Text snippets:

[1] 3rd Edition ’ S HARRISON NEUROLOGY IN CLINICAL MEDICINE TM

[2] Derived from Harrison’s Principles of Internal Medicine, 18th Edition Editors 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 DENNIS L. KASPER, MD William Ellery Channing Professor of Medicine, Professor of Microbiology and Molecular Genetics, Harvard Medical School; Director, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

[3] J. LARRY JAMESON, MD, PhD Robert G. Dunlop Professor of Medicine; Dean, University of Pennsylvania School of Medicine; Executive Vice-President of the University of Pennsylvania for the Health System, Philadelphia, Pennsylvania ANTHONY S. FAUCI, MD Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

[4] STEPHEN L. HAUSER, MD Robert A. Fishman Distinguished Professor and Chairman, Department of Neurology, University of California, San Francisco, San Francisco, California 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

[5] 3rd Edition HARRISON ’ S

[6] TM NEUROLOGY IN CLINICAL MEDICINE EDITOR Stephen L. Hauser, MD Robert A. Fishman Distinguished Professor and Chairman, Department of Neurology, University of California, San Francisco, San Francisco, California ASSOCIATE EDITOR S. Andrew Josephson, MD Associate Professor of Clinical Neurology C. Castro-Franceschi and G. Mitchell Endowed Neurohospitalist Chair Vice-Chairman, Parnassus Programs University of California, San Francisco, San Francisco, California

[7] New York Milan Chicago San Francisco New Delhi San Juan Lisbon London Seoul Singapore Madrid Sydney Mexico City Toronto

[8] Copyright © 2013 by McGraw-Hill Education, LLC. 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.

[9] ISBN: 978-0-07-181501-7 MHID: 0-07-181501-5 The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-181500-0, MHID: 0-07-181500-7. 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.

[10] Where such designations appear in this book, they have been printed with initial caps.

[11] 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 e-mail us at <PRESIDIO_ANONYMIZED_EMAIL_ADDRESS>. Dr. Fauci’s work as an 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.

[12] government. This book was set in Bembo by Cenveo® Publisher Services. The editors were James F. Shanahan and Kim J. Davis. The production supervisor was Catherine H. Saggese. Project management was provided by Tania Andrabi, Cenveo Publisher Services. The cover design was by Thomas DePierro. Cover image, lesion track atrophy, supplied by Stephen L. Hauser. TERMS OF USE This is a copyrighted work and McGraw-Hill Education, LLC.

[13] 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.

[14] 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.

[15] 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.

[16] 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.

[17] CONTENTS Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii SECTION I INTRODUCTION TO NEUROLOGY 1 Approach to the Patient with Neurologic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 Daniel H. Lowenstein, Joseph B. Martin, Stephen L. Hauser Daniel H. Lowenstein 3 Video Atlas of the Detailed Neurologic Martin A.

[18] Samuels William P. Dillon 5 Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, Michael J. Aminoff Elizabeth Robbins, Stephen L. Hauser 2 The Neurologic Screening Exam . . . . . . . . . . . .11 Examination . . . . . . . . . . . . . . . . . . . . . . . . . . .12 4 Neuroimaging in Neurologic Disorders . . . . . . .13 and EMG . . . . . . . . . . . . . . . . . . . . . . . .

[19] . . . . .26 6 Technique of Lumbar Puncture . . . . . . . . . . . . .35 SECTION II CLINICAL MANIFESTATIONS OF NEUROLOGIC DISEASE 7 Pain: Pathophysiology and Management . . . . . . .40 James P. Rathmell, Howard L. Fields Peter J. Goadsby, Neil H. Raskin John W. Engstrom, Richard A. Deyo Roy Freeman Mark F. Walker, Robert B. Daroff Michael J. Aminoff 8 Headache . . . . . . . . . . . . . . . . . . . .

[20] . . . . . . . . .51 9 Back and Neck Pain . . . . . . . . . . . . . . . . . . . . .71 10 Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .89 11 Dizziness and Vertigo . . . . . . . . . . . . . . . . . . . .98 12 Weakness and Paralysis. . . . . . . . . . . . . . . . . . . 103 13 Gait and Balance Disorders. . . . . . . . . . . . . . . . 110 Lewis Sudarsky Gail Kang, Nicholas B. Galiﬁanakis, Michael Geschwind Michael J.

[21] Aminoff, Arthur K. Asbury S. Andrew Josephson, Bruce L. Miller Allan H. Ropper 18 Aphasia, Memory Loss, and Other Focal M.-Marsel Mesulam 19 Video Atlas: Primary Progressive Aphasia, Memory Loss, and Other Focal Cerebral Maria Luisa Gorno-Tempini, Jennifer Ogar, Joel Kramer, Bruce L. Miller, Gil Rabinovici, Maria Carmela Tartaglia Charles A. Czeisler, John W. Winkelman, Gary S. Richardson Jonathan C.

[22] Horton Shirley H. Wray Richard L. Doty, Steven M. Bromley Anil K. Lalwani 14 Video Library of Gait Disorders . . . . . . . . . . . . 116 15 Numbness, Tingling, and Sensory Loss . . . . . . . 117 16 Confusion and Delirium . . . . . . . . . . . . . . . . . 125 17 Coma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Cerebral Disorders . . . . . . . . . . . . . . . . . . . . . . 142

[23] Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 20 Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . 158 21 Disorders of Vision . . . . . . . . . . . . . . . . . . . . . 174 22 Video Library of Neuro-Ophthalmology . . . . . 198 23 Disorders of Smell and Taste . . . . . . . . . .

[24] . . . . 199 24 Disorders of Hearing . . . . . . . . . . . . . . . . . . . . 207 SECTION III DISEASES OF THE NERVOUS SYSTEM 25 Mechanisms of Neurologic Diseases . . . . . . . . . 218 Stephen L. Hauser, M. Flint Beal Daniel H. Lowenstein Wade S. Smith, Joey D. English, S. Claiborne Johnston 26 Seizures and Epilepsy . . . . . . . . . . . . . . . . . . . . 231 27 Cerebrovascular Diseases . . . . . . .

[25] . . . . . . . . . . 256 v

[26] vi Contents 28 Neurologic Critical Care, Including 44 Paraneoplastic Neurologic Syndromes. . . . . . . . 558 Hypoxic-Ischemic Encephalopathy, and Subarachnoid Hemorrhage . . . . . . . . . . . . 294 J. Claude Hemphill, III, Wade S. Smith, Daryl R. Gress William W. Seeley, Bruce L. Miller 30 Parkinson’s Disease and Other Extrapyramidal 29 Alzheimer’s Disease and Other Dementias .

[27] . . . 310 Movement Disorders . . . . . . . . . . . . . . . . . . . . 333 C. Warren Olanow, Anthony H. V. Schapira Roger N. Rosenberg 31 Ataxic Disorders . . . . . . . . . . . . . . . . . . . . . . . 357 Josep Dalmau, Myrna R. Rosenfeld Anthony A. Amato, Richard J. Barohn 46 Guillain-Barré Syndrome and Other Stephen L. Hauser, Anthony A. Amato 47 Myasthenia Gravis and Other Diseases of Daniel B. Drachman 48 Muscular Dystrophies and Other

[28] 45 Peripheral Neuropathy. . . . . . . . . . . . . . . . . . . 566 Immune-Mediated Neuropathies . . . . . . . . . . . 599 the Neuromuscular Junction . . . . . . . . . . . . . . 609 Muscle Diseases . . . . . . . . . . . . . . . . . . . . . . . . 618 32 Amyotrophic Lateral Sclerosis and Other Motor Anthony A. Amato, Robert H. Brown, Jr. Neuron Diseases . . . . . . . . . . . . . . . . . . . . . . . 370

[29] Robert H. Brown, Jr. 49 Polymyositis, Dermatomyositis, and Inclusion Body Myositis . . . . . . . . . . . . . . . . . . . . . . . . . 648 33 Disorders of the Autonomic Nervous System . . . . 380 Marinos C. Dalakas Phillip A. Low, John W. Engstrom 50 Special Issues in Inpatient Neurologic 34 Trigeminal Neuralgia, Bell’s Palsy, and Consultation . . . . . . . . . . . . . . . . . . . . . . . . . . 660

[30] Other Cranial Nerve Disorders . . . . . . . . . . . . 392 S. Andrew Josephson, Martin A. Samuels M. Flint Beal, Stephen L. Hauser Stephen L. Hauser, Allan H. Ropper Allan H. Ropper 37 Primary and Metastatic Tumors of the Nervous Lisa M. DeAngelis, Patrick Y. Wen 38 Neurologic Disorders of the Pituitary and Shlomo Melmed, J. Larry Jameson 39 Multiple Sclerosis and Other Demyelinating Stephen L. Hauser, Douglas S.

[31] Goodin 40 Meningitis, Encephalitis, Brain Abscess, Karen L. Roos, Kenneth L. Tyler Walter J. Koroshetz, Morton N. Swartz Anthony S. Fauci, H. Clifford Lane Stanley B. Prusiner, Bruce L. Miller 51 Atlas of Neuroimaging . . . . . . . . . . . . . . . . . . . 668 35 Diseases of the Spinal Cord . . . . . . . . . . . . . . . 400 Andre Furtado, William P.

[32] Dillon SECTION IV 36 Concussion and Other Head Injuries . . . . . . . . 415 CHRONIC FATIGUE SYNDROME 52 Chronic Fatigue Syndrome . . . . . . . . . . . . . . . 704 Gijs Bleijenberg, Jos W. M. van der Meer System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 SECTION V PSYCHIATRIC DISORDERS Hypothalamus . . . . . . . . . . . . . . . . . . . . . . . . . 439 53 Biology of Psychiatric Disorders .

[33] . . . . . . . . . . . 710 Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474 and Empyema . . . . . . . . . . . . . . . . . . . . . . . . . 493 Robert O. Messing, John H. Rubenstein, Eric J. Nestler Victor I. Reus Charles W. Hoge 54 Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . 720 55 Neuropsychiatric Illnesses in War Veterans . . . . 742 41 Chronic and Recurrent Meningitis .

[34] . . . . . . . . . 527 SECTION VI ALCOHOLISM AND DRUG DEPENDENCY 42 HIV Neurology. . . . . . . . . . . . . . . . . . . . . . . . 536 43 Prion Diseases . . . . . . . . . . . . . . . . . . . . . . . . . 549 56 Alcohol and Alcoholism . . . . . . . . . . . . . . . . . . 752 Marc A. Schuckit Thomas R. Kosten 57 Opioid Drug Abuse and Dependence . . . . . . . . 761

[35] Contents vii 58 Cocaine and Other Commonly

[36] Abused Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 767 Nancy K. Mello, Jack H. Mendelson Review and Self-Assessment . . . . . . . . . . . . . . . 801 Charles Wiener,Cynthia D. Brown, Anna R. Hemnes Appendix Laboratory Values of Clinical Importance . . . . . . . 775 Alexander Kratz, Michael A. Pesce, Robert C. Basner, Andrew J. Einstein Index . . . . . . . . . . . . . . . . . . . . . .

[37] . . . . . . . . . . . . 851

[38] This page intentionally left blank

[39] CONTRIBUTORS Numbers in brackets refer to the chapter(s) written or cowritten by the contributor. Anthony A. Amato, MD Professor of Neurology, Harvard Medical School; Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts [45, 46, 48] Michael J. Aminoff, MD, DSc Professor of Neurology, University of California, San Francisco School of Medicine, San Francisco, California [5, 12, 15]

[40] Richard J. Barohn, MD Chairman, Department of Neurology; Gertrude and Dewey Ziegler Professor of Neurology, University of Kansas Medical Center, Kansas City, Kansas [45] Robert C. Basner, MD Professor of Clinical Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York [Appendix] M. Flint Beal, MD Chairman of Neurology and Neuroscience; Neurologist-in-Chief, New York Presbyterian Hospital; Weill Cornell Medical College, New York, New York [25, 34]

[41] Gijs Bleijenberg, PhD Professor; Head, Expert Centre for Chronic Fatigue, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands [52] Steven M. Bromley, MD Clinical Assistant Professor of Neurology, Department of Medicine, New Jersey School of Medicine and Dentistry–Robert Wood Johnson Medical School, Camden, New Jersey [23]

[42] Cynthia D. Brown, MD Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia [Review and Self-Assessment] Robert H. Brown, Jr., MD, PhD Chairman, Department of Neurology, University of Massachusetts Medical School, Worchester, Massachusetts [32, 48] Charles A. Czeisler, MD, PhD, FRCP Baldino Professor of Sleep Medicine; Director, Division of Sleep Medicine, Harvard Medical School; Chief, Division of Sleep Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [20]

[43] Marinos C. Dalakas, MD, FAAN Professor of Neurology, Department of Pathophysiology, National University of Athens Medical School, Athens, Greece [49] Josep Dalmau, MD, PhD ICREA Research Professor, Institute for Biomedical Investigations, August Pi i Sunyer (IDIBAPS)/Hospital Clinic, Department of Neurology, University of Barcelona, Barcelona, Spain; Adjunct Professor of Neurology University of Pennsylvania, Philadelphia, Pennsylvania [44]

[44] Robert B. Daroff, MD Professor and Chair Emeritus, Department of Neurology, Case Western Reserve University School of Medicine; University Hospitals–Case Medical Center, Cleveland, Ohio [11] Lisa M. DeAngelis, MD Professor of Neurology, Weill Cornell Medical College; Chair, Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York [37] Richard A. Deyo, MD, MPH Kaiser Permanente Professor of Evidence-Based Family Medicine, Department of Family Medicine, Department of Medicine, Department of Public Health and Preventive Medicine, Center for Research in Occupational and Environmental Toxicology, Oregon Health and Science University; Clinical Investigator, Kaiser Permanente Center for Health Research, Portland, Oregon [9]

[45] William P. Dillon, MD Elizabeth Guillaumin Professor of Radiology, Neurology and Neurosurgery; Executive Vice-Chair, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California [4, 51] Richard L. Doty, PhD Professor, Department of Otorhinolaryngology: Head and Neck Surgery; Director, Smell and Taste Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania [23]

[46] Daniel B. Drachman, MD Professor of Neurology and Neuroscience, W. W. Smith Charitable Trust Professor of Neuroimmunology, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland [47] Andrew J. Einstein, MD, PhD Assistant Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons; Department of Medicine, Division of Cardiology, Department of Radiology, Columbia University Medical Center and New York-Presbyterian Hospital, New York, New York [Appendix]

[47] Joey D. English, MD Assistant Clinical Professor, Department of Neurology, Univeristy of California, San Francisco, San Francisco, California [27]

[48] Bony lesions of the lateral recess or displacement of the thecal sac medially and the left L5 nerve root posteriorly in the left lateral recess. intervertebral foramen are optimally visualized by CTmyelography. The correlation of neuroradiologic ﬁndings to symptoms, particularly pain, is not simple. Contrastenhancing 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.

[49] Asymptomatic disk protrusions are also common and may 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 contrast enhancement are common incidental ﬁndings that, by themselves, should not dictate management decisions for patients with back pain.

[50] The diagnosis of nerve root injury is most secure when the history, examination, results of imaging studies, and the EMG are concordant. The correlation between CT and EMG for localization of nerve root injury is between 65 and 73%. Up to one-third of asymptomatic adults have a lumbar disk protrusion detected by CT or MRI scans. Management of lumbar disk disease is discussed later in the chapter.

[51] Cauda equina syndrome (CES) signiﬁes an injury of multiple lumbosacral nerve roots within the spinal canal distal to the termination of the spinal cord at L1-2. Low back pain, weakness and areﬂexia in the legs, saddle anesthesia, or loss of bladder function may occur. The problem must be distinguishedfrom disorders of the lower spinal cord (conus medullaris syndrome), acute transverse myelitis (Chap.

[52] 35), and Guillain-Barré syndrome (Chap. 46). Combined involvement of the conus medullaris and cauda equina can occur. CES is commonly due to a ruptured CHAPTER 9 Back and Neck Pain

[53] 78 lumbosacral intervertebral disk, lumbosacral spine fracture, hematoma within the spinal canal (e.g., following lumbar puncture in patients with coagulopathy), compressive tumor, or other mass lesion. Treatment options include surgical decompression, sometimes urgently, in an attempt to restore or preserve motor or sphincter function, or radiotherapy for metastatic tumors (Chap.

[54] 37). DEGENERATIVE CONDITIONS Lumbar spinal stenosis (LSS) describes a narrowed lumbar spinal canal and is frequently asymptomatic. Neurogenic claudication is the usual symptom, consisting of back and buttock or leg pain induced by walking or standing and relieved by sitting. Symptoms in the legs are usually bilateral. Lumbar stenosis, by itself, is frequently asymptomatic, and the correlation between the severity of symptoms and degree of stenosis of the spinal canal is poor.

[55] Laboratory testing is available to explore vestibulo-oculomotor and vestibulospinal 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 the patient with autoimmune subacute sensory neuropathy, sometimes a paraneoplastic disorder (Chap.

[56] 44). 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. There may be reduced awareness of balance impairment. Classic examples include patients with progressive supranuclear palsy and normal pressure hydrocephalus.

[57] Patients on sedating medications are also in this category. In prospective studies, cognitive impairment and the use of sedative medications substantially increase the risk for falls. FALLS Falls are common in the elderly; 30% of people older than age 65 years living in the community fall each year. Modest changes in balance function have been described in ﬁt older subjects as a result of normal aging.

[58] Subtle deﬁcits in sensory systems, attention, and motor reaction time contribute to the risk, and environmental hazards abound. Epidemiologic studies have identiﬁed a number of risk factors for falls, summarized in Table 13-3. A fall is not a neurologic problem, nor reason for referral to a specialist, but there are circumstances in which neurologic evaluation is appropriate. In a classic study, 90% of fall events occurred among 10% of individuals, a group known as recurrent fallers.

[59] Some of these are frail older persons with chronic diseases. Recurrent falls sometimes indicate the presence of serious balance impairment. Syncope, seizure, or falls related to loss of consciousness require appropriate evaluation and treatment (Chaps. 10 and 26). The descriptive classiﬁcation of falls is as difﬁcult as the classiﬁcation of gait disorders, for many of the same reasons. Postural control systems are widely distributed, and a number of disease-related abnormalities occur.

[60] Unlike gait problems that are apparent on observation, falls are rarely observed in the ofﬁce. The patient and family may have limited information about what triggered the fall. Injuries can complicate the physical examination. While there is no standard nosology of falls, common patterns can be identiﬁed. TABLE 13-3 RISK FACTORS FOR FALLS, A META-ANALYSIS: SUMMARY OF SIXTEEN CONTROLLED STUDIES

[61] RISK FACTOR Weakness Balance deﬁcit Gait disorder Visual deﬁcit Mobility limitation Cognitive impairment Impaired functional status Postural hypotension

[62] The CHAPTER 15 Numbness, Tingling, and Sensory Loss

[63] 120 TABLE 15-1 TESTING PRIMARY SENSATION SENSE Pain Temperature, heat Temperature, cold Touch Vibration Joint position TEST DEVICE Pinprick Warm metal object Cold metal object Cotton wisp, ﬁne brush Tuning fork, 128 Hz 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

[64] FIBER SIZE MEDIATING Small Small Small Large and small Large Large CENTRAL PATHWAY SpTh, also D SpTh SpTh Lem, also D and SpTh Lem, also D Lem, also D Abbreviations: D, diffuse ascending projections in ipsilateral and contralateral anterolateral columns; SpTh, spinothalamic projection, contralateral; Lem, posterior column and lemniscal projection, ipsilateral. Greater Lesser n. } occipital nerves

[65] I Great auricular n. II Great auricular n. Ant. cut. n. of neck III Ant. cut. n. of neck C5 C6 T2 3 4 5 T1 Post. cut. Supraclavicular n’s. Supraclavicular n’s. Axillary n. (circumflex) Axillary n. (circumflex) Ant. cut. rami of T2 3 4 5 6 7 8 9 10 11 12 Med. cut. n. of arm & intercostobrachial n. Med. cut. n. of forearm Iliohypogastric n. Radial n. Median n. Genital branch of genitofem. n. Post cut.

[66] n. of arm (from radial n.) 6 7 rami Lat. of cut. thor. rami n’s. L1 Med. cut. n. of arm & intercostobrachial n. Lower lat.cut. n. of arm (from radial n.) 8 Lat. 9 Post. cut. n. of forearm (from radial n.) cut. rami Lower Lat. cut. of arm (from radial n.) 10 11 thor. n’s. 12 Med. Lat. cut. n. of forearm (from musculocut n.) Lat. cut. of forearm (from musculocut. n.) Iliohypogastric n. Inf. med. cluneal n.

[67] Inf. med. n. of thigh S1 Post. rami of lumbar sacral & coccygeal n’s. cut. n. of forearm Radial n. Ilioinguinal n. Ulnar n. Femoral branch of genitofemoral n. (lumbo-inguinal n.) Lat. cut. n. of thigh Inf. lat. cluneal n’s. Median n. Ulnar n. Obturator n. Dorsal n. of penis Scrotal branch of perineal n. Obturator n. Lat.cut. n. of calf (from common peroneal n.) Superﬁcial peroneal n. (from common peroneal n.)

[68] Post cut. n. of thigh Intermed. & med. cut. n’s. of thigh (from femoral n.) Saphenous n. (from femoral n.) Med. cut. n. of thigh (from femoral n.) Lat. cut. n.of calf (from common femoral n.) Lat. plantar n. Saphenous n. (from femoral n.) Superficial peroneal n. (from common peroneal n.) Sural n. (from tibial n.) Calcanean branches of sural & tibial n’s. Med. plantar n. Lat. plantar n. Superficial peroneal n.

[69] Deep peroneal n. (from common peroneal n.) Saphenous n. Calcanean branches of tibial & sural n’s. Sural n. Med. & lat. plantar n’s. (from posttibial n.) Sural n. (from tibial n.) FIGURE 15-2 The cutaneous ﬁelds of peripheral nerves.

[70] In most patients, the demyelinating event was retrobulbar and the ocular fundus appeared normal on initial examination (Fig. 21-10), 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.

[71] 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 ﬁnal acuity (measured 6 months after the attack), but the recovery of visual function occurs more rapidly. For some patients, optic neuritis remains an isolated event. However, the ONTT showed that the 15-year cumulative probability of developing clinically deﬁnite

[72] SECTION II Clinical Manifestations of Neurologic Disease

[73] 185 FIGURE 21-10 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. multiple sclerosis after optic neuritis is 50%. In patients with two or more demyelinating plaques on brain magnetic resonance (MR) imaging, treatment with interferon β -1a can retard the development of more lesions.

[74] In summary, an MR scan is recommended in every patient with a ﬁrst attack of optic neuritis. When visual loss is severe (worse than 20/100), treatment with IV followed by oral glucocorticoids hastens recovery. If multiple lesions are present on the MR scan, treatment with interferon β -1a should be considered. Leber’s hereditary optic neuropathy This disease usually affects young men, causing gradual, painless, severe central visual loss in one eye, followed weeks or months later by the same process in the other eye.

[75] Acutely, the optic disc appears mildly plethoric with surface capillary telangiectases 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.

[76] Mitochondrial mutations that cause Leber’s neuropathy are inherited from the mother by all her children, but usually only sons develop symptoms. Toxic optic neuropathy This can result in acute visual loss with bilateral optic disc swelling and central or cecocentral scotomas. Such cases have been reported to result from exposure to ethambutol, methyl alcohol (moonshine), ethylene glycol (antifreeze), or carbon monoxide.

[77] Many neurologists recommend combining antiplatelet agents with anticoagulants for patients who “fail” anticoagulation (i.e., have another stroke or TIA). ANTICOAGULATION THERAPY AND NONCARDIOGENIC STROKE Data do not support the use of long-term VKAs for preventing atherothrombotic stroke for either intracranial or extracranial cerebrovascular disease. The Warfarin-Aspirin Reinfarction Stroke Study (WARSS) study found no benefit of warfarin sodium (INR, 1.4–2.8) over aspirin, 325 mg, for secondary prevention of stroke but did find a slightly higher bleeding rate in the warfarin group.

[78] A recent European study confirmed this finding. The WarfarinAspirin Symptomatic Intracranial Disease (WASID) study (see later) demonstrated no benefit of warfarin (INR, 2–3) over aspirin in patients with symptomatic intracranial atherosclerosis, and also found higher bleeding complications. Carotid Atherosclerosis TREATMENT Carotid atherosclerosis can be removed surgically (endarterectomy) or mitigated with endovascular stenting with or without balloon angioplasty.

[79] Anticoagulation has not been directly compared with antiplatelet therapy for carotid disease. Symptomatic carotid stenosis was studied in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST). Both showed a substantial benefit for surgery in patients with a stenosis of ≥70%. In NASCET, the average cumulative ipsilateral stroke risk at 2 years was 26% for patients treated medically and 9% for those receiving the same medical treatment plus a carotid endarterectomy.

[80] This 17% absolute reduction in the surgical group is a 65% relative risk reduction favoring surgery (Table 27-4). NASCET also showed a significant, although less robust, benefit for patients with 50–70% stenosis. ECST found harm for patients with stenosis <30% treated surgically. SURGICAL THERAPY A patient’s risk of stroke and possible benefit from surgery are related to the presence of retinal versus hemispheric symptoms, degree of arterial stenosis, extent of associated medical conditions (of note, NASCET and ECST excluded “high-risk” patients with significant cardiac, pulmonary, or renal disease), institutional surgical morbidity and mortality, timing of surgery relative to symptoms, and other factors.

[81] A recent meta-analysis of the NASCET and ECST trials demonstrated that endarterectomy is most beneficial when performed within 2 weeks of symptom onset. In addition, benefit is more pronounced in patients >75 years, and men appear to benefit more than women. In summary, a patient with recent symptomatic hemispheric ischemia, high-grade stenosis in the appropriate internal carotid artery, and an institutional perioperative morbidity and mortality rate of ≤6% generally should undergo carotid endarterectomy.

[82] If the perioperative stroke rate is >6% for any particular surgeon, however, the benefits of carotid endarterectomy are questionable. The indications for surgical treatment of asymptomatic carotid disease have been clarified by the results of the Asymptomatic Carotid Atherosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST). ACAS randomized asymptomatic patients with ≥60% stenosis to medical treatment with aspirin or the same medical treatment plus carotid endarterectomy.

[83] The surgical group had a risk over 5 years for ipsilateral stroke (and any perioperative stroke or death) of 5.1%, compared to a risk in the medical group of 11%. While this demonstrates a 53% relative risk reduction, the absolute risk reduction is only 5.9% over 5 years, or 1.2% annually (Table 27-4). Nearly one-half of the strokes in the surgery group were caused by preoperative angiograms.

[84] The recently published ACST randomized 3120 asymptomatic patients with >60% carotid stenosis to endarterectomy or medical therapy. The 5-year risk of stroke in the surgical group (including perioperative stroke or death) was 6.4%, compared to 11.8% in the medically treated group (46% relative risk reduction and 5.4% absolute risk reduction). In both ACAS and ACST, the perioperative complication rate was higher in women, perhaps negating any benefit in the reduction of stroke risk within 5 years.

[85] It is possible that with longer follow-up, a clear benefit in women will emerge. At present, carotid endarterectomy in asymptomatic women remains particularly controversial. In summary, the natural history of asymptomatic stenosis is a ∼2% per year stroke rate, while symptomatic patients experience a 13% per year risk of stroke. Whether to recommend carotid revascularization for an asymptomatic patient is somewhat controversial and depends on many factors, including patient prefer-

[86] SECTION III Diseases of the Nervous System

[87] ence, degree of stenosis, age, gender, and comorbidities. Medical therapy for reduction of atherosclerosis risk factors, including cholesterol-lowering agents and antiplatelet medications, is generally recommended for patients with asymptomatic carotid stenosis. As with atrial fibrillation, it is imperative to counsel the patient about TIAs so that therapy can be revised if symptoms develop.

[88] Balloon angioplasty coupled with stenting is being used with increasing frequency to open stenotic carotid arteries and maintain their patency. These techniques can treat carotid stenosis not only at the bifurcation but also near the skull base and in the intracranial segments. The Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial randomized high-risk patients (defined as patients with clinically significant coronary or pulmonary disease, contralateral carotid occlusion, restenosis after endarterectomy, contralateral laryngeal-nerve palsy, prior radical neck surgery or radiation, or age >80) with symptomatic carotid stenosis >50% or asymptomatic stenosis >80% to either stenting combined with a distal emboliprotection device or endarterectomy.

[89] The involved extremity is warm and edematous, and the joints are tender. Increased sweating and hair 389 CHAPTER 33 Disorders of the Autonomic Nervous System

[90] 390 growth develop. In phase II (3–6 months after onset), thin, shiny, cool skin appears. After an additional 3–6 months (phase III), atrophy of the skin and subcutaneous tissue plus ﬂexion contractures complete the clinical picture. The natural history of typical CRPS may be more benign than reﬂected in the literature.

[91] A variety of surgical and medical treatments have been developed, with conﬂicting reports of efﬁcacy. Clinical trials suggest that early mobilization with physical therapy or a brief course of glucocorticoids may be helpful for CRPS type I. Other medical treatments include the use of adrenergic blockers, nonsteroidal anti-inﬂammatory drugs, calcium channel blockers, phenytoin, opioids, and calcitonin.

[92] Stellate ganglion blockade is a commonly used invasive technique that often provides temporary pain relief, but the efﬁcacy of repetitive blocks is uncertain. Autonomic Failure TREATMENT Management of autonomic failure is aimed at specific treatment of the cause and alleviation of symptoms. Of particular importance is the removal of drugs or amelioration of underlying conditions that cause or aggravate the autonomic symptoms, especially in the elderly.

[93] For example, OH can be caused or aggravated by angiotensin-converting enzyme inhibitors, calcium channelblocking agents, tricyclic antidepressants, levodopa, alcohol, or insulin. A summary of drugs that can cause OH by class, putative mechanism, and magnitude of the BP drop, is shown in Table 33-6. Only a minority of patients with OH require drug treatment. All patients should be taught the mechanisms of postural normotension (volume status, resistance and capacitance bed, autoregulation) and the nature of orthostatic stressors (time of day and the influence of meals, heat, standing, and exercise).

[94] Patients should learn to recognize orthostatic symptoms early (especially subtle cognitive symptoms, weakness, and fatigue) and to modify or avoid activities that provoke episodes. Other helpful measures may include keeping a BP log and dietary education (salt/ fluids). Learning physical countermaneuvers that reduce standing OH and practicing postural and resistance training are helpful measures.

[95] PATIENT EDUCATION Nonpharmacologic approaches are summarized in Table 33-9. Adequate intake of salt and fluids to produce a voiding volume between 1.5 and 2.5 L of urine (containing >170 meq/L of Na+) each 24 h is essential. Sleeping with the head of the bed elevated will minimize the effects of supine nocturnal hypertension. Prolonged recumbency should be avoided when possible. Patients are advised to

[96] SYMPTOMATIC TREATMENT TABLE 33-9

[97] Tumor mass is reduced, and GH levels are RADIATION from S Melmed et al: J Clin Endocrinol Metab 94:1509–1517, 2009; © The Endocrine Society.) attenuated over time. However, 50% of patients require at least 8 years for GH levels to be suppressed to <5 μg/L; this level of GH reduction is achieved in about 90% of patients after 18 years but represents suboptimal GH suppression. Patients may require interim medical therapy for several years before attaining maximal radiation benefits.

[98] Most patients also experience hypothalamicpituitary damage, leading to gonadotropin, ACTH, and/ or TSH deficiency within 10 years of therapy. In summary, surgery is the preferred primary treatment for GH-secreting microadenomas (Fig. 38-9). The high frequency of GH hypersecretion after macroadenoma resection usually necessitates adjuvant or primary medical therapy for these larger tumors. Patients unable to receive or respond to unimodal medical treatment may benefit from combined treatments or can be offered radiation.

[99] ADRENOCORTICOTROPIC HORMONE SYNTHESIS ACTH-secreting corticotrope cells constitute about 20% of the pituitary cell population. ACTH (39 amino acids) is derived from the POMC precursor protein (266 amino acids) that also generates several other peptides, CHAPTER 38 Neurologic Disorders of the Pituitary and Hypothalamus

[100] 466 including β-lipotropin, β-endorphin, met-enkephalin, α-melanocyte-stimulating hormone (α-MSH), and corticotropin-like intermediate lobe protein (CLIP).

[101] The POMC gene is potently suppressed by glucocorticoids and induced by CRH, arginine vasopressin (AVP), and proinﬂammatory cytokines, including IL-6, as well as leukemia inhibitory factor. CRH, a 41-amino-acid hypothalamic peptide synthesized in the paraventricular nucleus as well as in higher brain centers, is the predominant stimulator of ACTH synthesis and release. The CRH receptor is a GPCR that is expressed on the corticotrope and signals to induce POMC transcription.

[102] SECRETION ACTH secretion is pulsatile and exhibits a characteristic circadian rhythm, peaking at 6 A.M. and reaching a nadir about midnight. Adrenal glucocorticoid secretion, which is driven by ACTH, follows a parallel diurnal pattern. ACTH circadian rhythmicity is determined by variations in secretory pulse amplitude rather than changes in pulse frequency. Superimposed on this endogenous rhythm, ACTH levels are increased by physical and psychological stress, exercise, acute illness, and insulin-induced hypoglycemia.

[103] Loss of cortisol feedback inhibition, as occurs in primary adrenal failure, results in extremely high ACTH levels. Glucocorticoid-mediated negative regulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs as a consequence of both hypothalamic CRH suppression and direct attenuation of pituitary POMC gene expression and ACTH release.

[104] Definitely limited Minimal walking Unintelligible Severely impaired Feeding tube Feeding tube Dyspnea at rest Examination BP Pulse Edema Vital capacity Cataracts? R EOMS Ptosis time Face Wt L Arm abduction time R Deltoids R Biceps R Triceps R Grip R Iliopsoas R Quadriceps R Hamstrings R Other R L L L L L L L L L FIGURE 47-3 Abbreviated interval assessment form for use in evaluating treatment for myasthenia gravis.

[105] testing or, preferably, quantitative dynamometry of limb muscles, especially proximal muscles, is also important. An interval form can provide a succinct summary of the patient’s status and a guide to treatment results; an abbreviated form is shown in Fig. 47-3. A progressive reduction in the patient’s AChR antibody level also provides clinically valuable conﬁrmation of the effectiveness of treatment; conversely, a rise in AChR antibody levels during tapering of immunosuppressive medication may predict clinical exacerbation.

[106] For reliable quantitative measurement of AChR antibody levels, it is best to compare antibody levels from prior frozen serum aliquots with current serum samples in simultaneously run assays. CHAPTER 47 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction

[107] CHAPTER 48 MUSCULAR DYSTROPHIES AND OTHER MUSCLE DISEASES Anthony A. Amato ■ Robert H. Brown, Jr. Skeletal muscle diseases, or myopathies, are disorders with structural changes or functional impairment of muscle.

[108] These conditions can be differentiated from other diseases of the motor unit (e.g., lower motor neuron or neuromuscular junction pathologies) by characteristic clinical and laboratory ﬁndings. Myasthenia gravis and related disorders are discussed in Chap. 47; dermatomyositis, polymyositis, and inclusion body myositis are discussed in Chap. 49. CLINICAL FEATURES Most myopathies present with proximal, symmetric limb weakness (arms or legs) with preserved reﬂexes and sensation.

[109] However, asymmetric and predominantly distal weakness can be seen in some myopathies. An associated sensory loss suggests injury to peripheral nerve or the central nervous system (CNS) rather than myopathy. On occasion, disorders affecting the motor nerve cell bodies in the spinal cord (anterior horn cell disease), the neuromuscular junction, or peripheral nerves can mimic ﬁndings of myopathy. Muscle weakness

[110] Symptoms of muscle weakness can be either intermittent or persistent. Disorders causing intermittent weakness (Fig. 48-1) include myasthenia gravis, periodic paralyses (hypokalemic, hyperkalemic, and paramyotonia congenita), and metabolic energy deﬁciencies of glycolysis (especially myophosphorylase deﬁciency), fatty acid utilization (carnitine palmitoyltransferase deﬁciency), and some mitochondrial myopathies.

[111] The states of energy deﬁciency cause activity-related muscle breakdown accompanied by myoglobinuria, appearing as light-brownto dark-brown-colored urine.

[112] As noted earlier, some of the genes implicated in autism or schizophrenia seem to cause bipolar disorder in some families. Large genomewide association studies have identiﬁed genes for diacylglycerol kinase η (DGKH), ankyrin G (ANK3), an L-type voltage-gated calcium channel (CACNA1C), and a gene-rich region on chromosome 16p12 as being associated with bipolar disorder, but these ﬁndings await conﬁrmation by additional studies.

[113] Numerous susceptibility genes have also been implicated in linkage and association studies, but none has yet been deﬁnitively established as a bona ﬁde depression gene. However, a few genes with variants that may modify depression risk are worthy of mention since they may be linked to mechanisms of pathogenesis (discussed later). These include genes for the type 1 receptor for corticotrophin-releasing factor (CRHR1); the glucocorticoid receptor gene (GR); FKBP5, which encodes a chaperone protein for the glucocorticoid receptor; the serotonin transporter gene (SLA6A4); the catechol-Omethyltransferase gene (COMT); and brain-derived neurotrophic factor (BDNF).

[114] PATHOGENESIS Human and animal research in depression has focused on the long-term effects of chronic stress on the brain SECTION V Psychiatric Disorders

[115] 715 FC Hyp NAc VTA DR HP LC Amy Glutamatergic GABAergic Dopaminergic Peptidergic FIGURE 53-1 Neural circuitry of depression and addiction. The ﬁgure shows a simpliﬁed summary of a series of limbic circuits in brain that regulate mood and motivation and are implicated in depression and addiction.

[116] Shown in the ﬁgure are the hippocampus (HP) and amygdala (Amy), regions of prefrontal cortex, nucleus accumbens (NAc), and hypothalamus (Hyp). Only a subset of the known interconnections among these brain regions is shown. Also shown is the innervation of several of these brain regions by monoaminergic neurons. and their reversal by antidepressant medications; prominent examples are discussed here.

[117] A subset of depressed patients show elevated levels of cortisol associated with increased production of corticotrophin-releasing factor from the hypothalamus and perhaps other brain regions (e.g., amygdala). In animals, sustained elevations in glucocorticoids impair hippocampal function, in part via direct damage to hippocampal neurons, which is consistent with reduced hippocampal volumes seen in some depressed humans.

[118] As the hippocampus exerts the major inhibitory inﬂuence over the hypothalamic-pituitaryadrenal axis, impairment of hippocampal function would lead to still further increases in glucocorticoid secretion, establishing a pathologic feed-forward loop. Stress-induced damage to the hippocampus, and perhaps other limbic regions (e.g., amygdala), in animals is also mediated in part by reduced levels of BDNF and other growth factors and cytokines.

[119] Not applicable Not applicable Not applicable Not applicable Not applicable Not applicable Not applicable Not applicable <40 kIU/L <35 kIU/L B-type natriuretic peptide (BNP) P Age and gender speciﬁc: <100 ng/L Bence Jones protein, serum qualitative S Not applicable S Bence Jones protein, serum quantitative Free kappa Free lambda K/L ratio 4.3–6.0 kPa 3.3–19.4 mg/L 5.7–26.3 mg/L 0.26–1.65 1.1–2.4 mg/L

[120] μmol/L μmol/L 5.1–22 1.7–6.8 3.4–15.2 μmol/L 22–30 meq/L 32–45 mmHg 7.35–7.45 72–104 mmHg 12–38 U/L ≤29 <25 AU/mL IU/L Negative ≤19 <1.0 ≤29 <20 <1:20 ≤19 ≤19 AU/mL U AU/mL Units AU/mL AU/mL Negative at 1:40 None detected <1.0 U <1.0 U <1.0 U <1.0 U <1.0 U Negative <40 IU/mL <35 IU/mL Age and gender speciﬁc: <100 pg/mL None detected 0.33–1.94 mg/dL 0.57–2.63 mg/dL 0.26–1.65 Beta-2-microglobulin Bilirubin

[121] S S 1.1–2.4 mg/L Total Direct Indirect 0.3–1.3 mg/dL 0.1–0.4 mg/dL 0.2–0.9 mg/dL (continued) APPENDIX Laboratory Values of Clinical Importance

[122] 780 TABLE 2 CLINICAL CHEMISTRY AND IMMUNOLOGY (CONTINUED) ANALYTE C peptide C1-esterase-inhibitor protein CA 125 CA 19-9 CA 15-3 CA 27-29 Calcitonin SPECIMEN S S S S S S S S WB P (sea level) WB S S S S S S S S S S S S S S SI UNITS 0.27–1.19 nmol/L 210–390 mg/L <35 kU/L <37 kU/L <33 kU/L 0–40 kU/L

[123] 0–7.5 ng/L 0–5.1 ng/L 2.2–2.6 mmol/L 1.12–1.32 mmol/L 22–30 mmol/L 0.0–0.015 0.04–0.09 >0.50 0.0–3.0 0.0–5.0 μg/L μg/L 250–630 mg/L 102–109 mmol/L 5–12 kU/L 0–50 μg/L 0.83–1.77 g/L 0.16–0.47 g/L 60–144 CAE units 138–690 nmol/L 138–414 nmol/L 0–276 nmol/L <10 mg/L Cardiac risk CONVENTIONAL UNITS 0.8–3.5 ng/mL 21–39 mg/dL <35 U/mL <37 U/mL <33 U/mL 0–40 U/mL Male 0–7.5 pg/mL 0–5.1 pg/mL Female Calcium Calcium, ionized Carbon dioxide content (TCO2) Carboxyhemoglobin (carbon monoxide content)

[124] Nonsmokers Smokers Loss of consciousness and death Carcinoembryonic antigen (CEA) Nonsmokers Smokers Ceruloplasmin Chloride Cholesterol: see Table 5 Cholinesterase Chromogranin A Complement C3 C4 Complement total Cortisol Fasting, 8 A.M.–12 noon 12 noon–8 P.M. 8 P.M.–8 A.M. C-reactive protein C-reactive protein, high sensitivity Creatine kinase (total) Females Males Creatine kinase-MB Mass Fraction of total activity (by electrophoresis) Creatinine Female Male Cryoglobulins Cystatin C

[125] 8.7–10.2 mg/dL 4.5–5.3 mg/dL 22–30 meq/L 0–1.5% 4–9% >50% 0.0–3.0 ng/mL 0.0–5.0 ng/mL 25–63 mg/dL 102–109 meq/L 5–12 U/mL 0–50 ng/mL 83–177 mg/dL 16–47 mg/dL 60–144 CAE units 5–25 5–15 0–10 μg/dL μg/dL μg/dL <10 mg/L Cardiac risk Low: <1.0 mg/L Average: 1.0–3.0 mg/L High: >3.0 mg/L Low: <1.0 mg/L Average: 1.0–3.0 mg/L High: >3.0 mg/L μkat/L μkat/L 0.66–4.0 0.875.0 0.0–5.5 μg/L 0–0.04 μmol/L μmol/L

[126] 44–80 53–106 Not applicable 0.5–1.0 mg/L 39–238 U/L 51–294 U/L 0.0–5.5 ng/mL 0–4.0% 0.5–0.9 mg/dL 0.6–1.2 mg/dL None detected 0.5–1.0 mg/L APPENDIX Laboratory Values of Clinical Importance

Instructions:

Compose summary of the document in a concise bullet list format, using provided text snippets from this document.
If the document is small with few distinct topics, provide a single bullet point list.
If the document covers multiple distinct topics, organize the summary into separate sections each of them containing a bullet-point list.
The answer should be short and concise and should not include any introductory or concluding text.
Each bullet point item should be no longer than 15 words.
The total number of bullet point items in the whole answer should be no more than 13.
Skip any information about publisher, license or copyright notices.
Every search result provided has an identifier, and you should use it for references.
Every single result reference must be a single digit, enclosed in a square brackets.
Add result references after text paragraphs in answer.
Format answers with markdown, highlight important points with bold text.
Prioritise user annotations when writing answer!
Answers should be in the language which corresponds to BCP-47 language tag identifier "en".