Harrison Neurology in Clinical Medicine Second Edition

Second Edition HARRISON’S Neurology in Clinical Medicine

Derived from Harrison’s Principles of Internal Medicine, 17th Edition Editors ANTHONY S. FAUCI, MD EUGENE BRAUNWALD, MD Chief, Laboratory of Immunoregulation; Distinguished Hersey Professor of Medicine, Director, National Institute of Allergy and Infectious Diseases, Harvard Medical School; Chairman,TIMI Study Group, National Institutes of Health, Bethesda Brigham and Women’s Hospital, Boston DENNIS L. KASPER, MD STEPHEN L. HAUSER, MD William Ellery Channing Professor of Medicine, Professor of Robert A. Fishman Distinguished Professor and Chairman, Microbiology and Molecular Genetics, Harvard Medical School; Department of Neurology, University of California, San Francisco Director, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston J. LARRY JAMESON, MD, PhD DAN L. LONGO, MD Professor of Medicine; Vice President for Medical Affairs Scientific Director, National Institute on Aging, National Institutes of Health, and Lewis Landsberg Dean, Bethesda and Baltimore Northwestern University Feinberg School of Medicine, Chicago JOSEPH LOSCALZO, MD, PhD Hersey Professor of Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital, Boston

Second Edition HARRISON’S Neurology in Clinical Medicine Editor Stephen L. Hauser, MD Robert A. Fishman Distinguished Professor and Chairman, Department of Neurology, University of California, San Francisco Associate Editor Scott Andrew Josephson, MD Assistant Clinical Professor of Neurology, University of California, San Francisco New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto

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Raymond D.Adams, MD 1911–2008 For Ray Adams, editor of Harrison’s Principles of Internal Medicine for more than three decades. A mentor who taught by example, a colleague who continues to inspire, and a friend who is deeply missed. Stephen L. Hauser, MD, for the Editors of Harrison’s

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CONTENTS Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi 12 Numbness,Tingling, and Sensory Loss . . . . . . . 116 Michael J.Aminoff,Arthur K.Asbury Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv 13 Confusion and Delirium . . . . . . . . . . . . . . . . . 122 SECTION I Scott Andrew Josephson, Bruce L. Miller INTRODUCTION TO NEUROLOGY 14 Coma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Allan H. Ropper 1 Approach to the Patient with Neurologic Disease . . . . . . . . . . . . . . . . . . . . . . . 2 15 Aphasia, Memory Loss, and Other Focal Daniel H. Lowenstein, Joseph B. Martin, Cerebral Disorders. . . . . . . . . . . . . . . . . . . . . . 140 Stephen L. Hauser M.-Marsel Mesulam 2 Neuroimaging in Neurologic Disorders . . . . . . . 11 16 Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . 155 William P. Dillon Charles A. Czeisler, John W.Winkelman, Gary S. Richardson 3 Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, 17 Disorders of Vision . . . . . . . . . . . . . . . . . . . . . 170 and EMG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Jonathan C. Horton Michael J.Aminoff 18 Disorders of Smell,Taste, and Hearing . . . . . . . 193 4 Lumbar Puncture . . . . . . . . . . . . . . . . . . . . . . . 33 Anil K. Lalwani Elizabeth Robbins, Stephen L. Hauser SECTION II SECTION III CLINICAL MANIFESTATIONS OF DISEASES OF THE CENTRAL NEUROLOGIC DISEASE NERVOUS SYSTEM 5 Pain: Pathophysiology and Management . . . . . . . 40 19 Mechanisms of Neurologic Diseases . . . . . . . . . 210 Howard L. Fields, Joseph B. Martin Stephen L. Hauser, M. Flint Beal 6 Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 20 Seizures and Epilepsy. . . . . . . . . . . . . . . . . . . . 222 Peter J. Goadsby, Neil H. Raskin Daniel H. Lowenstein 7 Back and Neck Pain . . . . . . . . . . . . . . . . . . . . . 70 21 Cerebrovascular Diseases . . . . . . . . . . . . . . . . . 246 John W. Engstrom Wade S. Smith, Joey D. English, S. Claiborne Johnston 8 Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Mark D. Carlson 22 Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and 9 Dizziness and Vertigo . . . . . . . . . . . . . . . . . . . . . 96 Subarachnoid Hemorrhage . . . . . . . . . . . . . . . 282 Robert B. Daroff J. Claude Hemphill, III,Wade S. Smith 10 Weakness and Paralysis. . . . . . . . . . . . . . . . . . . 102 23 Alzheimer’s Disease and Other Michael J.Aminoff Dementias. . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 Thomas D. Bird, Bruce L. Miller 11 Gait and Balance Disorders . . . . . . . . . . . . . . . 109 Lewis Sudarsky vii

viii Contents 24 Parkinson’s Disease and Other Extrapyramidal 39 Paraneoplastic Neurologic Syndromes . . . . . . . 516 Movement Disorders . . . . . . . . . . . . . . . . . . . . 320 Josep Dalmau, Myrna R. Rosenfeld Mahlon R. DeLong, Jorge L. Juncos 40 Peripheral Neuropathy. . . . . . . . . . . . . . . . . . . 525 25 Hyperkinetic Movement Disorders. . . . . . . . . . 337 Vinay Chaudhry C.Warren Olanow 41 Guillain-Barré Syndrome and Other 26 Ataxic Disorders . . . . . . . . . . . . . . . . . . . . . . . 346 Immune-Mediated Neuropathies . . . . . . . . . . . 550 Roger N. Rosenberg Stephen L. Hauser,Arthur K.Asbury 27 Amyotrophic Lateral Sclerosis and Other 42 Myasthenia Gravis and Other Diseases Motor Neuron Diseases . . . . . . . . . . . . . . . . . . 358 of the Neuromuscular Junction . . . . . . . . . . . . 559 Robert H. Brown, Jr. Daniel B. Drachman 28 Disorders of the Autonomic 43 Muscular Dystrophies and Other Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . 366 Muscle Diseases. . . . . . . . . . . . . . . . . . . . . . . . 568 Phillip A. Low, John W. Engstrom Robert H. Brown, Jr.,Anthony A.Amato, Jerry R. Mendell 29 Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders . . . . . . . . . . . . 377 44 Polymyositis, Dermatomyositis, and M. Flint Beal, Stephen L. Hauser Inclusion Body Myositis . . . . . . . . . . . . . . . . . 597 Marinos C. Dalakas 30 Diseases of the Spinal Cord . . . . . . . . . . . . . . . 385 Stephen L. Hauser,Allan H. Ropper 45 Special Issues in Inpatient Neurologic Consultation . . . . . . . . . . . . . . . . . . . . . . . . . . 609 31 Concussion and Other Head Injuries . . . . . . . . 400 Scott Andrew Josephson, Martin A. Samuels Allan H. Ropper 46 Atlas of Neuroimaging . . . . . . . . . . . . . . . . . . 617 32 Primary and Metastatic Tumors of the Andre Furtado,William P. Dillon Nervous System . . . . . . . . . . . . . . . . . . . . . . . 408 Stephen M. Sagar, Mark A. Israel SECTION IV 33 Neurologic Disorders of the Pituitary CHRONIC FATIGUE SYNDROME and Hypothalamus. . . . . . . . . . . . . . . . . . . . . . 423 Shlomo Melmed, J. Larry Jameson, 47 Chronic Fatigue Syndrome . . . . . . . . . . . . . . . 650 Gary L. Robertson Stephen E. Straus 34 Multiple Sclerosis and Other SECTION V Demyelinating Diseases . . . . . . . . . . . . . . . . . . 435 Stephen L. Hauser, Douglas S. Goodin PSYCHIATRIC DISORDERS 35 Meningitis, Encephalitis, Brain Abscess, 48 Biology of Psychiatric Disorders. . . . . . . . . . . . 654 and Empyema . . . . . . . . . . . . . . . . . . . . . . . . . 451 Steven E. Hyman, Eric Kandel Karen L. Roos, Kenneth L.Tyler 49 Mental Disorders. . . . . . . . . . . . . . . . . . . . . . . 662 36 Chronic and Recurrent Meningitis . . . . . . . . . 484 Victor I. Reus Walter J. Koroshetz, Morton N. Swartz SECTION VI 37 HIV Neurology . . . . . . . . . . . . . . . . . . . . . . . 493 Anthony S. Fauci, H. Clifford Lane ALCOHOLISM AND DRUG DEPENDENCY 38 Prion Diseases. . . . . . . . . . . . . . . . . . . . . . . . . 507 Stanley B. Prusiner, Bruce L. Miller 50 Alcohol and Alcoholism. . . . . . . . . . . . . . . . . . 686 Marc A. Schuckit

Contents ix 51 Opioid Drug Abuse and Dependence . . . . . . . . 696 Review and Self-Assessment . . . . . . . . . . . . . . . 709 Marc A. Schuckit Charles Wiener, Gerald Bloomfield, Cynthia D. Brown, Joshua Schiffer,Adam Spivak 52 Cocaine and Other Commonly Abused Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 702 Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739 Jack H. Mendelson, Nancy K. Mello

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CONTRIBUTORS Numbers in brackets refer to the chapter(s) written or co-written by the contributor. ANTHONY A. AMATO, MD ROBERT B. DAROFF, MD Associate Professor of Neurology, Harvard Medical School; Chief, Gilbert W. Humphrey Professor of Neurology and Interim Chair, Division of Neuromuscular Diseases, Department of Neurology, Department of Neurology, Case Western Reserve University Brigham and Women’s Hospital, Boston [43] School of Medicine and University Hospitals Case Medical Center, Cleveland [9] MICHAEL J. AMINOFF, MD, DSc Professor of Neurology, School of Medicine, MAHLON R. DELONG, MD University of California, San Francisco [3, 10, 12] Timmie Professor of Neurology, Emory University School of Medicine,Atlanta [24] ARTHUR K. ASBURY, MD Van Meter Professor of Neurology Emeritus, University of WILLIAM P. DILLON, MD Pennsylvania School of Medicine, Philadelphia [12, 41] Professor of Radiology, Neurology, and Neurosurgery;Vice-Chair, Department of Radiology; Chief, Neuroradiology, University of M. FLINT BEAL, MD California, San Francisco [2, 46] Anne Parrish Titzel Professor and Chair, Department of Neurology and Neuroscience,Weill Medical College of Cornell University; DANIEL B. DRACHMAN, MD Neurologist-in-Chief, New York Presbyterian Hospital, Professor of Neurology & Neuroscience;WW Smith Charitable New York [19, 29] Trust Professor of Neuroimmunology,The Johns Hopkins University School of Medicine, Baltimore [42] THOMAS D. BIRD, MD Professor, Neurology and Medicine, University of Washington; JOEY D. ENGLISH, MD, PhD Research Neurologist, Geriatric Research Education and Clinical Assistant Professor of Neurology, University of California, San Center,VA Puget Sound Health Care System, Seattle [23] Francisco [21] GERALD BLOOMFIELD, MD, MPH JOHN W. ENGSTROM, MD Department of Internal Medicine,The Johns Hopkins University Professor of Neurology; Clinical Chief of Service; Neurology School of Medicine, Baltimore [Review and Self-Assessment] Residency Program Director, University of California, San Francisco [7, 28] CYNTHIA D. BROWN, MD Department of Internal Medicine,The Johns Hopkins University ANTHONY S. FAUCI, MD, DSc (Hon), DM&S (Hon), DHL School of Medicine, Baltimore [Review and Self-Assessment] (Hon), DPS (Hon), DLM (Hon), DMS (Hon) Chief, Laboratory of Immunoregulation; Director, National Institute ROBERT H. BROWN, JR., MD, DPhil of Allergy and Infectious Diseases, National Institutes of Health, Neurologist, Massachusetts General Hospital; Professor of Neurology, Bethesda [37] Harvard Medical School, Boston [27, 43] HOWARD L. FIELDS, MD, PhD MARK D. CARLSON, MD, MA Professor of Neurology; Director,Wheeler Center for Neurobiology Chief Medical Officer and Senior Vice President, Clinical Affairs, St. of Addiction, University of California, San Francisco [5] Jude Medical, Sylmar;Adjunct Professor of Medicine, Case Western Reserve University, Cleveland [8] ANDRE FURTADO, MD Associate Specialist at the Department of Radiology, Neuroradiology VINAY CHAUDHRY, MD Section, University of California, San Francisco [46] Professor and Vice Chair,The Johns Hopkins University School of Medicine; Co-Director, EMG Laboratory, Johns Hopkins Hospital, PETER J. GOADSBY, MD, PhD, DSc Baltimore [40] Professor of Clinical Neurology, Institute of Neurology, Queen Square London; Professor of Neurology, Department of Neurology, CHARLES A. CZEISLER, MD, PhD University of California, San Francisco [6] Baldino Professor of Sleep Medicine, and Director, Division of Sleep Medicine, Harvard Medical School; Chief, Division of Sleep DOUGLAS S. GOODIN, MD Medicine, Department of Medicine, Brigham and Women’s Hospital, Professor of Neurology, University of California, San Francisco [34] Boston [16] STEPHEN L. HAUSER, MD MARINOS C. DALAKAS, MD Robert A. Fishman Distinguished Professor and Chairman, Professor of Neurology; Chief, Neuromuscular Diseases Section, Department of Neurology, University of California, San Francisco NINDS, National Institute of Health, Bethesda [44] [1, 4, 19, 29, 30, 34, 41] JOSEP DALMAU, MD, PhD J. CLAUDE HEMPHILL, III, MD, MAS Professor of Neurology, Division Neuro-Oncology, Department of Associate Professor of Clinical Neurology and Neurological Surgery, Neurology, Philadelphia [39] University of California, San Francisco; Director, Neurocritical Care Program, San Francisco General Hospital, San Francisco [22] xi

xii Contributors JONATHAN C. HORTON, MD, PhD NANCY K. MELLO, PhD William F. Hoyt Professor of Neuro-Ophthalmology; Professor of Professor of Psychology (Neuroscience), Harvard Medical School, Ophthalmology, Neurology, and Physiology, University of California, Boston [52] San Francisco [17] SHLOMO MELMED, MD STEVEN E. HYMAN, MD Senior Vice President,Academic Affairs;Associate Dean, Cedars Sinai Provost, Harvard University; Professor of Neurobiology, Harvard Medical Center, David Geffen School of Medicine at UCLA, Medical School, Boston [48] Los Angeles [33] MARK A. ISRAEL, MD JERRY R. MENDELL, MD Professor of Pediatrics and Genetics, Dartmouth Medical School; Professor of Pediatrics, Neurology and Pathology,The Ohio State Director, Norris Cotton Cancer Center, Dartmouth-Hitchcock University; Director, Center for Gene Therapy,The Research Medical Center, Lebanon [32] Institute at Nationwide Children’s Hospital, Columbus [43] J. LARRY JAMESON, MD, PhD JACK H. MENDELSON,† MD Professor of Medicine;Vice President for Medical Affairs and Lewis Professor of Psychiatry (Neuroscience), Harvard Medical School, Landsberg Dean, Northwestern University Feinberg School of Belmont [52] Medicine, Chicago [33] M.-MARSEL MESULAM, MD S. CLAIBORNE JOHNSTON, MD, PhD Director, Cognitive Neurology and Alzheimer’s Disease Center; Professor, Neurology; Professor, Epidemiology and Biostatistics; Dunbar Professor of Neurology and Psychiatry, Northwestern Director, University of California, San Francisco Stroke Service, University Feinberg School of Medicine, Chicago [15] San Francisco [21] BRUCE L. MILLER, MD SCOTT ANDREW JOSEPHSON, MD AW and Mary Margaret Clausen Distinguished Professor of Assistant Clinical Professor of Neurology, University of California, Neurology, University of California, San Francisco School of San Francisco [13, 45] Medicine, San Francisco [13, 23, 38] JORGE L. JUNCOS, MD C. WARREN OLANOW, MD Associate Professor of Neurology, Emory University School of Henry P. and Georgette Goldschmidt Professor and Chairman of the Medicine; Director of Neurology,Wesley Woods Hospital, Department of Neurology, Professor of Neuroscience,The Mount Atlanta [24] Sinai School of Medicine, New York [25] ERIC KANDEL, MD STANLEY B. PRUSINER, MD University Professor; Fred Kavli Professor and Director, Kavli Director, Institute for Neurodegenerative Diseases; Professor, Institute for Brain Sciences; Senior Investigator, Howard Hughes Department of Neurology; Professor, Department of Biochemistry Medical Institute, Columbia University, New York [48] and Biophysics, University of California, San Francisco [38] WALTER J. KOROSHETZ, MD NEIL H. RASKIN, MD Deputy Director, National Institute of Neurological Disorders and Professor of Neurology, University of California, San Francisco [6] Stroke, National Institutes of Health, Bethesda [36] VICTOR I. REUS, MD ANIL K. LALWANI, MD Professor, Department of Psychiatry, University of California, San Mendik Foundation Professor and Chairman, Department of Francisco School of Medicine;Attending Physician, Langley Porter Otolaryngology; Professor, Department of Pediatrics; Professor, Hospital and Clinics, San Francisco [49] Department of Physiology and Neuroscience, New York University School of Medicine, New York [18] GARY S. RICHARDSON, MD Assistant Professor of Psychiatry, Case Western Reserve University, H. CLIFFORD LANE, MD Cleveland; Senior Research Scientist, Sleep Disorders and Research Clinical Director; Director, Division of Clinical Research; Deputy Center, Henry Ford Hospital, Detroit [16] Director, Clinical Research and Special Projects; Chief, Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, ELIZABETH ROBBINS, MD National Institute of Allergy and Infectious Diseases, National Associate Clinical Professor, University of California, Institutes of Health, Bethesda [37] San Francisco [4] PHILLIP A. LOW, MD GARY L. ROBERTSON, MD Robert D and Patricia E Kern Professor of Neurology, Emeritus Professor of Medicine, Northwestern University Feinberg Mayo Clinic College of Medicine, Rochester [28] School of Medicine, Chicago [33] DANIEL H. LOWENSTEIN, MD KAREN L. ROOS, MD Professor of Neurology; Director, University of California, San John and Nancy Nelson Professor of Neurology, Indiana University Francisco Epilepsy Center;Associate Dean for Clinical/Translational School of Medicine, Indianapolis [35] Research, San Francisco [1, 20] ALLAN H. ROPPER, MD JOSEPH B. MARTIN, MD, PhD, MA (Hon) Executive Vice-Chair, Department of Neurology, Brigham and Dean Emeritus of the Faculty of Medicine, Edward R. and Women’s Hospital, Harvard Medical School, Boston [14, 30, 31] Anne G. Lefler Professor of Neurobiology, Harvard Medical School, Boston [1, 5] †Deceased.

Contributors xiii ROGER N. ROSENBERG, MD STEPHEN E. STRAUS,† MD Zale Distinguished Chair and Professor of Neurology, Department of Senior Investigator, Laboratory of Clinical Investigation, National Neurology, University of Texas Southwestern Medical Center, Institute of Allergy and Infectious Diseases; Director, National Dallas [26] Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda [47] MYRNA R. ROSENFELD, MD, PhD Associate Professor of Neurology, Division Neuro-Oncology, LEWIS SUDARSKY, MD Department of Neurology, University of Pennsylvania, Associate Professor of Neurology, Harvard Medical School; Philadelphia [39] Director of Movement Disorders, Brigham and Women’s Hospital, Boston [11] STEPHEN M. SAGAR, MD Professor of Neurology, Case Western Reserve School of Medicine; MORTON N. SWARTZ, MD Director of Neuro-Oncology, Ireland Cancer Center, University Professor of Medicine, Harvard Medical School; Chief, Jackson Firm Hospitals of Cleveland, Cleveland [32] Medical Service and Infectious Disease Unit, Massachusetts General Hospital, Boston [36] MARTIN A. SAMUELS, MD, DSc (Hon) Chairman, Department of Neurology, Brigham and Women’s KENNETH L. TYLER, MD Hospital; Professor of Neurology, Harvard Medical Center, Reuler-Lewin Family Professor of Neurology and Professor of Boston [45] Medicine and Microbiology, University of Colorado Health Sciences Center; Chief, Neurology Service, Denver Veterans Affairs Medical JOSHUA SCHIFFER, MD Center, Denver [35] Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] CHARLES WIENER, MD Professor of Medicine and Physiology;Vice Chair, Department of MARC A. SCHUCKIT, MD Medicine; Director, Osler Medical Training Program,The Johns Distinguished Professor of Psychiatry, School of Medicine, University Hopkins University School of Medicine, Baltimore of California, San Diego; Director,Alcohol Research Center,VA San [Review and Self-Assessment] Diego Healthcare System, San Diego [50, 51] JOHN W. WINKELMAN, MD, PhD WADE S. SMITH, MD, PhD Assistant Professor of Psychiatry, Harvard Medical School; Medical Professor of Neurology, Daryl R. Gress Endowed Chair of Director, Sleep Health Center, Brigham and Women’s Hospital, Neurocritical Care and Stroke; Director, University of California, Boston [16] San Francisco Neurovascular Service, San Francisco [21, 22] ADAM SPIVAK, MD Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] †Deceased.

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PREFACE The first edition of Harrison’s Neurology in Clinical Medicine problems. All of these forces, acting within the fast- was an unqualified success. Readers responded enthusiasti- paced environment of modern medical practice, can cally to the convenient, attractive, expanded, and updated lead to an overreliance on unfocused neuroimaging stand-alone volume, which was based upon the neurology tests, suboptimal patient care, and unfortunate out- and psychiatry sections from Harrison’s Principles of Internal comes. Because neurologists represent less than 1% of Medicine. Our original goal was to provide, in an easy-to- all physicians, the vast majority of neurologic care use format, full coverage of the most authoritative infor- must be delivered by nonspecialists who are often mation available anywhere of clinically important topics in generalists and usually internists. neurology and psychiatry, while retaining the focus on pathophysiology and therapy that has always been charac- The old adage that neurologists “know everything teristic of Harrison’s. but do nothing” has been rendered obsolete by advances in molecular medicine, imaging, bioengineering, and This new edition of Harrison’s Neurology in Clinical clinical research. Examples of new therapies include: Medicine has been extensively rewritten to highlight thrombolytic therapy for acute ischemic stroke; endovas- recent advances in the understanding, diagnosis, treat- cular recanalization for cerebrovascular disorders; inten- ment and prevention of neurologic and psychiatric sive monitoring of brain pressure and cerebral blood diseases. New chapters discuss the pathogenesis and flow for brain injury; effective therapies for immune- treatment of headache, the clinical approach to imbal- mediated neurologic disorders such as multiple sclerosis, ance, and the causes of confusion and delirium. Notable immune neuropathies, myasthenia gravis, and myositis; also are new chapters on essential tremor and move- new designer drugs for migraine; the first generation of ment disorders, peripheral neuropathy, and on neuro- rational therapies for neurodegenerative diseases; neural logic problems in hospitalized patients. Many illustrative stimulators for Parkinson’s disease; drugs for narcolepsy neuroimaging figures appear throughout the section, and other sleep disorders; and control of epilepsy by and a new atlas of neuroimaging findings has been surgical resection of small seizure foci precisely local- added. Extensively updated coverage of the dementias, ized by functional imaging and electrophysiology. The Parkinson’s disease, and related neurodegenerative dis- pipeline continues to grow, stimulated by a quickening orders highlight new findings from genetics, molecular tempo of discoveries generating opportunities for imaging, cell biology, and clinical research that have rational design of new diagnostics, interventions, and transformed understanding of these common problems. drugs. Another new chapter, authored by Steve Hyman and Eric Kandel, reviews progress in deciphering the patho- The founding editors of Harrison’s Principles of Inter- genesis of common psychiatric disorders and discusses nal Medicine acknowledged the importance of neurol- the remaining challenges to development of more effec- ogy but were uncertain as to its proper role in a text- tive treatments. book of internal medicine. An initial plan to exclude neurology from the first edition (1950) was reversed at For many physicians, neurologic diseases represent the eleventh hour, and a neurology section was hastily particularly challenging problems. Acquisition of the req- prepared by Houston Merritt. By the second edition, uisite clinical skills is often viewed as time-consuming, the section was considerably enlarged by Raymond D. difficult to master, and requiring a working knowl- Adams, whose influence on the textbook was profound. edge of obscure anatomic facts and laundry lists of The third neurology editor, Joseph B. Martin, brilliantly diagnostic possibilities. The patients themselves may led the book during the 1980s and 1990s as neurology be difficult, as neurologic disorders often alter an was transformed from a largely descriptive discipline to individual’s capacity to recount the history of an ill- one of the most dynamic and rapidly evolving areas of ness or to even recognize that something is wrong. medicine. With these changes, the growth of neurology An additional obstacle is the development of inde- coverage in Harrison’s became so pronounced that pendent neurology services, departments, and training Harrison suggested the book be retitled, “The Details of programs at many medical centers, reducing the ex- Neurology and Some Principles of Internal Medicine.” posure of trainees in internal medicine to neurologic His humorous comment, now legendary, underscores the xv

xvi Preface depth of coverage of neurologic medicine in Harrison’s be- NOTE TO READERS ON ELECTRONIC fitting its critical role in the practice of internal medicine. ACCESS TO THE FAMILY OF HARRISON’S PUBLICATIONS The Editors are indebted to our authors, a group of THE NEUROLOGIC METHOD internationally recognized authorities who have magnif- icently distilled a daunting body of information into the The Harrison’s collection of publications has expanded as in- essential principles required to understand and manage formation delivery technology has evolved. Harrison’s Online commonly encountered neurological problems. We are (HOL) is now one of the standard informational resources also grateful to Dr. Andrew Scott Josephson who over- used in medical centers throughout the United States. In saw the updating process for the second edition of addition to the full content of the parent text, HOL offers Harrison’s Neurology in Clinical Medicine. Thanks also to frequent updates from and links to the emerging scientific Dr. Elizabeth Robbins, who has served for more than a and clinical literature; an expanded collection of reference decade as managing editor of the neurology section of citations; audio recordings and Podcasts of lectures by Harrison’s; she has overseen the complex logistics re- authorities in the various specialties of medicine; and other quired to produce a multiauthored textbook, and has helpful supplementary materials such as a complete database promoted exceptional standards for clarity, language and of pharmacologic therapeutics, self-assessment questions for style. Finally, we wish to acknowledge and express our examination and board review; and an expanded collection great appreciation to our colleagues at McGraw-Hill. of clinical photographs. Video clips of cardiac and endo- This new volume was championed by James Shanahan scopic imaging are also available on HOL. Future iterations and impeccably managed by Kim Davis. of HOL will include expanded use of such supplementary multimedia materials to illustrate further key concepts and We live in an electronic, wireless age. Information is clinical approaches discussed in the parent text. downloaded rather than pulled from the shelf. Some have questioned the value of traditional books in this In 2006, in recognition of the increasing time pres- new era. We believe that as the volume of information, sures placed on clinicians and the increasing use of elec- and the ways to access this information, continues to tronic medical records systems, Harrison’s Practice of Medi- grow, the need to grasp the essential concepts of medical cine (HP) made its debut. HP is a comprehensive practice becomes even more challenging. One of our database of specific clinical topics built from the ground young colleagues recently remarked that he uses the up to provide authoritative guidance quickly at the Internet to find facts, but that he reads Harrison’s to learn point of care. HP is highly structured so that physicians medicine. Our aim has always been to provide and other health professionals can access the most salient the reader with an integrated, organic summary of the features of any one of more than 700 diseases and clini- science and the practice of medicine rather than a mere cal presentations within minutes. This innovative new compendium of chapters, and we are delighted and application is updated regularly and includes fully inte- humbled by the continuing and quite remarkable growth grated, detailed information on brand name and generic in popularity of Harrison’s at a time when many “classics” drugs. In addition, hyperlinks throughout HP enable in medicine seem less relevant than in years past. quick access to the primary literature via PubMed. HP is available via the Internet and on PDA. It is our sincere hope that you will enjoy using Harrison’s Neurology in Clinical Medicine, Second Edition as an authorita- Stephen L. Hauser, MD tive source for the most up-to-date information in clinical neurology.

NOTICE Medicine is an ever-changing science. As new research and clinical experi- ence 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. Review and self-assessment questions and answers were taken from Wiener C, Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J (editors) Bloomfield G, Brown CD, Schiffer J, Spivak A (contributing editors). Harrison’s Principles of Internal Medicine Self-Assessment and Board Review, 17th ed. New York, McGraw-Hill, 2008, ISBN 978-0-07-149619-3. The global icons call greater attention to key epidemiologic and clinical differences in the practice of medicine throughout the world. The genetic icons identify a clinical issue with an explicit genetic relationship.

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SECTION I INTRODUCTION TO NEUROLOGY

CHAPTER 1 APPROACH TO THE PATIENT WITH NEUROLOGIC DISEASE Daniel H. Lowenstein I Joseph B. Martin I Stephen L. Hauser I The Neurologic Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 I The Neurologic History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 I The Neurologic Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 I Neurologic Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Neurologic diseases are common and costly. According symptoms restricted to the nervous system, or do they to one estimate, 180 million Americans suffer from a arise in the context of a systemic illness? Is the problem nervous system disorder, resulting in an annual cost of in the central nervous system (CNS), the peripheral ner- over $700 billion. The aggregate cost is even greater vous system (PNS), or both? If in the CNS, is the cere- than that for cardiovascular disease (Table 1-1). Glob- bral cortex, basal ganglia, brainstem, cerebellum, or ally, these disorders are responsible for 28% of all years spinal cord responsible? Are the pain-sensitive meninges lived with a disability. Most patients with neurologic involved? If in the PNS, could the disorder be located in symptoms seek care from internists and other generalists peripheral nerves and, if so, are motor or sensory nerves rather than from neurologists. Because therapies now primarily affected, or is a lesion in the neuromuscular exist for many neurologic disorders, a skillful approach junction or muscle more likely? to diagnosis is essential. Errors commonly result from an overreliance on costly neuroimaging procedures and The first clues to defining the anatomic area of laboratory tests, which, although useful, do not substi- involvement appear in the history, and the examination tute for an adequate history and examination. The is then directed to confirm or rule out these impressions proper approach to the patient with a neurologic illness and to clarify uncertainties. A more detailed examina- begins with the patient and focuses the clinical problem tion of a particular region of the CNS or PNS is often first in anatomic and then in pathophysiologic terms; indicated. For example, the examination of a patient only then should a specific diagnosis be entertained. who presents with a history of ascending paresthesias This method ensures that technology is judiciously and weakness should be directed toward deciding, applied, a correct diagnosis is established in an efficient among other things, if the location of the lesion is in the manner, and treatment is promptly initiated. spinal cord or peripheral nerves. Focal back pain, a spinal cord sensory level, and incontinence suggest a spinal THE NEUROLOGIC METHOD cord origin, whereas a stocking-glove pattern of sensory loss suggests peripheral nerve disease; areflexia usually Locate the Lesion(s) indicates peripheral neuropathy but may also be present with spinal shock in acute spinal cord disorders. The first priority is to identify the region of the nervous system that is likely to be responsible for the symptoms. Deciding “where the lesion is” accomplishes the task Can the disorder be mapped to one specific location, is of limiting the possible etiologies to a manageable, finite it multifocal, or is a diffuse process present? Are the number. In addition, this strategy safeguards against making serious errors. Symptoms of recurrent vertigo, diplopia, and nystagmus should not trigger “multiple 2

TABLE 1-1 advancing visual scotoma with luminous edges, termed 3 CHAPTER 1 Approach to the Patient with Neurologic Disease fortification spectra, indicates spreading cortical depression, PREVALENCE OF NEUROLOGIC AND PSYCHIATRIC typically with migraine. DISEASES WORLDWIDE THE NEUROLOGIC HISTORY DISORDER PATIENTS, MILLIONS Attention to the description of the symptoms experi- Nutritional disorders and 352 enced by the patient and substantiated by family mem- neuropathies bers and others often permits an accurate localization 326 and determination of the probable cause of the com- Migraine 170 plaints, even before the neurologic examination is per- Trauma 154 formed. The history also helps to bring a focus to the Depression 91 neurologic examination that follows. Each complaint Alcoholism 61 should be pursued as far as possible to elucidate the Cerebrovascular diseases 50 location of the lesion, the likely underlying pathophysi- Epilepsy 25 ology, and potential etiologies. For example, a patient Schizophrenia 24 complains of weakness of the right arm. What are the Dementia 18 associated features? Does the patient have difficulty with Neurologic infections 15 brushing hair or reaching upward (proximal) or button- Drug abuse ing buttons or opening a twist-top bottle (distal)? Nega- tive associations may also be crucial. A patient with a Source: World Health Organization estimates, 2002–2005. right hemiparesis without a language deficit likely has a lesion (internal capsule, brainstem, or spinal cord) differ- sclerosis” as an answer (etiology) but “brainstem” or ent from that of a patient with a right hemiparesis and “pons” (location); then a diagnosis of brainstem arteri- aphasia (left hemisphere). Other pertinent features of the ovenous malformation will not be missed for lack of history include the following: consideration. Similarly, the combination of optic neuri- tis and spastic ataxic paraparesis should initially suggest 1. Temporal course of the illness. It is important to deter- optic nerve and spinal cord disease; multiple sclerosis mine the precise time of appearance and rate of (MS), CNS syphilis, and vitamin B12 deficiency are progression of the symptoms experienced by the treatable disorders that can produce this syndrome. Once patient. The rapid onset of a neurologic complaint, the question, “Where is the lesion?” is answered, then occurring within seconds or minutes, usually indi- the question,“What is the lesion?” can be addressed. cates a vascular event, a seizure, or migraine. The onset of sensory symptoms located in one extremity Define the Pathophysiology that spread over a few seconds to adjacent portions of that extremity and then to the other regions of Clues to the pathophysiology of the disease process may the body suggests a seizure. A more gradual onset also be present in the history. Primary neuronal (gray and less well localized symptoms point to the possi- matter) disorders may present as early cognitive distur- bility of a transient ischemic attack (TIA). A similar bances, movement disorders, or seizures, whereas white but slower temporal march of symptoms accompa- matter involvement produces predominantly “long nied by headache, nausea, or visual disturbance sug- tract” disorders of motor, sensory, visual, and cerebellar gests migraine. The presence of “positive” sensory pathways. Progressive and symmetric symptoms often symptoms (e.g., tingling or sensations that are diffi- have a metabolic or degenerative origin; in such cases cult to describe) or involuntary motor movements lesions are usually not sharply circumscribed. Thus, a suggests a seizure; in contrast, transient loss of func- patient with paraparesis and a clear spinal cord sensory tion (negative symptoms) suggests a TIA. A stutter- level is unlikely to have vitamin B12 deficiency as the ing onset where symptoms appear, stabilize, and explanation. A Lhermitte symptom (electric shock–like then progress over hours or days also suggests cere- sensations evoked by neck flexion) is due to ectopic brovascular disease; an additional history of transient impulse generation in white matter pathways and occurs remission or regression indicates that the process is with demyelination in the cervical spinal cord; among more likely due to ischemia rather than hemor- many possible causes, this symptom may indicate MS in rhage. A gradual evolution of symptoms over hours a young adult or compressive cervical spondylosis in an or days suggests a toxic, metabolic, infectious, or older person. Symptoms that worsen after exposure to inflammatory process. Progressing symptoms associ- heat or exercise may indicate conduction block in ated with the systemic manifestations of fever, stiff demyelinated axons, as occurs in MS. A patient with recurrent episodes of diplopia and dysarthria associated with exercise or fatigue may have a disorder of neuro- muscular transmission such as myasthenia gravis. Slowly

SECTION I Introduction to Neurology 4 neck, and altered level of consciousness imply an patient with underlying cancer. Patients with malig- infectious process. Relapsing and remitting symp- nancy may also present with a neurologic paraneo- toms involving different levels of the nervous system plastic syndrome (Chap. 39) or complications from suggest MS or other inflammatory processes; these chemotherapy or radiotherapy. Marfan’s syndrome and disorders can occasionally produce new symptoms related collagen disorders predispose to dissection of that are rapidly progressive over hours. Slowly pro- the cranial arteries and aneurysmal subarachnoid gressive symptoms without remissions are character- hemorrhage; the latter may also occur with polycystic istic of neurodegenerative disorders, chronic infec- kidney disease. Various neurologic disorders occur tions, gradual intoxications, and neoplasms. with dysthyroid states or other endocrinopathies. It is especially important to look for the presence of sys- 2. Patients’ descriptions of the complaint. The same words temic diseases in patients with peripheral neuropathy. often mean different things to different patients. Most patients with coma in a hospital setting have a “Dizziness” may imply impending syncope, a sense metabolic, toxic, or infectious cause. of disequilibrium, or true spinning vertigo. “Numb- 6. Drug use and abuse and toxin exposure. It is essential to ness” may mean a complete loss of feeling, a positive inquire about the history of drug use, both pre- sensation such as tingling, or paralysis. “Blurred scribed and illicit. Aminoglycoside antibiotics may vision” may be used to describe unilateral visual exacerbate symptoms of weakness in patients with loss, as in transient monocular blindness, or diplopia. disorders of neuromuscular transmission, such as The interpretation of the true meaning of the words myasthenia gravis, and may cause dizziness sec- used by patients to describe symptoms becomes ondary to ototoxicity. Vincristine and other anti- even more complex when there are differences in neoplastic drugs can cause peripheral neuropathy, primary languages and cultures. and immunosuppressive agents such as cyclosporine can produce encephalopathy. Excessive vitamin 3. Corroboration of the history by others. It is almost always ingestion can lead to disease; for example vitamin A helpful to obtain additional information from fam- and pseudotumor cerebri, or pyridoxine and ily, friends, or other observers to corroborate or peripheral neuropathy. Many patients are unaware expand the patient’s description. Memory loss, apha- that over-the-counter sleeping pills, cold prepara- sia, loss of insight, intoxication, and other factors tions, and diet pills are actually drugs. Alcohol, the may impair the patient’s capacity to communicate most prevalent neurotoxin, is often not recognized normally with the examiner or prevent openness as such by patients, and other drugs of abuse such as about factors that have contributed to the illness. cocaine and heroin can cause a wide range of neu- Episodes of loss of consciousness necessitate that rologic abnormalities. A history of environmental or details be sought from observers to ascertain pre- industrial exposure to neurotoxins may provide an cisely what has happened during the event. essential clue; consultation with the patient’s co- workers or employer may be required. 4. Family history. Many neurologic disorders have an 7. Formulating an impression of the patient. Use the underlying genetic component. The presence of a opportunity while taking the history to form an Mendelian disorder, such as Huntington’s disease or impression of the patient. Is the information forth- Charcot-Marie-Tooth neuropathy, is often obvious coming, or does it take a circuitous course? Is there if family data are available. More detailed questions evidence of anxiety, depression, or hypochondriasis? about family history are often necessary in poly- Are there any clues to defects in language, memory, genic disorders such as MS, migraine, and many insight, or inappropriate behavior? The neurologic types of epilepsy. It is important to elicit family his- assessment begins as soon as the patient comes into tory about all illnesses, in addition to neurologic and the room and the first introduction is made. psychiatric disorders. A familial propensity to hyper- tension or heart disease is relevant in a patient who THE NEUROLOGIC EXAMINATION presents with a stroke.There are numerous inherited neurologic diseases that are associated with multisys- The neurologic examination is challenging and com- tem manifestations that may provide clues to the plex; it has many components and includes a number of correct diagnosis (e.g., neurofibromatosis, Wilson’s skills that can be mastered only through repeated use of disease, neuro-ophthalmic syndromes). the same techniques on a large number of individuals with and without neurologic disease. Mastery of the 5. Medical illnesses. Many neurologic diseases occur in the complete neurologic examination is usually important context of systemic disorders. Diabetes mellitus, only for physicians in neurology and associated specialties. hypertension, and abnormalities of blood lipids predis- However, knowledge of the basics of the examination, pose to cerebrovascular disease. A solitary mass lesion in the brain may be an abscess in a patient with valvu- lar heart disease, a primary hemorrhage in a patient with a coagulopathy, a lymphoma or toxoplasmosis in a patient with AIDS (Chap. 37), or a metastasis in a

especially those components that are effective in screen- The mental status examination is underway as soon as 5 CHAPTER 1 Approach to the Patient with Neurologic Disease ing for neurologic dysfunction, is essential for all clini- the physician begins observing and talking with the cians, especially generalists. patient. If the history raises any concern for abnormali- ties of higher cortical function or if cognitive problems There is no single, universally accepted sequence of are observed during the interview, then detailed testing the examination that must be followed, but most clini- of the mental status is indicated. The patient’s ability to cians begin with assessment of mental status followed by understand the language used for the examination, cul- the cranial nerves, motor system, sensory system, coordi- tural background, educational experience, sensory or nation, and gait. Whether the examination is basic or motor problems, or comorbid conditions need to be comprehensive, it is essential that it be performed in an factored into the applicability of the tests and interpreta- orderly and systematic fashion to avoid errors and seri- tion of results. ous omissions. Thus, the best way to learn and gain expertise in the examination is to choose one’s own The Folstein mini-mental status examination (MMSE) approach and practice it frequently and do it in exactly (Table 23-5) is a standardized screening examination of the same sequence each time. cognitive function that is extremely easy to administer and takes <10 min to complete. Using age-adjusted val- The detailed description of the neurologic examina- ues for defining normal performance, the test is ~85% tion that follows describes the more commonly used sensitive and 85% specific for making the diagnosis of parts of the examination, with a particular emphasis on dementia that is moderate or severe, especially in edu- the components that are considered most helpful for the cated patients. When there is sufficient time available, assessment of common neurologic problems. Each sec- the MMSE is one of the best methods for documenting tion also includes a brief description of the minimal the current mental status of the patient, and this is espe- examination necessary for adequate screening for abnor- cially useful as a baseline assessment to which future malities in a patient who has no symptoms suggesting scores of the MMSE can be compared. neurologic dysfunction. A screening examination done in this way can be completed in 3–5 min. Individual elements of the mental status examination can be subdivided into level of consciousness, orienta- Several additional points about the examination are tion, speech and language, memory, fund of information, worth noting. First, in recording observations, it is insight and judgment, abstract thought, and calculations. important to describe what is found rather than to apply a poorly defined medical term (e.g., “patient groans to Level of consciousness is the patient’s relative state of sternal rub” rather than “obtunded”). Second, subtle awareness of the self and the environment, and ranges CNS abnormalities are best detected by carefully com- from fully awake to comatose. When the patient is not paring a patient’s performance on tasks that require fully awake, the examiner should describe the responses simultaneous activation of both cerebral hemispheres to the minimum stimulus necessary to elicit a reaction, (e.g., eliciting a pronator drift of an outstretched arm ranging from verbal commands to a brief, painful stimu- with the eyes closed; extinction on one side of bilaterally lus such as a squeeze of the trapezius muscle. Responses applied light touch, also with eyes closed; or decreased that are directed toward the stimulus and signify some arm swing or a slight asymmetry when walking). Third, degree of intact cerebral function (e.g., opening the eyes if the patient’s complaint is brought on by some activity, and looking at the examiner or reaching to push away a reproduce the activity in the office. If the complaint is painful stimulus) must be distinguished from reflex of dizziness when the head is turned in one direction, responses of a spinal origin (e.g., triple flexion response— have the patient do this and also look for associated signs flexion at the ankle, knee, and hip in response to a on examination (e.g., nystagmus or dysmetria). If pain painful stimulus to the foot). occurs after walking two blocks, have the patient leave the office and walk this distance and immediately Orientation is tested by asking the patient to state his return, and repeat the relevant parts of the examination. or her name, location, and time (day of the week and Finally, the use of tests that are individually tailored to date); time is usually the first to be affected in a variety the patient’s problem can be of value in assessing of conditions. changes over time. Tests of walking a 7.5-m (25-ft) dis- tance (normal, 5–6 s; note assistance, if any), repetitive Speech is assessed by observing articulation, rate, finger or toe tapping (normal, 20–25 taps in 5 s), or hand- rhythm, and prosody (i.e., the changes in pitch and writing are examples. accentuation of syllable and words). Mental Status Examination Language is assessed by observing the content of the patient’s verbal and written output, response to spoken • The bare minimum: During the interview, look for difficul- commands, and ability to read. A typical testing ties with communication and determine whether the patient has sequence is to ask the patient to name successively more recall and insight into recent and past events. detailed components of clothing, a watch or a pen; repeat the phrase “No ifs, ands, or buts”; follow a three- step, verbal command; write a sentence; and read and respond to a written command.

SECTION I Introduction to Neurology 6 Memory should be analyzed according to three main visual fields in the plane that is equidistant between you time scales: (1) immediate memory can be tested by say- and the patient. Instruct the patient to look directly at ing a list of three items and having the patient repeat the the center of your face and to indicate when and where list immediately, (2) short-term memory is assessed by he or she sees one of your fingers moving. Beginning asking the patient to recall the same three items 5 and with the two inferior quadrants and then the two supe- 15 min later, and (3) long-term memory is evaluated by rior quadrants, move your index finger of the right determining how well the patient is able to provide a hand, left hand, or both hands simultaneously and coherent chronologic history of his or her illness or per- observe whether the patient detects the movements. A sonal events. single small-amplitude movement of the finger is suffi- Fund of information is assessed by asking questions cient for a normal response. Focal perimetry and tangent about major historic or current events, with special screen examinations should be used to map out visual attention to educational level and life experiences. field defects fully or to search for subtle abnormalities. Abnormalities of insight and judgment are usually Optic fundi should be examined with an ophthalmo- detected during the patient interview; a more detailed scope, and the color, size, and degree of swelling or ele- assessment can be elicited by asking the patient to vation of the optic disc noted, as well as the color and describe how he or she would respond to situations texture of the retina. The retinal vessels should be having a variety of potential outcomes (e.g., “What checked for size, regularity, arterial-venous nicking at would you do if you found a wallet on the sidewalk?”). crossing points, hemorrhage, exudates, etc. Abstract thought can be tested by asking the patient to describe similarities between various objects or concepts CN III, IV, VI (Oculomotor, Trochlear, Abducens) (e.g., apple and orange, desk and chair, poetry and sculp- Describe the size and shape of pupils and reaction to ture) or to list items having the same attributes (e.g., a light and accommodation (i.e., as the eyes converge list of four-legged animals). while following your finger as it moves toward the Calculation ability is assessed by having the patient bridge of the nose). To check extraocular movements, carry out a computation that is appropriate to the ask the patient to keep his or her head still while track- patient’s age and education (e.g., serial subtraction of 7 ing the movement of the tip of your finger. Move the from 100 or 3 from 20; or word problems involving target slowly in the horizontal and vertical planes; simple arithmetic). observe any paresis, nystagmus, or abnormalities of smooth pursuit (saccades, oculomotor ataxia, etc.). If Cranial Nerve Examination necessary, the relative position of the two eyes, both in primary and multidirectional gaze, can be assessed by • The bare minimum: Check the fundi, visual fields, pupil size comparing the reflections of a bright light off both and reactivity, extraocular movements, and facial movements. pupils. However, in practice it is typically more useful to determine whether the patient describes diplopia in any The cranial nerves (CN) are best examined in direction of gaze; true diplopia should almost always numerical order, except for grouping together CN III, resolve with one eye closed. Horizontal nystagmus is IV, and VI because of their similar function. best assessed at 45° and not at extreme lateral gaze (which is uncomfortable for the patient); the target must CN I (Olfactory) often be held at the lateral position for at least a few sec- Testing is usually omitted unless there is suspicion for onds to detect an abnormality. inferior frontal lobe disease (e.g., meningioma). With eyes closed, ask the patient to sniff a mild stimulus such CN V (Trigeminal) as toothpaste or coffee and identify the odorant. Examine sensation within the three territories of the branches of the trigeminal nerve (ophthalmic, maxillary, CN II (Optic) and mandibular) on each side of the face. As with other Check visual acuity (with eyeglasses or contact lens cor- parts of the sensory examination, testing of two sensory rection) using a Snellen chart or similar tool. Test the modalities derived from different anatomic pathways visual fields by confrontation, i.e., by comparing the (e.g., light touch and temperature) is sufficient for a patient’s visual fields to your own. As a screening test, it screening examination. Testing of other modalities, the is usually sufficient to examine the visual fields of both corneal reflex, and the motor component of CN V (jaw eyes simultaneously; individual eye fields should be clench—masseter muscle) is indicated when suggested tested if there is any reason to suspect a problem of by the history. vision by the history or other elements of the examina- tion, or if the screening test reveals an abnormality. Face CN VII (Facial) the patient at a distance of approximately 0.6–1.0 m Look for facial asymmetry at rest and with spontaneous (2–3 ft) and place your hands at the periphery of your movements. Test eyebrow elevation, forehead wrinkling,

eye closure, smiling, and cheek puff. Look in particular Tone 7 for differences in the lower versus upper facial muscles; weakness of the lower two-thirds of the face with Muscle tone is tested by measuring the resistance to pas- preservation of the upper third suggests an upper motor neuron lesion, whereas weakness of an entire side sug- sive movement of a relaxed limb. Patients often have dif- CHAPTER 1 Approach to the Patient with Neurologic Disease gests a lower motor neuron lesion. ficulty relaxing during this procedure, so it is useful to CN VIII (Vestibulocochlear) Check the patient’s ability to hear a finger rub or whis- distract the patient to minimize active movements. In pered voice with each ear. Further testing for air versus mastoid bone conduction (Rinne) and lateralization of a the upper limbs, tone is assessed by rapid pronation and 512-Hz tuning fork placed at the center of the forehead (Weber) should be done if an abnormality is detected by supination of the forearm and flexion and extension at history or examination. Any suspected problem should be followed up with formal audiometry. For further discus- the wrist. In the lower limbs, while the patient is supine sion of assessing vestibular nerve function in the setting of dizziness or coma, see Chaps. 9 and 14, respectively. the examiner’s hands are placed behind the knees and CN IX, X (Glossopharyngeal, Vagus) rapidly raised; with normal tone the ankles drag along Observe the position and symmetry of the palate and uvula at rest and with phonation (“aah”). The pharyn- the table surface for a variable distance before rising, geal (“gag”) reflex is evaluated by stimulating the poste- rior pharyngeal wall on each side with a sterile, blunt whereas increased tone results in an immediate lift of object (e.g., tongue blade), but the reflex is often absent in normal individuals. the heel off the surface. Decreased tone is most com- CN XI (Spinal Accessory) monly due to lower motor neuron or peripheral nerve Check shoulder shrug (trapezius muscle) and head rota- tion to each side (sternocleidomastoid) against resistance. disorders. Increased tone may be evident as spasticity CN XII (Hypoglossal) (resistance determined by the angle and velocity of Inspect the tongue for atrophy or fasciculations, position with protrusion, and strength when extended against the motion; corticospinal tract disease), rigidity (similar inner surface of the cheeks on each side. resistance in all angles of motion; extrapyramidal dis- Motor Examination ease), or paratonia (fluctuating changes in resistance; • The bare minimum: Look for muscle atrophy and check extrem- ity tone. Assess upper extremity strength by checking for pronator frontal lobe pathways or normal difficulty in relaxing). drift and strength of wrist or finger extensors.Tap the biceps, patel- lar, and Achilles reflexes.Test for lower extremity strength by having Cogwheel rigidity, in which passive motion elicits jerky the patient walk normally and on heels and toes. interruptions in resistance, is seen in parkinsonism. The motor examination includes observations of muscle appearance, tone, strength, and reflexes. Although Strength gait is in part a test of motor function, it is usually evalu- Testing for pronator drift is an extremely useful method ated separately at the end of the examination. for screening upper limb weakness.The patient is asked to hold both arms fully extended and parallel to the ground Appearance with eyes closed. This position should be maintained for Inspect and palpate muscle groups under good light and ~10 s; any flexion at the elbow or fingers or pronation of with the patient in a comfortable and symmetric posi- the forearm, especially if asymmetric, is a sign of potential tion. Check for muscle fasciculations, tenderness, and weakness. Muscle strength is further assessed by having atrophy or hypertrophy. Involuntary movements may be the patient exert maximal effort for the particular muscle present at rest (e.g., tics, myoclonus, choreoathetosis), or muscle group being tested. It is important to isolate the during maintained posture (pill-rolling tremor of Parkin- muscles as much as possible, i.e., hold the limb so that son’s disease), or with voluntary movements (intention only the muscles of interest are active. It is also helpful to tremor of cerebellar disease or familial tremor). palpate accessible muscles as they contract. Grading mus- cle strength and evaluating the patient’s effort is an art that takes time and practice. Muscle strength is tradition- ally graded using the following scale: 0 = no movement 1 = flicker or trace of contraction but no associated movement at a joint 2 = movement with gravity eliminated 3 = movement against gravity but not against resistance 4– = movement against a mild degree of resistance 4 = movement against moderate resistance 4+ = movement against strong resistance 5 = full power However, in many cases it is more practical to use the following terms: Paralysis = no movement Severe weakness = movement with gravity eliminated

SECTION I Introduction to Neurology 8 Moderate weakness = movement against gravity but toward the stimulated quadrant.With upper motor neu- not against mild resistance ron lesions, these reflexes are absent.They are most help- ful when there is preservation of the upper (spinal cord Mild weakness = movement against moderate level T9) but not lower (T12) abdominal reflexes, indi- resistance cating a spinal lesion between T9 and T12, or when the response is asymmetric. Other useful cutaneous reflexes Full strength include the cremasteric (ipsilateral elevation of the testi- cle following stroking of the medial thigh; mediated by Noting the pattern of weakness is as important as L1 and L2) and anal (contraction of the anal sphincter assessing the magnitude of weakness. Unilateral or bilat- when the perianal skin is scratched; mediated by S2, S3, eral weakness of the upper limb extensors and lower S4) reflexes. It is particularly important to test for these limb flexors (“pyramidal weakness”) suggests a lesion of reflexes in any patient with suspected injury to the the pyramidal tract, bilateral proximal weakness suggests spinal cord or lumbosacral roots. myopathy, and bilateral distal weakness suggests periph- eral neuropathy. Primitive Reflexes With disease of the frontal lobe pathways, several primi- Reflexes tive reflexes not normally present in the adult may Muscle Stretch Reflexes appear. The suck response is elicited by lightly touching Those that are typically assessed include the biceps (C5, the center of the lips, and the root response the corner C6), brachioradialis (C5, C6), and triceps (C7, C8) of the lips, with a tongue blade; the patient will move reflexes in the upper limbs and the patellar or quadri- the lips to suck or root in the direction of the stimulus. ceps (L3, L4) and Achilles (S1, S2) reflexes in the lower The grasp reflex is elicited by touching the palm limbs. The patient should be relaxed and the muscle between the thumb and index finger with the exam- positioned midway between full contraction and exten- iner’s fingers; a positive response is a forced grasp of the sion. Reflexes may be enhanced by asking the patient to examiner’s hand. In many instances stroking the back of voluntarily contract other, distant muscle groups (Jen- the hand will lead to its release. The palmomental drassik maneuver). For example, upper limb reflexes may response is contraction of the mentalis muscle (chin) be reinforced by voluntary teeth-clenching, and the ipsilateral to a scratch stimulus diagonally applied to the Achilles reflex by hooking the flexed fingers of the two palm. hands together and attempting to pull them apart. For each reflex tested, the two sides should be tested Sensory Examination sequentially, and it is important to determine the small- est stimulus required to elicit a reflex rather than the • The bare minimum: Ask whether the patient can feel light maximum response. Reflexes are graded according to touch and the temperature of a cool object in each distal the following scale: extremity. Check double simultaneous stimulation using light touch on the hands. 0 = absent 1 = present but diminished Evaluating sensation is usually the most unreliable 2 = normoactive part of the examination, because it is subjective and is 3 = exaggerated difficult to quantify. In the compliant and discerning 4 = clonus patient, the sensory examination can be extremely help- ful for the precise localization of a lesion. With patients Cutaneous Reflexes who are uncooperative or lack an understanding of the The plantar reflex is elicited by stroking, with a noxious tests, it may be useless. The examination should be stimulus such as a tongue blade, the lateral surface of the focused on the suspected lesion. For example, in spinal sole of the foot beginning near the heel and moving cord, spinal root, or peripheral nerve abnormalities, all across the ball of the foot to the great toe. The normal major sensory modalities should be tested while looking reflex consists of plantar flexion of the toes. With upper for a pattern consistent with a spinal level and der- motor neuron lesions above the S1 level of the spinal matomal or nerve distribution. In patients with lesions cord, a paradoxical extension of the toe is observed, at or above the brainstem, screening the primary sensory associated with fanning and extension of the other toes modalities in the distal extremities along with tests of (termed an extensor plantar response, or Babinski sign). “cortical” sensation is usually sufficient. Superficial abdominal reflexes are elicited by gently stroking the abdominal surface near the umbilicus in a The five primary sensory modalities—light touch, diagonal fashion with a sharp object (e.g., the wooden pain, temperature, vibration, and joint position—are end of a cotton-tipped swab) and observing the move- tested in each limb. Light touch is assessed by stimulat- ment of the umbilicus. Normally, the umbilicus will pull ing the skin with single, very gentle touches of the examiner’s finger or a wisp of cotton. Pain is tested

using a new pin, and temperature is assessed using a patient is asked to touch his or her index finger repeti- 9 CHAPTER 1 Approach to the Patient with Neurologic Disease metal object (e.g., tuning fork) that has been immersed tively to the nose and then to the examiner’s out- in cold and warm water.Vibration is tested using a 128-Hz stretched finger, which moves with each repetition. A tuning fork applied to the distal phalynx of the great toe similar test in the lower extremity is to have the patient or index finger just below the nailbed. By placing a fin- raise the leg and touch the examiner’s finger with the ger on the opposite side of the joint being tested, the great toe. Another cerebellar test in the lower limbs is examiner compares the patient’s threshold of vibration the heel-knee-shin maneuver; in the supine position the perception with his or her own. For joint position test- patient is asked to slide the heel of each foot from the ing, the examiner grasps the digit or limb laterally and knee down the shin of the other leg. For all these move- distal to the joint being assessed; small 1- to 2-mm ments, the accuracy, speed, and rhythm are noted. excursions can usually be sensed.The Romberg maneu- ver is primarily a test of proprioception. The patient is Gait Examination asked to stand with the feet as close together as neces- sary to maintain balance while the eyes are open, and • The bare minimum: Observe the patient while walking nor- the eyes are then closed. A loss of balance with the eyes mally, on the heels and toes, and along a straight line. closed is an abnormal response. Watching the patient walk is the most important part “Cortical” sensation is mediated by the parietal lobes of the neurologic examination. Normal gait requires that and represents an integration of the primary sensory multiple systems—including strength, sensation, and modalities; testing cortical sensation is only meaningful coordination—function in a highly integrated fashion. when primary sensation is intact. Double simultaneous Unexpected abnormalities may be detected that prompt stimulation is especially useful as a screening test for cor- the examiner to return, in more detail, to other aspects of tical function; with the patient’s eyes closed, the exam- the examination. The patient should be observed while iner lightly touches one or both hands and asks the walking and turning normally, walking on the heels, patient to identify the stimuli. With a parietal lobe walking on the toes, and walking heel-to-toe along a lesion, the patient may be unable to identify the stimulus straight line. The examination may reveal decreased arm on the contralateral side when both hands are touched. swing on one side (corticospinal tract disease), a stooped Other modalities relying on the parietal cortex include posture and short-stepped gait (parkinsonism), a broad- the discrimination of two closely placed stimuli as sepa- based unstable gait (ataxia), scissoring (spasticity), or a rate (two-point discrimination), identification of an high-stepped, slapping gait (posterior column or periph- object by touch and manipulation alone (stereognosis), eral nerve disease), or the patient may appear to be stuck and the identification of numbers or letters written on in place (apraxia with frontal lobe disease). the skin surface (graphesthesia). NEUROLOGIC DIAGNOSIS Coordination Examination The clinical data obtained from the history and exami- • The bare minimum:Test rapid alternating movements of the nation are interpreted to arrive at an anatomic localiza- hands and the finger-to-nose and heel-knee-shin maneuvers. tion that best explains the clinical findings ( Table 1-2), to narrow the list of diagnostic possibilities, and to select Coordination refers to the orchestration and fluidity the laboratory tests most likely to be informative. The of movements. Even simple acts require cooperation of laboratory assessment may include (1) serum elec- agonist and antagonist muscles, maintenance of posture, trolytes; complete blood count; and renal, hepatic, and complex servomechanisms to control the rate and endocrine, and immune studies; (2) cerebrospinal fluid range of movements. Part of this integration relies on examination; (3) focused neuroimaging studies (Chap. 2); normal function of the cerebellar and basal ganglia sys- or (4) electrophysiologic studies (Chap. 3).The anatomic tems. However, coordination also requires intact muscle localization, mode of onset and course of illness, other strength and kinesthetic and proprioceptive informa- medical data, and laboratory findings are then integrated tion. Thus, if the examination has disclosed abnormali- to establish an etiologic diagnosis. ties of the motor or sensory systems, the patient’s coor- dination should be assessed with these limitations in The neurologic examination may be normal even in mind. patients with a serious neurologic disease, such as seizures, chronic meningitis, or a TIA. A comatose Rapid alternating movements in the upper limbs are patient may arrive with no available history, and in such tested separately on each side by having the patient cases the approach is as described in Chap. 14. In other make a fist, partially extend the index finger, and then patients, an inadequate history may be overcome by a tap the index finger on the distal thumb as quickly as succession of examinations from which the course of possible. In the lower limb, the patient rapidly taps the the illness can be inferred. In perplexing cases it is useful foot against the floor or the examiner’s hand. Finger-to- to remember that uncommon presentations of common nose testing is primarily a test of cerebellar function; the

10 TABLE 1-2 FINDINGS HELPFUL FOR LOCALIZATION WITHIN THE NERVOUS SYSTEM SECTION I Introduction to Neurology Cerebrum SIGNS Brainstem Abnormal mental status or cognitive impairment Spinal cord Seizures Unilateral weaknessa and sensory abnormalities including Spinal roots Peripheral nerve head and limbs Visual field abnormalities Neuromuscular Movement abnormalities (e.g., diffuse incoordination, junction tremor, chorea) Muscle Isolated cranial nerve abnormalities (single or multiple) “Crossed” weaknessa and sensory abnormalities of head and limbs (e.g., weakness of right face and left arm and leg) Back pain or tenderness Weaknessa and sensory abnormalities sparing the head Mixed upper and lower motor neuron findings Sensory level Sphincter dysfunction Radiating limb pain Weaknessb or sensory abnormalities following root distribution (see Figs. 12-2 and 12-3) Loss of reflexes Mid or distal limb pain Weaknessb or sensory abnormalities following nerve distribution (see Figs. 12-2 and 12-3) “Stocking or glove” distribution of sensory loss Loss of reflexes Bilateral weakness including face (ptosis, diplopia, dysphagia) and proximal limbs Increasing weakness with exertion Sparing of sensation Bilateral proximal or distal weakness Sparing of sensation aWeakness along with other abnormalities having an “upper motor neuron” pattern (i.e., spas- ticity, weakness of extensors > flexors in the upper extremity and flexors > extensors in the lower extremity, hyperreflexia). bWeakness along with other abnormalities having a “lower motor neuron” pattern (i.e., flaccidity and hyporeflexia). diseases are more likely than rare etiologies. Thus, even compression or other treatable mass lesions and arrange in tertiary care settings, multiple strokes are usually due for immediate care. to emboli and not vasculitis, and dementia with myoclonus is usually Alzheimer’s disease and not due to FURTHER READINGS a prion disorder or a paraneoplastic cause. Finally, the most important task of a primary care physician faced BLUMENTHAL H: Neuroanatomy Through Clinical Cases, 2d ed. Sunder- with a patient who has a new neurologic complaint is to land, Massachusetts, Sinauer Associates, 2010 assess the urgency of referral to a specialist. Here, the imperative is to rapidly identify patients likely to have CAMPBELL WW: DeJong’s The Neurological Examination, 6th ed. nervous system infections, acute strokes, and spinal cord Philadelphia, Lippincott Williams & Wilkins, 2005 ROPPER AH, SAMUELS MA: Principles of Neurology, 9th ed. New York, McGraw-Hill, 2009

CHAPTER 2 NEUROIMAGING IN NEUROLOGIC DISORDERS William P. Dillon I Computed Tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 I Spine Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 I Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . . . . . 15 Discography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Selective Nerve Root and Epidural Spinal Injections . . . . . . . . 22 Complications and Contraindications . . . . . . . . . . . . . . . . . . . 17 I Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 I Magnetic Resonance Angiography . . . . . . . . . . . . . . . . . . . . . 18 Spinal Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 I Echo-Planar MR Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 I Interventional Neuroradiology . . . . . . . . . . . . . . . . . . . . . . . . . 23 I Magnetic Resonance Neurography . . . . . . . . . . . . . . . . . . . . . 21 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 I Positron Emission Tomography (PET) . . . . . . . . . . . . . . . . . . . 21 I Myelography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 The clinician caring for patients with neurologic symp- acute ischemic stroke and is also useful in the detection toms is faced with an expanding number of imaging of encephalitis, abscesses, and prion diseases. CT, how- options, including computed tomography (CT), CT ever, can be quickly obtained and is widely available, angiography (CTA), perfusion CT (pCT), magnetic making it a pragmatic choice for the initial evaluation of resonance imaging (MRI), MR angiography (MRA), patients with acute changes in mental status, suspected functional MRI (fMRI), MR spectroscopy (MRS), MR acute stroke, hemorrhage, and intracranial or spinal neurography, diffusion and diffusion track imaging trauma. CT is also more sensitive than MRI for visualiz- (DTI), and perfusion MRI (pMRI). In addition, an ing fine osseous detail and is indicated in the initial eval- increasing number of interventional neuroradiologic uation of conductive hearing loss as well as lesions techniques are available, including angiography; emboliza- affecting the skull base and calvarium. tion, coiling, and stenting of vascular structures; and spine interventions such as discography, selective nerve COMPUTED TOMOGRAPHY root injection, and epidural injections. Recent develop- ments, such as multidetector CTA and gadolinium- TECHNIQUE enhanced MRA, have narrowed the indications for con- ventional angiography, which is now reserved for The CT image is a cross-sectional representation of patients in whom small-vessel detail is essential for diag- anatomy created by a computer-generated analysis of the nosis or for whom interventional therapies are planned attenuation of x-ray beams passed through a section of (Table 2-1). the body. As the x-ray beam, collimated to the desired In general, MRI is more sensitive than CT for the slice width, rotates around the patient, it passes through detection of lesions affecting the central nervous system selected regions in the body. X-rays that are not attenu- (CNS), particularly those of the spinal cord, cranial ated by the body are detected by sensitive x-ray detectors nerves, and posterior fossa structures. Diffusion MR, a aligned 180° from the x-ray tube. A computer calculates sequence that detects reduction of microscopic motion a “back projection” image from the 360° x-ray attenua- of water, is the most sensitive technique for detecting tion profile. Greater x-ray attenuation, e.g., as caused by 11

12 TABLE 2-1 GUIDELINES FOR THE USE OF CT, ULTRASOUND, AND MRI SECTION I Introduction to Neurology CONDITION RECOMMENDED TECHNIQUE Hemorrhage CT, MR Acute parenchymal MRI Subacute/chronic CT, CTA, lumbar puncture → angiography Subarachnoid hemorrhage Angiography > CTA, MRA Aneurysm CT or MRI Ischemic infarction MRI > CT, CTA, angiography MRI/MRA Hemorrhagic infarction CTA, MRI/MRA Bland infarction CTA > Doppler ultrasound, MRA Carotid or vertebral dissection Vertebral basilar insufficiency MRI + contrast Carotid stenosis MRI + contrast Suspected mass lesion MRI + contrast Neoplasm, primary or metastatic MRI +/– angiography Infection/abscess MRI Immunosuppressed with focal findings MRI +/– contrast Vascular malformation MRI > CT White matter disorders Demyelinating disease CT (noncontrast) Dementia MRI Trauma CT (noncontrast) / MRI Acute trauma Shear injury/chronic hemorrhage CT as screen +/– contrast Headache/migraine MRI with coronal T2W imaging Seizure MRI with contrast First time, no focal neurologic deficits MRI with contrast Partial complex/refractory Cranial neuropathy MRI or CT after 4 weeks Meningeal disease MRI > CT MRI or CT Spine MRI or CT myelography MRI + contrast, CT Low back pain MRI + contrast > myelography No neurologic deficits MRI, myelography/angiography With focal deficits Spinal stenosis Cervical spondylosis Infection Myelopathy Arteriovenous malformation Note: CT, computed tomography; MRI, magnetic resonance imaging; MRA, MR angiography; CTA, CT angiography; T2W, T2-weighted. bone, results in areas of high “density,” whereas soft tissue a “helix” of information that can be reformatted into structures, which have poor attenuation of x-rays, are various slice thicknesses. Single or multiple (from 4 to 256) lower in density. The resolution of an image depends on detectors positioned 180° to the x-ray source may result the radiation dose, the detector size or collimation (slice in multiple slices per revolution of the beam around the thickness), the field of view, and the matrix size of the patient. Advantages of MDCT include shorter scan display. A modern CT scanner is capable of obtaining times, reduced patient and organ motion, and the ability sections as thin as 0.5–1 mm with submillimeter resolu- to acquire images dynamically during the infusion of tion at a speed of 0.5–1 s per rotation; complete studies intravenous contrast that can be used to construct CT of the brain can be completed in 2–10 s. angiograms of vascular structures and CT perfusion images (Figs. 2-1B, 2-2B, and 2-3B). CTA images are Helical or multidetector CT (MDCT) is now stan- post-processed for display in three dimensions to yield dard in most radiology departments. Continuous CT angiogram-like images (Fig. 2-1C and see Fig. 21-4). information is obtained while the patient moves through CTA has proved useful in assessing the cervical and the x-ray beam. In the helical scan mode, the table moves intracranial arterial and venous anatomy. continuously through the rotating x-ray beam, generating

Intravenous iodinated contrast is often administered 13 CHAPTER 2 Neuroimaging in Neurologic Disorders prior to or during a CT study to identify vascular struc- tures and to detect defects in the blood-brain barrier (BBB) that are associated with disorders such as tumors, infarcts, and infections. In the normal CNS, only vessels and structures lacking a BBB (e.g., the pituitary gland, choroid plexus, and dura) enhance after contrast admin- istration. The use of iodinated contrast agents carries a risk of allergic reaction and adds additional expense and radiation dose. Although helpful in characterizing mass lesions as well as essential for the acquisition of CTA studies, the decision to use contrast material should always be considered carefully. INDICATIONS CT is the primary study of choice in the evaluation of an acute change in mental status, focal neurologic find- ings, acute trauma to the brain and spine, suspected sub- arachnoid hemorrhage, and conductive hearing loss (Table 2-1). CT is complementary to MR in the evalua- tion of the skull base, orbit, and osseous structures of the spine. In the spine, CT is useful in evaluating patients with osseous spinal stenosis and spondylosis, but MRI is often preferred in those with neurologic deficits. CT can also be obtained following intrathecal contrast injec- tion to evaluate the intracranial cisterns (CT cisternogra- phy) for cerebrospinal fluid (CSF) fistula, as well as the spinal subarachnoid space (CT myelography). FIGURE 2-1 COMPLICATIONS CT angiography (CTA) of ruptured anterior cerebral artery aneurysm in a patient presenting with acute headache. CT is safe, fast, and reliable. Radiation exposure depends A. Noncontrast CT demonstrates subarachnoid hemorrhage on the dose used but is normally between 3 and 5 cGy and mild obstructive hydrocephalus. B. Axial maximum for a routine brain CT study. Care must be taken to intensity projection from CT angiography demonstrates reduce exposure when imaging children. With the enlargement of the anterior cerebral artery (arrow). C. 3D sur- advent of MDCT, CTA, and CT perfusion, care must be face reconstruction using a workstation confirms the anterior taken to appropriately minimize radiation dose when- cerebral aneurysm and demonstrates its orientation and rela- ever possible. The most frequent complications are asso- tionship to nearby vessels (arrow). CTA image is produced by ciated with use of intravenous contrast agents. Two 0.5–1 mm helical CT scans performed during a rapid bolus broad categories of contrast media, ionic and nonionic, infusion of intravenous contrast medium. are in use. Although ionic agents are relatively safe and inexpensive, they are associated with a higher incidence of reactions and side effects (Table 2-2). As a result, ionic agents have been largely replaced by safer nonionic compounds. Contrast nephropathy may result from hemodynamic changes, renal tubular obstruction and cell damage, or immunologic reactions to contrast agents. A rise in serum creatinine of at least 85 μmol/L (1 mg/dL) within 48 h of contrast administration is often used as a definition of contrast nephropathy, although other causes of acute renal failure must be excluded.The prog- nosis is usually favorable, with serum creatinine levels returning to baseline within 1–2 weeks. Risk factors for contrast nephropathy include advanced age (>80 years),

14 SECTION I Introduction to Neurology FIGURE 2-2 right middle cerebral artery (arrow). Reconstitution of flow via Acute left hemiparesis due to middle cerebral artery collaterals is seen distal to the occlusion; however, the occlusion. A. Axial noncontrast CT scan demonstrates high patient sustained a right basal ganglia infarction. D. Sagittal density within the right middle cerebral artery (arrow) associ- reformation through the right internal carotid artery demon- ated with subtle low density involving the right putamen strates a low-density lipid laden plaque (arrowheads) narrow- (arrowheads). B. Mean transit time map calculated from a CT ing the lumen (black arrow) E. 3D surface CTA images from a perfusion study; prolongation of the mean transit time is visi- different patient demonstrate calcification and narrowing of ble throughout the right hemisphere (arrows). C. Axial maxi- the right internal carotid artery (arrow), consistent with ather- mum intensity projection from a CTA study through the Circle osclerotic disease. of Willis demonstrates an abrupt occlusion of the proximal

TABLE 2-2 TABLE 2-4 15 GUIDELINES FOR USE OF INTRAVENOUS CONTRAST GUIDELINES FOR PREMEDICATION OF PATIENTS CHAPTER 2 Neuroimaging in Neurologic Disorders IN PATIENTS WITH IMPAIRED RENAL FUNCTION WITH PRIOR CONTRAST ALLERGY SERUM CREATININE, 12 h prior to examination: Prednisone, 50 mg PO or methylprednisolone, 32 mg PO λmol/L (mg/dL)a RECOMMENDATION 2 h prior to examination: <133 (<1.5) Use either ionic or nonionic at Prednisone, 50 mg PO or methylprednisolone, 133–177 (1.5–2.0) 2 mL/kg to 150 mL total 32 mg PO and >177 (>2.0) Nonionic; hydrate diabetics Cimetidine, 300 mg PO or ranitidine, 150 mg PO 177–221 (2.0–2.5) 1 mL/kg per hour × 10 h >265 (>3.0) Consider noncontrast CT or MRI; Immediately prior to examination: nonionic contrast if required Benadryl, 50 mg IV (alternatively, can be given PO 2 h Nonionic only if required (as above); prior to exam) contraindicated in diabetics Nonionic IV contrast given only to which range from mild hives to bronchospasm, acute patients undergoing dialysis within anaphylaxis, and death.The pathogenesis of these allergic 24 h reactions is not fully understood but is thought to include the release of mediators such as histamine, aRisk is greatest in patients with rising creatinine levels. antibody-antigen reactions, and complement activation. Note: CT, computed tomography; MRI, magnetic resonance imaging. Severe allergic reactions occur in ~0.04% of patients receiving nonionic media, sixfold fewer than with ionic preexisting renal disease (serum creatinine exceeding media. Risk factors include a history of prior contrast 2.0 mg/dL), solitary kidney, diabetes mellitus, dehydration, reaction, food allergies to shellfish, and atopy (asthma paraproteinemia, concurrent use of nephrotoxic medica- and hay fever). In such patients, a noncontrast CT or tion or chemotherapeutic agents, and high contrast dose. MRI procedure should be considered as an alternative Patients with diabetes and those with mild renal failure to contrast administration. If iodinated contrast is should be well hydrated prior to the administration of absolutely required, a nonionic agent should be used in contrast agents, although careful consideration should be conjunction with pretreatment with glucocorticoids and given to alternative imaging techniques, such as MR antihistamines (Table 2-4). Patients with allergic reac- imaging or noncontrast examinations. Nonionic, low- tions to iodinated contrast material do not usually react osmolar media produce fewer abnormalities in renal to gadolinium-based MR contrast material, although blood flow and less endothelial cell damage but should such reactions do occur. It would be wise to pretreat still be used carefully in patients at risk for allergic reac- patients with a prior allergic history to MR contrast tion (Table 2-3). administration in a similar fashion. Other side effects are rare but include a sensation of MAGNETIC RESONANCE IMAGING warmth throughout the body and a metallic taste during intravenous administration of iodinated contrast media. TECHNIQUE The most serious side effects are anaphylactic reactions, Magnetic resonance is a complex interaction between TABLE 2-3 hydrogen protons in biologic tissues, a static magnetic field (the magnet), and energy in the form of radiofre- INDICATIONS FOR USE OF NONIONIC CONTRAST quency (Rf) waves of a specific frequency introduced by MEDIA coils placed next to the body part of interest. Field strength of the magnet is directly related to signal-to- • Prior adverse reaction to contrast media, with the noise ratio. Although 1.5 Telsa magnets have become the exception of heat, flushing, or an episode of nausea or standard high-field MRI units, 3T–8T magnets are now vomiting available and have distinct advantages in the brain and musculoskeletal systems. Spatial localization is achieved by • Asthma or other serious lung disease magnetic gradients surrounding the main magnet, which • History of atopic allergies (pretreatment with impart slight changes in magnetic field throughout the imaging volume. The energy state of the hydrogen pro- steroid/antihistamines recommended) tons is transiently excited by Rf, which is administered at • Children younger than 2 years a frequency specific for the field strength of the magnet. • Renal failure or creatinine >177 μmol/L (>2.0 mg/dL) The subsequent return to equilibrium energy state • Cardiac dysfunction, including recent or imminent car- diac decompensation, severe arrhythmias, unstable angina pectoris, recent myocardial infarction, and pul- monary hypertension • Diabetes • Severe debilitation

SECTION I Introduction to Neurology16 (relaxation) of the protons results in a release of Rf energy (Fig. 2-3). T2W images are more sensitive than T1W (the echo), which is detected by the coils that delivered the images to edema, demyelination, infarction, and chronic Rf pulses. The echo is transformed by Fourier analysis hemorrhage, whereas T1W imaging is more sensitive to into the information used to form an MR image. The subacute hemorrhage and fat-containing structures. MR image thus consists of a map of the distribution of hydrogen protons, with signal intensity imparted by both Many different MR pulse sequences exist, and each density of hydrogen protons and differences in the relax- can be obtained in various planes (Figs. 2-3, 2-4, 2-5). ation times (see below) of hydrogen protons on different The selection of a proper protocol that will best answer molecules. Although clinical MRI currently makes use of a clinical question depends on an accurate clinical history the ubiquitous hydrogen proton, research into sodium and indication for the examination. Fluid-attenuated and carbon imaging appears promising. inversion recovery (FLAIR) is a useful pulse sequence that produces T2W images in which the normally high T1 and T2 Relaxation Times signal intensity of CSF is suppressed (Fig. 2-5A). FLAIR images are more sensitive than standard spin echo images The rate of return to equilibrium of perturbed protons for any water-containing lesions or edema. Gradient is called the relaxation rate. The relaxation rate varies echo imaging is most sensitive to magnetic susceptibility among normal and pathologic tissues. The relaxation generated by blood, calcium, and air and is indicated in rate of a hydrogen proton in a tissue is influenced by patients with traumatic brain injury to assess for subtle local interactions with surrounding molecules and contusions and shear microhemorrhages. MR images atomic neighbors.Two relaxation rates,T1 and T2, influ- can be generated in any plane without changing the ence the signal intensity of the image.The T1 relaxation patient’s position. Each sequence, however, must be time is the time, measured in milliseconds, for 63% of obtained separately and takes 1–5 min on average to the hydrogen protons to return to their normal equilib- complete. Three-dimensional volumetric imaging is also rium state, while the T2 relaxation is the time for 63% possible with MRI, resulting in a volume of data that of the protons to become dephased owing to interac- can be reformatted in any orientation on a workstation tions among nearby protons. The intensity of the signal to highlight certain disease processes. within various tissues and image contrast can be modu- lated by altering acquisition parameters, such as the MR Contrast Material interval between Rf pulses (TR) and the time between the Rf pulse and the signal reception (TE). So-called The heavy-metal element gadolinium forms the basis T1-weighted (T1W) images are produced by keeping of all currently approved intravenous MR contrast the TR and TE relatively short. T2-weighted (T2W) agents. Gadolinium is a paramagnetic substance, which images are produced by using longer TR and TE times. means that it reduces the T1 and T2 relaxation times of Fat and subacute hemorrhage have relatively shorter T1 nearby water protons, resulting in a high signal on T1W relaxation rates and thus higher signal intensity than images and a low signal on T2W images (the latter brain on T1W images. Structures containing more requires a sufficient local concentration, usually in the water, such as CSF and edema, have long T1 and T2 form of an intravenous bolus). Unlike iodinated con- relaxation rates, resulting in relatively lower signal inten- trast agents, the effect of MR contrast agents depends sity on T1W images and a higher signal intensity on on the presence of local hydrogen protons on which it T2W images (Table 2-5). Gray matter contains 10–15% must act to achieve the desired effect. Gadolinium is more water than white matter, which accounts for much chelated to DTPA (diethylenetriaminepentaacetic acid), of the intrinsic contrast between the two on MRI which allows safe renal excretion. Approximately 0.2 mL/kg body weight is administered intravenously; the TABLE 2-5 cost is ~$60 per dose. Gadolinium-DTPA does not nor- mally cross the intact BBB immediately but will SOME COMMON INTENSITIES ON T1- AND enhance lesions lacking a BBB (Fig. 2-4A) and areas of T2-WEIGHTED MRI SEQUENCES the brain that normally are devoid of the BBB (pitu- itary, choroid plexus). However, gadolinium contrast has SIGNAL INTENSITY been noted to slowly cross an intact BBB if given over time and especially in the setting of reduced renal IMAGE TR TE CSF FAT BRAIN EDEMA clearance.The agents are generally well tolerated; severe allergic reactions are rare but have been reported. The T1W Short Short Low High Low Low adverse reaction rate in patients with a prior history of T2W Long Long High Low High High atopy or asthma is 3.7%; however, the reaction rate increases to 6.3% in those patients with a prior history Note: TR, interval between radiofrequency (Rf) pulses; TE, interval of unspecified allergic reaction to iodinated contrast between Rf pulse and signal reception; CSF, cerebrospinal fluid; agents. Gadolinium contrast material can be administered T1W and T2W, T1- and T2-weighted.

17 CHAPTER 2 Neuroimaging in Neurologic Disorders FIGURE 2-3 volume map shows reduced CBV involving an area within the A. Axial noncontrast CT scan in a patient with left hemipare- defect shown in B, indicating infarction (arrows). D. Coronal sis shows a subtle low density involving the right temporal maximum intensity projection from MRA shows right middle and frontal lobes (arrows). The hyperdense middle cerebral cerebral artery (MCA) occlusion (arrow). E and F. Axial diffu- artery (arrowhead) indicates an embolic occlusion of the mid- sion weighted image (E) and apparent diffusion coefficient dle cerebral artery. B. Mean transit time CT perfusion para- image (F) documents the presence of a right middle cerebral metric map indicating prolonged mean transit time involving artery infarction. the right middle cerebral territory (arrows). C. Cerebral blood safely to children as well as adults, although these agents widespread fibrosis of the skeletal muscle, bone, lungs, are generally avoided in those younger than 6 months. pleura, pericardium, myocardium, kidney, muscle, bone, Renal failure does not occur. testes, and dura. A rare complication, nephrogenic systemic fibrosis COMPLICATIONS AND CONTRAINDICATIONS (NSF), has recently been reported in patients with renal insufficiency, who have been exposed to gadolinium From the patient’s perspective, an MRI examination can contrast agents. The onset of NSF has been reported be intimidating, and a higher level of cooperation is between 5 and 75 days following exposure; histologic fea- required than with CT.The patient lies on a table that is tures include thickened collagen bundles with surrounding moved into a long, narrow gap within the magnet. clefts, mucin deposition, and increased numbers of Approximately 5% of the population experiences severe fibrocytes and elastic fibers in skin. In addition to dermatologic symptoms, other manifestations include

18 SECTION I Introduction to Neurology FIGURE 2-4 Cerebral abscess in a patient with fever and a right hemiparesis. A. Coronal postcontrast T1-weighted image demonstrates a ring enhanc- ing mass in the left frontal lobe. B. Axial diffusion-weighted image demonstrates restricted diffusion (high signal intensity) within the lesion, which in this setting is highly suggestive of cerebral abscess. C. Single voxel proton spec- troscopy (TE of 288 ms) reveals a reduced Naa peak and abnormal peaks for acetate, alanine (Ala), lactate (Lac), and amino acids (AA). These findings are highly suggestive of cerebral abscess; at biopsy a streptococcal abscess was identified. claustrophobia in the MR environment. This can be is indicated in those with a history of metal work or reduced by mild sedation but remains a problem for ocular metallic foreign bodies. Implanted cardiac pace- some. Unlike CT, movement of the patient during an makers are generally a contraindication to MRI owing MR sequence distorts all the images; therefore, uncoop- to the risk of induced arrhythmias; however, some erative patients should either be sedated for the MR study newer pacemakers have been shown to be safe. All or scanned with CT. Generally, children younger than health care personnel and patients must be screened and 10 years usually require conscious sedation in order to com- educated thoroughly to prevent such disasters as the plete the MR examination without motion degradation. magnet is always “on.” Table 2-6 lists common con- traindications for MRI. MRI is considered safe for patients, even at very high field strengths (>3–4 T). Serious injuries have been MAGNETIC RESONANCE caused, however, by attraction of ferromagnetic objects ANGIOGRAPHY into the magnet, which act as missiles if brought too close to the magnet. Likewise, ferromagnetic implants, MR angiography (MRA) is a general term describing sev- such as aneurysm clips, may torque within the magnet, eral MR techniques that result in vascular-weighted causing damage to vessels and even death. Metallic for- images. These provide a vascular flow map rather than eign bodies in the eye have moved and caused intraocu- lar hemorrhage; screening for ocular metallic fragments

19 FIGURE 2-5 left medial temporal lobe and hippocampus (arrows). This is CHAPTER 2 Neuroimaging in Neurologic Disorders Herpes simplex encephalitis in a patient presenting with most consistent with neuronal death and can be seen in acute altered mental status and fever. A. Coronal T2-weighted infarction as well as encephalitis and other inflammatory con- FLAIR image demonstrates expansion and high signal intensity ditions. The suspected diagnosis of herpes simplex encephali- involving the left medial temporal lobe, insular cortex, and left tis was confirmed by CSF PCR analysis. (Courtesy of Howard cingulate gyrus. B. Diffusion-weighted image demonstrates Rowley, MD, University of Wisconsin; with permission.) high signal intensity indicating restricted diffusion involving the the anatomic map shown by conventional angiography. intensity of moving protons in contrast to the low signal On routine spin echo MR sequences, moving protons background intensity of stationary tissue. This creates (e.g., flowing blood, CSF) exhibit complex MR signals angiography-like images, which can be manipulated in that range from high to low signal intensity relative to three dimensions to highlight vascular anatomy and background stationary tissue. Fast-flowing blood returns relationships. no signal (flow void) on routine T1W or T2W spin echo MR images. Slower-flowing blood, as occurs in Time-of-flight (TOF) imaging, currently the tech- veins or distal to arterial stenosis, may appear high in nique used most frequently, relies on the suppression of signal. However, using special pulse sequences called gra- nonmoving tissue to provide a low-intensity back- dient echo sequences, it is possible to increase the signal ground for the high signal intensity of flowing blood entering the section; arterial or venous structures may TABLE 2-6 be highlighted. A typical TOF angiography sequence results in a series of contiguous, thin MR sections COMMON CONTRAINDICATIONS TO MR IMAGING (0.6–0.9 mm thick), which can be viewed as a stack and manipulated to create an angiographic image data set Cardiac pacemaker or permanent pacemaker leads that can be reformatted and viewed in various planes Internal defibrillatory device and angles, much like that seen with conventional Cochlear prostheses angiography (Fig. 2-3D). Bone growth stimulators Spinal cord stimulators Phase-contrast MRA has a longer acquisition time Electronic infusion devices than TOF MRA, but in addition to providing anatomic Intracranial aneurysm clips (some but not all) information similar to that of TOF imaging, it can be Ocular implants (some) or ocular metallic foreign body used to reveal the velocity and direction of blood flow McGee stapedectomy piston prosthesis in a given vessel. Through the selection of different Omniphase penile implant imaging parameters, differing blood velocities can be Swan-Ganz catheter highlighted; selective venous and arterial MRA images Magnetic stoma plugs can thus be obtained. One advantage of phase-contrast Magnetic dental implants MRA is the excellent suppression of high signal inten- Magnetic sphincters sity background structures. Ferromagnetic IVC filters, coils, stents—safe 6 weeks MRA can also be acquired during infusion of con- after implantation trast material. Advantages include faster imaging times Tattooed eyeliner (contains ferromagnetic material and (1–2 min vs. 10 min), fewer flow-related artifacts, and may irritate eyes) higher-resolution images. Recently, contrast-enhanced

SECTION I Introduction to Neurology20 MRA has become the standard for extracranial vascular for processing an image is accumulated in 50–150 ms, MRA. This technique entails rapid imaging using coro- and the information for the entire brain is obtained in nal three-dimensional TOF sequences during a bolus 1–2 min, depending on the degree of resolution infusion of 15–20 mL of gadolinium-DTPA. Proper required or desired. Fast MRI reduces patient and organ technique and timing of acquisition relative to bolus motion, permitting diffusion imaging and tractography arrival are critical for success. (Figs. 2-3, 2-4, 2-5, 2-6; and see Fig. 21-16), perfusion MRA has lower spatial resolution compared with imaging during contrast infusion, fMRI, and kinematic conventional film-based angiography, and therefore the motion studies. detection of small-vessel abnormalities, such as vasculitis and distal vasospasm, is problematic. MRA is also less Perfusion and diffusion imaging are EPI techniques sensitive to slowly flowing blood and thus may not reli- that are useful in early detection of ischemic injury of ably differentiate complete from near-complete occlu- the brain and may be useful together to demonstrate sions. Motion, either by the patient or by anatomic infarcted tissue as well as ischemic but potentially viable structures, may distort the MRA images, creating arti- tissue at risk of infarction (e.g., the ischemic penumbra). facts. These limitations notwithstanding, MRA has Diffusion-weighted imaging (DWI) assesses microscopic proved useful in evaluation of the extracranial carotid motion of water; restriction of motion appears as relative and vertebral circulation as well as of larger-caliber high signal intensity on diffusion-weighted images. DWI intracranial arteries and dural sinuses. It has also proved is the most sensitive technique for detection of acute useful in the noninvasive detection of intracranial cerebral infarction of <7 days’ duration and is also sensi- aneurysms and vascular malformations. tive to encephalitis and abscess formation, all of which have reduced diffusion and result in high signal on diffu- ECHO-PLANAR MR IMAGING sion-weighted images. Recent improvements in gradients, software, and high- Perfusion MRI involves the acquisition of EPI images speed computer processors now permit extremely rapid during a rapid intravenous bolus of gadolinium contrast MRI of the brain. With echo-planar MRI (EPI), fast material. Relative perfusion abnormalities can be identi- gradients are switched on and off at high speeds to cre- fied on images of the relative cerebral blood volume, ate the information used to form an image. In routine mean transit time, and cerebral blood flow. Delay in spin echo imaging, images of the brain can be obtained mean transit time and reduction in cerebral blood vol- in 5–10 min. With EPI, all of the information required ume and cerebral blood flow are typical of infarction. In the setting of reduced blood flow, a prolonged mean transit time of contrast but normal or elevated cerebral blood volume may indicate tissue supplied by collateral FIGURE 2-6 tractography superimposed on the image. This shows the Diffusion tractography in cerebral glioma. A. An axial fast position of the internal capsule (arrows) relative to the enhanc- spin echo T2-weighted image shows a high signal intensity ing tumor. glioma of the insular cortex lateral to the fibers of the internal capsule. B and C. Axial post-gadolinium images with diffusion

flow that is at risk of infarction. pMRI imaging can also MAGNETIC RESONANCE 21 be used in the assessment of brain tumors to differenti- NEUROGRAPHY ate intraaxial primary tumors from extraaxial tumors or metastasis. MR neurography is an MR technique that shows promise CHAPTER 2 Neuroimaging in Neurologic Disorders in detecting increased signal in irritated, inflamed, or Diffusion tract imaging (DTI) is derived from diffu- infiltrated peripheral nerves. Images are obtained with sion MRI techniques. Preferential microscopic motion fat-suppressed fast spin echo imaging or short inversion of water along white matter tracts is detected by diffu- recovery sequences. Irritated or infiltrated nerves will sion MR, which can also indicate the direction of white demonstrate high signal on T2W imaging. matter fiber tracts. This new technique has great poten- tial in the assessment of brain maturation as well as dis- POSITRON EMISSION ease entities that undermine the integrity of the white TOMOGRAPHY (PET) matter architecture (Fig. 2-7). PET relies on the detection of positrons emitted during fMRI of the brain is an EPI technique that localizes the decay of a radionuclide that has been injected into a regions of activity in the brain following task activation. patient. The most frequently used moiety is 2-[18F] Neuronal activity elicits a slight increase in the delivery fluoro-2-deoxy-D-glucose (FDG), which is an ana- of oxygenated blood flow to a specific region of acti- logue of glucose and is taken up by cells competitively vated brain.This results in an alteration in the balance of with 2-deoxyglucose. Multiple images of glucose oxyhemoglobin and deoxyhemoglobin, which yields a uptake activity are formed after 45–60 min. Images 2–3% increase in signal intensity within veins and local reveal differences in regional glucose activity among capillaries. Further studies will determine whether these normal and pathologic brain structures. A lower activity techniques are cost-effective or clinically useful, but cur- of FDG in the parietal lobes has been associated with rently preoperative somatosensory and auditory cortex Alzheimer’s disease. FDG PET is used primarily for the localization is possible. This technique has proved useful detection of extracranial metastatic disease. Combina- to neuroscientists interested in interrogating the local- tion PET-CT scanners, in which both CT and PET are ization of certain brain functions. obtained at one sitting, are replacing PET scans alone for most clinical indications. Functional images super- imposed on high-resolution CT scans result in more precise anatomic diagnoses. FIGURE 2-7 MYELOGRAPHY Diffusion tractography in a healthy individual obtained at 3T demonstrates the normal subcortical fiber pathways. The TECHNIQUE direction of the tracts have been color-coded (red, left-right; green, anterior-posterior; blue, superior-inferior). (Courtesy of Myelography involves the intrathecal instillation of spe- Pratik Mukherjee, MD, PhD; with permission.) cially formulated water-soluble iodinated contrast medium into the lumbar or cervical subarachnoid space. CT scanning is usually performed after myelography (CT myelography) to better demonstrate the spinal cord and roots, which appear as filling defects in the opacified subarachnoid space. Low-dose CT myelography, in which CT is performed after the subarachnoid injection of a small amount of relatively dilute contrast material, has replaced conventional myelography for many indica- tions, thereby reducing exposure to radiation and con- trast media. Newer multidetector scanners now obtain CT studies quickly so that reformations in sagittal and coronal planes, equivalent to traditional myelography projections, are now routine. INDICATIONS Myelography has been largely replaced by CT myelog- raphy and MRI for diagnosis of diseases of the spinal

SECTION I Introduction to Neurology22 canal and cord (Table 2-1). Remaining indications for arachnoid space. Seizures occur following myelography conventional plain-film myelography include the evalu- in 0.1–0.3% of patients. Risk factors include a preexist- ation of suspected meningeal or arachnoid cysts and the ing seizure disorder and the use of a total iodine dose of localization of spinal dural arteriovenous or CSF fistulas. >4500 mg. Other reported complications include Conventional myelography and CT myelography pro- hyperthermia, hallucinations, depression, and anxiety vide the most precise information in patients with prior states.These side effects have been reduced by the devel- spinal fusion and spinal fixation hardware. opment of nonionic, water-soluble contrast agents, as well as by head elevation and generous hydration fol- CONTRAINDICATIONS lowing myelography. Myelography is relatively safe; however, it should be per- SPINE INTERVENTIONS formed with caution in any patient with elevated intracranial pressure, evidence of a spinal block, or a his- DISCOGRAPHY tory of allergic reaction to intrathecal contrast media. In patients with a suspected spinal block, MR is the pre- The evaluation of back pain and radiculopathy may require ferred technique. If myelography is necessary, only a diagnostic procedures that attempt either to reproduce small amount of contrast medium should be instilled the patient’s pain or relieve it, indicating its correct below the lesion in order to minimize the risk of neuro- source prior to lumbar fusion. Discography is performed logic deterioration. Lumbar puncture is to be avoided in by fluoroscopic placement of a 22- to 25-gauge needle patients with bleeding disorders, including patients into the intervertebral disc and subsequent injection of receiving anticoagulant therapy, as well as in those with 1–3 mL of contrast media. The intradiscal pressure is infections of the soft tissues. recorded, as is an assessment of the patient’s response to the injection of contrast material. Typically little or no COMPLICATIONS pain is felt during injection of a normal disc, which does not accept much more than 1 mL of contrast material, Headache, nausea, and vomiting are the most frequent even at pressures as high as 415–690 kPa (60–100 complications of myelography and are reported to occur lbs/in2). CT and plain films are obtained following the in up to 38% of patients. These symptoms result from procedure. either neurotoxic effects of the contrast agent, persistent leakage of CSF at the puncture site, or psychological SELECTIVE NERVE ROOT AND EPIDURAL reactions to the procedure.Vasovagal syncope may occur SPINAL INJECTIONS during lumbar puncture; it is accentuated by the upright position used during lumbar myelography. Adequate Percutaneous selective nerve root and epidural blocks hydration before and after myelography will reduce the with glucocorticoid and anesthetic mixtures may be incidence of this complication. Postural headache both therapeutic and diagnostic, especially if a patient’s (post–lumbar puncture headache) is generally due to pain is relieved. Typically, 1–2 mL of an equal mixture leakage of CSF from the puncture site, resulting in CSF of a long-acting glucocorticoid such as betamethasone hypotension. Management of post-lumbar-puncture and a long-acting anesthetic such as bupivicain 0.75% is headache is discussed in Chap. 4. instilled under CT or fluoroscopic guidance in the intraspinal epidural space or adjacent to an existing nerve If significant headache persists for longer than 48 hours, root. placement of an epidural blood patch should be consid- ered. Hearing loss is a rare complication of myelography. ANGIOGRAPHY It may result from a direct toxic effect of the contrast medium or from an alteration of the pressure equilib- Catheter angiography is indicated for evaluating rium between CSF and perilymph in the inner ear. intracranial small-vessel pathology (such as vasculitis), for Puncture of the spinal cord is a rare but serious compli- assessing vascular malformations and aneurysms, and in cation of cervical (C1–2) and high lumbar puncture. endovascular therapeutic procedures (Table 2-1).Angiog- The risk of cord puncture is greatest in patients with raphy has been replaced for many indications by CT/CTA spinal stenosis, Chiari malformations, or conditions that or MRI/MRA. reduce CSF volume. In these settings, a low-dose lum- bar injection followed by thin-section CT or MRI is a Angiography carries the greatest risk of morbidity of safer alternative to cervical puncture. Intrathecal contrast all diagnostic imaging procedures, owing to the necessity reactions are rare, but aseptic meningitis and encephalopa- of inserting a catheter into a blood vessel, directing the thy may occur. The latter is usually dose-related and catheter to the required location, injecting contrast material associated with contrast entering the intracranial sub-

to visualize the vessel, and removing the catheter while SPINAL ANGIOGRAPHY 23 maintaining hemostasis. Therapeutic transcatheter proce- dures (see below) have become important options for the Spinal angiography may be indicated to evaluate vascular CHAPTER 2 Neuroimaging in Neurologic Disorders treatment of some cerebrovascular diseases. The decision malformations and tumors and to identify the artery of to undertake a diagnostic or therapeutic angiographic Adamkiewicz (Chap. 30) prior to aortic aneurysm repair. procedure requires careful assessment of the goals of the The procedure is lengthy and requires the use of relatively investigation and its attendant risks. large volumes of contrast; the incidence of serious com- plications, including paraparesis, subjective visual blurring, To improve tolerance to contrast agents, patients and altered speech, is ~2%. Gadolinium-enhanced MRA undergoing angiography should be well hydrated before has been used successfully in this setting, as has iodinated and after the procedure. Since the femoral route is used contrast CTA, which has promise for replacing diagnostic most commonly, the femoral artery must be compressed spinal angiography for some indications. after the procedure to prevent a hematoma from devel- oping. The puncture site and distal pulses should be INTERVENTIONAL NEURORADIOLOGY evaluated carefully after the procedure; complications can include thigh hematoma or lower extremity emboli. This rapidly developing field is providing new therapeu- tic options for patients with challenging neurovascular COMPLICATIONS problems. Available procedures include detachable coil therapy for aneurysms, particulate or liquid adhesive A common femoral arterial puncture provides retro- embolization of arteriovenous malformations, balloon grade access via the aorta to the aortic arch and great angioplasty and stenting of arterial stenosis or vasospasm, vessels. The most feared complication of cerebral transarterial or transvenous embolization of dural arteri- angiography is stroke. Thrombus can form on or inside ovenous fistulas, balloon occlusion of carotid-cavernous the tip of the catheter, and atherosclerotic thrombus or and vertebral fistulas, endovascular treatment of vein- plaque can be dislodged by the catheter or guide wire or of-Galen malformations, preoperative embolization of by the force of injection and can embolize distally in the tumors, and thrombolysis of acute arterial or venous cerebral circulation. Risk factors for ischemic complica- thrombosis. Many of these disorders place the patient at tions include limited experience on the part of the high risk of cerebral hemorrhage, stroke, or death. angiographer, atherosclerosis, vasospasm, low cardiac output, decreased oxygen-carrying capacity, advanced The highest complication rates are found with the age, and prior history of migraine. The risk of a neuro- therapies designed to treat the highest-risk diseases. The logic complication varies but is ~4% for transient advent of electrolytically detachable coils has ushered in ischemic attack and stroke, 1% for permanent deficit, a new era in the treatment of cerebral aneurysms. One and <0.1% for death. randomized trial found a 28% reduction of morbidity and mortality at 1 year among those treated for anterior Ionic contrast material injected into the cerebral vas- circulation aneurysm with detachable coils compared culature can be neurotoxic if the BBB is breached, with neurosurgical clipping. It remains to be determined either by an underlying disease or by the injection of what the role of coils will be relative to surgical options, hyperosmolar contrast agent. Ionic contrast media are but in many centers, coiling has become standard ther- less well tolerated than nonionic media, probably apy for many aneurysms. because they can induce changes in cell membrane elec- trical potentials. Patients with dolichoectasia of the basi- FURTHER READINGS lar artery can suffer reversible brainstem dysfunction and acute short-term memory loss during angiography, DONNAN GA et al: Penumbral selection of patients for trials of acute owing to the slow percolation of the contrast material stroke therapy. Lancet Neurol. 8:261, 2009 and the consequent prolonged exposure of the brain. Rarely, an intracranial aneurysm ruptures during an ROVARIS M et al: Diffusion tensor MR imaging. Neuroimaging Clin angiographic contrast injection, causing subarachnoid N Am 19:37, 2009 hemorrhage, perhaps as a result of injection under high pressure. SCHAEFER PW: Diffusion-weighted imaging in acute stroke. Magn Reson Imaging Clin N Am 14:141, 2006 VERNOOIJ MW et al: Incidental findings on brain MRI in the gen- eral population. N Engl J Med 357:1821, 2007

CHAPTER 3 ELECTRODIAGNOSTIC STUDIES OF NERVOUS SYSTEM DISORDERS: EEG, EVOKED POTENTIALS, AND EMG Michael J. Aminoff I Electroencephalography . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 The EEG and Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 The EEG and Coma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 The EEG in Other Neurologic Disorders . . . . . . . . . . . . . . . . . 27 I Evoked Potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Sensory Evoked Potentials . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Clinical Utility of SEPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Electrophysiologic Studies of Muscle and Nerve . . . . . . . . . . 28 Electromyography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 ELECTROENCEPHALOGRAPHY procedures are generally undertaken in an attempt to provoke abnormalities. Such procedures commonly The electrical activity of the brain [the electroencephalo- include hyperventilation (for 3 or 4 min), photic stimu- gram (EEG)] is easily recorded from electrodes placed on lation, sleep, and sleep deprivation on the night prior to the scalp. The potential difference between pairs of elec- the recording. trodes on the scalp (bipolar derivation) or between indi- vidual scalp electrodes and a relatively inactive common Electroencephalography is relatively inexpensive and may aid clinical management in several different contexts. reference point (referential derivation) is amplified and displayed on a computer monitor, oscilloscope, or paper. THE EEG AND EPILEPSY The characteristics of the normal EEG depend on the patient’s age and level of arousal. The rhythmic activity The EEG is most useful in evaluating patients with sus- normally recorded represents the postsynaptic potentials pected epilepsy. The presence of electrographic seizure of vertically oriented pyramidal cells of the cerebral cor- activity—i.e., of abnormal, repetitive, rhythmic activity tex and is characterized by its frequency. In normal having an abrupt onset and termination and a character- awake adults lying quietly with the eyes closed, an 8- to istic evolution—clearly establishes the diagnosis. The 13-Hz alpha rhythm is seen posteriorly in the EEG, absence of such electrocerebral accompaniment does intermixed with a variable amount of generalized faster not exclude a seizure disorder, however, because there (beta) activity (>13 Hz); the alpha rhythm is attenuated may be no change in the scalp-recorded EEG during when the eyes are opened (Fig. 3-1). During drowsiness, simple or complex partial seizures. With generalized the alpha rhythm is also attenuated; with light sleep, tonic-clonic seizures, however, the EEG is always abnor- slower activity in the theta (4–7 Hz) and delta (<4 Hz) mal during the episode. It is often not possible to obtain ranges becomes more conspicuous. an EEG during clinical events that may represent seizures, The EEG is best recorded from several different elec- especially when such events occur unpredictably or infre- trode arrangements (montages) in turn, and activating quently. Continuous monitoring for prolonged periods 24

Eyes open 25 Fp1-F3 F3-C3 CHAPTER 3 Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG F3-C3 C3-P3 C3-P3 P3-O1 P3-O1 F4-C4 Fp2-F4 C4-P4 F4-C4 P4-O2 C4-P4 T3-CZ P4-O2 CZ-T4 A B F3-A1 Fp1-F3 F3-C3 C3-A1 C3-P3 P3-O1 P3-A1 Fp2-F4 F4-C4 O1-A1 C4-P4 P4-O2 F4-A2 D C4-A2 300 μV in other panels. (From Aminoff, 1999.) In this and the P4-A2 following figure, electrode placements are indicated at the left of each panel and accord with the international 10:20 O2-A2 system. A, earlobe; C, central; F, frontal; Fp, frontal polar; C P, parietal; T, temporal; O, occipital. Right-sided placements are indicated by even numbers, left-sided placements by FIGURE 3-1 odd numbers, and midline placements by Z. A. Normal EEG showing a posteriorly situated 9-Hz alpha rhythm that attenuates with eye opening. B. Abnormal EEG showing irregular diffuse slow activity in an obtunded patient with encephalitis. C. Irregular slow activity in the right central region, on a diffusely slowed background, in a patient with a right parietal glioma. D. Periodic complexes occurring once every second in a patient with Creutzfeldt-Jakob disease. Horizontal calibration: 1 s; vertical calibration: 200 μV in A, in video-EEG telemetry units for hospitalized patients episodic generalized spike-wave activity that occurs dur- or the use of portable equipment to record the EEG ing and between seizures in patients with typical continuously on cassettes for 24 h or longer in ambula- absence epilepsy contrasts with focal interictal epilepti- tory patients has made it easier to capture the electro- form discharges or ictal patterns found in patients with cerebral accompaniments of such clinical episodes. complex partial seizures. These latter seizures may have Monitoring by these means is sometimes helpful in con- no correlates in the scalp-recorded EEG or may be asso- firming that seizures are occurring, characterizing the ciated with abnormal rhythmic activity of variable fre- nature of clinically equivocal episodes, and determining quency, a localized or generalized distribution, and a the frequency of epileptic events. stereotyped pattern that varies with the patient. Focal or lateralized epileptogenic lesions are important to recog- The EEG findings may also be helpful in the interictal nize, especially if surgical treatment is contemplated. period by showing certain abnormalities that are strongly Intensive long-term monitoring of clinical behavior and supportive of a diagnosis of epilepsy. Such epileptiform the EEG is required for operative candidates, however, activity consists of bursts of abnormal discharges contain- and this generally also involves recording from intracra- ing spikes or sharp waves. The presence of epileptiform nially placed electrodes (which may be subdural, activity is not specific for epilepsy, but it has a much extradural, or intracerebral in location). greater prevalence in epileptic patients than in normal individuals. However, even in an individual who is The findings in the routine scalp-recorded EEG may known to have epilepsy, the initial routine interictal EEG indicate the prognosis of seizure disorders: in general, a may be normal up to 60% of the time. Thus, the EEG normal EEG implies a better prognosis than otherwise, cannot establish the diagnosis of epilepsy in many cases. whereas an abnormal background or profuse epilepti- form activity suggests a poor outlook.The EEG findings The EEG findings have been used in classifying are not helpful in determining which patients with head seizure disorders and selecting appropriate anticonvul- injuries, stroke, or brain tumors will go on to develop sant medication for individual patients (Fig. 3-2). The

SECTION I Introduction to Neurology26 F3-C3 occur after withdrawal of anticonvulsant medication despite a normal EEG or, conversely, may not occur C3-P3 despite a continuing EEG abnormality. The decision to P3-O1 discontinue anticonvulsant medication is made on clini- F4-C4 cal grounds, and the EEG does not have a useful role in C4-P4 this context except for providing guidance when there P4-O2 is clinical ambiguity or the patient requires reassurance T3-CZ about a particular course of action. CZ-T4 A The EEG has no role in the management of tonic- clonic status epilepticus except when there is clinical Fp1-F7 uncertainty whether seizures are continuing in a F7-T3 comatose patient. In patients treated by pentobarbital- induced coma for refractory status epilepticus, the EEG T3-T5 findings are useful in indicating the level of anesthesia T5-O1 and whether seizures are occurring. During status Fp2-F8 epilepticus, the EEG shows repeated electrographic seizures or continuous spike-wave discharges. In non- F8-T4 convulsive status epilepticus, a disorder that may not be T4-T6 recognized unless an EEG is performed, the EEG may T6-O2 also show continuous spike-wave activity (“spike-wave B stupor”) or, less commonly, repetitive electrographic seizures (complex partial status epilepticus). Fp1-A1 THE EEG AND COMA F7-A1 T3-A1 In patients with an altered mental state or some degree of T5-A1 obtundation, the EEG tends to become slower as con- Fp2-A2 sciousness is depressed, regardless of the underlying cause F8-A2 (Fig. 3-1). Other findings may also be present and may T4-A2 suggest diagnostic possibilities, as when electrographic T6-A2 seizures are found or there is a focal abnormality indicat- C ing a structural lesion.The EEG generally slows in meta- bolic encephalopathies, and triphasic waves may be pre- FIGURE 3-2 sent. The findings do not permit differentiation of the Electrographic seizures. A. Onset of a tonic seizure showing underlying metabolic disturbance but help to exclude generalized repetitive sharp activity with synchronous onset other encephalopathic processes by indicating the diffuse over both hemispheres. B. Burst of repetitive spikes occur- extent of cerebral dysfunction. The response of the EEG ring with sudden onset in the right temporal region during a to external stimulation is helpful prognostically because clinical spell characterized by transient impairment of external electrocerebral responsiveness implies a lighter level of awareness. C. Generalized 3-Hz spike-wave activity occur- coma than a nonreactive EEG. Serial records provide a ring synchronously over both hemispheres during an absence better guide to prognosis than a single record and supple- (petit mal) attack. Horizontal calibration: 1 s; vertical calibra- ment the clinical examination in following the course of tion: 400 mV in A, 200 mV in B, and 750 mV in C. (From events. As the depth of coma increases, the EEG becomes Aminoff, 1999.) nonreactive and may show a burst-suppression pattern, with bursts of mixed-frequency activity separated by seizures, because in such circumstances epileptiform intervals of relative cerebral inactivity. In other instances activity is commonly encountered regardless of whether there is a reduction in amplitude of the EEG until even- seizures occur. The EEG findings are sometimes used to tually activity cannot be detected. Such electrocerebral determine whether anticonvulsant medication can be silence does not necessarily reflect irreversible brain dam- discontinued in epileptic patients who have been age, because it may occur in hypothermic patients or with seizure-free for several years, but the findings provide drug overdose. The prognosis of electrocerebral silence, only a general guide to prognosis: further seizures may when recorded using an adequate technique, depends upon the clinical context in which it is found. In patients with severe cerebral anoxia, for example, electrocerebral silence in a technically satisfactory record implies that useful cognitive recovery will not occur.

In patients with clinically suspected brain death, an stimuli have to be recorded and averaged with a com- 27 CHAPTER 3 Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG EEG, when recorded using appropriate technical stan- puter in order to permit their recognition and defini- dards, may be confirmatory by showing electrocerebral tion. The background EEG activity, which has no fixed silence. However, complicating disorders that may pro- temporal relationship to the stimulus, is averaged out by duce a similar but reversible EEG appearance (e.g., this procedure. hypothermia or drug intoxication) must be excluded. The presence of residual EEG activity in suspected brain Visual evoked potentials (VEPs) are elicited by monocular death fails to confirm the diagnosis but does not exclude stimulation with a reversing checkerboard pattern and are it.The EEG is usually normal in patients with locked-in recorded from the occipital region in the midline and on syndrome and helps in distinguishing this disorder from either side of the scalp. The component of major clinical the comatose state with which it is sometimes confused importance is the so-called P100 response, a positive peak clinically. having a latency of approximately 100 ms. Its presence, latency, and symmetry over the two sides of the scalp are THE EEG IN OTHER NEUROLOGIC noted. Amplitude may also be measured, but changes in DISORDERS size are much less helpful for the recognition of pathology. VEPs are most useful in detecting dysfunction of the In the developed countries, CT scanning and MRI have visual pathways anterior to the optic chiasm. In patients taken the place of EEG as a noninvasive means of screen- with acute severe optic neuritis, the P100 is frequently lost ing for focal structural abnormalities of the brain, such as or grossly attenuated; as clinical recovery occurs and visual tumors, infarcts, or hematomas (Fig. 3-1). Nonetheless, acuity improves, the P100 is restored but with an increased the EEG is still used for this purpose in many parts of the latency that generally remains abnormally prolonged world, although infratentorial or slowly expanding indefinitely.TheVEP findings are therefore helpful in indi- lesions may fail to cause any abnormalities. Focal slow- cating previous or subclinical optic neuritis.They may also wave disturbances, a localized loss of electrocerebral be abnormal with ocular abnormalities and with other activity, or more generalized electrocerebral disturbances causes of optic nerve disease, such as ischemia or compres- are common findings but provide no reliable indication sion by a tumor. Normal VEPs may be elicited by flash about the nature of the underlying pathology. stimuli in patients with cortical blindness. In patients with an acute encephalopathy, focal or lat- Brainstem auditory evoked potentials (BAEPs) are elicited eralized periodic slow-wave complexes, sometimes with by monaural stimulation with repetitive clicks and are a sharpened outline, suggest a diagnosis of herpes sim- recorded between the vertex of the scalp and the mas- plex encephalitis, and periodic lateralized epileptiform toid process or earlobe. A series of potentials, designated discharges (PLEDs) are commonly found with acute by roman numerals, occurs in the first 10 ms after the hemispheric pathology such as a hematoma, abscess, or stimulus and represents in part the sequential activation rapidly expanding tumor.The EEG findings in dementia of different structures in the pathway between the audi- are usually nonspecific and do not distinguish between tory nerve (wave I) and the inferior colliculus (wave V) the different causes of cognitive decline except in rare in the midbrain. The presence, latency, and interpeak instances when, for example, the presence of complexes latency of the first five positive potentials recorded at occurring with a regular repetition rate (so-called peri- the vertex are evaluated. The findings are helpful in odic complexes) supports a diagnosis of Creutzfeldt- screening for acoustic neuromas, detecting brainstem Jakob disease (Fig. 3-1) or subacute sclerosing panen- pathology, and evaluating comatose patients.The BAEPs cephalitis. In most patients with dementias, the EEG is are normal in coma due to metabolic/toxic disorders or normal or diffusely slowed, and the EEG findings alone bihemispheric disease but abnormal in the presence of cannot indicate whether a patient is demented or distin- brainstem pathology. guish between dementia and pseudodementia. Somatosensory evoked potentials (SEPs) are recorded EVOKED POTENTIALS over the scalp and spine in response to electrical stimu- lation of a peripheral (mixed or cutaneous) nerve. The SENSORY EVOKED POTENTIALS configuration, polarity, and latency of the responses depend on the nerve that is stimulated and on the record- The noninvasive recording of spinal or cerebral poten- ing arrangements. SEPs are used to evaluate proximal tials elicited by stimulation of specific afferent pathways (otherwise inaccessible) portions of the peripheral nervous is an important means of monitoring the functional system and the integrity of the central somatosensory integrity of these pathways but does not indicate the pathways. pathologic basis of lesions involving them. Such evoked potentials (EPs) are so small compared to the back- CLINICAL UTILITY OF SEPs ground EEG activity that the responses to a number of EP studies may detect and localize lesions in afferent pathways in the central nervous system (CNS). They

SECTION I Introduction to Neurology28 have been used particularly to investigate patients with latency in many patients with dementia, whereas it is suspected multiple sclerosis (MS), the diagnosis of which generally normal in patients with depression or other requires the recognition of lesions involving several dif- psychiatric disorders that might be mistaken for demen- ferent regions of the central white matter. In patients tia. ERPs are therefore sometimes helpful in making this with clinical evidence of only one lesion, the electro- distinction when there is clinical uncertainty, although a physiologic recognition of abnormalities in other sites response of normal latency does not exclude dementia. helps to suggest or support the diagnosis but does not establish it unequivocally. Multimodality EP abnormali- Motor Evoked Potentials ties are not specific for multiple sclerosis (MS); they may occur in AIDS, Lyme disease, systemic lupus erythe- The electrical potentials recorded from muscle or the matosus, neurosyphilis, spinocerebellar degenerations, spinal cord following stimulation of the motor cortex or familial spastic paraplegia, and deficiency of vitamin E central motor pathways are referred to as motor evoked or B12, among other disorders. The diagnostic utility of potentials. For clinical purposes such responses are the electrophysiologic findings therefore depends on the recorded most often as the compound muscle action circumstances in which they are found. Abnormalities potentials elicited by transcutaneous magnetic stimula- may aid in the localization of lesions to broad areas of tion of the motor cortex. A strong but brief magnetic the CNS, but attempts at precise localization on electro- field is produced by passing a current through a coil, and physiologic grounds are misleading because the genera- this induces stimulating currents in the subjacent neural tors of many components of the EP are unknown. tissue. The procedure is painless and apparently safe. The EP findings are sometimes of prognostic rele- Abnormalities have been described in several neurologic vance. Bilateral loss of SEP components that are gener- disorders with clinical or subclinical involvement of ated in the cerebral cortex implies that cognition may central motor pathways, including MS and motor neu- not be regained in posttraumatic or postanoxic coma, ron disease. In addition to a possible role in the diagnosis and EP studies may also be useful in evaluating patients of neurologic disorders or in evaluating the extent of with suspected brain death. In patients who are comatose pathologic involvement, the technique provides infor- for uncertain reasons, preserved BAEPs suggest either a mation of prognostic relevance (e.g., in suggesting the metabolic-toxic etiology or bihemispheric disease. In likelihood of recovery of motor function after stroke) patients with spinal cord injuries, SEPs have been used to and is useful as a means of monitoring intraoperatively indicate the completeness of the lesion. The presence or the functional integrity of central motor tracts. early return of a cortically generated response to stimula- tion of a nerve below the injured segment of the cord ELECTROPHYSIOLOGIC STUDIES indicates an incomplete lesion and thus a better progno- OF MUSCLE AND NERVE sis for functional recovery than otherwise. In surgery, intraoperative EP monitoring of neural structures placed The motor unit is the basic element subserving motor at risk by the procedure may permit the early recogni- function. It is defined as an anterior horn cell, its axon tion of dysfunction and thereby permit a neurologic and neuromuscular junctions, and all the muscle fibers complication to be averted or minimized. innervated by the axon.The number of motor units in a Visual and auditory acuity may be determined using EP muscle ranges from approximately 10 in the extraocular techniques in patients whose age or mental state precludes muscles to several thousand in the large muscles of the traditional ophthalmologic or audiologic examinations. legs.There is considerable variation in the average num- ber of muscle fibers within the motor units of an indi- Cognitive Evoked Potentials vidual muscle, i.e., in the innervation ratio of different muscles.Thus the innervation ratio is <25 in the human Certain EP components depend on the mental attention external rectus or platysma muscle and between 1600 of the subject and the setting in which the stimulus occurs, and 1700 in the medial head of the gastrocnemius mus- rather than simply on the physical characteristics of the cle. The muscle fibers of individual motor units are stimulus. Such “event-related” potentials (ERPs) or divided into two general types by distinctive contractile “endogenous” potentials are related in some manner to properties, histochemical stains, and characteristic the cognitive aspects of distinguishing an infrequently responses to fatigue. Within each motor unit, all of the occurring target stimulus from other stimuli occurring muscle fibers are of the same type. more frequently. For clinical purposes, attention has been directed particularly at the so-called P3 compo- ELECTROMYOGRAPHY nent of the ERP, which is also designated the P300 component because of its positive polarity and latency The pattern of electrical activity in muscle [i.e., the of approximately 300–400 ms after onset of an auditory electromyogram (EMG)], both at rest and during activ- target stimulus. The P3 component is prolonged in ity, may be recorded from a needle electrode inserted

A 100 μV recorded (Fig. 3-3). The parameters of normal motor 29 CHAPTER 3 Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG unit action potentials depend on the muscle under study 10 ms and age of the patient, but their duration is normally between 5 and 15 ms, amplitude is between 200 μV and B 100 μV 2 mV, and most are bi- or triphasic.The number of units activated depends on the degree of voluntary activity. An 100 ms increase in muscle contraction is associated with an increase in the number of motor units that are activated 100 μV (recruited) and in the frequency with which they dis- charge.With a full contraction, so many motor units are C DE normally activated that individual motor unit action potentials can no longer be distinguished, and a com- 10 ms plete interference pattern is said to have been produced. FIGURE 3-3 The incidence of small, short-duration, polyphasic Activity recorded during EMG. A. Spontaneous fibrillation motor unit action potentials (i.e., having more than four potentials and positive sharp waves. B. Complex repetitive phases) is usually increased in myopathic muscle, and an discharges recorded in partially denervated muscle at rest. excessive number of units is activated for a specified C. Normal triphasic motor unit action potential. D. Small, degree of voluntary activity. By contrast, the loss of short-duration, polyphasic motor unit action potential such motor units that occurs in neuropathic disorders leads to as is commonly encountered in myopathic disorders. E. Long- a reduction in number of units activated during a maxi- duration polyphasic motor unit action potential such as may mal contraction and an increase in their firing rate, i.e., be seen in neuropathic disorders. there is an incomplete or reduced interference pattern. The configuration and dimensions of the potentials may into the muscle.The nature and pattern of abnormalities also be abnormal, depending on the duration of the relate to disorders at different levels of the motor unit. neuropathic process and on whether reinnervation has occurred.The surviving motor units are initially normal Relaxed muscle normally is electrically silent except in configuration but, as reinnervation occurs, they in the end plate region, but abnormal spontaneous increase in amplitude and duration and become activity (Fig. 3-3) occurs in various neuromuscular dis- polyphasic (Fig. 3-3). orders, especially those associated with denervation or inflammatory changes in affected muscle. Fibrillation Action potentials from the same motor unit some- potentials and positive sharp waves (which reflect mus- times fire with a consistent temporal relationship to each cle fiber irritability) and complex repetitive discharges other, so that double, triple, or multiple discharges are are most often—but not always—found in denervated recorded, especially in tetany, hemifacial spasm, or muscle and may also occur after muscle injury and in myokymia. certain myopathic disorders, especially inflammatory dis- orders such as polymyositis. After an acute neuropathic Electrical silence characterizes the involuntary, sus- lesion, they are found earlier in proximal rather than dis- tained muscle contraction that occurs in phosphorylase tal muscles and sometimes do not develop distally in the deficiency, which is designated a contracture. extremities for 4–6 weeks; once present, they may persist indefinitely unless reinnervation occurs or the muscle EMG enables disorders of the motor units to be degenerates so completely that no viable tissue remains. detected and characterized as either neurogenic or myo- Fasciculation potentials (which reflect the spontaneous pathic. In neurogenic disorders, the pattern of affected activity of individual motor units) are characteristic of muscles may localize the lesion to the anterior horn slowly progressive neuropathic disorders, especially those cells or to a specific site as the axons traverse a nerve with degeneration of anterior horn cells (such as amy- root, limb plexus, and peripheral nerve to their terminal otrophic lateral sclerosis). Myotonic discharges—high- arborizations.The findings do not enable a specific etio- frequency discharges of potentials derived from single logic diagnosis to be made, however, except in conjunc- muscle fibers that wax and wane in amplitude and tion with the clinical findings and results of other labo- frequency—are the signature of myotonic disorders such ratory studies. as myotonic dystrophy or myotonia congenita but occur occasionally in polymyositis or other, rarer, disorders. The findings may provide a guide to the severity of an acute disorder of a peripheral or cranial nerve (by Slight voluntary contraction of a muscle leads to acti- indicating whether denervation has occurred and the vation of a small number of motor units. The potentials completeness of the lesion) and whether the pathologic generated by any muscle fibers of these units that are process is active or progressive in chronic or degenera- within the pick-up range of the needle electrode will be tive disorders such as amyotrophic lateral sclerosis. Such information is important for prognostic purposes. Various quantitative EMG approaches have been developed.The most common is to determine the mean

SECTION I Introduction to Neurology30 duration and amplitude of 20 motor unit action poten- studies are performed by determining the conduction tials using a standardized technique. The technique of velocity and amplitude of action potentials in sensory macro-EMG provides information about the number fibers when these fibers are stimulated at one point and and size of muscle fibers in a larger volume of the motor the responses are recorded at another point along the unit territory and has also been used to estimate the course of the nerve. In adults, conduction velocity in the number of motor units in a muscle. Scanning EMG is a arms is normally between 50 and 70 m/s, and in the legs computer-based technique that has been used to study is between 40 and 60 m/s. the topography of motor unit action potentials and, in particular, the spatial and temporal distribution of activ- Nerve conduction studies complement the EMG ity in individual units. The technique of single-fiber examination, enabling the presence and extent of EMG is discussed separately later. peripheral nerve pathology to be determined. They are particularly helpful in determining whether sensory Nerve Conduction Studies symptoms are arising from pathology proximal or distal to the dorsal root ganglia (in the former instance, Recording of the electrical response of a muscle to peripheral sensory conduction studies will be normal) stimulation of its motor nerve at two or more points and whether neuromuscular dysfunction relates to along its course (Fig. 3-4) permits conduction velocity peripheral nerve disease. In patients with a mononeu- to be determined in the fastest-conducting motor fibers ropathy, they are invaluable as a means of localizing a between the points of stimulation.The latency and ampli- focal lesion, determining the extent and severity of the tude of the electrical response of muscle (i.e., of the underlying pathology, providing a guide to prognosis, compound muscle action potential) to stimulation of its and detecting subclinical involvement of other periph- motor nerve at a distal site are also compared with values eral nerves. They enable a polyneuropathy to be distin- defined in normal subjects. Sensory nerve conduction guished from a mononeuropathy multiplex when this is not possible clinically, an important distinction because Recording Ground of the etiologic implications. Nerve conduction studies electrodes provide a means of following the progression and thera- peutic response of peripheral nerve disorders and are Reference being used increasingly for this purpose in clinical trials. Active They may suggest the underlying pathologic basis in Cathode individual cases. Conduction velocity is often markedly Anode slowed, terminal motor latencies are prolonged, and compound motor and sensory nerve action potentials Stimulating Stimulating may be dispersed in the demyelinative neuropathies electrodes electrodes (such as in Guillain-Barré syndrome, chronic inflamma- tory polyneuropathy, metachromatic leukodystrophy, or Stimulation certain hereditary neuropathies); conduction block is site frequent in acquired varieties of these neuropathies. By contrast, conduction velocity is normal or slowed only Wrist mildly, sensory nerve action potentials are small or absent, and there is EMG evidence of denervation in Below axonal neuropathies such as occur in association with elbow metabolic or toxic disorders. Above The utility and complementary role of EMG and elbow nerve conduction studies are best illustrated by reference to a common clinical problem. Numbness and paresthe- Axilla 5 mV sia of the little finger and associated wasting of the intrinsic muscles of the hand may result from a spinal 10 ms cord lesion, C8/T1 radiculopathy, brachial plexopathy (lower trunk or medial cord), or a lesion of the ulnar FIGURE 3-4 nerve. If sensory nerve action potentials can be recorded Arrangement for motor conduction studies of the ulnar nerve. normally at the wrist following stimulation of the digital Responses are recorded with a surface electrode from the fibers in the affected finger, the pathology is probably abductor digiti minimi muscle to supramaximal stimulation of proximal to the dorsal root ganglia, i.e., there is a radicu- the nerve at different sites, and are shown in the lower panel. lopathy or more central lesion; absence of the sensory (From Aminoff, 1998.) potentials, by contrast, suggests distal pathology. EMG examination will indicate whether the pattern of affected muscles conforms to radicular or ulnar nerve

territory, or is more extensive (thereby favoring a plex- stimulation of a motor nerve at 2–3 Hz with stimuli 31 CHAPTER 3 Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG opathy). Ulnar motor conduction studies will generally delivered at intervals after voluntary contraction of the also distinguish between a radiculopathy (normal find- muscle for about 20–30 s, even though preceding activ- ings) and ulnar neuropathy (abnormal findings) and will ity in the junctional region influences the release of often identify the site of an ulnar nerve lesion: the nerve acetylcholine and thus the size of the end plate poten- is stimulated at several points along its course to deter- tials elicited by a test stimulus. This is because more mine whether the compound action potential recorded acetylcholine is normally released than is required to from a distal muscle that it supplies shows a marked bring the motor end plate potentials to the threshold for alteration in size or area or a disproportionate change in generating muscle fiber action potentials. In disorders of latency, with stimulation at a particular site.The electro- neuromuscular transmission this safety factor is reduced. physiologic findings thus permit a definitive diagnosis to Thus in myasthenia gravis, repetitive stimulation, partic- be made and specific treatment instituted in circum- ularly at a rate of between 2 and 5 Hz, may lead to a stances where there is clinical ambiguity. depression of neuromuscular transmission, with a decre- ment in size of the response recorded from affected F Wave Studies muscles. Similarly, immediately after a period of maxi- mal voluntary activity, single or repetitive stimuli of the Stimulation of a motor nerve causes impulses to travel motor nerve may elicit larger muscle responses than antidromically (i.e., toward the spinal cord) as well as before, indicating that more muscle fibers are respond- orthodromically (to the nerve terminals). Such antidromic ing. This postactivation facilitation of neuromuscular impulses cause a few of the anterior horn cells to dis- transmission is followed by a longer-lasting period of charge, producing a small motor response that occurs depression, maximal between 2 and 4 min after the con- considerably later than the direct response elicited by nerve ditioning period and lasting for as long as 10 min or so, stimulation.The F wave so elicited is sometimes abnormal during which responses are reduced in size. (absent or delayed) with proximal pathology of the periph- eral nervous system, such as a radiculopathy, and may Decrementing responses to repetitive stimulation at therefore be helpful in detecting abnormalities when 2–5 Hz are common in myasthenia gravis but may also conventional nerve conduction studies are normal. In occur in the congenital myasthenic syndromes. In general, however, the clinical utility of F wave studies has Lambert-Eaton myasthenic syndrome, in which there is been disappointing, except perhaps in Guillain-Barré defective release of acetylcholine at the neuromuscular syndrome, where they are often absent or delayed. junction, the compound muscle action potential elicited by a single stimulus is generally very small. With repeti- H Reflex Studies tive stimulation at rates of up to 10 Hz, the first few responses may decline in size, but subsequent responses The H reflex is easily recorded only from the soleus mus- increase. If faster rates of stimulation are used (20–50 Hz), cle (S1) in normal adults. It is elicited by low-intensity the increment may be dramatic so that the amplitude of stimulation of the tibial nerve and represents a monosy- compound muscle action potentials eventually reaches a naptic reflex in which spindle (Ia) afferent fibers consti- size that is several times larger than the initial response. tute the afferent arc and alpha motor axons the efferent In patients with botulism, the response to repetitive pathway. The H reflexes are often absent bilaterally in stimulation is similar to that in Lambert-Eaton syn- elderly patients or with polyneuropathies and may be drome, although the findings are somewhat more vari- lost unilaterally in S1 radiculopathies. able and not all muscles are affected. Muscle Response to Repetitive Single-Fiber Electromyography Nerve Stimulation This technique is particularly helpful in detecting disor- The size of the electrical response of a muscle to supra- ders of neuromuscular transmission. A special needle maximal electrical stimulation of its motor nerve relates electrode is placed within a muscle and positioned to to the number of muscle fibers that are activated. Neu- record action potentials from two muscle fibers belong- romuscular transmission can be tested by several differ- ing to the same motor unit. The time interval between ent protocols, but the most helpful is to record with sur- the two potentials will vary in consecutive discharges; face electrodes the electrical response of a muscle to this is called the neuromuscular jitter. The jitter can be supramaximal stimulation of its motor nerve by repeti- quantified as the mean difference between consecutive tive (2–3 Hz) shocks delivered before and at selected interpotential intervals and is normally between 10 and intervals after a maximal voluntary contraction. 50 μs.This value is increased when neuromuscular trans- mission is disturbed for any reason, and in some There is normally little or no change in size of the instances impulses in individual muscle fibers may fail to compound muscle action potential following repetitive occur because of impulse blocking at the neuromuscular