (nonparametric methods) Affected sib and relative pair analyses Sib pair analysis

Control population not required if allele frequencies are known

 

Statistical power can be increased by including parents and relatives

Association Studies

 

Case-control studies

Suitable for identification of susceptibility genes in polygenic and multifactorial disorders Linkage disequilibrium Suitable for testing specific allelic variants of known candidate loci Transmission Facilitated by disequilibrium test (TDT) comprehensive catalogs of genotypes and variants Whole-genome Does not necessarily association studies need relatives

LIMITATIONS

 

Difficult to collect sufficient number of subjects Difficult to obtain sufficient statistical power for complex traits Reduced power compared to classical linkage, but not sensitive to specification of genetic mode  

  Requires large sample size and matched control population False-positive results in the absence of suitable control population Candidate gene approach does not permit detection of novel genes and pathways Susceptibility genes can vary among different populations

Next-Generations Sequencing Technologies   Whole exome or genome Unbiased approach, sequencing analysis can be performed without reference sequences from parents or siblings

Targeted sequencing of gene panels

Captures multiple candidate genes and loci with hybridization techniques followed by deep sequencing

Requires appropriate bioinformatics, may have low sensitivity if CNV analysis is not included, detects numerous VUS, can lead to the detection of unrelated deleterious alleles Permits analyses of multiple candidate genes in parallel. Facilitates molecular characterization of disorders with locus heterogeneity.

Abbreviations: CNV, copy number variation; GWAS, genome-wide association study; VUS, variants of unknown significance.

One has to keep in mind, however, that there is pronounced allelic heterogeneity and that the disease can be caused by about 2000 other mutations. The search for these less common mutations would substantially increase costs, but not the effectiveness of the screening program as a whole. Next-generation genome sequencing permits comprehensive and cost-effective mutational analyses after selective enrichment of candidate genes. For example, tests that sequence all

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Mutational Analyses  DNA sequence analysis is now widely used as a diagnostic tool and has significantly enhanced diagnostic accuracy. It is used for determining carrier status and for prenatal testing in monogenic disorders. Numerous techniques, discussed in previous versions of this chapter, are available for the detection of mutations. In a very broad sense, one can distinguish between techniques that allow for screening of known mutations (screening mode) or techniques that definitively characterize mutations. Analyses of large alterations in the genome are possible using classic methods such as karyotype analysis, cytogenetics, fluorescent in situ hybridization (FISH), as well as more sensitive array- or beadbased techniques that search for multiple single exon deletions or duplications. More discrete sequence alterations rely heavily on the use of PCR, which allows rapid gene amplification and analysis. Moreover, PCR makes it possible to perform genetic testing and mutational analysis with small amounts of DNA extracted from leukocytes or even from single cells, buccal cells, or hair roots. DNA sequencing can be performed directly on PCR products or on fragments cloned into plasmid vectors amplified in bacterial host cells. Sequencing of the whole genome, exome, selected chromosomes, or sequencing of numerous candidate genes in a single run, is now possible with next-generation sequencing platforms and has entered the clinical realm. Genomic tests are also widely used for the detection of pathogens and for the identification of viral or bacterial sequence variations. The integration of genomic tests into clinical medicine is, however, associated with a number of ongoing challenges related to costs, variable sensitivities of the tests, bioinformatics analyses, storage and sharing of data, and the difficulty of interpreting all genetic variants identified with comprehensive testing. The discovery of incidental (or secondary) findings that are unrelated to the indication for the sequencing analysis but indicators of other disorders of potential relevance for patient care can pose a difficult ethical dilemma. It can lead to the detection of undiagnosed medically actionable genetic conditions, but can also reveal deleterious mutations that cannot be influenced, as numerous sequence variants are of unknown significance. A general algorithm for the approach to mutational analysis is outlined in Fig. 456-17. The importance of a detailed clinical phenotype cannot be overemphasized. This is the step where one should also consider the possibility of genetic heterogeneity and phenocopies. If obvious candidate genes are suggested by the phenotype, they can be analyzed directly. After identification of a mutation, it is essential to demonstrate that it segregates with the phenotype. The functional characterization of novel mutations is labor intensive and may require analyses in vitro or in transgenic models in order to document the relevance of the genetic alteration. Prenatal diagnosis of numerous genetic diseases in instances with a high risk for certain disorders is now possible by direct DNA analysis. Amniocentesis involves the removal of a small amount of amniotic fluid, usually at 16 weeks of gestation. Cells can be collected and submitted for karyotype analyses, FISH, and mutational analysis of selected genes Table 456-4). The main indications for amniocentesis include advanced maternal age (>35 years), presence of an abnormality of the fetus on ultrasound examination, an abnormal serum “quad” test (α-fetoprotein, β human chorionic gonadotropin, inhibin-A, and unconjugated estriol), a family history of chromosomal abnormalities, or a Mendelian disorder amenable to genetic testing.

3367

CHAPTER 456 Principles of Human Genetics

METHOD

the common genes causing hereditary deafness or hereditary pheochromocytomas are commercially available. Occupational screening programs aim to detect individuals with increased risk for certain professional activities (e.g., α1 antitrypsin deficiency and smoke or dust exposure). Integrating genomic data into electronic medical records is evolving and can provide significant decision support at the point of care, for example, by providing the clinician with genomic data and decision algorithms for the prescription of drugs that are subject to pharmacogenetic influences.

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3368 Characterization of phenotype Familial or sporadic genetic disorder

Population-based genetic screening

PART 16

Pedigree analysis

Genes, the Environment, and Disease

Gene unknown

Gene known or candidate genes

Linkage analysis

Mutational analysis

Susceptibility genes or loci

Enrichment of linked region Deep-sequencing Determine functional properties of identified mutations in vitro and in vivo

Genetic counseling Testing of other family members

Treatment based on pathophysiology

FIGURE 456-17  Approach to genetic disease.

Prenatal diagnosis can also be performed by chorionic villus sampling (CVS), in which a small amount of the chorion is removed by a transcervical or transabdominal biopsy. Chromosomes and DNA obtained from these cells can be submitted for cytogenetic and mutational analyses. CVS can be performed earlier in gestation (weeks 9–12) than amniocentesis, an aspect that may be of relevance when termination of pregnancy is a consideration. Later in pregnancy, beginning at about 18 weeks of gestation, percutaneous umbilical blood sampling (PUBS) permits collection of fetal blood for lymphocyte culture and analysis. These approaches enable screening for clinically relevant and deleterious alleles inherited from the parents, as well as for de novo germline mutations, and they may have the potential to change the diagnosis of genetic disorders in the prenatal setting. Although genomic sequencing of fetal DNA circulating in the bloodstream of the mother has been achieved, it is not commonly used for non-invasive prenatal testing. In combination with in vitro fertilization (IVF) techniques, it is possible to perform genetic diagnoses in a single cell removed from the four- to eight-cell embryo or to analyze the first polar body from an oocyte. Preconceptual diagnosis thereby avoids therapeutic abortions but is costly and labor intensive. It should be emphasized that excluding a specific disorder by any of these approaches is never equivalent to the assurance of having a normal child. Postnatal indications for cytogenetic analyses in infants or children include multiple congenital anomalies, suspicion of a known cytogenetic syndrome, developmental delay, dysmorphic features, autism, short stature and disorders of sexual development, among others (Table 456-4). Mutations in certain cancer susceptibility genes such as BRCA1 and BRCA2 may identify individuals with an increased risk for the development of malignancies and result in risk-reducing interventions. The detection of cytogenetic alterations and mutations is an important diagnostic and prognostic tool in leukemias and somatic mutational analysis is transforming oncology by providing diagnostic and prognostic information, and it informs the choice of targeted therapies. However, the cancer may recur due to treatment resistance of subclones due to the continuously evolving genomic landscape. The demonstration of the presence or absence of mutations and polymorphisms is also relevant for the rapidly evolving field of pharmacogenomics, including the identification of differences in drug treatment response or metabolism as a function of genetic background. For example, the thiopurine drugs 6-mercaptopurine and azathioprine are commonly used cytotoxic

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and immunosuppressive agents. They are metabolized by thiopurine methyltransferase (TPMT), an enzyme with variable activity associated with genetic polymorphisms in 10% of whites and complete deficiency in about 1 in 300 individuals. Patients with intermediate or deficient TPMT activity are at risk for excessive toxicity, including fatal myelosuppression. Characterization of these polymorphisms allows mercaptopurine doses to be modified based on TPMT genotype. Pharmacogenomics may increasingly permit individualized drug therapy, improve drug effectiveness, reduce adverse side effects, and provide cost-effective pharmaceutical care (Chap. 64). ETHICAL ISSUES Determination of the association of genetic defects with disease, comprehensive data of an individual’s genome, and studies of genetic variation raise many ethical and legal issues. Genetic information is generally regarded as sensitive information that should not be readily accessible without explicit consent (genetic privacy). The disclosure of genetic information may risk possible discrimination by insurers or employers. The scientific components of the Human Genome Project have been paralleled by efforts to examine ethical, social, and legal implications. An important milestone emerging from these endeavors consists in the Genetic Information Nondiscrimination Act (GINA), signed into law in 2008, which aims to protect asymptomatic individuals against the misuse of genetic information for health insurance and employment. It does not, however, protect the symptomatic individual. Provisions of the U.S. Patient Protection and Affordable Care Act, effective in 2014, have, in part, filled this gap and prohibit exclusion from, or termination of, health insurance based on personal health status. Potential threats to the maintenance of genetic privacy consist in the emerging integration of genomic data into electronic medical records, compelled disclosures of health records, and direct-to-consumer genetic testing. It is widely accepted that identifying disease-causing genes can lead to improvements in diagnosis, treatment, and prevention. However, the information gleaned from genotypic results can have quite different impacts, depending on the availability of strategies to modify the course of disease. For example, the identification of mutations that cause MEN 2 or hemochromatosis allows specific interventions for affected family members. On the other hand, at present, the identification of an Alzheimer’s or Huntington’s disease gene does not currently alter therapy and outcomes. Most genetic disorders are likely to fall into an intermediate category where the

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Acknowledgment Selected sections and Table 456-4 have been integrated from the chapter on Chromosome Disorders by Dr. Nancy B. Spinner and Dr. Laura K. Conlin, published in the 19th edition of Harrison’s Principles in Internal Medicine. The data and concept for Figure 456-16 have been graciously provided by Dr. Miriam Udler and Dr. Jose Florez, Massachusetts General Hospital and Harvard Medical School, Boston.

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■■FURTHER READING

3369

Ashley EA: Towards precision medicine. Nat Rev Genet 17:507, 2016. Jameson JL, Longo DL: Precision medicine—personalized, problematic, and promising. N Engl J Med 372:2229, 2015. Jarvik GP, Evans JP: Mastering genomic terminology. Genet Med 19: 491, 2017. Joly Y et al: Comparative approaches to genetic discrimination: Chasing shadows? Trends Genet 33: 299, 2017. Manolio TA: Bringing genome-wide association findings into clinical use. Nat Rev Genet 14:549, 2013. Manolio TA et al: Bedside back to bench: Building bridges between basic and clinical genomic research. Cell 169:6, 2017. Rehm HL: Evolving health care through personal genomics. Nat Rev Genet 18:259, 2017. Richards S et al: ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405, 2015. Sidow A, Spies N: Concepts in solid tumor evolution. Trends Genet 31:208, 2015. Wauters A, Van Hoyweghen I: Global trends on fears and concerns of genetic discrimination: A systematic literature review. J Hum Genet 61:275, 2016. Wolf SM et al: Mapping the ethics of translational genomics: Situating return of results and navigating the research-clinical divide. J Law Med Ethics 43:486, 2015. World Health Organization: Genomics and World Health: Report of the Advisory Committee on Health Research. 1-254, 2002. Zheng S et al: Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 29:723, 2016.

CHAPTER 457 The Practice of Genetics in Clinical Medicine

opportunity for prevention or treatment is significant but limited. However, the progress in this area is unpredictable, as underscored by the finding that angiotensin II receptor blockers may slow disease progression in Marfan’s syndrome. Genetic test results can generate anxiety in affected individuals and family members. Comprehensive sequence analyses are particularly challenging because most individuals can be expected to harbor several serious recessive gene mutations. Moreover, the sensitivity of comprehensive sequence analyses are not always greater, for example, if CNV analysis is not integrated, but can be associated with higher costs. The impact of genetic testing on health care costs remain unclear. It does vary among disorders and depends on the availability of effective therapeutic modalities. A significant problem arises from the marketing of genetic testing directly to consumers by commercial companies. The validity of these tests is, in part, not well defined, and there are persisting concerns about the lack of appropriate regulatory oversight, the accuracy and confidentiality of genetic information, the availability of counseling, and the handling of these results. Many issues raised by the genome project are familiar, in principle, to medical practitioners. For example, an asymptomatic patient with increased low-density lipoprotein (LDL) cholesterol, high blood pressure, or a strong family history of early myocardial infarction is known to be at increased risk of coronary heart disease. In such cases, it is clear that the identification of risk factors and an appropriate intervention are beneficial. Likewise, patients with phenylketonuria, cystic fibrosis, or sickle cell anemia are often identified as having a genetic disease early in life. These precedents can be helpful for adapting policies that relate to genetic information. We can anticipate similar efforts, whether based on genotypes or other markers of genetic predisposition, to be applied to many disorders. One confounding aspect of the rapid expansion of information is that our ability to make clinical decisions often lags behind initial insights into genetic mechanisms of disease. For example, when genes that predispose to breast cancer such as BRCA1 are described, they generate tremendous public interest in the potential to predict disease, but many years of clinical research are still required to rigorously establish genotype and phenotype correlations. Genomics may contribute to improvements in global health by providing a better understanding of pathogens and diagnostics, and through contributions to drug development. There is, however, ongoing concern about the development of a “genomics divide” because of the costs associated with these developments and uncertainty as to whether these advances will be accessible to the populations of developing countries faced with pressing health needs associated with poverty, infectious diseases, and the relative lack of essential infrastructure. The World Health Organization has summarized these issues and inequities surrounding genomic medicine in a detailed report titled “Genomics and World Health.” Whether related to informed consent, participation in research, or the management of a genetic disorder that affects an individual or his or her family, there is a great need for more information about fundamental principles of genetics. The pervasive nature of the role of genetics in medicine makes it important for physicians and other health care professionals to become more informed about genetics and to provide advice and counseling in conjunction with trained genetic counselors (Chap. 457). The application of screening and prevention strategies does therefore require continuing patient and physician education, changes in health care financing, and legislation to protect patient’s rights.

Practice of Genetics 457 The in Clinical Medicine

Susan M. Domchek, J. Larry Jameson, Susan Miesfeldt

APPLICATIONS OF MOLECULAR GENETICS IN CLINICAL MEDICINE

Genetic testing for inherited abnormalities associated with disease risk is increasingly used in the practice of clinical medicine. Germline alterations include chromosomal abnormalities specific gene mutations with autosomal dominant or recessive patterns of transmission (Chap. 456), and single nucleotide polymorphisms (SNPs) with small relative risks associated with disease. Germline alterations are responsible for disorders beyond classic Mendelian conditions with genetic susceptibility to common adult-onset diseases such as asthma, hypertension, diabetes mellitus, macular degeneration, and a number of types of cancer. For many of these diseases, there is a complex interplay of genes (often multiple) and environmental factors that effect lifetime risk, age of onset, disease severity, and treatment options. The expansion of human genetic knowledge is changing our understanding of pathophysiology and influencing our classification of diseases. Awareness of genetic etiology can have an impact on clinical management, including prevention and screening for or treatment of a range of diseases. Primary care physicians are relied upon to help patients navigate testing and treatment options. Consequently, they must understand the genetic basis for a large number of genetically influenced diseases, incorporate personal and family history to determine the risk for a specific mutation, and be positioned to provide counseling. Even if patients are seen by genetic specialists who assess

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3370 genetic risk and coordinate testing, primary care providers should offer

PART 16 Genes, the Environment, and Disease

information to their patients regarding the indications, limitations, risks, and benefits of genetic counseling and testing. They must also be prepared to offer risk-based management following genetic risk assessment. Given the pace of genetics, this is an increasingly difficult task. The field of clinical genetics has rapidly transitioned from single gene testing to multigene panel testing, with techniques such as wholeexome and genome sequencing on the horizon, increasing the complexity of test selection and interpretation, as well as patient education and medical decision-making.

COMMON ADULT-ONSET GENETIC DISORDERS ■■INHERITANCE PATTERNS

Adult-onset hereditary diseases follow multiple patterns of inheritance. Some are autosomal dominant conditions. These include many common cancer susceptibility syndromes such as hereditary breast and ovarian cancer (due to germline BRCA1 and BRCA2 mutations) and Lynch syndrome (caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2). In both of these examples, inherited mutations are associated with a high penetrance (lifetime risk) of cancer, although penetrance is incomplete (risk is not 100%). In other conditions, although there is autosomal dominant transmission, penetrance is lower, thereby making the disorders more difficult to recognize. For example, germline mutations in CHEK2 increase the risk of breast cancer, but with a moderate lifetime risk in the range of 20–30%, as opposed to 50–70% for mutations in BRCA1 or BRCA2. Other adult-onset hereditary diseases are transmitted in an autosomal recessive fashion where two mutant alleles are necessary to cause full expression of disease. Examples include hemochromatosis and MUTYH-associated polyposis. There are more pediatric-onset autosomal recessive disorders, such as lysosomal storage diseases and cystic fibrosis. The genetic risk for many adult-onset disorders is multifactorial. Risk can be conferred by genetic factors at a number of loci (polygenic), which individually have very small effects (usually with relative risks of 10 genes including MYBPC3, MYH7, TNNT2, TPM1 >10 genes including KCNQ1, SCN5A, KCNE1, KCNE2 FBN1

Echocardiographic screening; pharmacologic intervention; myomectomy Electrocardiographic screening; pharmacologic intervention; implantable cardiac defibrillator devices Echocardiographic screening; prophylactic beta blockers; aortic valve replacement as indicated

Gastrointestinal

 

 

 

Familial Mediterranean fever Hemochromatosis

AR AR

MEFV HFE

Colchicine Phlebotomy

Pulmonary

 

 

 

α1 Antitrypsin deficiency Cystic fibrosis

AR

SERPINA1

Avoidance of smoking and occupational and environmental toxins

AR

CFTR

Chest physiotherapy; agents to promote airway secretion clearance; CFTR modulators (G551D mutations); lung transplantation

Endocrine

 

 

 

Neurohypophyseal diabetes insipidus Familial hypocalciuric hypercalcemia Multiple endocrine neoplasia type 2

AD AD AD

AVP CASR RET

Replace vasopressin Avoidance of parathyroidectomy Prophylactic thyroidectomy; screening for pheochromocytoma and hyperparathyroidism

Renal

 

 

 

Polycystic kidney disease

AD, AR

PKD1, PKD2, PKHD1

Nephrogenic diabetes insipidus

XL, AR

AVPR2, AQP2

Prevention of hypertension; prevention of urinary tract infections; kidney transplantation Fluid replacement; thiazides with or without amiloride

Neurologic

 

 

 

Malignant hyperthermia Hyperkalemic periodic paralysis

AD AD

RYR1, CACNA1S SCN4A

Duchenne’s and Becker’s muscular dystrophy Wilson’s disease

XL

DMD

Avoidance of precipitating anesthetics Diet rich in calcium and low in potassium; thiazides or acetazolamide Corticosteroids; physical therapy

AR

ATP7B

Zinc, trientene

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; HNPCC, hereditary nonpolyposis colorectal cancer; MRI, magnetic resonance imaging; XL, X-linked.

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■■FURTHER READING

Anya ER et al: Genetic information, non-discrimination, and privacy protections in genetic counseling practice. J Genet Couns 23:891, 2014. Clayton EW: Ethical, legal, and social implications of genomic medicine. N Engl J Med 349:562, 2003. Hampel H et al: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: Referral indications for cancer predisposition assessment. Genet Med 17:70, 2015. Resta R et al: A new definition of genetic counseling: National Society of Genetic Counselors’ Task Force report. J Genet Couns 15:77, 2006. Roberts JS, Ostergren J: Direct-to-consumer genetic testing and personal genomics services: A review of recent empirical studies. Curr Genet Med Rep 1:182, 2013. Robson ME et al: American Society of Clinical Oncology policy statement update: Genetic and genomic testing for cancer susceptibility. J Clin Oncol 33:3660, 2015.

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3375

Gene and Cell Based 458 Therapy in Clinical Medicine Katherine A. High, Malcolm K. Brenner

Gene transfer is a novel area of therapeutics in which the active agent is a nucleic acid sequence rather than a protein or small molecule. Because delivery of naked DNA or RNA to a cell is an inefficient process, most gene transfer is carried out using a vector, or gene delivery vehicle. These vehicles have generally been engineered from viruses by deleting some or all of the viral genome and replacing it with the therapeutic gene of interest under the control of a suitable promoter (Table 458-1). Gene transfer strategies can thus be described in terms of three essential elements: (1) a vector; (2) a gene to be delivered, sometimes called the transgene; and (3) a physiologically relevant target cell to which the DNA or RNA is delivered. The series of steps in which the vector and donated DNA enter the target cell and express the transgene is referred to as transduction. Gene delivery can take place in vivo, in which the vector is directly injected into the patient, or, in the case of hematopoietic and some other target cells, ex vivo, with removal of the target cells from the patient, followed by return of the gene-modified autologous cells to the patient after manipulation in the laboratory. The latter approach effectively combines gene transfer techniques with cellular therapies (Chap. 473). Gene transfer is one of the most powerful concepts in modern molecular medicine and has the potential to address a host of diseases for which there are currently no available treatments. Clinical trials of gene therapy have been under way since 1990; the first gene therapy product to be licensed in the United States or Europe was licensed in 2012 (see below). Given that vector-mediated gene therapy is arguably one of the most complex therapeutics yet developed, consisting of both a nucleic acid and a protein component, this time course from first clinical trial to licensed product is noteworthy for being similar to those seen with other novel classes of therapeutics, i.e., monoclonal antibodies. Over 5000 subjects have been enrolled in gene transfer studies, and serious adverse events have been rare. Some of the initial trials were characterized by an overabundance of optimism and a failure to be appropriately critical of preclinical studies in animals; in addition, it was in some contexts not fully appreciated that animal studies are only a partial guide to safety profiles of products in humans (e.g., insertional mutagenesis, and human immune responses to the vector). Initial exuberance was driven by many factors, including an intense desire to develop therapies for hitherto untreatable diseases, lack of understanding of risks, and, in some cases, undisclosed financial conflicts of interest. After a teenager died of complications related to vector infusion, the field underwent a retrenchment; continued efforts led to a more nuanced understanding of the risks and benefits of these new therapies and more sophisticated selection of disease targets. Currently, gene therapies are being developed for a variety of disease entities (Table 458-2).

CHAPTER 458 Gene and Cell Based Therapy in Clinical Medicine

early, the disorder can be managed effectively with therapeutic phlebotomy. Therefore, when the diagnosis of hemochromatosis has been made in a proband, it is important to counsel other family members in order to minimize the impact of the disorder. Preventative measures and therapeutic interventions are not restricted to metabolic disorders. Identification of familial forms of long QT syndrome, associated with ventricular arrhythmias, allows early electrocardiographic testing and the use of prophylactic antiarrhythmic therapy, overdrive pacemakers, or defibrillators. Individuals with familial hypertrophic cardiomyopathy can be screened by ultrasound, treated with beta blockers or other drugs, and counseled about the importance of avoiding strenuous exercise and dehydration. Those with Marfan’s syndrome can be treated with beta blockers or angiotensin II receptor blockers and monitored for the development of aortic aneurysms. The field of pharmacogenetics identifies genes that alter drug metabolism or confer susceptibility to toxic drug reactions. Pharmacogenetics seeks to individualize drug therapy in an attempt to improve treatment outcomes and reduce toxicity. Examples include thiopurine methyltransferase (TPMT) deficiency, dihydropyrimidine dehydrogenase deficiency, malignant hyperthermia, and glucose-6-phosphate deficiency. Despite successes in this area, it is not always clear how to incorporate pharmacogenetics into clinical care. For example, although there is an association with CYP2C6 and VKORC1 genotypes and warfarin dosing, there is no evidence that incorporating genotyping into clinical practice improves patient outcomes compared with clinical algorithms. The identification of germline abnormalities that increase the risk of specific types of cancer is rapidly changing clinical management. Identifying family members with mutations that predispose to FAP or Lynch syndrome leads to recommendations of early cancer screening and prophylactic surgery, as well as consideration of chemoprevention and attention to healthy lifestyle habits. Similar principles apply to familial forms of melanoma as well as cancers of the breast, ovary, and thyroid. In addition to increased screening and prophylactic surgery, the identification of germline mutations associated with cancer may also lead to the development of targeted therapeutics, for example, the U.S. Food and Drug Administration (FDA) approval of the poly– ADP ribose polymerase (PARP) inhibitors olaparib and rucaparib for BRCA1/2-associated recurrent ovarian cancer. Although the role of genetic testing in the clinical setting continues to evolve, such testing holds the promise of allowing early and more targeted interventions that can reduce morbidity and mortality. Rapid technologic advances are changing the ways in which genetic testing is performed. As genetic testing becomes less expensive and technically easier to perform, it is anticipated that there will be an expansion of its use. This will present challenges, but also opportunities. It is critical that physicians and other health care professionals keep current with advances in genetic medicine in order to facilitate appropriate referral for genetic counseling and judicious use of genetic testing, as well as to provide state-of-the-art, evidence-based care for affected or at-risk patients and their relatives.

GENE TRANSFER FOR GENETIC DISEASE

Gene transfer strategies for genetic disease generally involve gene addition therapy, an approach characterized by transfer of the missing gene to a physiologically relevant target cell. However, other strategies are possible, including supplying a gene that achieves a similar biologic effect through an alternative pathway (e.g., factor VIIa for hemophilia A); supplying an antisense oligonucleotide to splice out a mutant exon if the sequence is not critical to the function of the protein (as has been done with the dystrophin gene in Duchenne’s muscular dystrophy); or downregulating a harmful effect through a small interfering RNA (siRNA). Two distinct strategies are used to achieve long-term gene expression: one is to transduce stem cells with an integrating vector, so that all progeny cells will carry the donated gene; and the other is to transduce long-lived cells, such as skeletal muscle or neurons. In the

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3376

TABLE 458-1  Characteristics of Gene Delivery Vehicles VIRAL VECTORS

PART 16 Genes, the Environment, and Disease

FEATURES Viral genome Cell division requirement Packaging limitation Immune responses to vector Genome integration Long-term expression Main advantages

Main disadvantages

RETROVIRAL RNA Yes

LENTIVIRAL RNA G1 phase

ADENOVIRAL DNA No

AAV DNA No

HUMAN FOAMY VIRUS RNA No

HSV-1 DNA No

ALPHA VIRUSES RNA No

8 kb

8 kb

8–30 kb

5 kb

8.5 kb

40–150 kb

5 kb

Few

Few

Extensive

Few

Few

Few in recombinant virus

Few

Yes

Yes

Poor

Poor

Yes

No

No

Yes

Yes

No

Yes

Yes

No

No

Persistent gene transfer in dividing cells

Persistent gene transfer in transduced tissues Might induce oncogenesis in some cases (not yet observed)

Highly effective in transducing various tissues

Persistent gene expression in both dividing and nondividing cells In need of a stable packaging system

Large packaging capacity with persistent gene transfer Residual cytotoxicity with neuron specificity

Limited immune responses against the vector

Theoretical risk of insertional mutagenesis (occurred in multiple cases)

Elicits few inflammatory responses, nonpathogenic Viral capsid elicits Limited packaging strong immune capacity responses

Transduced gene expression is transient

Abbreviations: AAV, adeno-associated virus; HSV, herpes simplex virus.

case of long-lived cells, integration into the target cell genome is unnecessary. Instead, because the cells are nondividing, the donated DNA, if stabilized in an episomal form, will give rise to expression for the life of the cell. This approach thus avoids problems related to integration and insertional mutagenesis.

■■IMMUNODEFICIENCY DISORDERS: PROOF OF PRINCIPLE

Early attempts to effect gene replacement into hematopoietic stem cells (HSCs) were stymied by the relatively low transduction efficiency of retroviral vectors, which require dividing target cells for integration. Because HSCs are normally quiescent, they are a formidable transduction target. However, identification of cytokines that induced cell division without promoting differentiation of stem cells, along with technical improvements in the isolation and transduction of HSCs, led to modest but real gains in transduction efficiency. The first convincing therapeutic effect from gene transfer occurred with X-linked severe combined immunodeficiency disease (SCID), which results from mutations in the gene (IL2RG) encoding the γc subunit of cytokine receptors required for normal development of T and natural killer (NK) cells (Chap. 344). Affected infants present in the first few months of life with overwhelming infections and/or failure to thrive. In this disorder, it was recognized that the transduced cells, even if few in number, would have a proliferative advantage compared to the nontransduced cells, which lack receptors for the cytokines required for lymphocyte development and maturation. Complete reconstitution of the immune system, including documented responses to standard childhood vaccinations, clearing of infections, and remarkable gains in growth occurred in most of the treated children. However, among 20 children treated in the initial trials, five eventually developed a syndrome similar to T cell acute lymphocytic leukemia, with splenomegaly, rising white counts, and the emergence of a single clone of TABLE 458-2  Most Common Indications in Gene Therapy Trials INDICATION Cancer Monogenic diseases Infectious diseases

NUMBER 1554 248 180

Source: Adapted from J Gene Med http://www.abedia.com/wiley/indications.php, 2016.

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T cells. Molecular studies revealed that, in most of these children, the retroviral vector had integrated within a gene, LMO-2 (LIM only-2), which encodes a component of a transcription factor complex involved in hematopoietic development. The retroviral long terminal repeat increases the expression of LMO-2, resulting in T cell leukemia. The X-linked SCID studies were a watershed event in the evolution of gene therapy. They demonstrated conclusively that gene therapy could cure disease; of the 20 children treated in these initial trials, 18 achieved correction of the immunodeficiency disorder. Unfortunately, 5 of the 20 patients later developed a leukemia-like disorder, and one died of this complication; the rest are alive and free of complications at time periods ranging up to 17 years after initial treatment. These studies demonstrated that insertional mutagenesis leading to cancer was more than a theoretical possibility (Table 458-3). As a result of the experience in these trials, all protocols using integrating vectors in hematopoietic cells must include a plan for monitoring sites of insertion and clonal proliferation. Strategies to overcome this complication have included using a “suicide” gene cassette in the vector, so that errant clones can be quickly ablated, or using “insulator” elements in the cassette, which can limit the activation of genes surrounding the insertion site. Lentiviral vectors, which can efficiently transduce nondividing target cells, are also likely to be safer than retroviral vectors, based on patterns of integration; the field is thus gradually moving toward these to replace retroviral vectors. More clear-cut success has been achieved in a gene therapy trial for another form of SCID, adenosine deaminase (ADA) deficiency (Chap. 344). ADA-SCID is clinically similar to X-linked SCID, although it can be treated by enzyme replacement therapy with a pegylated form

TABLE 458-3  Potential Complications of Gene Therapy Gene silencing—repression of promoter Genotoxicity—complications arising from insertional mutagenesis Phenotoxicity—complications arising from overexpression or ectopic expression of the transgene Immunotoxicity—harmful immune response to either the vector or transgene; or a harmful immune response of the vector (e.g. CAR T cells) Risks of horizontal transmission—shedding of infectious vector into environment Risks of vertical transmission—germline transmission of donated DNA

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■■NEURODEGENERATIVE DISEASES: EXTENSION OF PRINCIPLE

The SCID trials gave support to the hypothesis that gene transfer into HSCs could be used to treat any disease for which allogeneic bone marrow transplantation was therapeutic. Moreover, the use of genetically modified autologous cells carried several advantages including no risk of graft-versus-host disease, guaranteed availability of a “donor” (unless the disease itself damages the stem cell population of the patient), and low likelihood of failure of engraftment. Cartier and Aubourg capitalized on this realization to conduct the first trial of lentiviral vector transduction of HSCs for a neurodegenerative disorder, X-linked adrenoleukodystrophy (ALD). X-linked ALD is a fatal demyelinating disease of the central nervous system caused by mutations in the gene encoding an adenosine triphosphate–binding cassette transporter. Deficiency of this protein leads to accumulation of verylong-chain fatty acids in oligodendrocytes and microglia, disrupting myelin maintenance by these cells. Affected boys present with clinical and neuroradiographic evidence of disease at age 6–8 and usually die before adolescence. Following lentiviral transduction of autologous HSCs in young boys with the disease, dramatic stabilization of disease occurred, demonstrating that stem cell transduction could work for neurodegenerative as well as immunologic disorders. Investigators in Milan carried this observation one step further to develop a treatment for another neurodegenerative disorder that has previously responded poorly to bone marrow transplantation. Metachromatic leukodystrophy is a lysosomal storage disorder caused by mutations in the gene encoding arylsulfatase A (ARSA). The late infantile form of the disease is characterized by progressive motor and cognitive impairment, and death within a few years of onset, due to accumulation of the ARSA substrate sulfatide in oligodendrocytes, microglia, and some neurons. Recognizing that endogenous levels of production of ARSA were too low to provide cross-correction by allogeneic transplant, Naldini and colleagues engineered a lentiviral vector that directed supraphysiologic levels of ARSA expression in transduced cells. Transduction of autologous HSCs from children born with the disease, at a point when they were still presymptomatic, led to preservation and continued acquisition of motor and cognitive milestones at time periods as long as 32 months after affected siblings had begun to lose milestones. These results illustrate that the ability to engineer levels of expression can allow gene therapy approaches to succeed where allogeneic bone marrow transplantation cannot. It is likely that a similar approach will be used in other neurodegenerative conditions. Transduction of HSCs to treat the hemoglobinopathies is an obvious extension of studies already conducted but represents a higher hurdle in terms of the extent of transduction required to achieve a therapeutic effect. Trials are now under way for thalassemia and sickle cell disease, and for a number of other hematologic disorders, including Wiskott-Aldrich syndrome, and chronic granulomatous disease.

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LONG-TERM EXPRESSION IN GENETIC DISEASE: IN VIVO GENE TRANSFER WITH RECOMBINANT ADENO-ASSOCIATED VIRAL VECTORS

Recombinant adeno-associated viral (AAV) vectors have emerged as attractive gene delivery vehicles for genetic disease. Engineered from a small replication-defective DNA virus, they are devoid of viral coding sequences and trigger very little immune response in experimental animals. They are capable of transducing nondividing target cells, and the donated DNA is stabilized primarily in an episomal form, thus minimizing risks arising from insertional mutagenesis. Because the vector has a tropism for certain long-lived cell types, such as skeletal muscle, the central nervous system (CNS), and hepatocytes, long-term expression can be achieved even in the absence of integration.

■■FIRST LICENSED PRODUCT

These features of AAV were used to develop the first licensed gene therapy product in Europe, an AAV vector for treatment of the autosomal recessive disorder lipoprotein lipase (LPL) deficiency. This rare disorder (1–2/million) is due to loss-of-function mutations in the gene encoding LPL, an enzyme normally produced in skeletal muscle and required for the catabolism of triglyceride-rich lipoproteins and chylomicrons. Affected individuals have lipemic serum and may have eruptive xanthomas, hepatosplenomegaly, and in some cases, recurrent bouts of acute pancreatitis. Clinical trials demonstrated the safety of intramuscular injection of AAV-LPL and its efficacy in reducing frequency of pancreatitis episodes in affected individuals, leading to drug approval in Europe. Additional clinical trials currently under way that use AAV vectors in the setting of genetic disease include those for muscular dystrophies, spinal muscular atrophy, Parkinson’s disease, Batten’s disease, ornithine transcarbamylase deficiency, hemophilia B and A, several forms of congenital blindness, and a variety of other inherited conditions.

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CHAPTER 458 Gene and Cell Based Therapy in Clinical Medicine

of the enzyme (PEG-ADA), which leads to immune reconstitution but not always to normal T cell counts. Enzyme replacement therapy is expensive (annual costs: $200,000–$300,000). The initial trials of gene therapy for ADA-SCID were unsuccessful, but modifications of this protocol to include the use of HSCs rather than T cells as the target for transduction; discontinuation of PEG-ADA at the time of vector infusion, so that the transduced cells have a proliferative advantage over the nontransduced; and the use of a mild conditioning regimen to facilitate engraftment of the transduced autologous cells have led to success without the complications seen in the X-linked SCID trials. There have been no complications in the 10 children treated on the Milan protocol, with a median follow-up of >11 years. This therapy was approved in 2016 by the European Medicines Agency. ADA-SCID, then, is an example where gene therapy has changed therapeutic options for patients. For those with a human leukocyte antigen (HLA)-identical sibling, bone marrow transplantation is still the best treatment option, but this includes only a minority of those affected. For those without an HLA-identical match, gene therapy has comparable efficacy to PEGADA, does not require repetitive injections, and does not present the risk of development of neutralizing antibodies to the bovine enzyme.

■■HEMOPHILIA

Hemophilia (Chap. 61) has long been considered a promising disease model for gene transfer, because the gene product does not require precise regulation of expression and biologically active clotting factors can be synthesized in a variety of tissue types, permitting latitude in the choice of target tissue. Moreover, raising circulating factor levels from 5 years) expression of factor VIII or factor IX in the hemophilic dog model. Administration to skeletal muscle of an AAV vector expressing factor IX in patients with hemophilia B was safe and resulted in long-term expression as measured on muscle biopsy, but circulating levels never rose to >1% for sustained periods, and a large number of IM injections (>80–100) was required to access a large muscle mass. Intravascular vector delivery has been used to access large areas of skeletal muscle in animal models of hemophilia and will likely be tested as a route of administration for muscular dystrophy disorders in upcoming trials. The first trial of an AAV vector expressing factor IX delivered to the liver in humans with hemophilia B resulted in therapeutic circulating levels at the highest dose tested, but expression at these levels (>5%) lasted for only 6–10 weeks before declining to baseline (7 years, with observation ongoing) of factor IX, in the range of 2–7%, in men with severe hemophilia B. By using as the transgene a high specific activity variant of FIX, it has been possible to lower the vector dose required, reducing the risk of the immune response, and increasing the plateau levels of FIX into the range of 15–45%. Current efforts are focused on expanding these trials, and extending the approach to hemophilia A.

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■■RETINAL GENE THERAPY

PART 16 Genes, the Environment, and Disease

A logical conclusion from the early experience with AAV in liver in the hemophilia trial was that avoidance of immune responses was key to long-term expression. Thus immunoprivileged sites such as the retina began to attract substantial interest as therapeutic targets. This inference has been elegantly confirmed in the setting of the retinal degenerative disease Leber congenital amaurosis (LCA). Characterized by early-onset blindness, LCA was not previously treatable and is caused by mutations in several different genes; ~10% of cases of LCA are due to a mutation in a gene, RPE65, encoding a retinal pigment epithelial-associated 65-kDa protein. In dogs with a null mutation in RPE65, sight was restored after subretinal injection of an AAV vector expressing RPE65. Transgene expression appears to be stable, with the first animals treated >10 years ago continuing to manifest electroretinal and behavioral evidence of visual function. A Phase 3 trial, the first randomized controlled trial in human gene therapy, of an AAV vector encoding RPE65 was completed, and demonstrated improvement in multiple measures of retinal and visual function. This product has now been licensed by the U.S. Food and Drug Administration (FDA), and is the first licensed AAV gene therapy product in the United States. Trials for other inherited retinal degenerative disorders such as choroideremia are under way, as are studies for certain complex acquired disorders such as age-related macular degeneration, which affects several million people worldwide. The neovascularization that occurs in age-related macular degeneration can be inhibited by expression of vascular endothelial growth factor (VEGF) inhibitors such as angiostatin or through the use of RNA interference (RNAi)-mediated knockdown of VEGF. Early-phase trials of an AAV vector designed to achieve long-term inhibition of the biological effects of VEGF through a soluble VEGF receptor, however, failed to provide convincing evidence of efficacy, illustrating the challenges of developing genetic approaches for complex acquired disorders.

GENE THERAPY FOR CANCER

The majority of clinical gene transfer experience has been in subjects with cancer. The intent has been to increase the precision of cancer therapies and thereby make them less toxic and more effective. Most approaches have either modified the tumor directly, or altered the host’s response to the malignancy to produce immune effector cells that are precisely targeted to the tumor phenotype.

■■MODIFYING THE CANCER

Since cancer is an (acquired) genetic disorder, initial efforts were directed at correcting the genetic deficits of the tumor or introducing lethal genes. Two major and persisting obstacles, however, are the poor biodistribution and transduction efficiency of all currently available vectors, and the heterogeneity and genetic instability of the tumor targets themselves, so that correction of single driver mutations does not preclude the evolution of a resistant population.

■■MODIFYING THE HOST Recruiting the Immune System  The successful use of mono-

clonal antibodies that produce anti-tumor activity by activating the immune response has demonstrated the feasibility of manipulating the immune system to recognize the abnormal pattern of antigen expression on tumor cells. Immune cells are capable of almost unlimited expansion and persistence and can provide long-term tumor control. They can also traffic to tumor sites irrespective of location and, in principle, have the potential to evolve with the changing pattern of tumor cell phenotype and function.

Vaccination  This strategy promotes more efficient recognition of tumor cells by the immune system, but the development of a therapeutic as opposed to the preventative vaccines required to combat infectious diseases has proved to be a considerable challenge. Approaches have included transduction of tumor cells with immune-enhancing genes encoding cytokines, chemokines, or co-stimulatory molecules, and the ex vivo manipulation of dendritic cells to enhance the presentation of tumor antigens. A dendritic cell vaccine for treatment of recurrent prostate cancer has received approval in the United States but its limited potency and high cost constrained commercial success. Adoptive Cell Transfer  Host immune cells such as T cells, NK cells, and others can be modified to express new transgenic receptors intended to recognize tumor cells and their microenvironment (Fig. 458-1). Retargeting may use a modification of the cells’ own receptor or a synthetic chimeric antigen receptor (CAR) that is usually composed of the antigen recognition portion of an antibody and the signaling components of the cell’s native antigen receptor. Both approaches have been successful, with significant responses reported with native receptors targeted to melanoma and synovial cell sarcoma and—most dramatically—with CARs targeted to CD19, an antigen expressed at high levels on normal and many malignant B cells. Infused CAR T cells can expand many thousand fold in vivo, persist long term, and have produced >90% complete response rates when targeting intractable B-acute lymphoblastic leukemia. Many responses are sustained long term and the approach has been licensed by the U.S. FDA. Broader application of adoptive T cell approaches is limited by: (1) The immune inhibitory microenvironment associated with most tumors; recent studies further modify the T cells with countermeasures to tumor inhibitory signals; (2) Acute and sometimes fatal systemic inflammatory and neurological toxicities during the phase of T-cell Native T cells CL

CH

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TM

α

β

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FIBB CD3ζ

α β

Pro-Drug Metabolizing Genes  Efforts to overcome the above

limitations have included the introduction of a prodrug or a suicide gene that would increase sensitivity of tumor cells to cytotoxic drugs. A frequently used strategy has been intratumoral injection of an adenoviral vector expressing the thymidine kinase (TK) gene. Cells that take up and express the TK gene can be killed after the administration of gancyclovir, which is phosphorylated to a toxic nucleoside by TK. The advantage of this approach is that the effects of transducing even a limited number of tumor cells are amplified by the spread of active drug to adjacent tumor cells. Although the approach continues to be examined in aggressive brain tumors and locally recurrent prostate, breast, and colon tumors, progress remains slow, and systemic benefits against metastatic disease have not been established.

Target cell

VL

CH2

Tumor Correction  One widely used direct intratumoral approach

was adenoviral-mediated expression of the tumor suppressor p53, which is mutated in many different cancers. Initial studies showed some complete and partial responses in squamous cell carcinoma of the head and neck, esophageal cancer, and non-small cell lung cancer, but as yet there have been no successful product licensing studies for this approach except in China.

VL

CAR T cells

MHC I

3378

CAR γ ε γε

εδζζ

ε δ ζ ζζ

T cells

TCR complex

TCR complex

FIGURE 458-1  T cell receptors. A native T cell receptor (TCR) recognizes processed peptide antigens bound to major histocompatibility (MHC) molecules through its αβ chains. Signaling then occurs through a multichain intracellular CD3 complex. A chimeric antigen receptor (CAR) usually contains an extracellular receptor component derived from the antigen binding portion (VH and VL) of a monoclonal antibody. This produces a receptor that can recognize either protein or non-protein antigens independent of the MHC. A transmembrane (TM) domain then connects this receptor to the ζ chain of the CD3 complex derived from the native TCR.

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Non-Immunological Modifications to Host  Gene transfer

can be used to protect normal cells from the toxicities of chemotherapy and thereby increase the therapeutic index of these drugs. The most extensively studied approach has been to transduce hematopoietic cells with genes encoding resistance to chemotherapeutic agents, including the multidrug resistance gene MDRI or the gene encoding O6-methylguanine DNA methyltransferase (MGMT). Although such approaches reduce hematologic toxicity, cytotoxic dose escalation quickly reveals dose-limiting toxicities to other organ systems. Finally, gene transfer can be used to inhibit the host angiogenesis required for tumor support, for example by constitutive expression of inhibitors such as angiostatin and endostatin, or the transfer of T cells genetically modified to recognize antigens specific to newly forming vasculature. These studies are early-phase.

■■COMBINATION APPROACHES—MODIFICATION OF HOST AND TUMOR BY VIROTHERAPY Immuno Oncolytic Viruses  These viruses are genetically modified to replicate in malignant but not normal cells. The replicating vectors thus proliferate and spread within the tumor, facilitating eventual tumor clearance. However, physical limitations to viral spread, including fibrosis, intermixed normal cells, basement membranes, and necrotic areas within the tumor, may reduce clinical efficacy, and their activity against metastatic disease has proved limited. Recently, the FDA granted licensing approval to talimogene laherparepvec, an oncolytic herpes virus containing the human GM-CSF gene, for treatment of melanoma. This success has led to resurgent interest in combining the local tumor destruction and tumor antigen release mediated directly by oncolytic viruses with the recruitment of a systemic immune response mediated by immunostimulatory genes contained within the oncolytic virus. In principle such immune-oncolytic viruses should produce responses in both local and metastatic disease. Numerous novel viral agents are now entering early phase clinical testing. ■■OTHER APPROACHES

This chapter has focused on gene addition therapy, in which a normal gene is transferred to a target tissue to drive expression of a gene product with therapeutic effects. Another powerful technique under development is genome editing, in which a mutation is corrected in situ, generating a wild-type copy under the control of the endogenous regulatory signals. This approach makes use of novel reagents including zinc finger nucleases, TALENs and CRISPR, which introduce double-stranded breaks into the DNA near the site of the mutation and then rely on a donated repair sequence and cellular mechanisms for repair of double-strand breaks to reconstitute a functioning gene. These approaches have only recently entered the stage of clinical investigation. Another strategy recently introduced into clinical trials is the use of siRNAs or short hairpin RNAs as transgenes to knock down expression of deleterious genes (e.g., mutant huntingtin in Huntington’s disease or genes of the hepatitis C genome in infected individuals).

SUMMARY

The power and versatility of gene transfer approaches are such that there are few serious disease entities for which gene transfer therapies are not under development. The development of new classes of therapeutics typically takes two to three decades; monoclonal antibodies and recombinant proteins are recent examples. Gene therapeutics, which entered clinical testing in the early 1990s, traversed the same time course. Examples of clinical success are now abundant, and gene therapy approaches are likely to become increasingly important as a therapeutic modality in the twenty-first century. A central question to be addressed is the long-term safety of gene transfer, and regulatory

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TABLE 458-4  Taking History from Subjects Enrolled in Gene Transfer Studies

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Elements of History for Subjects Enrolled in Gene Transfer Trials 1. What vector was administered? Is it predominantly integrating (retroviral, lentiviral, herpesvirus [latency and reactivation]) or nonintegrating (plasmid, adenoviral, adeno-associated viral)? 2.  What was the route of administration of the vector? 3.  What was the target tissue? 4.  What gene was transferred in? A disease-related gene? A marker? 5.  Were there any adverse events noted after gene transfer? Screening Questions for Long-Term Follow-Up in Gene Transfer Subjectsa 1.  Has a new malignancy been diagnosed? 2. Has a new neurologic/ophthalmologic disorder, or exacerbation of a preexisting disorder, been diagnosed? 3.  Has a new autoimmune or rheumatologic disorder been diagnosed? 4.  Has a new hematologic disorder been diagnosed?

CHAPTER 459 The Human Microbiome

expansion and tumor killing; (3) The off-target/or on-target but off-tumor effects that may damage normal host tissues (such as normal B cells following CD19 CAR therapy); (4) The cost, time, and complexity of manufacture; a particular problem when antigens unique to each tumor’s individual mutations are targeted (neoantigens), rather than widely shared tumor associated antigens.

a Factors influencing long-term risk include: integration of the vector into the genome, vector persistence without integration, and transgene-specific effects.

agencies have mandated a 15-year follow-up for subjects enrolled in gene therapy trials (Table 458-4). Realization of the therapeutic benefits of modern molecular medicine will depend on continued progress in gene transfer technology.

■■FURTHER READING

Aiuti A, Roncarolgo MG: Ten years of gene therapy for primary immune deficiencies. Hematology Am Soc Hematol Educ Program 2009:682, 2009. Fesnak AD et al: Engineered T cells: The promise and challenges of cancer immunotherapy. Nat Rev Cancer. 16:566, 2016. Hocquemiller M et al: Adeno-associated virus-based gene therapy for CNS diseases. Hum Gene Ther 27:478, 2016. Klebanoff CA et al: Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat Med 22:26, 2016. Kumar SR et al: Clinical development of gene therapy: Results and lessons from recent successes. Mol Ther Methods Clin Dev 3:16034, 2016. Rai P, Malik P: Gene Therapy for hemoglobin disorders—a minireview. J Rare Dis Res Treat 1:25, 2016. Ramos CA et al: CAR-T cell therapy for lymphoma. Annu Rev Med 67:165, 2016.

459 The Human Microbiome Neeraj K. Surana, Dennis L. Kasper

“All disease begins in the gut.” –Hippocrates Nearly two and a half millennia after Hippocrates made this statement, we are just coming to truly appreciate its profundity. Since the beginning of humankind, scholars have been investigating the underpinnings of disease with an almost singular focus on the human side of the equation. Microbes were not recognized as an important cause of disease until the inception of the “germ theory” in the late nineteenth century. During the first century of medical microbiology, research largely centered on the role of microbes as pathogens. Only recently has there been a resurgence of interest in understanding how commensal organisms—the bacteria, viruses, fungi, and Archaea that

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3380 make up the microbiota—impact human physiology. The idea that these

PART 16 Genes, the Environment, and Disease

microorganisms are vital to the well-being of humans has challenged our traditional notions of “self.” Indeed, a human being can most accurately be described as a holobiont: a complex assemblage of human cells and microorganisms interacting in an elaborate pas de deux that drives normal physiologic processes. Aimed at a better understanding of this relationship, myriad studies during the past decade have begun to catalogue the microbiota at various body sites and in a multitude of disease conditions. Diseases in virtually every organ system have been associated with changes in the microbiota. Indeed, the microbiota has been linked to intestinal disorders, disturbances in metabolic function, autoimmune diseases, and psychiatric conditions and has been shown to influence susceptibility to infection and the efficacy of pharmaceutical therapies. Knowledge of the specific mechanism(s) underlying most of these microbe–disease associations is lacking; it remains unclear whether the diseaseassociated alterations in the microbiota represent mere biomarkers of disease, a causal relationship, or a combination of the two. Although cause-and-effect relationships are still being elucidated for many diseases, it is clear that humans coexist in an intricate relationship with commensal organisms. This chapter explores in detail the nature of these host–commensal interactions, focusing on how this information might be translated into clinically meaningful interventions.

Although Leeuwenhoek first reported the existence of bacteria and their association with humans at the end of the seventeenth century, the significance of commensal bacteria was not realized until late in the nineteenth century. In 1885, Pasteur suggested that animals could not survive if they were “artificially and completely deprived of the common microbes.” Although Pasteur’s preconceived ideas were proven incorrect in 1912 by the advent of germ-free animals (animals raised without exposure to any microorganisms), the underlying concept that commensal organisms are critical to health has held up. Élie Metchnikoff made another conceptual advance in this field by suggesting at the beginning of the twentieth century that clinical outcomes could be altered by the administration of specific beneficial organisms (probiotics). In particular, Metchnikoff believed that aging was caused by toxic bacteria in the gut and that lactic acid–producing bacteria (e.g., Lactobacillus species) present in sour milk and yogurt could mitigate against this process. The data behind this specific claim are still lacking, but recent discoveries offer continued hope that the microbiome can be effectively harnessed to protect against and treat a variety of diseases. Thus, although the field of microbiome research is sometimes considered to have emerged over the last one or two decades, the basic tenets—that the microbiota varies according to body site and clinical characteristics, that microbes are critical for human health, and that specific modulation of the microbiota may lead to improved clinical outcomes—are far from new.

HISTORICAL PERSPECTIVE

A PRIMER ON TAXONOMY

Massive undertakings, such as the Human Microbiome Project (HMP) sponsored by the National Institutes of Health and MetaHIT sponsored by the European Commission, have catalogued all the bacteria present at multiple body sites in people with and without disease. Coupled with the confluence of advances in sequencing technologies (Chap. 474), gnotobiotic animal availability, and microbial culture, significant progress has been made toward an understanding of the interplay between the microbiota and human health. However, recent findings were foreshadowed by work done centuries ago. The human microbiota was first explored in 1683 when Antony van Leeuwenhoek described in a letter to the Royal Society of London the “very little living animalcules, very prettily a-moving” that he had observed in the plaque between his teeth. Leeuwenhoek went on to perform the first comparative “microbiota” studies by assessing how fecal and oral bacteria differ, how oral microbes change in the setting of disease (e.g., alcoholism and tobacco use), and how microbial composition changes across the age spectrum (e.g., in young children versus old men). He attempted—unsuccessfully—to eliminate these bacteria. Although Leeuwenhoek was not taken seriously when he first reported his findings, his studies laid the groundwork for what is now the field of microbiome research, and investigators are still trying to answer many of the same overarching questions that he raised more than three centuries ago.

Bacteria

Given that microbiome-based studies have identified and compared microbes at different levels of taxonomic resolution (Fig. 459-1), some understanding of taxonomy is essential for better comprehension of the implications of these studies. Of the ~100 bacterial phyla that exist in nature, only five (Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, and Proteobacteria) are dominant members of the human microbiome. Each of these phyla can be further categorized into multiple classes, orders, families, genera, and species. Early studies on the microbiota focused on changes in the relative abundance at the phylum level between different groups (e.g., obese versus normal-weight patients); however, these comparisons are at such a broad taxonomic level that they often provide little or no biological insight. As illustrated in Fig. 459-1, drawing comparisons between organisms in two different bacterial phyla is analogous to comparing humans to sea stars: the evolutionary distance between the two is tremendous. The limitations of current bioinformatic tools require lumping together of taxonomically related strains and thus cloud the richness of microbial ecology. Examining microbial profiles at the phylum, family, or even genus level—as is often done at present—ignores the great heterogeneity within different strains of the same bacterial species. The analytical pipelines are just now beginning to enable strain-level comparisons, and these improvements will likely facilitate our ongoing investigation of host–commensal interactions.

Domain Kingdom

Firmicutes Bacilli Bacillales Staphylococcaceae Staphylococcus S. aureus

G. haemolysans S. pneumoniae E. coli M. equipercicus E. faecalis B. fragilis S. epidermidis L. monocytogenes C. botulinum S. lugdunensis B. anthracis C. difficile E. rhusiopathiae

Phylum Class Order Family Genus

Eukarya Animalia Chordate Mammalia Primate Hominidae Homo

Species

FIGURE 459-1  Juxtaposition of bacterial and human taxonomy highlights the evolutionary distance between different taxonomic levels. The listed species represent exemplars that are members of the taxon to which they are connected but that are not contained within the next-lower-level taxon listed. For example, Clostridium botulinum, Clostridium difficile, and Erysipelothrix rhusiopathiae are members of the phylum Firmicutes, but are in classes other than Bacilli. Similarly, starfish and humans are both members of the kingdom Animalia, but they are in different phyla.

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THE MICROBIOTA AND HUMAN HEALTH ■■OVERVIEW OF THE HUMAN MICROBIOTA

CHAPTER 459 The Human Microbiome

The overwhelming majority of microbiota studies have focused on stool, given that this sample type represents the most ecologically rich anatomic site, is easy to obtain, and can readily be followed longitudinally in the same individual. A landmark study by the HMP sought to define the “normal” microbiota throughout the entire body in healthy Western adults. To this end, the microbial populations at 15–18 body sites were characterized in 242 people. One striking finding was that all samples from a given body region (e.g., skin) were more similar to each other than they were to samples from a different body region (e.g., stool), even in the same individual (Fig. 459-2A). In essence, the effect of the anatomic site on microbial composition is far greater than the effect of heterogeneity between individuals. That said, there was a remarkable amount of inter-individual variation at any given body site (Fig. 459-2B). In stool, for example, the abundance of the phylum Bacteroidetes ranged from ~10% in some individuals to >90% in others. Remarkably, even with person-to-person variability and differences among body sites, the functional capacity of the microbiota—assessed using metagenomic data to identify gene pathways—was quite similar across different people and different body sites (Fig. 459-2C). This discrepancy between the substantial differences in microbial composition and the little or no resulting change in the functional properties of the microbiota reflects an important ecologic property of the microbiota: the microbial communities at different body sites and in different people assemble in such a way that all the core metabolic functions are maintained. This finding also hints at the likely possibility of

significant functional redundancy within the microbiota, with different 3381 species executing the same biological functions at different anatomic sites. While the HMP provided the first large-scale catalogue of the microbiome in multiple people and at many different body sites, the amount of data generated by what, at the time, was by far the largest microbiome study has been dwarfed by subsequent studies. These more recent studies have confirmed the HMP’s major tenets: the composition of the microbiota differs by body site, there is tremendous inter-individual variation, and the microbial gene content is relatively conserved irrespective of the body site or individual. No microbial species are ubiquitous in all individuals and at all body sites, but some species are highly prevalent at a given body site: in the HMP study, Staphylococcus epidermidis was present in 93% of nares samples and Escherichia coli in 61% of stool samples. These findings highlight the remarkable personalization of the human microbiome. While the human genome is typically >99.5% identical in different people, the microbiotas of two individuals may not overlap at all. Although the “precision medicine” approach currently focuses on teasing out how differences in the human genome relate to different clinical end points, the human microbiome clearly represents a critical component for consideration.

■■THE MICROBIOTA BY THE NUMBERS

It has long been known that the human-associated microbiota is numerically dense. Leeuwenhoek estimated that there were more “animals living in the scrum on the teeth in man’s mouth than there are men in a kingdom.” Specific enumeration of the components of the microbiota has been challenging, in part because of its variability across time,

A

PC2 (4.4%)

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Urogenital

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Firmicutes Actinobacteria Bacteroidetes Proteobacteria Fusobacteria Tenericutes Spirochaetes Cyanobacteria Verrucomicrobia TM7

C

Metabolic pathways Central carbohydrate metabolism Cofactor and vitamin biosynthesis Oligosaccharide and polyol transport system Purine metabolism ATP synthesis Phosphate and amino acid transport system Aminoacyl tRNA Pyrimidine metabolism Ribosome Aromatic amino acid metabolism

Anterior nares

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FIGURE 459-2  The human microbiome exhibits significant taxonomic variability among body sites and between individuals while maintaining core metabolic pathways. A. Principal coordinates (PC) plot showing variation among samples demonstrates that primary clustering is by body area, with the oral, gastrointestinal, skin, and urogenital habitats separate; the nares habitat bridges oral and skin habitats. Each circle represents an individual sample. B, C. Vertical bars represent microbiome samples by body habitat, with each bar within a given body site representing a different individual. Bars indicate relative abundances colored by microbial phyla (B) and metabolic pathways (C). The legend on the right indicates the most abundant phyla/pathways. RC, retroauricular crease. (Reprinted by permission from Macmillan Publishers Ltd: Human Microbiome Project Consortium: Structure, function and diversity of the healthy human microbiome. Nature 486:207, 2012.)

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3382 space (body region), and clinical conditions. Moreover, the majority

PART 16 Genes, the Environment, and Disease

of human-associated microbes are not readily cultivable—a situation that raises questions about the best methodology for such quantitation. Initial back-of-the-envelope calculations performed in the 1970s suggested that there were roughly tenfold more bacteria in the body than there were human cells. This rather astounding estimate suggested that humans are really only ~10% “human” and that by far the greatest part of the holobiont is represented by microbes. This stark numerical discrepancy has prompted some to question “who parasitizes whom.” However, a more recent estimate has suggested that there are “only” ~1.3 times more bacteria in the body than there are human cells and thus that humans are ~56% “bacterial.” Of note, this more recent study does not include the numbers of viruses (known to generally be approximately tenfold more abundant than other microbes), fungi, or Archaea. Given these additional microorganisms, the notion that microbes constitute >90% of the cells present in a human body is likely correct. These ratios are even starker when one considers the genetic potential of human cells versus that of commensal organisms. In contrast to the ~20,000 genes in the human genome, the estimated total number of genes in the microbiota (which together constitute the microbiome)—i.e., >2,000,000—indicates that the human genome contributes 10,000 different bacterial species are present in the human microbiota; the intestines alone contain >1000 species. At any given time, the body of any given individual harbors 500–1000 bacterial species, with 100–200 bacterial species in the gut alone. If one considers different strains of the same bacterial species, which may be functionNares ally different from one another, the diversity of the microbiota is probably at least a magnitude greater. Although marked diversity exists at the strain and species level, only limited bacterial phyla are generally found in the human microbiota at any given body site (Fig. 459-3).

heritable than others. Thus, some inter-individual variation may be due to underlying differences in host genetics; however, it is likely that other factors explain more of the observed variability. That said, the host’s genetic contribution to the microbiota, albeit small, may be meaningful. Studies in mice have demonstrated that genetic variation in the major histocompatibility complex, a specific set of immunerelated genes, leads to changes in the microbiota that alter susceptibility to an autoimmune disease. These studies offer a proof of concept for the notion that the genetic predisposition observed for certain diseases may actually be mediated by indirect alterations in the microbiota.

Age  Burgeoning evidence now indicates that microbial exposure begins in utero: bacterial DNA has been identified in otherwise healthy placentas, in amniotic fluid obtained at early stages of gestation, and in meconium of term newborns. Although some controversy persists about whether these results reflect contamination and/or the presence of nonviable bacteria, they raise the possibility that human exposure to the microbial world begins before birth. The delivery mode (vaginal versus cesarean section) and the method of feeding (breast milk versus formula, timing of solid food introduction) are major determinants of an infant’s early microbiota. After birth, the infant’s microbiota goes through a stereotyped succession process; with increases in bacterial diversity and functional capacity, the child’s microbiota resembles that of an adult by the age of 2–3 years. Cross-sectional studies that have examined the microbiota across the entire age spectrum have revealed a general stability of the fecal microbiota after 2–3 years of age; however, the microbiota of the elderly (persons >80 years of age) demonstrates notable differences from those of their younger counterparts, with increases in Bacteroides and Eubacterium species and decreases in the bacterial family Lachnospiraceae. Supragingival plaque

■■INFLUENCES ON THE MICROBIOTA

An individual’s specific microbial configuration is dynamic and is quickly altered in response to subtle changes in the microenvironments in which the bacteria reside. On a day-to-day basis, these changes usually reflect alterations in the relative abundance of the various microbes. However, some exposures have a greater effect on the microbiota and can shift the microbial population to a new equilibrium via the loss of specific species and/ or the acquisition of others; this new microbial equilibrium can be associated with either health or a disease state (Fig. 459-4). Identification of the factors that influence the microbiota’s composition is critical to an understanding of what leads to and controls intra- and inter-individual variation. Moreover, an understanding of the influences on the microbiota will facilitate the design and proper interpretation of microbiota studies. While it is clear that the microbiota can be altered through these various mechanisms, it is not yet clear whether these changes are biologically significant.

Genetics  Studies of monozygotic and dizy-

gotic twins have revealed that host genetics have a small but statistically significant effect on the microbiota’s composition. Notably, some taxa, such as Christensenella species, are more

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Buccal mucosa

Skin

GI/Stool

Vagina

KEY

Actinobacteria Bacteroidetes

Fusobacteria Proteobacteria

Firmicutes Other

FIGURE 459-3  Different anatomic sites harbor very different microbiomes. The figure indicates the relative proportion of sequences determined at the taxonomic phylum level at six anatomic sites. (Data for stool, vagina, nares, buccal mucosa, and supragingival plaque are from the Human Microbiome Project; data for the skin is from EA Grice et al: Topographical and temporal diversity of the human skin microbiome. Science 324:1190, 2009.)

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Disease state

Unstable Healthy state 1 Current microbial state

Stable

FIGURE 459-4  A stability landscape of the human microbial ecosystem. A stable state, illustrated as a depression in the landscape, can be associated with either a healthy state or a disease state. The topology of an individual’s landscape reflects that person’s genetics, age, diet, medications, medical history, and lifestyle. The position of the green ball represents the current microbial state. Clinical changes (e.g., administration of antibiotics, development of disease) can influence both the current state and the overall topology.

Diet  Diet is a strong determinant of human health. The impact of

diet is mediated, in part, by its effects on the composition of the gut microbiota. This makes intuitive sense, as the human diet provides nutrients needed not only by our own cells but also by the microbes living in the alimentary tract. In young children, this dietary influence is marked by major shifts (e.g., a decrease in Bifidobacterium species) in the intestinal microbiota that occur at weaning and with the introduction of solid food. In adults, long-term dietary patterns are associated with relatively stable microbial compositions. However, drastic changes in short-term macronutrient availability cause rapid (within 1 day) and reproducible fluctuations in the fecal microbiota that reflect the biological processes needed to degrade and metabolize the nutrients in the new diet. For example, vegetarian diets are associated with a microbiota that has an increased ability to metabolize plant polysaccharides (e.g., Roseburia species, Eubacterium rectale, Ruminococcus bromii), while animal-based diets result in an increased abundance of bile-tolerant organisms (e.g., Alistipes, Bilophila, and Bacteroides species). At the completion of dietary interventions and the resumption of the individual’s normal dietary pattern, the microbial communities revert back to their previous states, probably because the individual resumes his or her typical diet. Taken together, dietary studies confirm that the microbiota is highly adaptable and varies in relation to changes in the diet. Of note, virtually all of these studies have focused on how the diet influences the fecal microbiota. It will be interesting to determine whether dietary changes similarly influence the microbiota at nonintestinal sites.

Drugs  Virtually all drugs have the capacity to change the microbi-

ota by altering the chemical landscape in which the microorganisms live (e.g., statins, bile acid sequestrants), modulating the host’s ability to recognize and react to microbes (e.g., immunosuppressants), and/or directly interfering with the microbiota’s constituents (e.g., antibiotics). These potential effects have made critical interpretation of microbiota studies much more difficult. A prominent study that claimed to identify a fecal microbiota signature associated with type 2 diabetes was later found actually to have identified a signature for patients taking metformin instead; the effects of this drug on the microbiota were far greater than the effects of the disease itself. These results highlight the importance of controlling for clinical variables in microbiota studies. Antibiotics are the most obvious and best-studied class of drugs that modulate the microbiota. Multiple groups have demonstrated that antibiotics exert a considerable effect on the gut microbiota by depleting antibiotic-sensitive strains. What is more surprising is that many strains resistant to the antibiotic tested are also eliminated. This observation highlights the intricate microbe–microbe interactions that

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CHAPTER 459 The Human Microbiome

Healthy state 2

are fundamental to maintenance of the overall microbial community. 3383 For example, treatment with ciprofloxacin, which has little to no activity against clinically relevant anaerobes, leads to a loss of roughly onethird of the bacterial taxa in the gut. This broad effect is likely mediated by the depletion of certain “keystone” species that are required for the persistence of other, unrelated species. While many of the observed antibiotic effects (e.g., loss of specific taxa) are shared across many different individuals, some effects vary greatly among people. For example, studies found that microbiota recovery following antibiotic treatment differed significantly in terms of timing and degree. The microbiota of most healthy people who received ciprofloxacin for 5 days had completely recovered within 4 weeks, whereas microbiologic changes lasted up to 6 months in other individuals. Moreover, the degree of variation was compounded by repeated antibiotic administration, with fewer individuals reverting to their baseline microbiota after a second course of ciprofloxacin given 6 months after the first. These findings are consistent with those of microbial ecology experiments, which also showed that this type of repeated disturbance leads to less predictable results.

Lifestyle  Many seemingly innocuous lifestyle decisions can impact the human microbiota. For example, a person’s skin and fecal microbiotas are more similar to those of their household members, regardless of genetic relatedness, than to those of residents of different households. The degree of similarity in skin microbiotas is even greater if a dog also lives in the home; in contrast, the presence of a young child does not accentuate this microbial relatedness. The presumption is that the dog serves as a more effective “vector” for transmitting microbes during its frequent direct contact with adults in the household. The type of setting in which a person lives also impacts the microbiota. Living in a rural or farm setting leads to a different fecal microbiota than living in an urban environment. Similarly, the individual’s country of residence affects the microbiota. An analysis of daily fecal samples from an individual who temporarily (i.e., for a couple of months) moved from the United States to Thailand demonstrated a large shift in the fecal microbiota that coincided with arrival in Thailand and a reversion in most respects to the “American” microbial configuration upon return to the United States. These geography-driven changes probably reflect a combination of environmental and dietary differences between locations. Circadian Rhythms  Many human biological processes follow

a circadian clock; aspects of physiology are tuned by external cues, including the degree and timing of ambient light, temperature, and availability of nutrients. This endogenous biological clock enables animals to efficiently adapt to changing environmental conditions. Similarly, the microbiota maintains a circadian rhythm that is linked to the host’s circadian clock. If circadian oscillations are disrupted in the host, they are similarly disrupted in the microbiota, and vice versa. These bacterial vacillations occur at the level of spatial localization within the intestine, relative species abundance, and bacterial metabolite secretion. Work in the 1960s showed that mice exhibited daily periodicity of susceptibility to infection with either S. pneumoniae or E. coli lipopolysaccharide. Although the fundamental basis for this difference was not known at the time, it is likely to be related, in part, to the microbial circadian clock. Derangements of these microbial oscillations have also been linked to the development of metabolic diseases and may underlie some of the health hazards associated with shift work and jet lag.

THE MICROBIOTA AND DISEASE ■■THE HYGIENE HYPOTHESIS

Over the past few decades, abundant epidemiologic data have revealed an inverse correlation between exposure to microbes and the incidence of autoimmune and/or atopic diseases (Fig. 459-5). This type of epidemiologic correlation led to the proposal of the “hygiene hypothesis” in 1989. Initially, this hypothesis focused on the development of atopic diseases in young children, with the idea that these epidemiologic observations could “be explained if allergic diseases were prevented by infection in early childhood, transmitted by unhygienic contact with older siblings, or acquired prenatally from a mother infected by contact

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Rheumatic fever 100

Hepatitis A

Tuberculosis

50

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A

Mumps Measles

0 1950 1960 1970 1980 1990 2000

Incidence of immune disorders (%)

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Incidence of infectious diseases (%)

3384

B

400

300

200

Crohn’s disease Multiple sclerosis

Type 1 diabetes Asthma

100 1950 1960 1970 1980 1990 2000

FIGURE 459-5  There was an inverse relationship between the incidence of select infectious diseases and the incidence of autoimmune disorders during the latter half of the twentieth century. A. Relative incidence of prototypical infectious diseases from 1950 to 2000. B. Relative incidence of select autoimmune disorders from 1950 to 2000. (From JF Bach: The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911, 2002. Copyright ©2002, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

with her older children.”1 In fact, this notion that differences in living conditions and environmental exposures contribute to susceptibility to hay fever (summer catarrh) dates back to at least the early nineteenth century. The hygiene hypothesis has continued to evolve over the past three decades and now posits that inadequacies in microbial exposure—in combination with genetic susceptibilities—lead to a collapse of the normally highly coordinated, homeostatic immune response. At its core, the hygiene hypothesis holds that specific early-life microbial exposures are required to prevent subsequent disease and that the “Westernization” of society has led to a decrease in such exposures. This concept is now being applied beyond atopic diseases to other inflammatory and autoimmune diseases and is thought to reflect processes that occur in later life as well.

■■RELATIONSHIP BETWEEN THE MICROBIOTA AND SPECIFIC DISEASE STATES

The ideas inherent in the hygiene hypothesis—in sum, that microbial exposure can affect long-term health outcomes—laid the theoretical foundation for translational microbiome studies. While most of the studies described earlier sought to describe how the microbiota responds to specific and often transient influences (e.g., a course of antibiotics, dietary interventions, travel), a multitude of studies have characterized the microbiota in patients with various diseases in the hope that a better understanding of the nature of disease-specific microbial communities will provide insight into disease pathogenesis and potentially uncover novel treatment modalities. Remarkably, virtually all of these studies have demonstrated differences between the microbiotas of healthy controls and patients, irrespective of the specific disease process examined. Although it is difficult to generalize across all studies, a couple of general themes have emerged. First, disease states are typically associated with microbiotas that are less diverse than those of healthy individuals. This loss of diversity can be measured either as a decrease in the number of species (alpha diversity; often measured as the number of operational taxonomic units, which are the bioinformatic equivalent of species) or as a reduction in the microbial relatedness of the species present (beta diversity). Often, both alpha and beta diversity decrease in the setting of disease. Second, states of inflammation—regardless of site or underlying disease process—are often associated with a relative increase in the abundance of the bacterial family Enterobacteriaceae and a decrease in the abundance of Lachnospiraceae.

Dissecting Correlation and Causality  Given that most of these investigations have been designed as case–control studies, it is difficult to determine whether microbiologic findings are the cause or the effect of the disease. Even studies that examine treatment-naïve D Strachan: BMJ 299:1259, 1989.

1

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patients at the time of initial diagnosis are still confounded by this “chicken or egg” issue. Moreover, prospective, longitudinal clinical studies—still rare in the microbiome field—may simply yield correlations between the microbiome and subclinical disease rather than necessarily proving causality. Experiments in animals—specifically, studies using gnotobiotic mice (germ-free mice that have been colonized with specified microbial communities)—have been critical in this regard as they allow investigation of specific differences in microbial components while controlling for the host’s genetics, diet, and housing conditions. Moreover, human microbes can be transplanted into gnotobiotic mice to permit in-depth mechanistic studies of how these microbial communities affect disease pathogenesis. This marriage of human samples and animal experiments has facilitated the identification of causal roles played by some microbes in disease pathogenesis; these findings provide a critical proof of concept for the interplay of the microbiota with human health. However, the vast majority of microbiome studies are still at the level of correlation. The next several sections describe the clinical and animal data for many different disease processes. Given the voluminous and rapidly changing nature of this field, it is impossible to cover all of the disease associations known to date; rather, the following discussion represents a combination of the leading exemplars of microbiome data and nascent areas of significant clinical interest. In all cases, the hope is that further study of the role of the microbiota will provide novel diagnostics, new therapeutic modalities, and/or additional insight into disease pathogenesis.

Gastrointestinal Diseases  Given that the intestines harbor the

largest number and greatest diversity of organisms in the body, much work has focused on how the microbiota impacts gastrointestinal diseases. Even though the luminal surface area of the gastrointestinal tract is 30–40 square meters (~90% of which is contained within the small intestine) and features marked anatomic and functional differences that result in many discrete macro- and micro-ecosystems, stool is often used as a surrogate for the intestinal microbiota given the relative ease of collecting samples. A few studies that have compared the microbial profile in stool with the mucosa-adherent organisms present in biopsy samples have demonstrated that stool is, in fact, a reasonable proxy for biopsy samples; however, the relative microbial “noise” present in stool can sometimes overwhelm the “signal,” making biopsy samples more informative for some scientific questions. The key issue is to ensure that the biopsy samples evaluated represent relatively similar intestinal regions, as there are significant differences between the organisms present in the crypt and the tip of the villus and between microbes found in the ascending versus the descending colon. Obesity is a worsening epidemic throughout the world, and multiple studies have linked the composition of the intestinal microbiota to the development of obesity in animal models and in humans. Indeed, many of the initial translational microbiome studies

OBESITY 

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MALNUTRITION  Representing the other end of the metabolic spectrum from obesity, malnutrition is also linked to an altered microbiome. Analysis of Malawian twin pairs (≤3 years of age) who were discordant for kwashiorkor—a severe form of malnutrition—revealed that kwashiorkor is associated with a microbiologically “immature” fecal microbiota that resembles that of a chronologically younger child. Transplantation of the fecal microbiota from these discordant twins into gnotobiotic mice that were fed a diet similar in composition to a typical Malawian diet established that the kwashiorkor-associated microbiome is causally related to poor weight gain. Subsequent studies demonstrated these same general trends in malnourished Bangladeshi children. Investigators were able to identify five bacterial species (Faecalibacterium prausnitzii, Ruminococcus gnavus, Clostridium nexile, Clostridium symbiosum, and Dorea formicigenerans) that—when administered together as a “cocktail” to mice colonized with a kwashiorkor-associated microbiome—was able to prevent growth impairments. These results demonstrate that rationally designed modulation of the murine microbiota can lead to improved health outcomes. The clinical significance of these findings for humans remains to be clarified.

Ulcerative colitis and Crohn’s disease, the two predominant forms of inflammatory bowel disease (IBD), are chronic gastrointestinal inflammatory conditions that differ in their locations and patterns of inflammation (Chap. 319). The following observations have led to the suggestion that IBD is the result of an immune response to a dysbiotic microbiota in a genetically susceptible individual: genes account for only ~20% of susceptibility to IBD (and many of the relevant genes are related to host–microbe interactions),

INFLAMMATORY BOWEL DISEASE 

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antibiotic treatment reduces the clinical severity of disease, and 3385 relapses of Crohn’s disease are prevented by diversion of the fecal stream. While the microbiota clearly is not the only driver of disease, it is considered to be an important element. Accordingly, numerous animal and clinical studies have been designed to tease out the nature of the relationship between the microbiota and IBD. Most of these studies have focused on comparing the microbiome’s composition in IBD patients with that in healthy controls, concentrating on microbial diversity and specific bacterial taxa that are associated with health or disease. Unfortunately, few, if any, results have been universally obtained, probably because of differences in study design, inclusion criteria, and methodology (e.g., the use of stool, rectal swabs, or biopsy samples; the choice of sequencing primers; the analysis pipeline). Even with these differences among studies, patients with IBD have been shown typically to have reduced alpha and beta diversity in their fecal microbiotas. Moreover, Clostridium clusters IV and XIVa, which are polyphyletic and encompass several different bacterial families, are generally reduced in patients with IBD. F. prausnitzii is a notable example from Clostridium cluster IV that is often underrepresented in the stool of patients who have Crohn’s disease, with more mixed results in biopsy samples. The bacterial family Lachnospiraceae, which is largely contained in Clostridium cluster XIVa, and other butyrate-producing organisms are also reduced in the stool of patients with IBD. Some of these species produce butyrate by using acetate generated by other members of the microbiome, and some of these acetate-producing species are similarly reduced (e.g., Ruminococcus albus). These complex interactions and dependencies among bacterial species pose unique challenges to definitive ascertainment of the cause–effect relationships between microbes and disease. Even before researchers were able to assess the entire microbiome at once, they often noted that patients with Crohn’s disease had a higher representation of adherent invasive E. coli in the ileal mucosa, an observation consistent with the increased abundance of Enterobacteriaceae seen in more recent microbiome studies. Beyond bacteria, burgeoning evidence supports a role for Caudovirales bacteriophages in IBD pathogenesis, though these findings may merely reflect the underlying dysbiosis related to the loss of bacterial diversity in IBD. Moreover, some data suggest that IBD is also associated with fungal dysbiosis; several studies have demonstrated an increased ratio of Basidiomycota to Ascomycota. It is still unclear whether any of these microbial associations reflect the cause of IBD or merely serve as biomarkers of disease. Studies of antibiotic-treated mice and gnotobiotic mice colonized with IBD-associated microbiotas have been useful in confirming that the microbiota affects colitis severity. Several bacterial species have been identified as either promoting colitis in mice (e.g., Klebsiella pneumoniae, Prevotella copri) or protecting against it (e.g., Bacteroides fragilis, Clostridium species); however, these organisms do not always correlate with the taxa identified as differentially abundant across multiple clinical studies. In contrast, IgA-coated commensal organisms isolated from patients with IBD promote more severe colitis in mice than either IgA-uncoated bacteria from patients with IBD or IgA-coated bacteria from healthy controls. These data suggest that functional categorization of the microbiota based on immune recognition (e.g., IgA coating) may be a useful approach for identifying pathogenic organisms.

CHAPTER 459 The Human Microbiome

performed in mice at the beginning of the twenty-first century focused on obesity. These early studies suggested that the ratio of the relative abundance of Bacteroidetes to Firmicutes was lower in obese mice than in control animals. Moreover, a causal relationship between the microbiota and obesity was established by the finding that gnotobiotic mice colonized with the microbiota from obese individuals had more rapid and more extensive weight gain than gnotobiotic mice colonized with the microbiota from lean individuals. Biologically, it is posited on the basis of metagenomic surveys that the obesity-associated microbiome has an increased capacity to harvest energy from the diet. Notably, the relationship between the Bacteroidetes/Firmicutes ratio and obesity did not hold in initial human studies; however, the finding that this ratio increased in obese patients who lost weight while on a fat- or carbohydrate-restricted diet suggested some generalizability between mice and humans. Beyond this ratio of major bacterial phyla, obesity was linked to a microbiome with a lower alpha diversity. Over the past ~15 years, numerous human studies examining the relationship between the microbiome and obesity have been completed, all with mixed results. A recent meta-analysis of 10 studies including nearly 3000 individuals revealed an apparent lack of relationship between the Bacteroidetes/Firmicutes ratio and obesity, though there is ~2% lower diversity associated with obesity that is statistically significant but of unclear biological significance. This finding highlights a problem common to microbiome studies: i.e., there is no sense as to what magnitude of change is biologically meaningful. Ultimately, although murine studies have indicated a causal link between the microbiota and obesity, the human data are less convincing, and their significance may be limited by the studies’ having primarily examined only highlevel taxonomic information rather than also assessing transcriptional or metabolic differences. The rise in obesity has elicited a plethora of ideas about the type of diet that might be most successful in leading to sustained weight loss. It has become clear that the same dietary ingredient can have highly diverse effects on blood glucose measurements in different people and that this effect is mediated largely by the microbiome. These observations suggest that the “optimal” diet needs to be individualized in the context of the person’s microbiome, which itself may continue to change over the course of the diet. An intriguing parallel question is whether the microbiota may also influence dietary preferences; such an influence would suggest important feedback loops between the microbiome and diet.

Cardiovascular Disease  Inflammation helps drive the pathogenesis of atherosclerosis, and it has long been postulated that microbes are involved in the atherosclerotic process. Early work demonstrated that patients with cardiovascular disease have higher titers of antibody to Chlamydia pneumoniae than control patients, that C. pneumoniae is present within atherosclerotic lesions, and that C. pneumoniae can both initiate and exacerbate atherosclerotic lesions in animal models. This type of analysis has been extended to other bacteria, such as Porphyromonas gingivalis, with the idea that multiple different bacteria may play some role in the pathogenesis of atherosclerosis. More recent studies have demonstrated clinical correlations between serum levels of trimethylamine N-oxide (TMAO) and atherosclerotic heart disease. Given that red meat, eggs, and dairy products are important sources of carnitine and choline (both precursors of TMAO), it is not

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3386 surprising that levels of TMAO are higher in omnivores than in vegans.

PART 16 Genes, the Environment, and Disease

Animal studies have confirmed that transfer of the gut microbiota from atherosclerosis-susceptible strains of mice to atherosclerosis-resistant animals leads to increased serum levels of TMAO and a dietary choline-dependent increase in atherosclerotic plaques; this observation confirms the role of the gut microbiota in the generation of TMAO and atherosclerosis. Moreover, treatment of atherosclerosis-susceptible strains of mice with a structural analogue of choline that inhibits the first enzymatic step in TMAO formation leads to decreased circulating TMAO levels and, more importantly, restrains macrophage foam-cell formation and atherosclerotic lesion development. In a study of more than 4000 patients, plasma TMAO levels were also predictive of incident thrombosis risk (myocardial infarction, stroke). Gnotobiotic animals were used to demonstrate that this risk was dependent on the microbiota; although eight bacterial taxa were identified as being associated with both plasma TMAO levels and thrombotic risk, organisms with choline-utilization genes that represent the first step of TMAO production were not more abundant in animals at greater risk for thrombosis. This discrepancy highlights the complexity of the microbiota and suggests that other aspects of the overall dynamics of the microbial community may be in play.

Oncology  Recent studies exploring the link between the microbiota

and cancer have demonstrated that specific members of the microbiota can affect treatment efficacy in both a positive and a negative manner. For example, therapy with antibody to programmed cell death ligand 1 (anti-PD-L1) has proven highly effective for a number of different cancers (Chap. 69); however, a significant proportion of patients do not respond even when their tumors have high PD-L1 expression levels, a prerequisite for this type of checkpoint blockade inhibition. Using a murine melanoma model, investigators showed that variations in the microbiota resulted in differences in melanoma growth, an impact that was accentuated by anti-PD-L1 therapy. Ultimately, Bifidobacterium species were bioinformatically associated with improved anti-tumor responses, and administration of a “cocktail” of Bifidobacterium species (B. bifidum, B. longum, B. lactis, and B. breve) to melanoma-susceptible mice resulted in improved tumor-specific immunity and responses to anti-PD-L1 therapy. In a separate set of studies involving both patient data and animal experiments, the efficacy of therapy with antibody to cytotoxic T lymphocyte–associated antigen 4 (anti-CTLA-4) was associated with T-cell responses specific for either Bacteroides thetaiotaomicron or B. fragilis. In particular, administration of B. fragilis to germ-free or antibiotic-treated mice restored the normally absent anticancer response to anti-CTLA-4 therapy. While both of these examples demonstrate potentiation of anti-cancer therapies by the microbiota, other therapies can be antagonized. Some cancers, such as pancreatic ductal adenocarcinoma, contain intratumor bacteria, particularly Gammaproteobacteria, that can metabolize the chemotherapeutic agent gemcitabine and thereby contribute to the drug resistance of these tumors. Overall, these examples highlight the microbiota’s critical impact—both direct and indirect—on the efficacy of drugs. Many other notable examples have been described (e.g., involving cyclophosphamide, digoxin, levodopa, and sulfasalazine), and many more likely remain to be discovered. The application of microbiome science to hematopoietic stem cell transplantation (HSCT) is an area of expanding interest, particularly given the significant morbidity and mortality related to graft-versushost disease (GVHD). In light of studies in the 1970s showing that germ-free mice developed less frequent and less severe gut GVHD than wild-type mice, clinicians began to use antibiotics to decontaminate the gut of patients undergoing HSCT. This decontamination approach yielded mixed results, probably because of differences in the antibiotic regimens used. The natural history of patients undergoing allogeneic HSCT includes a substantial loss of diversity in the fecal microbiota, with lower levels of bacterial diversity associated with increased mortality. Moreover, a retrospective analysis of ~850 patients undergoing allogeneic HSCT revealed that receipt of imipenem-cilastatin or piperacillin-tazobactam for neutropenic fever was associated with increased GVHD-related mortality at 5 years; this observation suggested that

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specific bacteria may help protect against GVHD-related mortality. More detailed analyses revealed an association between the abundance of Blautia species and protection against GVHD and mortality, though this correlation is still being examined with regard to its causal relationship. Despite significant interest in examining these microbial relationships with HSCT, little has yet been studied in the context of solid organ transplantation, which likely represents the next frontier of transplantation-related microbiome investigation.

Autoimmune Diseases  The dramatic rise in the incidence of many autoimmune diseases over the past few decades has been far more rapid than can be explained simply by genetic factors (Fig. 459-5). It is increasingly thought that environmental triggers, including the microbiome, are partially responsible for the development of these autoimmune diseases. TYPE 1 DIABETES  Type 1 diabetes (T1D) is an autoimmune disorder characterized by T cell–mediated destruction of insulin-producing pancreatic islets (Chap. 396). There is a clear genetic predisposition for the disease: ~70% of patients with T1D have human leukocyte antigen (HLA) risk alleles. However, only 3–7% of children with these risk alleles actually develop disease, an observation that suggests a role for other environmental factors. Studying a prospective, densely sampled, longitudinal cohort of at-risk, HLA-matched children from Finland and Estonia, investigators detailed changes in the microbiota prior to development of disease. Although only 4 of the 33 children studied developed T1D within the time frame of the study, a marked decrease of ~25% in alpha diversity occurred after seroconversion but before disease diagnosis. The low number of cases in this study unfortunately precluded identification of any specific disease-associated taxa. A follow-up study compared the microbiomes of a larger cohort of these high-risk northern European children with those of low-risk Russian children who lived in geographic proximity. Bacteroides species were more abundant in the high-risk group than in the low-risk group, particularly at early ages. This difference was postulated to be associated with an altered structure of the bacterial lipopolysaccharide to which children were exposed at a young age. It was further suggested that Bacteroides-derived lipopolysaccharide was not able to provide the immunogenic stimulus necessary to prevent T1D. These two studies offer attractive—though logistically complicated—options for future clinical investigations aimed at exploring the role of the microbiome. The first approach—longitudinally following individuals who are at high risk for a given disease—may provide insight into host–microbe relationships by mapping temporal changes in the microbiome with disease onset. An important caveat with this type of study, though, is that the associations identified may reflect preclinical disease rather than specifically indicating causality for any observed changes. The second approach illustrates how careful selection of study participants may offer an opportunity to uncover more meaningful associations that can subsequently be experimentally verified.

Similar to many other autoimmune diseases, rheumatoid arthritis (RA) is a multifactorial disease that comes to clinical attention after an environmental factor triggers symptoms in an individual with pre-existing autoantibodies. Multiple lines of evidence support the notion that RA pathogenesis is reliant on the microbiota, including the findings that germ-free mice do not develop symptoms in several RA models and that antibiotic treatment of mice mitigates against RA development. Several taxa (e.g., Bacteroides species, Lactobacillus bifidus, and segmented filamentous bacteria) have been implicated in promoting RA in murine models, and analysis of the fecal microbiota of patients with newly diagnosed RA have indicated that P. copri is a biomarker of disease. That this association with P. copri does not exist for chronic, treated RA or for psoriatic arthritis suggests some specificity for new-onset RA. A major limitation of this approach is that the identified association is shown to be a biomarker of disease (and, in this case, potentially of response to treatment) but no added insight is gained into a possible causal relationship between P. copri and RA. In fact, many of the patients with new-onset RA had no Prevotella detected, and several of the healthy controls had significant levels of

RHEUMATOID ARTHRITIS 

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of the AD lesions. Nevertheless, this is one of a limited number of 3387 studies that is beginning to extend microbiome-related findings into clinical trials.

MULTIPLE SCLEROSIS  Epidemiologic studies of twin pairs and at-risk individuals moving between high- and low-risk geographic areas indicate that genetics plays a minor component in multiple sclerosis (MS) susceptibility relative to environmental factors. For example, in monozygotic twin pairs in which one sibling has MS, the other sibling also develops MS in only ~30% of cases. Although MS is a disease of the central nervous system (CNS), there is growing evidence of a link between MS and the microbiota, specifically that of the gut. Germfree animals and antibiotic-treated animals display reduced disease incidence and severity in an MS model. Similarly, some clinical studies suggest improved disease outcomes in patients with MS who have been treated with minocycline, while patients treated with long-term penicillin appear to have an increased disease risk. Although several studies have compared the fecal microbiotas of healthy controls to those of patients with MS, these studies have all been relatively small and have yielded few results (if any) that are common throughout. Although work relating the microbiome to MS is ongoing, it has opened the door to exploring this link with other neurologic diseases. Already, there are animal data demonstrating links between the microbiota and both Parkinson’s disease and autism, and there are clinical data assessing fecal microbiomes in relation to a variety of neurologic conditions. It is not quite clear how the gut microbiota is communicating with the CNS—i.e., whether communication takes place via bacterial metabolites that travel in the bloodstream and cross the blood–brain barrier, via migration of whole organisms into the CNS, or via feedback through the vagus nerve. Although our understanding of this brain–gut axis is still in its infancy, research in this area has elicited tremendous excitement as a tractable approach to potential treatments for these challenging diseases.

ASTHMA 

Atopic Diseases  The incidence and prevalence of allergic diseases continue to steadily increase, as do more severe clinical presentations. Life-threatening food allergies are now such a public health issue that nut-free classrooms are the norm in many cities. The development of allergic diseases often follows a stereotyped progression that begins with atopic dermatitis (AD) and continues, in order, with food allergy, asthma, and allergic rhinitis. The microbiome has been linked to all of these conditions and has the potential to modulate effects anywhere along this spectrum. ATOPIC DERMATITIS  The skin is the largest organ in the body, and its different anatomic sites (e.g., antecubital fossa, volar forearm, alar crease) represent distinct ecologic niches and harbor unique microbial communities. Moreover, given that the skin serves as a critical interface between the body and the external environment (e.g., microbes), it must be able to respond to unwanted microbes with an adequate immune response. AD is an inflammatory skin disorder involving immune dysfunction and a dysbiotic skin microbiota that is typically marked by greater abundances of Staphylococcus aureus and a lesser degree of bacterial diversity. Effective treatment of AD does not require complete elimination of S. aureus but is associated with restoration of the normal level of diversity. It is likely that this increase in bacterial diversity re-establishes normal immune homeostasis in the skin; specific members of the skin microbiota have been shown to induce protective skin-restricted immune responses. Coagulasenegative staphylococci (CoNS; primarily S. epidermidis and S. hominis) obtained from lesional and nonlesional skin of patients with AD were functionally screened and compared to CoNS from healthy controls; AD-lesional CoNS were much less often able to produce antimicrobial peptides (lantibiotics) directed against S. aureus. To demonstrate that these lantibiotic-producing CoNS were biologically relevant, they were incorporated into a lotion and applied to the arms of patients with AD. Surprisingly, a single application of the probiotic-laced lotion led to a decrease in the abundance of S. aureus recovered; no such decrease was observed when lantibiotic-negative strains were used. The authors of this study did not specifically comment on the clinical improvement

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Asthma is characterized by the clinical triad of airflow obstruction, bronchial hyperresponsiveness, and inflammation in the lower respiratory tract. Although the long-standing dogma was that the lungs are sterile, there is now convincing evidence for a constant ebb and flow of bacteria within the lower airways. In healthy states, the mucociliary escalator continually eliminates these bacteria soon after they land in the airways; in disease states (e.g., cystic fibrosis, chronic obstructive pulmonary disease), these bacteria establish longterm colonization of the airways and influence disease pathogenesis. In asthma specifically, both fecal and airway microbes have been linked to clinical outcomes. Early studies of the microbiome’s influence on asthma used culture-based methods to assess the hypopharyngeal microbiota of asymptomatic 1-month-old infants. Intriguingly, in one study, early-life colonization with Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, or a combination of these organisms—but not S. aureus—was significantly associated with persistent wheeze and asthma at 5 years of age. Eosinophilia and total IgE levels at 4 years of age were also increased in children who were neonatally colonized with these organisms. Although this study examined a fairly focused set of bacteria, it laid the experimental groundwork indicating that early-life microbial exposures influence subsequent development of asthma. A later longitudinal investigation of the fecal microbiota in a general-population birth cohort of more than 300 children demonstrated that lower abundances of the genera Lachnospira, Veillonella, Faecalibacterium, and Rothia at 3 months of age were associated with an increased risk for development of asthma. The fact that these bacterial changes were no longer apparent when the children were 1 year of age is consistent with the notion that microbial exposures early in life are important to disease pathogenesis later in life. Transplantation of stool samples from 3-month-old children at risk for asthma into gnotobiotic mice resulted in significant airway inflammation in a murine model of asthma; pre- and postnatal exposure of mice to a four-species cocktail (F. prausnitzii, Veillonella parvula, Rothia mucilaginosa, and Lachnospira multipara) inhibited airway inflammation, with a marked reduction in neutrophil numbers in bronchoalveolar lavage fluid. These data suggest that early-life modulation of the microbiome may be an effective strategy to help prevent asthma, though the specific logistics (e.g., strains, dose, timing of exposure, patient selection) remain to be clarified.

CHAPTER 459 The Human Microbiome

Prevotella. The lack of a strict concordance between the presence (or absence) of a specific taxon and a given disease state argues against a possible causal role.

Infectious Diseases  The increased susceptibility of antibiotic-treated mice to infection with a wide range of enteric pathogens was initially observed in the 1950s and led soon thereafter to the concept of colonization resistance, which holds that the normal intestinal microbiota plays a critical role in preventing colonization—and therefore disease production—by invading pathogens. Seminal work in the 1970s demonstrated that this protection is largely reliant on clostridial organisms, and the subsequent half-century has been spent trying to identify the specific microbes involved. Although much of the work relating the microbiota to infection has focused on enteric pathogens, the intestinal microbiota has also been clearly linked to bacterial pneumonia in mouse models, and changes in the microbial composition of the gut have been causally related to changes in the severity of disease. Although this gut–lung axis clearly exists in animals, its relevance in humans is still unclear. Several groups are beginning to study the human lung microbiome in the context of pneumonia and tuberculosis. Moreover, the relationships between the microbiota and both systemic infections (e.g., HIV infection, sepsis) and the response to vaccination are starting to be explored. ENTERIC INFECTIONS  Clostridium difficile infection (CDI) represents a growing worldwide epidemic and is the leading cause of antibioticassociated diarrhea (Chap. 129). Roughly 15–30% of patients who are successfully treated for CDI end up with recurrent disease. The strong association between antibiotic exposure and CDI initially raised the idea that the microbiota is inextricably linked to acquisition of disease,

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3388 presumably because of the loss of colonization resistance. Consistent

PART 16 Genes, the Environment, and Disease

with the epidemiologic data, characterization of the fecal microbiota of patients with CDI revealed that it is a markedly less diverse, dysbiotic community. Fecal microbiota transplantation (FMT)—the “transplantation” of stool from a healthy individual into patients with disease—was successfully used in the 1950s to treat four patients with severe CDI and has recently been demonstrated in numerous studies to be an effective therapy for recurrent CDI, with clinical cure in 85–90% of patients (as detailed below). Thus, FMT for recurrent CDI has become the “poster child” for the idea that microbiome-based therapies may transform the management of many diseases previously considered to be refractory to medical therapy. Although FMT is agnostic as to the underlying mechanism of protection, work is ongoing to identify specific microbes and host pathways that can protect against CDI. Studying mice with differential susceptibilities to CDI due to antibiotic-induced changes in their microbiota, investigators identified a cocktail of four bacteria (Clostridium scindens, Barnesiella intestihominis, Pseudoflavonifractor capillosus, and Blautia hansenii) that conferred protection against CDI in a mouse model. Intriguingly, treatment of mice with just C. scindens offered significant, though not complete, protection in a bile acid– dependent manner. Clinical data from patients who underwent HSCT also associated C. scindens with protection from CDI, an observation that suggests the possibility of translating these findings from mice to humans. This study provides another example of the identification of relevant bacterial factors through examination of microbial differences in populations that differ in disease risk. Microbiome-related changes associated with Vibrio cholerae infection include a striking loss of diversity (largely due to V. cholerae’s becoming the dominant member of the microbiota) and an altered composition that rapidly follows the onset of disease. These changes, which occur in a reproducible and stereotypical manner, are reversible with treatment of the disease. This recovery phase involves a microbial succession that is similar to the assembly and maturation of the microbiota of healthy infants. In addition to V. cholerae, streptococcal and fusobacterial species bloom during the early phases of diarrhea, and the relative abundances of Bacteroides, Prevotella, Ruminococcus/ Blautia, and Faecalibacterium species increase during the resolution phase and mark the return to a healthy adult microbiota. Analysis of these microbial changes occurring in patients with cholera and in healthy children led to the selection of 14 bacteria that were transplanted into gnotobiotic mice, which were then challenged with V. cholerae. Bioinformatic analysis of specific taxa changing during cholera determined that Ruminococcus obeum restrained V. cholerae growth. Subsequently, this relationship was experimentally confirmed, and the R. obeum quorum-sensing molecule AI-2 (autoinducer 2) was found to be responsible for restricting V. cholerae colonization via an unclear mechanism. These studies highlight the potential for use of microbiomebased therapies to prevent and/or treat infectious diseases. Moreover, they suggest that temporal analysis of longitudinal microbiome data may be an effective strategy for identifying microbes with causal relationships to disease. The augmentation of HIV pathogenesis by some viral, bacterial, and parasitic co-infections suggests that a patient’s underlying microbial environment can influence the severity of HIV disease. Moreover, it has been hypothesized that the intestinal immune system plays a significant role in regulating HIV-induced immune activation; this seems particularly likely since the intestines are an early site for viral replication and exhibit immune defects before peripheral CD4+ T cell counts decrease. Several studies have examined the intestinal microbiotas of HIV-infected individuals. Initial studies performed in nonhuman primates infected with simian immunodeficiency virus found no alteration in the bacterial components of the fecal microbiota; however, there were profound changes in the enteric virome. In contrast, many recent studies exploring this issue in patients have identified substantial differences in the HIV-associated fecal microbiota that correlate with systemic markers of inflammation. Curiously, these microbial changes do not necessarily normalize with antiretroviral therapy; this finding suggests that the microbiota may have some “memory” of the previously high HIV loads and/or that HIV infection

HIV INFECTION 

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helps reset the “normal” microbiota. This memory-like capacity of the microbiota has been demonstrated in animal models in the context of other infections and in response to dieting. Given that the majority of new HIV transmission events follow heterosexual intercourse, there has been significant interest in examining the relationship between the vaginal microbiota and HIV acquisition. A longitudinal study of South African adolescent girls who underwent high-frequency testing for incident HIV infection facilitated the identification of bacteria that were associated with reduced risk of HIV acquisition (Lactobacillus species other than L. iners) or with enhanced risk (Prevotella melaninogenica, Prevotella bivia, Veillonella montpellierensis, Mycoplasma, and Sneathia sanguinegens). In mice inoculated intravaginally with Lactobacillus crispatus or P. bivia, the latter organism induced a greater number of activated CD4+ T cells in the female genital tract, a result suggesting that the increased risk of HIV acquisition associated with P. bivia may be secondary to the increased presence of target cells. In a separate study, the composition of the vaginal microbiota was shown to modulate the antiviral efficacy of a tenofovir gel microbicide. Although tenofovir reduced HIV acquisition by 61% in women who had a Lactobacillus-dominant vaginal microbiota, it reduced HIV acquisition by only 18% in women whose vaginal microbiota comprised primarily Gardnerella vaginalis and other anaerobes. This difference in efficacy was due to the ability of G. vaginalis to metabolize tenofovir faster than the target cells can take up the drug and convert it into its active form, tenofovir diphosphate. These findings illustrate how microbial ecology can be an important consideration in choosing effective treatment regimens. Second only to the provision of clean water, vaccination has been the most effective public health intervention in the prevention of serious infectious diseases. Its effects are mediated by antigen-specific antibodies and, in some cases, effector T-cell responses. Although vaccines are clearly effective on a population scale, the magnitude of the immune response to vaccines can vary among individuals by tenfold to a hundredfold. Although many factors (e.g., genetics, maternal antibody levels, prior antigen exposures) can affect vaccine immunogenicity, the microbiota is now recognized as another important factor. Analysis of the fecal microbiotas of ~50 Bangladeshi children identified specific taxa that exhibited positive associations (e.g., Actinomyces, Rothia, and Bifidobacterium species) and negative associations (e.g., Acinetobacter, Prevotella, and staphylococcal species) with responses to vaccines against polio, tuberculosis (bacille Calmette-Guérin), tetanus, and hepatitis B. A study of infants from Ghana revealed an inverse relationship between the fecal abundance of Bacteroidetes and a response to the rotavirus vaccine. Moreover, the nasal microbiota has been implicated as a factor that contributes to the IgA response to live, attenuated influenza vaccines. These correlations based on clinical data have been partially confirmed in animal studies. The best example is the demonstration that the responses to nonadjuvanted viral subunit vaccines (inactivated influenza and polio vaccines) are reliant on the microbiota, whereas the responses to live or adjuvanted vaccines (live attenuated yellow fever, Tdap/alum, an HIV envelope protein/alum vaccine) are not. An interesting note is that the antibody response to inactivated influenza vaccine is dependent on recognition of the microbiota by Toll-like receptor 5, presumably via flagellin-expressing microbes. These data suggest that the microbiota may serve as an adjuvant for certain vaccine types. Confirmation of these findings in clinical settings may suggest ways to improve vaccine efficacy in the future.

RESPONSE TO VACCINATION 

MECHANISMS OF MICROBIOME-MEDIATED EFFECTS

As highlighted in the examples above, numerous associations have been made between the microbiome and various disease states. These correlations have often been established at broad taxonomic levels, with little or no insight into causality. Given that most clinical studies of these relationships have a fairly small sample size (often