Nerve Biopsy Rarely Is a Helpful Diagnostic Procedure 17 Peter D

Cr o ssfi r e : C o n t r o v e r si e s i n Ne u r o m u sc u l a r a n d El e ct r o d i a g n o stic Me d ici n e

Steve R. Geiringer, MD Robert A. Werner, MD, MS P. James B. Dyck, MD Peter D. Donofrio, MD Zachary Simmons, MD Lisa S. Krivickas, MD

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2007 AANEM Course H

AANEM 54thAnnual Meeting Phoenix, Arizona American of Association Neuromuscular & Electrodiagnostic Medicine

Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine

Steve R. Geiringer, MD Robert A. Werner, MD, MS P. James B. Dyck, MD Peter D. Donofrio, MD Zachary Simmons, MD Lisa S. Krivickas, MD

2007 COURSE H AANEM 54th Annual Meeting Phoenix, Arizona

Pr i n t e d b y Jo h n s o n Pr i n t i n g Co m p a n y , In c . ii Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine

Faculty Steve R. Geiringer, MD P. James B. Dyck, MD Clinical Professor Associate Professor Department of Physical Medicine and Rehabilitation Department of Neurology Wayne State University Mayo Clinic College of Medicine Westland, Michigan Rochester, Minnesota Dr. Geiringer graduated from medical school and physical medicine and Dr. Dyck is a consultant in neurology at Mayo Clinic Rochester, and is an rehabilitation (PMR) residency training at the University of Michigan associate professor of neurology at the Mayo Clinic College of Medicine. Medical School in Ann Arbor. He spent 9 years as faculty there before Dr. Dyck received his medical degree from the University of Minnesota; moving to the Wayne State University School of Medicine in 1991, where performed a neurology residency at Washington University in St. Louis; he remains as a clinical professor. Dr. Geiringer’s solo clinical practice is and performed peripheral nerve, electromyography (EMG), and research devoted to acute and subacute musculoskeletal medicine and electrodi- fellowships at the Mayo Clinic, where he he joined the neurology faculty agnostic medicine. He is a director of the American Board of PMR, and in 1999. Dr. Dyck is Director of the Peripheral Nerve Neuromuscular the chair of its Credentials Committee. He also serves as the chair of the Pathology Laboratory; the head of the peripheral nerve section; and a Medical Education committee for the American Academy of PMR, which board member of the United Council of Neurologic Subspecialties. He re- oversees all educational efforts of that organization. Dr. Geiringer’s hand- ceives research support from a National Institute of Neurological Disorders book, Anatomic Localization in Needle Electromyography, is used worldwide, and Stroke grant. His main research interest has focused on the histopa- and he has lectured extensively on that and other topics comprising the thology of nerve in diabetic and nondiabetic lumbosacral radiculoplexus realm of his practice. neuropathy. He has helped describe the peripheral neuropathies associated with bariatric surgery, and a newly recognized form of sensory chronic inflammatory demyelinating polyneuropathy. In a multidisciplinary Robert A. Werner, MD, MS approach, Dr. Dyck has pioneered the use of high-resolution magnetic Professor resonance imaging to identify focal or multifocal nerve lesions in proximal nerves (nerve root, plexus, or proximal nerve), that are then biopsied to Department of Physical Medicine and Rehabilitation identify the histopathology. This targeted fascicular nerve biopsy approach Ann Arbor VA Medical Center improves the physician’s ability to detect, characterize, and treat focal nerve Ann Arbor, Michigan lesions of proximal nerves and represents a major new advance in diagnosis Dr. Werner is a professor in the Department of Physical Medicine and and management. Rehabilitation and Chief of the Physical Medicine and Rehabilitation service at the Ann Arbor Veteran's Adminstration (VA) Medical Center. He also has a faculty appointment in Occupational Medicine within the School of Public Health and in the Center for Ergonomics within Industrial and Operations Engineering. He is a 1983 graduate of the University of Connecticut's School of Medicine and completed his physical medicine and rehabilitation residency at the University of Michigan Medical Center. He completed a research fellowship sponsored through the National Institute on Disability and Rehabilitation Research in 1991. Dr. Werner’s interests include electromyography, pain management, and industrial rehabilitation. Dr. Werner is Co-director of the Ann Arbor VA Chronic Pain Clinic. He has over 70 publications in peer-reviewed jour- nals and has been successful in receiving grant funding from several sources including the National Institute of Health, the Center for Disease Control, the National Institute for Occupational Safety and Health, Johns Hopkins University Center for Visual Display Terminals and Health Research, and the United States Postal Service. Dr. Werner has received awards for research writing from the Association of Academic Physiatrists, the American Academy of PM&R and the American College of Occupational and Environmental Medicine. Dr. Werner is on the editorial board for Archives of Physical Medicine and Rehabilitation, Muscle & Nerve, Journal of Occupational Rehabilitation, and Topics in Stroke Rehabilitation. Course Chair: Zachary Simmons, MD

The ideas and opinions expressed in this publication are solely those of the specific authors and do not necessarily represent those of the AANEM. iii

Peter D. Donofrio, MD Lisa S. Krivickas, MD Professor Associate Professor Department of Neurology Department of Physical Medicine and Rehabilitation Chief Harvard Medical School Neuromuscular Section Boston, Massachusetts Vanderbilt University Dr. Krivickas is Associate Professor of Physical Medicine and Nashville, Tennessee Rehabilitation (PMR) at Harvard Medical School, Associate Chief of Dr. Donofrio is a graduate of The Ohio State University School of PMR at Massachusetts General Hospital, and Director of EMG at Medicine. He completed a medicine residency at Good Samaritan Spaulding Rehabilitation Hospital. She received her medical degree from Hospital in Cincinnati, Ohio, and a neurology residency and neuro- Harvard Medical School. She completed a residency in PMR at the muscular fellowship at the University of Michigan. After several years University of Medicine and Dentistry, New Jersey, New Jersey Medical on the faculty at the University of Michigan, he moved to Wake Forest School and Kessler Institute of Rehabilitation, and a fellowship in EMG University where he remained for 20 years before moving to Vanderbilt and neuromuscular disease at the Cleveland Clinic. Dr. Krivickas’ current University Medical Center in 2006. He is Professor of Neurology and research involves the study of muscle physiology in neuromuscular disor- Chief of the Neuromuscular Section, the EMG Laboratory, the Muscular ders and aging, investigation of new electrophysiologic techniques for the Dystrophy Aassociation Clinic, and the Amyolateral Sclerosis (ALS) Clinic assessment of neuromuscular disorders, and clinical trials for amyotrophic at Vanderbilt. His research interests included clinical trials in ALS, inflam- lateral sclerosis, and other neuromuscular diseases. She is a director on matory neuropathies, and electrodiagnosis of peripheral neuropathy. Dr. the American Board of Electrodiagnostic Medicine and a member of Donofrio has served on the Board of Directors of the AANEM and is the Neuromuscular Medicine Examination Committee of the American currently President-elect of the organization. Board of Psychiatry and Neurology. In 2006, she received the Young Academician Award from the Association of Academic Physiatrists. Zachary Simmons, MD Professor Department of Neurology Penn State University Director Neuromuscular Program and Clinical Neurophysiology Laboratory Penn State Hershey Medical Center Hershey, Pennsylvania Dr. Simmons received his medical degree from the University of Florida, and then trained in neurology at the University of Iowa, and in neuromuscular diseases and electromyography at the University of Michigan. He now serves as Professor of Neurology at Penn State Hershey Medical Center, where he is Director of the Neuromuscular Program, the Muscular Dystrophy Association Clinic, and the Clinical Neurophysiology Laboratory. He founded and directs the Hershey Medical Center Amyotrophic Lateral Sclerosis (ALS) Clinic, an ALS Association-certified center of excellence. Active ALS clinical research programs under his supervision include studies of quality of life, cognitive function, and the development of evidence-based practice protocols. Dr. Simmons has served on the AANEM Training Program, Workshop, and Program Committees, has been chair of the ABEM Maintenance of Certification Committee, and is currently the chair of the ABEM Authors had nothing to disclose. Examination Committee.

Please be aware that some of the medical devices or pharmaceuticals discussed in this handout may not be cleared by the FDA or cleared by the FDA for the specific use described by the authors and are “off-label” (i.e., a use not described on the product’s label). “Off-label” devices or pharmaceuticals may be used if, in the judgement of the treating physician, such use is medically indicated to treat a patient’s condition. Information regarding the FDA clearance status of a particular device or pharmaceutical may be obtained by reading the product’s package labeling, by contacting a sales representative or legal counsel of the manufacturer of the device or pharmaceutical, or by contacting the FDA at 1-800-638-2041. iv v Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine

Contents

Faculty ii

Objectives iii

Preactivity Questions vii

Course Committee viii

Carpal Tunnel Syndrome Usually is Occupationally Related 1 Steve R. Geiringer, MD

Carpal Tunnel Syndrome Usually is Not Occupationally Related 5 Robert A. Werner, MD, MS

Nerve Biopsy Often is a Helpful Diagnostic Procedure 11 P. James B. Dyck, MD

Nerve Biopsy Rarely is a Helpful Diagnostic Procedure 17 Peter D. Donofrio, MD

Electrodiagnostic Studies Generally are Helpful in the Evaluation of Patients 21 With Weakness and Normal Neurological Examinations Zachary Simmons, MD

Electrodiagnostic Studies Generally are not Helpful in the Evaluation of Patients 27 With Weakness and Normal Neurological Examinations Lisa S. Krivickas, MD

Activity and Faculty Evaluation 33

CME Self-Assessment Test 35

O b j e c t i v e s —After attending this course, participants will develop an understanding of, and be able to incorporate into their practice, arguments in favor of and against the following: (1) the classification of carpal tunnel syndrome as an occupationally related disorder; (2) the use of nerve biopsy as a diagnostic procedure; and (3) the use of electrodiagnostic studies for the evaluation of patients with symptoms of generalized weakness. P rerequisite —This course is designed as an educational opportunity for residents, fellows, and practicing clinical EDX physicians at an early point in their career, or for more senior EDX practitioners who are seeking a pragmatic review of basic clinical and EDX principles. It is open only to persons with an MD, DO, DVM, DDS, or foreign equivalent degree. A c c r e d i t a t i o n St a t e m e n t —The AANEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. CME Cr e d i t —The AANEM is accredited by the ACCME to provide continuing medical education (CME) for physicians. The AANEM designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s) TM. Each physician should only claim credit commensurate with the extent of their participation in the activity. This event is an Accredited Group Learning Activity as defined by the Maintenance of Certification Program of The Royal College of Physicians and Surgeons of Canada. CME for this activity is available 10/07 - 10/10. vi AANEM Course AANEM Course vii

Pre-activity Questions

BEFORE YOU BEGIN THIS ACTIVITY

We need your feedback in order to improve future educational activities.

On the scantron sheet provided, please rate how important each of the following aspects of the CME activity are to you using this scale:

A. Extremely

B. Somewhat Instructions for C. Very Little filling out your parSCORE D. Not at all sheet It is important that the CME activity: Using a #2 pencil, fill in your answers 1. Address my most pressing questions. beginning with question #1. 2. Address competencies identified by my specialty.

3. Provide fair and balanced content. After completion of this activity, go to the 4. Provide clear evidence to support content. back of the book and fill in your answers 5. Include opportunities to learn interactively from faculty and par- beginning with ques- ticipants. tion #10. 6. Provide me with supporting materials or tools for my office (re-

minders, patient materials, etc.). here Fill in answers

7. Include opportunities to solve patient cases.

8. Translate trial data to patients I see in my practice.

9. Address barriers to my optimal patient management.

Complete the questions at the back of the book following this activity. viii

2006-2007 AANEM COURSE COMMITTEE Anthony E. Chiodo, MD, Chair Ann Arbor, Michigan

Thomas Hyatt Brannagan, III, MD Subhadra Nori, MD Simon Zimnowodzki, MD New York, New York Bronx, New York Chicago, Illinois

Brian A. Crum, MD Thomas Y.C. Pang, MD Sasa Zivkovic, MD Rochester, Minnesota Chicago, Illinois Pittsburgh, Pennsylvania

Erick A. Grana, MD T. Darrell Thomas, MD Tampa, Florida Knoxville, Tennessee

2006-2007 AANEM PRESIDENT Kathryn A. Stolp, MD, MS Rochester, Minnesota Carpal Tunnel Syndrome Usually Is Occupationally Related

Steve R. Geiringer, MD Clinical Professor Department of Physical Medicine and Rehabilitation Wayne State University Westland, Michigan

INTRODUCTION would conclude, the nonsymptomatic hand would show normal NCS results. It is commonly held knowledge that carpal tunnel syndrome (CTS) is the most prevalent of all entrapment neuropathies. It is by far the The flaw in this argument also should be common knowledge. It most common condition encountered by electrodiagnostic (EDX) is well known that the entrapment syndrome is often unilaterally physicians across the country, and any argument otherwise would symptomatic. Up to 80% of contralateral hands will show conduc- be widely seen as nonsense. tion abnormalities; however, in nearly all cases, the dominant hand becomes symptomatic. In this author’s experience, the exceptional It is also universally accepted that there are myriad intrinsic predis- cases arise because the nondominant hand happens to be doing the posing factors for CTS. Chief among these are pregnancy, obesity, lion’s share of the offending activity that led to the CTS. An inher- smoking, diabetes, female gender, and being a postmenopausal ent component of this is the difference between an entrapment woman. None of these predisposing factors would appear to be in neuropathy that one can detect with careful NCSs and a clinically dispute. relevant syndrome.

Based on informal conversations among peers, a thorough literature review, and this author’s 25 years of experience with electrodiagno- RELEVANCE OF WORK-RELATEDNESS sis in the realm of musculoskeletal medicine, it is widely accepted that CTS is often related to ergonomic and exposure factors in the Why does it matter whether or not CTS is actually related to work work place. These include forceful gripping, direct pressure applied activities? There are several important reasons; the first is how to to the carpal ligament area at the heel of the palm, vibration expo- treat it. There are different treatment recommendations depending sure, and exposure to cold temperatures, especially when one or any on the patient’s work activities, but if the CTS was not work-re- combination of the above occurs in repetitive fashion. lated, there would be no need for work modifications (e.g., impact gloves or restricted duty). Treatment responsibility is another factor. Why, then, is there a debate about whether CTS is work-related? The Worker’s Compensation system would not be responsible for This author has seen reports from “defense” physicians who are the patient’s CTS if there were no relationship between CTS and typically part of an independent medical evaluation that attempt the patient’s work. Instead, the patient’s sickness and accident to make the counterargument. The most common tack is to dem- insurance would be responsible. However, in some jurisdictions, onstrate, through the use of nerve conduction studies (NCSs), that the line is blurred. For example, in Michigan, if an employee a worker with median entrapment symptoms on one side only has with preexisting CTS and a history of diabetes has their CTS ag- bilateral electrical abnormalities. Using this line of reasoning, the gravated by work activities, the employer is responsible for 100% patient has a preexisting, nonwork-related condition on both sides. of the treatment until the employee returns to preinjury baseline. If the patient’s CTS is in fact work-related, as the defense physician Financially, if an employee required time off from work for CTS 2 CTS Usually is Occupationally Related AANEM Course treatment, he or she would not be eligible (in typical scenarios) for concluded, most with no uncertainty, that in some patients CTS extensive (if any) medical and/or lost wage benefits if the CTS was is definitely work-related. Of course, there might also be personal not work-related. Finally, if the patient’s CTS was not work-related, or intrinsic factors, as noted earlier. These studies included the fol- this author speculates there would be little incentive for employers lowing occupations: to study the ergonomics of offending jobs, tools, or postures in order to prevent the condition. • Video-display terminal operators • Clerical • Television assembly LITERATURE REVIEW • Auto assembly • Manufacturing/assembly As of June 2007, there were more than 6000 articles found on a • Grocery workers PubMed literature search conducted for “carpal tunnel syndrome” • Typists (no limits were attached to this search). After adding search limits • Meat/fish processors for the “English language” and “human studies only”, 75% of • Operators of orbital sanders those articles remained. After adding the criterion of a random- • Cashiers ized, controlled trial, only 158 articles remained. The remaining • Dental hygienists articles cover comparisons among surgical techniques, comparisons between operative and nonoperative treatments, the effect of yoga and CTS, the effectiveness of chiropractic treatment, those EDX Apart from the 20 citations just covered, 2 articles8,18 raised doubt techniques that correlated best with surgical outcomes, and the about the otherwise widely accepted conclusion that CTS can arise use of different anesthetics, corticosteroids, and/or the number of from job factors. Both of these articles were published by Australian injections of each of these materials. authors in the Australia New Zealand Journal of Surgery. One article is single-authored by a medicolegal consultant who is clear What will not be found is even one article categorized as random- about his preconceived notion that CTS only arises from personal ized and controlled that pertains to whether CTS is work-related. factors.18 The first author of the other article8 is a government When searching for “carpal tunnel syndrome work-related,” five employee in New South Wales. The only work factor he allows as articles are found and none address the primary issue of work- a factor leading to CTS is prolonged exposure to extreme cold, as relatedness. The only two that come close compare the ergonomics with butchers. Otherwise, he concludes that resources are inap- of different handles for dental tools. propriately allocated, because no other work factors are primary causes of CTS. He does allow that the other job components men- When one searches for “CTS work-related” and limits on the type tioned earlier could be the “last straw” in the course of CTS, but of article are removed, 183 articles result. All anecdotal and case it never occurs without some predisposing factor that is personal reports were then removed, as well as all publications that did not in nature. directly address the issue currently under debate—which unfortunately comprised the great majority. The outcome was 20 articles; What follows is a passage from the abstract of one of the articles in some were prospective in design, some had controls, and none were support of CTS having work-related causes: “CTS is common in randomized or blinded.1-7,9-17,19-22 the industrial setting, but there are still some advocates who argue that CTS is not a work-related problem.” It concludes with “CTS Even this relatively small sample of articles led to some interesting has both work-related and personal risk factors.” This thoughtful, observations. For example, within these articles, the inclusion of useful article19 takes a common-sense, understandable, and defensi- patients as having verifiable CTS was based on: having had surgical ble approach, that while there are certainly personal contributors, it release; EDX testing (approximately 5 of the 21 articles); physical is quite clear that there are offending work-related factors as well. examination; “clinical” criteria, usually meaning typical symptoms; review of worker compensation records; review of medical notes; self-report from the patient; ergonomic information from the SUMMARY employer; or a combination of all of these factors (distressingly seldom). What has this exercise taught us? First, any attempt to identify literature that applies careful research criteria to the question of the Most of these articles started with an assumption, i.e., that it was a work-relatedness of CTS fails. There simply are no such studies, at “given” that CTS is work-related. So much for Cochrane criteria; least none that incorporate all or most of the design features this it is no wonder that careful research design is not found in this author would like to see. cohort of articles. The conclusions included that CTS is correlated with: number of years worked; repetitiveness of the job; vibration Having said that, consensus of expert opinion does qualify as one exposure; working full-time compared with part-time; ergonomic level of “evidence.” Nineteen of the 20 articles reviewed in this factors; and the “workload.” search concluded that CTS can be related to work factors, although not exclusively so. The lone dissenter was only equivocal—not One article that studied dental hygienists21 was equivocal about negative—on that question. The other articles lean more toward whether the CTS diagnosed was work-related. The other 19 articles “opinion pieces” or editorials that reflect the “conventional wisdom” AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 3 dictated by the authors’ employment situations. Overall, there is no 10. Giersiepen K, Eberle A, Pohlabein H. Gender differences in carpal disputing that expert consensus exists here: while personal factors tunnel syndrome? Occupational and non-occupational risk factors in are also pertinent, CTS is definitely work-related. a population-based case-control study. Ann Epidemiol 2000;10:481. 11. Kim JY, Kim JI, Son JE, Yun SK. Prevalence of carpal tunnel syndrome in meat and fish processing plants. J Occup Health 2004;46:230-234. REFERENCES 12. Lam N, Thurston A. Association of obesity, gender, age and occupation with carpal tunnel syndrome. ANZ J Surg 1998;68:190-193. 1. Abbas MA, Afifi AA, Zhang ZW, Kraus JF. Meta-analysis of pub- 13. Latko WA, Armstrong TJ, Franzblau A, Ulin SS, Werner RA, Albers lished studies of work-related carpal tunnel syndrome. Int J Occup JW. Cross-sectional study of the relationship between work and the Environ Health 1998;4:160-167. prevalence of upper limb musculoskeletal disorders. Am J Ind Med 2. Abbas MF, Faris RH, Harber PI, Mishriky AM, El-Shahaly HA, 1999;36:248-259. Waheeb YH, Kraus JF. Worksite and personal factors associated with 14. Matias AC, Salvendy G, Kuczek T. Predictive models of carpal carpal tunnel syndrome in an Egyptian electronics assembly factory. tunnel syndrome causation among VDT operators. Ergonomics Int J Occup Environ Health 2001;7:31-26. 1998;41:213-216. 3. Bekkelund SI, Pierre-Jerome C, Torbergsen T, Ingebrigtsen T. 15. Melchior M, Roquelaure Y, Evanoff B, Chastang JF, Ha C, Imbernon Impact of occupational variables in carpal tunnel syndrome. Acta E, and colleagues. Why are manual workers at high risk of upper limb Neurol Scand 2001;103:193-197. disorders? The role of physical work factors in a random sample of 4. Bonfiglioli R, Mattioli S, Fiorentini C, Graziosi F, Curti S, Violante workers in France (the Pays de la Loire study). Occup Environ Med FS. Relationship between repetitive work and the prevalence of 2006;63:754-761. carpal tunnel syndrome in part-time and full-time female supermar- 16. Nordstrom DL, Vierkant RA, DeStefano F, Layde PM. Risk factors ket cashiers: a quasi-experimental study. Int Arch Occup Environ for carpal tunnel syndrome in a general population. Occup Environ Health 2007;80:248-253. Med 1997;54:734-740. 5. Bonfiglioli R, Mattioli S, Spagnolo MR, Violante FS. Course of 17. Roquelaure Y, Ha C, Leclerc A, Touranchet A, Sauteron M, Melchior symptoms and median nerve conduction values in workers perform- M, and colleagues. Epidemiologic surveillance of upper-extremity ing repetitive jobs at risk for carpal tunnel syndrome. Occup Med musculoskeletal disorders in the working population. Arthritis (Lond) 2006;56:115-121. Rheum 2006;55:765-778. 6. Bovensi M, Della Vedova A, Nataletti P, Alessandrini B, Poian T. 18. Stapleton MJ. Occupation and carpal tunnel syndrome. ANZ J Surg Work-related disorders of the upper limb in female workers using 2006;76:494-496. orbital sanders. Int Arch Occup Environ Health 2005;78:303-310. 19. Werner RA. Evaluation of work-related carpal tunnel syndrome. J 7. Davis L, Wellman H, Punnett L. Surveillance of work-related carpal Occup Rehabil 2006;16:207-222. tunnel syndrome in Massachusetts, 1992-1997: a report from the 20. Werner RA, Franzblau A, Gell N, Hartigan AG, Ebersole M, Massachusetts Sentinel Event Notification System for Occupational Armstrong TJ. Incidence of carpal tunnel syndrome among auto- Risks (SENSOR). Am J Ind Med 2001;39:58-71. mobile assembly workers and assessment of risk factors. J Occup 8. Falkiner S, Myers S. When exactly can carpal tunnel syndrome be Environ Med 2005;47:1044-1050. considered work-related? ANZ J Surg 2002;72:204-209. 21. Werner RA, Hamann C, Franzblau A, Rodgers PA. Prevalence of 9. Gell N, Werner RA, Franzblau A Ulin SS, Armstrong TJ. A longi- carpal tunnel syndrome and upper extremity tendinitis among dental tudinal study of industrial and clerical workers: incidence of carpal hygienists. J Dent Hyg 2002;76:126-132. tunnel syndrome and assessment of risk factors. J Occup Rehabil 22. Yagev Y, Carel RS, Yagev R. Assessment of work-related risk factors 2005;15:47-55. for carpal tunnel syndrome. Isr Med Assoc J 2001;3:569-571. 4 AANEM Course 5

Carpal Tunnel Syndrome is Usually Not Occupationally Related

Robert A. Werner, MD, MS Chief Department of Physical Medicine and Rehabilitation Ann Arbor VAMC University of Michigan Health System Ann Arbor, Michigan

NON WORK-RELATED RISK FACTORS AND CTS Table 1 Nonbiomechanical Risk Factors for Carpal Tunnel Syndrome Multiple occupational risk factors have been proposed for carpal tunnel syndrome (CTS). Biomechanical factors such as repetition and force are thought to influence the development of CTS, but Medical Conditions: diabetes, rheumatoid arthritis, thyroid disease, growing numbers of investigators in Europe, Japan, and the United connective tissue disorders, vitamin B6 deficiency, pregnancy States are reporting associations between nonbiomechanical aspects Body Mass Index: Weight, Stature of work and CTS. Gender Wrist dimension/Anatomical size and shape of the carpal canal To fully understand the etiology of musculoskeletal disorders, it is important to examine physical and health-related factors intrinsic Age to the individual worker in addition to work-related biomechanical General conditioning: strength, aerobic conditioning and nonbiomechanical factors. For example, age, obesity, chronic Genetics illness, and anatomical variation all have been studied to evaluate their contribution to the development of musculoskeletal disease. This manuscript focuses on the nonbiomechanical factors, the per- Several investigators have suggested that CTS is a primary result of sonal characteristics of the worker, and the relative strength of the health habits and lifestyle and secondary to biomechanical stress.40- biomechanical versus personal characteristics. 45,58,59 Of the numerous personal co-factors reported, only a few have demonstrated a statistical significant association. In instances Personal Factors where the relative risk has been determined, attempts at modeling the disease based upon these factors have only explained a small There are many personal co-factors that have been related to the percentage of the variance. The same limitation can be stated re- development of CTS (Table 1). Obesity (body mass index [BMI]), garding the strength of work-related factors. When modeling the square wrist configuration, small carpal canal area, diabetes, as well incidence of CTS using both ergonomic and nonwork-related risk as several other connective tissue disorders and poor general fitness factors, the studies have not demonstrated a significant ergonomic have all been associated with higher prevalence of CTS. The ulti- risk factor. Those studies that have demonstrated a significant mate mechanism of injury is likely ischemia; therefore, anything work-related factor have consistently demonstrated that nonwork- that influences the health of the vascular system may compromise related factors explain an overwhelming majority of the variance in the soft tissues (e.g., nerve, muscle, and tendon). the model. 6 CTS Usually is Not Occupationally Related AANEM Course

The National Academy of Science reviewed the epidemiologic The biologic plausibility is moderate. However, the strength of evidence that nonmechanical factors were associated with CTS the relationship is weak, except in severe vitamin B6 deficiency and found strong epidemiologic evidence for a positive associa- (which is rare). The cross-sectional studies of active workers and tion between the development of CTS and increasing age, certain population-based studies are sound enough to claim that there is medical conditions, higher BMI, and gender. Other factors were not a significant relationship between B6 levels and CTS. less well-established (e.g., genetics, general conditioning, psychological issues, and wrist dimension).20 Pregnancy/Gynecologic History

Systemic Disorders Pregnancy is considered an independent risk factor (estimated RR of 2.5) for the development of CTS due to increased vasculature Many systemic disorders place an individual at higher risk for and interstitial fluids.30,36,52,54 These studies have adequate sample the development of soft tissue injuries. Diabetes and rheumatoid size and statistical analysis. This is a strong association with strong arthritis are the most obvious risk factors affecting the develop- biologic plausibility. Fortunately, this condition is time-limited and ment of overuse syndromes.2,4,54,55 Rheumatoid arthritis patients, there is usually resolution of symptoms at the end of the pregnancy as well as those with other connective tissue disorders, are at higher or shortly thereafter. risk for development of joint abnormalities as well as muscle and nerve injuries.54 Diabetes is known to be a risk factor for CTS and Both the use of oral contraceptives and gynecologic surgery have other compression mononeuropathies.2,54 Stevens and colleagues54 been hypothesized as risk factors for CTS based on epidemio- calculated a standardized morbidity ratio for rheumatoid arthritis logical data, but this has not been consistently identified as a risk (3.6), diabetes (2.3), and pregnancy (2.5). Thyroid disease and factor.11,14,51 The biological significance and rationale for this is kidney disease also have many connective tissue side effects placing not well-established, although increased interstitial fluid as a result the individual at higher risk for nerve injuries. Thyroid disease may of hormonal changes is a suggested mechanism. This is a weak as- also lead to muscle disease. Systemic disease causes the nerves to be sociation with modest biologic plausibility. These studies are large more susceptible to compression and ischemia. The biologic plau- cross-sectional studies with statistically significant findings in some sibility of this association is high and the association is strong, but of the studies, but the clinical significance is low. these disorders affect a small percentage of active workers. Atcheson and colleagues4 suggest that these disorders are more common Body Mass Index among workers diagnosed with CTS compared to other cumulative trauma disorders and may be under-recognized in the industrial Several investigators have reported that individuals with CTS were setting. The studies reviewed in this area use a methodology based heavier and shorter than the general population. Cannon and col- upon population-based data or large cross-sectional data. There is leagues11 noted that 27% of individuals (8 of 30) with CTS were little bias associated with sample selection and the statistics are ap- obese compared to 12% (11 of 90) in a control population; this propriate for the sample. difference did not reach statistical significance. Dieck and Kelsey15 found an increased prevalence of CTS within an adult female

Vitamin B6 population among individuals with short stature, greater weight, and recent weight gain. The BMI was significantly higher in the In 1973, Ellis and Presley17-19 suggested an association between CTS group (27 kg/m2 versus 25 kg/m2, p = 0.01). Vessey and col- 57 vitamin B6 deficiency and CTS. Over the next two decades, several leagues found that the risk for CTS among obese women was additional reports appeared which suggest that this association is double that of slender women. causal in many cases. The impact of these studies on physician understanding and treatment of CTS is substantial. Vitamin defi- Within an industrial population, Nathan and colleagues45 demon- ciency is mentioned in a prominent textbook of occupational medi- strated that a higher BMI was associated with a higher prevalence cine34 as a possible CTS risk factor, implying that such deficiency of median mononeuropathy. They found a relative risk of 4.1 for contributes to CTS among workers. obese individuals compared to slender individuals. This relationship was more pronounced in men (RR=5.1) than in women Unfortunately, the studies which demonstrate an association (RR=2.7). This study did have a number of methodological flaws of between vitamin B6 status and CTS usually include small numbers which the most prominent was an analysis by the number of hands of non-randomly selected subjects, frequently rely on nonstandard instead of by the number of patients in the study. The findings of or entirely subjective measures of outcome, and occasionally suffer Werner and colleagues58,60 support the hypothesis that individuals from serious design flaws. Recent prospective and population-based with a higher BMI are at increased risk for CTS. studies have not borne out this relationship.3,17-19,21,22,24,25,38 The recent population-based studies and large cross-sectional studies In terms of obesity, the pathophysiology that would explain this are without the selection bias of earlier studies and use appropriate relationship is not well understood. Letz and Gerr28 found the same statistical analysis. The recent study by Keniston and colleagues33 relationship between obesity and slow conduction of the median suggesting a relationship between vitamin B6 deficiency, vitamin C, nerve across the wrist in a large population-based study, but an and CTS (among women but not men) has methodological as well inverse relationship was found between obesity and other periph- as statistical flaws.24 eral nerve measures. The conduction velocity of the peroneal, sural, AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 7 and ulnar nerves all tended to improve among subjects who were The finding that women were more likely to have a higher more obese whereas only the median sensory nerve across the wrist prevalence of CTS than men is supported by population-based demonstrated slowing. The finding that BMI is correlated with studies54,55 but differs from the worker compensation-based data the median but not ulnar sensory distal latencies suggest that the on CTS reported by Franklin and colleagues.23 In the workplace, condition of obesity affects the nerves differently. The additional the risk for women is only 10%-20% higher than men as opposed finding that the difference in the latencies is more strongly corre- to 300% reported in population-based studies (Franklin and col- lated with BMI than the median latency alone further supports this leagues23; and Werner and colleagues60). It was believed that the contention. This large cross-sectional study of Vietnam veterans has carpal canal was smaller in women thus exposing them to more greater validity due to the large sample size (more than 6000) and compression of the median nerve. Further investigation of carpal the uniformity in electrodiagnostic testing. canal dimension among women has not demonstrated any relationship between CTS and canal dimensions (as discussed below). If a causal relationship between obesity and a slowing of median conduction across the wrist exists, it may relate to increased fatty Wrist Size and Carpal Tunnel Syndrome tissue within the carpal canal or to increased hydrostatic pressure throughout the carpal canal in obese individuals compared A narrow carpal canal, a squarer shape of the wrist, and a smaller to normal or slender individuals. The median nerve at the wrist sized hand have all been associated with a higher prevalence of is more compartmentalized than the ulnar, peroneal, or sural CTS.9,27,31,39,61 This is a moderately strong association with high nerves and may be subjected to compression due to fatty build-up biologic plausibility. within the carpal canal among obese individuals. Conversely, heavier individuals may simply place more mechanical stress on Several studies have demonstrated a relationship between a more their hands and wrists and thus place the median nerve at higher square shaped wrist and a finding of median mononeuropathy risk as opposed to some intrinsic change within the carpal canal. at the wrist,31,49 but this relationship was not confirmed by other The possible association between obesity and the development studies.60 The relationship described by Radecki49 was in a clinic of early type II diabetes may be a confounder, but is not related population of referred patients while the population studied by to the workers’ report of diabetes. Alternatively, thinner subjects Werner and colleagues60 was a random selection of active workers, may be a surrogate of a person’s overall conditioning which may regardless of symptoms. The pathophysiology of this association, if in turn influence the performance of the median nerve. Thinner it exists, has not been demonstrated. A squarer wrist has not been subjects may be healthier and thus their nerves are healthier and associated with a smaller cross-sectional area although this mecha- perform better when tested. Their thinness is not the important nism has been proposed. This is a relatively weak association with issue, health is the issue but they may be go hand in hand. There poor biologic plausibility. is a very strong association between obesity and the health of the median nerve. The more obese the patient, the worse the nerve Anomalous muscles extending into the carpal canal have been function. There appears to be a strong dose-response relation- reported as etiologies for CTS.6,7,10,12,46 Muscle variants implicated ship between obesity and nerve function: when one goes up, the include the muscle bellies of the flexor superficialis, palmaris other closely follows. Studies on obesity and median nerve health longus, lumbrical muscles, abductor digiti quinti, and the acces- are either case control or large cross-sectional studies with sound sory palmaris longus muscle. These are rare occurrences and do not statistical analysis. The biologic plausibility is still under question. account for the typical person with CTS. Likewise, there are other Whether this is based upon biomechanical or metabolic factors is space-occupying lesions such as lipoma, haemangioma, synovial not known. The pathophysiology that would explain this relation- sarcoma, tendon sheath fibroma, ganglion, or calcified mass that ship is not well understood. Although this is a strong relationship have been reported as etiologies of CTS, but these are also rare oc- with an apparent dose-response effect, this factor at best explains currences. This is a strong association with high biologic plausibil- only a small portion of the variance (less than 8%) related to the ity but again represents a rare anatomical variant.6,46 diagnosis of CTS or electrodiagnostic abnormalities involving the median nerve.41,45,58,60 Despite the small amount of the variance Aging and Carpal Tunnel Syndrome explained by obesity, the addition of work-related factors did not substantially improve the model. Nathan and colleagues41,42 did Increasing age has consistently been associated with slowing of the not find any significant work-related factor in their model while median nerve across the wrist and the incidence of CTS.16,35,45,53,58 Werner and colleagues60 found some independent ergonomic risk These studies have consistently demonstrated a strong association factors. However, these factors contributed little to the strength of with high biologic plausibility. Tissue repair declines with aging the model. and may be the basis for this relationship.

Gender General Fitness

Gender has been suggested as an independent risk factor for the There has been an association between lower exercise levels and a development of CTS.5,8,32,47,48,55,56 This risk factor is not well ex- higher prevalence of CTS as well as slowing of the median nerve plained although historically women had a higher use of the health across the carpal canal.43 Most studies demonstrate a close cor- care system and this may represent another spectrum of higher relation between poor general fitness with higher BMI, alcohol/ use. tobacco use, and age of the patient. Even when general fitness is 8 CTS Usually is Not Occupationally Related AANEM Course identified as a significant independent factor, it only accounts for tive model of factors that play a role in the development of CTS. a small component of the variance (3% or less). However, this is This prospective longitudinal study followed 432 workers over 5.4 as large an influence as most ergonomic factors have shown.43 The years. Incident cases were defined as workers who had no prior association between general fitness and CTS is modest, but it is still history of CTS at baseline testing and who were diagnosed with stronger than most independent ergonomic risk factors. CTS during the follow-up period or at the follow-up screening. Based on logistic regression, significant predictors for CTS in- Genetics cluded a baseline prolongation of the median-ulnar peak latency difference, a history of wrist/hand/finger tendonitis, a history of There are a limited number of studies that explore the relationship numbness, tingling, burning, and/or pain in the hand, and work between specific genetic markers and the incidence of CTS.13,50 It above the action level of the “peak force and hand activity level” is clear that genetics plays a role in the risks associated with gender, threshold limit value (TLV) (as defined by the American Congress obesity, carpal canal size, and several connective tissue disorders, of Government Industrial Hygienists).1 The majority of the vari- but apart from these relationships, the role of genetics in the ance explained came from the nonwork-related risk factors. The etiology of CTS is not well-established. Radecki50 demonstrated peak force/hand activity level threshold explained a minimum of a higher prevalence of carpal canal surgery or clinical history of the model variance. CTS among family members with a documented slowing of the median nerve at the wrist compared to the families of other pa- Werner and colleagues59 reported a longitudinal study of workers tients without slowing of the median nerve. There were 27% of from an auto assembly plant in the southern United States. Of subjects with a documented median mononeuropathy who had a the 1700 assembly plant workers, 475 agreed to participate in the positive family history of CTS compared to 13% without evidence study, but only 279 subjects completed the initial detailed symptom of median mononeuropathy (p<0.001). The familial occurrence of questionnaire and sensory nerve conduction studies. There were CTS has usually been reported as one or two families involving two 189 workers who completed the 13-month follow-up evaluation. or three generations. An autosomal dominant inheritance has been This study identified diabetes as a significant predictor of new postulated. The mechanism for a hereditary etiology for CTS is onset CTS. Several prior cross-sectional studies had demonstrated unclear, but may relate to a thicker carpal tunnel ligament, smaller a threefold increase in CTS among diabetics both in the workplace carpal canal or altered geometry, or it may be related to obesity. and the general population. They found a 6.5-fold increase in inci- Although the sample sizes in these studies are relatively small, the dent CTS cases among diabetics. This study demonstrated that an relationship is robust and suggests a strong association. More study obese person (i.e., BMI=30) was 2.5 times more likely to develop is necessary to establish the strength of the relationship. CTS compared to person with a normal person (BMI=25) even when controlling for diabetes. They found a fourfold increase in Longitudinal Studies the risk of CTS among female workers, but the 95% confidence interval included 1.0 and therefore was not statistically significant, There are few longitudinal studies that have assessed work although the trend was in the same direction as previous studies. and personal attributes as they relate to the development of They did not find that hand repetition or force were significant CTS.26,29,40,41,42,59 In 1984, Nathan and colleagues40,41,42 initiated predictors. Elbow posture was a significant risk factor although the a prospective study of factors associated with research-defined proportion of the variance explained by this variable was nominal, CTS in 471 industrial workers. They assessed the medical history, i.e., the nonmechanical factors, were much more prominent in lifestyle factors, and job tasks. The CTS case status was based on predicting incident cases of CTS. both symptoms and electrophysiologic findings. The workers were reexamined in 1989, 1994-1995, and 2001-2002. These studies reported both baseline and aggregated risk factors associated with Conclusion increased risk of CTS. There were 256 still in the study by 1998 and 166 participants were successfully reexamined in 2001-2002. The nonbiomechanical risk factors for developing CTS are the An analysis of baseline risk factors showed that fewer repetitive most predictive factors in determining who will develop CTS. tasks at work, female gender, and greater relative weight were asso- Biomechanical factors may also play a role but it is a minor role ciated with any occurrence of CTS during follow-up. In an analysis compared to the personal factors. The only factor that has demon- of aggregate risk factor scores from the 1994 to 1995 study, only strated a dose-response relationship is obesity (i.e., the more there greater relative weight and female gender were associated with CTS is, the more likely the problem). The mechanism of all the personal in the 2001 to 2002 follow-up study. Although obesity and gender factors may not be understood, but its impact is measurable and it are consistent predictors of CTS, workplace demands appear to is profound. bear an uncertain relationship to CTS.

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2. Albers JW, Brown MB, Sima AA, Greene DA. Frequency of median 23. Franklin GM, Haug J, Heyer N, Checkoway H, Peck N. Occupational mononeuropathy in patients with mild diabetic neuropathy in the carpal tunnel syndrome in Washington state, 1984-1988. Am J Public early diabetes intervention trial. Muscle Nerve 1996;19:140-146. Health 1991;81:741-746. 3. Amadio PC. Pyridoxine as an adjunct in the treatment of carpal 24. Franzblau A, Rock CL, Werner RA, Albers JW. Vitamin B6, vitamin tunnel syndrome. J Hand Surg 1985;10:237-241. C, and carpal tunnel syndrome. J Occup Environ Med 1998;40:305- 4. Atcheson SG, Ward JR, Lowe W. Concurrent medical disease in work- 309. related carpal tunnel syndrome. Arch Intern Med 1998;158:1506- 25. Franzblau A, Rock CL, Werner RA, Albers JW, Kelly MP, Johnston 1512. E. The relationship of vitamin B6 to median nerve function and 5. Atisook R, Benjapibal M, Sunsaneevithayakul P, Roongpisuthipong carpal tunnel syndrome among active industrial workers. 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Covariates of human peripheral nerve function: I. 16. Dyck PJ, Litchy WJ, Lehman KA, Hokanson JL, Low PA, O'Brien nerve conduction velocity and amplitude. Neurotoxicol and Teratol PC. Variables influencing neuropathic endpoints: the Rochester dia- 1994;16:95-104. betic neuropathy study of healthy subjects. Neurology 1995;45:1115- 36. Massey EW. Carpal tunnel syndrome in pregnancy. Obstet Gynecol 1121. Surg 1978;33:145-147. 17. Ellis J, Folkers K, Watanabe T, Kaji M, Saji S, Caldwell JW, and col- 37. Mesgaradeh M, Schneck CD, Bonakdarpour A, Mitra A, Conaway leagues. Clinical results of a cross-over treatment with pyridoxine and D. Carpal tunnel: MR imaging part II. Carpal tunnel syndrome. placebo of the carpal tunnel syndrome. J Clin Nutr 1979;32:2046- Radiology 1989;171:749-754. 2070. 38. McCann VJ, Davis RE. Carpal tunnel syndrome, diabetes and pyri- 18. Ellis JM, Folkers K, Levy M, Shizukuishi S, Lewandowski J, Nishii doxal. Aust NZJ Med 1978;8:638-640. S, and colleagues. Response to vitamin B6 deficiency and the 39. Nakamichi K, Tachibana S. Small hand as a risk factor for idiopathic carpal tunnel syndrome to pyridoxine. Proc Natl Acad Sci USA carpal tunnel syndrome. Muscle Nerve 1995;18:664-666. 1982;79:7494-7498. 40. Nathan P, Keniston RC, Myers LD, Meadows KD, Lockwood RS. 19. Ellis JM, Folkers K, Levy M, Takemura K, Shizukuishi S, Ulrich R, Natural history of median nerve sensory conduction in industry: Harrison P. Therapy with vitamin B6 with and without surgery for relationship to symptoms and carpal tunnel syndrome in 558 hands treatment of patients having the idiopathic carpal tunnel syndrome. over 11 years. Muscle Nerve 1998;21:711-721. Res Commun Chem Pathol Pharmacol 1981;33:331-344. 41. Nathan P, Meadows KD, Istvan JA. Predictors of carpal tunnel 20. Faucett J, Werner RA. Non-biomechanical factors potentially affect- syndrome: an 11-year study of industrial workers. J Hand Surg Am ing musculoskeletal disorders. Washington DC: National Academy 2002;27:644-651. Press; 1999. p 175-199. 42. Nathan PA, Istvan JA, Meadows KD. A longitudinal study of pre- 21. Folkers K, Ellis J, Watanabe T, Saji S, Kaji M. Biomechanical evidence dictors of research-defined carpal tunnel syndrome in industrial for a deficiency of vitamin B6 in the carpal tunnel syndrome based workers: findings at 17 years. J Hand Surg Br 2005;30:593-598. on a crossover clinical study. Proc Natl Acad Sci USA 1978;75:3410- 43. Nathan PA, Keniston RC. Carpal tunnel syndrome and its relation to 3412. general physical condition. Hand Clin 1993;9:253-261. 22. Folkers K, Willis R, Takemura K. Biochemical correlations of a de- 44. Nathan PA, Keniston RC, Lockwood RS, Meadows KD. Tobacco, ficiency in vitamin B6, the carpal tunnel syndrome and the Chinese caffeine, alcohol, and carpal tunnel syndrome in American indus- restaurant syndrome. Int Commun Sys J Med 1985;9:441. try. A cross-sectional study of 1464 workers. 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45. Nathan PA, Keniston RC, Myers LD, Meadows KD. Obesity as a 55. Stevens JC, Sun S, Beard CM, O’Fallon WM, Kurland LT. Carpal risk factor for slowing of sensory conduction of the median nerve tunnel syndrome in Rochester, Minnesota, 1961-1980. Neurology in industry. A cross-sectional and longitudinal study involving 429 1988;38:134-138. workers. J Occup Med 1992;34:379-383. 56. Tanzer R. The carpal tunnel syndrome. J Bone Joint Surg Am 46. Neviaser RJ. Flexor digitorum superficialis indicis and carpal tunnel 1959;41:626-634. syndrome. Hand 1974;6:155-156. 57. Vessey MP, Villard-Mackintosh L, Yeates D. Epidemiology of carpal 47. Phalen G. The carpal tunnel syndrome: clinical evaluation of 598 tunnel syndrome in women of childbearing age. Findings in a large hands. Clin Orthop Relat Res 1972;83:29-40. cohort study. Int J Epidemiol 1990;19:655-659. 48. Phillips RS. Carpal tunnel syndrome as a manifestation of systemic 58. Werner R, Albers JW, Franzblau A, Armstrong TJ. The relationship disease. Ann Rheum Dis 1967;26:59-63. between body mass index and the diagnosis of carpal tunnel syn- 49. Radecki P. A gender specific wrist ratio and the likelihood of a drome. Muscle Nerve 1994;17:632-636. median nerve abnormality at the carpal tunnel. Am J Phys Med 59. Werner R, Franzblau A, Gell N, Hartigan AG, Ebersole M, Rehabil 1994;73:157-162. Armstrong TJ. Incidence of carpal tunnel syndrome among auto 50. Radecki P. The familial occurrence of carpal tunnel syndrome. assembly workers and assessment of risk factors. J Occup Environ Muscle Nerve 1994;17:325-330. Med 2005;47:1044-1050. 51. Sabour M, Fadel H. The carpal tunnel syndrome: a new complication 60. Werner RA, Albers JW, Franzblau A, Armstrong TJ. The influence ascribed to the pill. Am J Obstet Gynecol 1970;107:1265-1267. of body mass index and work activity in determining the prevalence 52. Soferman N, Weissman SL, Haimov M. Acroparesthesias in preg- of median mononeuropathy at the wrist. J Occup Environ Med nancy. Am J Obstet Gynecol 1964;89:528-531. 1997;54:268-271. 53. Stetson DS, Albers JW, Silverstein BA, Wolfe RA. Effects of age, sex, 61. Winn FJ, Habes DJ. Carpal tunnel area as a risk factor for carpal and anthropometric factors on nerve conduction measures. Muscle tunnel syndrome. Muscle Nerve 1990;13:254-258. Nerve 1992;15:1095-1104. 54. Stevens JC, Beard CM, O’Fallon WM, Kurland LT. Conditions associated with carpal tunnel syndrome. Mayo Clin Proc 1992;67:541- 548. 11

Nerve Biopsy Often is a Helpful Diagnostic Procedure

P. James B. Dyck, MD Associate Professor Department of Neurology Jennifer A. Tracy, MD Mayo Clinic College of Medicine Rochester, Minnesota

Introduction body are the ones going to the feet, he quickly decided that biopsies of distal cutaneous leg nerves produce a higher yield. He also found Over the past 40 years, nerve biopsies have been one of the main that the postoperative sensory disturbance in the lower extremity tools used by physicians in evaluating patients with peripheral neu- was less bothersome than that of the posterior neck and back of ropathies. However with improvements in laboratory, radiographic, the ear. Consequently, he switched to using the sural nerve slightly and electrophysiological evaluations and the introduction of quan- proximal to the ankle as the standard site for nerve biopsy. Others titative sensory and autonomic testing, the need for nerve biopsy have argued that the superficial peroneal nerve may be preferable has been on the decline. Furthermore, with a better understanding because it lies near the peronei muscles and, therefore, a nerve and of disease pathophysiology, it has become clear that biopsies are muscle biopsy can be taken simultaneously.2 This strategy is often not needed in some classes of neuropathies (such as inherited neu- useful when there is high suspicion of necrotizing vasculitis (when ropathies) or in others (even if treatable) can be recognized by the two tissues can be sampled instead of one). Nevertheless, the pre- disease characteristics (such as chronic inflammatory demyelinat- ferred site of routine nerve biopsy in the Mayo Clinic laboratory ing polyneuropathy). These observations and trends have led some has remained the sural nerve. neuromuscular experts to question if there is still an ongoing need for nerve biopsy at all.8 The sural nerve is a pure sensory nerve and biopsy of this nerve does create some sensory deficits; however, if the cases are appropriately selected these side effects are acceptable. In one series, 1 Background year after biopsy 60% of patients report no symptoms, 30% had intermittent symptoms which ultimately resolved, and 10% had a The use of nerve biopsy is relatively recent. German neuropatholo- greater amount of pain or paresthesia.3 New sensory symptoms are gists as early as the 1800s introduced ways of looking at autopsy more likely if the patient had a detectable sural response on nerve nerve specimens. During the mid-20th century, an occasional conduction studies (NCSs) prior to biopsy.6 Overall it is a well- nerve biopsy was performed, but it was not until the 1960s that tolerated procedure, and usually should be taken from a sensory Dr. Peter J. Dyck (Mayo Clinic, Rochester, MN) and Dr. P. K. distribution that is already significantly affected by the underlying Thomas (Guy’s Hospital, London, UK) systematically introduced neuropathy and so few additional symptoms or signs will be created the technique of nerve biopsy. Traditionally, nerve biopsy of a by the biopsy itself. cutaneous nerve or a skin sensory nerve is performed. The main reasons these nerves are selectively used is because they are purely The diagnostic yield of cutaneous sensory nerve biopsies has also sensory and when they are taken the patient has no motor deficit been studied. Argov and colleagues performed a retrospective and only a limited sensory deficit. Originally, Dr. Peter J. Dyck analysis of 120 patients with peripheral neuropathy who were often used the greater auricular nerve in the posterior part of the evaluated in their electrodiagnostic clinic, and found that in 48% neck for most of his biopsies. However, because most neuropathies of patients, a diagnosis was reached without the performance of a are length-dependent processes and since the longest nerves in the sural nerve biopsy. In the patients who were biopsied, 38% of the 12 Nerve Biopsy Often is a Helpful Diagnostic Procedure AANEM Course biopsies yielded diagnostic or important contributory findings. It and ischemic injury to nerve. In the past, this author would biopsy was concluded overall that the management of 50% of the biopsied most cases that were suspected diabetic lumbosacral radiculoplexus patients was favorably affected by the histological findings.1 Oh neuropathies. However now that the underlying pathology of the reviewed 385 cases in which sural nerve biopsies were performed disease is better understood, if a case appears to be straightforward over a 15-year period. He found that in 45% of the cases, clini- and the patitent is in the early stages of the disease, the patient is cally helpful or relevant information was added by the biopsy, and usually treated without a nerve biopsy. However, in longstanding a specific diagnosis was obtained in 24% of patients as a result of cases of diabetic lumbosacral radiculoplexus neuropathy, it may the biopsy.7 be difficult to know if the disease is still active or if the patient is suffering from the residual nerve damage from the microvasculitis. The difficulty with interpreting this type of data is that clearly the A nerve biopsy may be performed in such a patient. The purpose yield of nerve biopsy is heavily dependent upon the selection of ap- of the biopsy is not as much to make a diagnosis of the underlying propriate patients for biopsy as well as selection of an appropriate condition as it is to discover whether the microvasculitis is active. nerve to biopsy. Care must be taken in extrapolating the results of In these cases, if there was active evidence of microvasculitis, the any such study without undertaking an analysis of these selection patient would likely be treated; if inflammation was not seen, then criteria. It is the author’s opinion that the vast majority of patients there would be less likelihood of treatment. Consequently, one with peripheral neuropathy do not need a nerve biopsy; however, major use of nerve biopsy is to judge disease activity and the neces- in selected circumstances, this procedure can provide very impor- sity of treatment. tant information for diagnosis and treatment. Consequently, just quoting studies that provide percentages of diagnostic yield is not a sufficient way to analyze the issue. Selecting Patients to Biopsy

One of the most important questions to ask is which patients Site of Biopsy should undergo nerve biopsy. Unlike many muscle diseases in which muscle biopsy is needed to diagnose the type of myopathy, The use of the sural nerve as the predominant site for nerve most cases of peripheral neuropathy do not need to have a nerve biopsy certainly does have limitations. If the underlying disease biopsy performed. It should be the exception rather than the rule. is only a motor process, using a cutaneous sensory nerve will not Patients should undergo a thorough workup for their neuropathy provide useful information. Similarly, if the disorder is multifocal before nerve biopsy is considered or performed. This includes a or predominantly proximal, the sural nerve may not be involved. neurologic history, a neurologic examination, NCSs and needle Therefore, the evaluating physician needs to be sure that the nerve EMG, quantitative sensory studies, autonomic reflex screen, labo- biopsied is clinically involved. Results of NCSs and needle elec- ratory evaluations for potential underlying causes of neuropathy, tromyography (EMG), as well as clinical findings, are helpful in and, in some cases, spinal fluid evaluation. In general, it is only this determination. Consequently, the sural nerve should not just after these evaluations have been performed that nerve biopsy be used as the site of nerve biopsy in an automatic fashion. Biopsy should be considered. There are, of course, exceptions. sites need to be considered on a case-by-case basis and the most appropriate nerve needs to be selected when performing a nerve A nerve biopsy should not be performed just because the evaluating biopsy. For example, chronic inflammatory sensory polyradicul- physician does not know the cause of the neuropathy. It is common opathy is an inflammatory demyelinating neuropathy selectively that a thorough evaluation does not elucidate an underlying cause. involving the sensory root, and a sural nerve biopsy would be This is especially the case in small fiber neuropathies. In spite of not normal, whereas a sensory rootlet biopsy would show onion-bulbs having a diagnosis, most of these patients should not undergo nerve and macrophages.9 biopsy. Frequently, a physician will order a thyroid function study, a fasting blood sugar, heavy metals, and an Athena antibody panel; Before performing a nerve biopsy, it should be deteremined that and if these tests are negative, often the next step will be to perform it is, in fact, a justifiable procedure. For example in most cases of a nerve biopsy. There needs to be a better indication for performing small fiber neuropathy, the damage to small fibers is not sufficient a nerve biopsy than that the evaluating physician does not know enough to warrant treatment with prednisone, cyclophosphamide, what to do next. When deciding whether or not to perform a nerve and other immunosuppressive drugs. Consequently, even if a mi- biopsy, several important criteria emerge. crovasculitis is suspected as the underlying cause of a small fiber neuropathy, in general a nerve biopsy should not be performed Perhaps the most important criterion for determining whether or because systemic vasculitis with only mild small fiber involvement not to perform a nerve biopsy is that a suspected diagnosis can would not be treated. When deciding to perform a biopsy, the only be reached by having a pathological nerve biopsy specimen. In physician has to ensure that the neuropathy is sufficiently severe to this case, the physician is considering a specific diagnosis in which justify the side effects of potential treatment. In general, a physician pathological/histological nerve material is needed. Such diagnoses is performing a nerve biopsy to make a diagnosis of the underlying include necrotizing vasculitis, amyloidosis, sarcoidosis, leprosy, process, but alsomay perform a nerve biopsy to see if that process lymphoma, metastatic tumor, and others. Before ordering a biopsy is still active and needs ongoing treatment. For example, diabetic for these conditions, the physician needs to consider their likeli- lumbosacral radiculoplexus neuropathy is caused by microvasculitis hood in a particular patient. AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 13

Another important issue to consider when performing a nerve When writing biopsy reports, two diagnoses should be listed. biopsy is whether the potential side effects of the nerve biopsy are The first diagnosis should describe the neuropathic abnormalities, outweighed by the potential gain. Part of this question is judging whereas the second diagnosis should describe the interstitial abnor- the severity of the neuropathy. Since immune causes are one of the malities. In most cases, the primary reason to obtain a nerve biopsy major side effects in neuropathy, the physician might decide that is not to learn about neuropathic abnormalities. In fact, significant the potential side effects of immunotherapy (cyclophosphamide, information about neuropathic abnormalities should already be steroids, etc.) are worse than the neuropathy itself. Another issue in known based on the neurologic history, neurologic examination, deciding whether to perform a nerve biopsy is the temporal course. and physiological studies including NCSs, EMG, quantitative sen- If the neuropathy is rapidly worsening and is of a severe character, sation, quantitative autonomic and thermoregulatory sweat tests. this is a more compelling reason to perform a nerve biopsy. In For instance, the distinction between a demyelinating neuropathy general, motor deficits are more disabling than sensory deficits. If and an axonal neuropathy can usually be inferred from the electro- the patient is rapidly weakening, this is a more compelling reason physiological studies; nerve biopsy is not necessary to determine if to perform a nerve biopsy than if the patient is just experiencing there is demyelination. some tingling or numbness. Again, remember that when performing a sural nerve biopsy, only sensory nerve tissue is obtained and In contrast, the main reason to perform a nerve biopsy is to under- not motor tissue. stand the interstitial abnormalities. These interstitial abnormalities can only be discovered by directly viewing the nerve histology (specifically the interstitium) and not by any other methods. The Information Gained by Nerve Biopsies most important group of disorders in which interstitial abnormalities are searched are the inflammatory/immune neuropathies. The Nerve biopsies give information about the nerve fibers themselves inflammatory neuropathies are among the most treatable causes and also about the interstitium surrounding them. Since nerves are of peripheral neuropathies. It is important to have pathological valuable tissue that re-grow slowly, once they are cut, as much in- evidence of inflammation to help tailor treatment, because many formation as possible should be obtained. Consequently, physicians of the available treatments have significant side effects, they may should perform multiple preparations on nerve tissue received. need to be administered long term, and they are often very expen- These include teased fiber preparations, which can be exceedingly sive. The inflammatory neuropathies include necrotizing vasculitis, helpful in analyzing abnormalities that occur in a patchy manner inflammatory demyelination, granulomatous (such as sarcoidosis), along the length of a nerve fiber (i.e., segmental demyelination). sometimes paraneoplastic, and others. Another interstitial abnor- Other myelin abnormalities can be assessed, such as tomaculae, as mality that is very important to recognize is amyloidosis. Tumor well as the rate of axonal degeneration and empty nerve strands. infiltration of nerve needs to be recognized, and biopsy can often be Many of these abnormalities are better seen in longitudinal prepara- useful to address issues of tumor recurrence versus radiation change tions than in cross-section, but still are best seen on teased fibers. (more relevant for proximal nerve biopsies).

Paraffin sections are obtained (both cross-section and longitudi- The importance of adequate understanding of interstitial abnor- nal), with hematoxylin and eosin stain, Luxol Fast Blue Periodic malities is why whole rather than fascicular distal cutaneous (sural) Acid Schiff (LFB-PAS), and trichrome stains. Congo red and nerve biopsies are preferred. Whole biopsies generally include gen- methyl violet slides are prepared primarily to assess for amyloid. erous interstitium to analyze for diagnostic and potentially treatable Epoxy preparations stained with methyl blue are ideal for assessing abnormalities. Occasionally there are neuropathic abnormalities density of myelinated fibers and the different fiber populations that are diagnostic of underlying neuropathy like amyloidosis, sar- (large myelinated, small myelinated and maybe unmyelinated). The coidosis, necrotizing vasculitis, perineurioma, etc. In most cases of author’s routine immunohistochemistry preparations are leukocyte peripheral neuropathy, however, the pathological findings suggest common antigen, (cd45) and kp-1 (macrophage preparation) an underlying process, but are not diagnostic of one. Often these (cd68). Further studies are based upon suspicion for particular suggestive findings are inflammatory infiltrates. disease entities, either by clinical/laboratory grounds, or by results obtained from the tissue preparations already assessed (e.g., smooth When performing a nerve biopsy, three different compartments muscle actin for suspected microvasculitis, S-100 for assessment within the nerve are reviewed (endoneurium, perineurium, and of onion bulbs, tumor markers for various suspected neoplasms). epineurium). The endoneurium historically was thought of as only Electron microscopy can be performed for evaluation of abnormali- the nerve fibers themselves, but references to the endoneurium in ties of small myelinated and unmyelinated fibers as well as axonal this manuscript include all the tissue within the confines of the inclusions and a host of other entities. Overall, there is a tremen- perineurium, including microvessels, Schwann cells, fibroblasts, dous amount of information potentially obtainable from nerve and the actual nerve fibers. The perineurium is the lining around biopsy, provided an appropriately affected nerve is obtained, and the fascicles and is made up of perineurial cells and some microves- the appropriate stains and preparations are performed for suspected sels. It is the smallest of the three components and contributes disease entities. to the blood-nerve barrier. The epineurium is the area outside 14 Nerve Biopsy Often is a Helpful Diagnostic Procedure AANEM Course the confines of the perineurium and includes collagen and many nerve intact.5 This technique was mostly used on distal cutaneous blood vessels of different sizes. Most of the inflammation seen in nerves since, until recently, there were no good method of targeting neuropathies is in the epineurium, but other areas of inflamma- proximal nerves. tion, if found, have important pathologic significance as well. (For example, inflammation of the perineurium is frequently seen in Over the last several years, there has been considerable advance- sarcoidosis.) ment in the ability of magnetic resonance imaging (MRI) and ultrasound to look at nerves. This author has developed a special The information obtained from a nerve biopsy and electrophysi- practice at the Mayo Clinic with a peripheral nerve neurologist, a ological studies is not the same. They provide complementary radiologist with special expertise in viewing nerves, a peripheral information rather than redundant information. When perform- nerve neurosurgeon expert in performing fascicular nerve biopsies, ing electrophysiological studies, the information gathered is about and a peripheral nerve pathology laboratory expert in preparing many nerves, both motor and sensory, over widespread areas of and interpreting nerve pathology. This has been a great benefit the body. This makes it less likely to miss a pathologically affected because many patients are evaluated with focal neuropathies involv- site, which can be a problem with the small sample size of a nerve ing the brachial plexus, lumbosacral plexus, and other individual biopsy. A nerve biopsy assesses a very small area but it provides nerves including sciatic, ulnar, and median and roots. These cases much more information about that particular sampled area within are evaluated with special attention to the involved proximal nerve the nerve than electrophysiological studies. Usually the informa- segments with high-powered imaging techniques (3-Tesla MRI). tion is only about a sensory nerve, given that is typically what is Through this integrated practice a general idea about the location biopsied. In contrast to the electrophysiology studies that only look of a clinical problem based on neurologic history and examination at the largest myelinated nerve fibers, nerve biopsies supplies infor- can be formed. The radiologist can then further refine this local- mation about large myelinated fibers, small myelinated fibers and ization by examining the identified nerves in great detail with the unmyelinated fibers. Consequently, nerve biopsies provide more use of high-resolution MRI. In general, these MRI scans are best information about different fiber populations than electrophysi- for identifying a lesion and giving a limited differential diagnosis ological studies. Also, NCSs provide pathophysiological data that is However, by themselves they are not diagnostic of the disease inferred, whereas nerve pathology shows the direct evidence of the process and pathological specimens are still needed. With the in- neuropathic abnormalities as well as interstitial abnormalities. The formation provided by the MRI, the peripheral nerve neurosurgeon examining physician needs to remember that different information can perform a targeted fascicular nerve biopsy and remove a fascicle is being gathered from these evaluations. or two from the nerve at the site of the lesion and leave the rest of the nerve intact. The nerve biopsy is then processed in the peripheral nerve laboratory, and special preparations are made to evaluate Targeted Fascicular Nerve Biopsy it further and to diagnose the cause of the focal neuropathy.

One of the new, exciting aspects of nerve biopsies is the use of With this integrated approach, this author and colleagues have targeted fascicular nerve biopsy, a very important advancement in performed approximately 150 nerve biopsies over the last 4 or 5 the use of nerve pathology. In the past, physicians have typically years. A diagnostic rate of the underlying process was determined not been able to specifically target nerve biopsies because of an in- in 84% of the patients in the series. In these patients, targeted ability to image nerves well enough. Occasionally, this author has fascicular nerve biopsy from proximal nerves versus blind distal cu- performed some targeted biopsies through the use of electrophysi- taneous nerve biopsy, there is a highly significant increased rate of ological abnormalities. An example is in multifocal motor neuropa- diagnostic findings from the proximal fascicular nerve biopsy (84% thy with conduction block where the nerve is sampled at the site positive) versus from the distal nerve (33% positive). Consequently, of conduction block by using intraoperative monitoring. However, this technique of targeted fascicular biopsy has become an im- until recently, this author has mostly performed distal cutaneous portant clinical tool. These diagnoses often are also potentially nerve biopsies in length-dependent peripheral neuropathies. In treatable conditions that would have otherwise gone undiagnosed; general, the distal segments of the sural nerve will show more pa- this makes a real difference to the patients. The morbidity of the thology than the proximal segments. This was shown by the work procedure has been low. Only patients with with problematic defi- of Dr. Peter J. Dyck on uremic neuropathy and Friedreich’s ataxia.4 cits are biopsied, and therefore all of these patients have neurologic Consequently, biopsying the distal segment of nerves in length- impairment before surgery. Little new weakness or sensory loss has dependent processes is recommended. been caused by the procedure. It is not uncommon for patients to develop some transient pain and numbness but this is usually However, in some neuropathic conditions, the process is not a short-lived and the patient returns to baseline. This technique has length-dependent, symmetrical process, but rather a multifocal been a major success. process that often involves proximal nerves. There has always been a concern about the risk of biopsying proximal nerves because of The conditions that have been diagnosed through these types of the potential neuropathic deficits since most proximal nerves are approaches include inflammatory, immune conditions such as focal mixed motor and sensory nerves. A technique to sample some, but inflammatory demyelinating lesions, granulomatous lesions, sarcoi- not all, of a nerve (fascicular nerve biopsy) was introduced by Dr. dosis, and necrotizing vasculitis. Many different types of tumors Peter J. Dyck and colleagues in the 1960s. The authors describe re- have also been seen. Some of these tumors are benign tumors, moving one or two fascicles of the nerve and leaving the rest of the like perineurioma. Schwannoma and neurofibroma have been less AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 15 common. Malignant tumors such as lymphoma and metastatic (4) semithin epoxy sections looking at the ultrastructural features breast and prostate cancer to the nerves have been identified. In ad- of the nerve, and potentially electron microscopy if needed; and dition, focal amyloid infiltration of the nerve (amyloidoma), as well (5) immunohistochemical preparations including CD45 (lympho- as vascular malformations in the nerve, and some infection of the cytes) and CD68 (macrophages) and more should be performed nerve such as leprosy has been seen. Overall, approximately 75% of as necessary. Finally, it is imperative to have colleagues in general the conditions diagnosed have been treatable. pathology with whom one can confer for issues of malignancy (especially hematological) and other in areas of pathology. Recently some neuropathologists have concluded that the use of nerve biopsy has become a dying art and they argue that with the In conclusion, the practice of nerve pathology is still a vital com- availability of other laboratory and noninvasive techniques, nerve ponent of the evaluation of patients with peripheral neuropathies. biopsy will no longer be needed. This does not seem to be the case Nerve biopsies should not be performed in most patients with at all. There are, in fact, more varied ways to perform nerve biop- neuropathies, and when performed, need to be carefully selected. sies and to make diagnoses where physicians were not able to do so However, nerve pathology still is the only way to assess the inter- in the past. Through the use of targeted fascicular nerve biopsies, stitium and diagnose many disorders (especially the inflammatory many patients who previously would not have received a nerve and immune disorders) and still is an invaluable tool in diagnosing biopsy, may now be biopsied and their neuropathies diagnosed. and treating patients with neuropathy. With improved imaging, Because of the specialized expertise required for these biopsies, new techniques of using nerve biopsy (targeted fascicular biopsy) they should be performed at centers that have extensive experience have become apparent and are a vital tool for the physician. with these techniques. In order to perform these targeted fascicular nerve biopsies, four criteria need to be met. There must be a: Supported in part by a grant obtained from the National Institute (1) physician with special expertise in peripheral nerve disorders, of Neurological Disease and Stroke (NINDS 36797). (2) radiologist with special expertise in looking at proximal nerves, (3) peripheral nerve neurosurgeon with expertise in removing a fascicular biopsy, and (4) peripheral nerve laboratory with expertise REFERENCES in processing peripheral nerve. 1. Argov Z, Steiner I, Soffer D. The yield of sural nerve biopsy in the evaluation of peripheral neuropathies. Acta Neurol Scand Conclusions 1989;79:243-245. 2. Collins MP, Mendell JR, Periquet MI, Sahenk Z, Amato AA, Gronseth Peripheral nerve biopsies are still an important technique in evalu- GS, and colleagues. Superficial peroneal nerve/peroneus brevis ating people with peripheral neuropathies. Nerve biopsy should muscle biopsy in vasculitic neuropathy. Neurology 2000;55:636-643. only be used in a minority of patients with neuropathy. It is very 3. Dyck PJ, Dyck PJB, Engelstad J. Pathologic alterations of nerves. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy, 4th edition, valuable in conditions such as necrotizing vasculitis, amyloidosis, volume 1. Philadelphia: Elsevier; 2005. p 733-830. lymphoma, metastatic tumor, perineurioma, inflammatory demy- 4. Dyck PJ, Johnson WJ, Lambert EH, O’Brien PC. Segmental demyeli- elination, and other conditions. Nerve biopsy should be performed nation secondary to axonal degeneration in uremic neuropathy. Mayo mostly in academic centers and not at the local level. An option for Clin Proc 1971;46:400-431. those physicians not in an academic center is to have the nerve tissue 5. Dyck PJ, Lofgren EP. Method of fascicular biopsy of human periph- harvested locally and then processed and interpreted at an academic eral nerve for electrophysiologic and histologic study. Mayo Clin Proc center. An important point to remember is that if a physician is 1966;41:778-784. going to perform a nerve biopsy, a nerve is being cut and valuable 6. Gabriel CM, Howard R, Kinsella N, Lucas S, McColl I, Saldanha G, tissue is being destroyed. It is important to ensure that as much and colleagues. Prospective study of the usefulness of sural nerve information as possible is obtained from the biopsy. Consequently, biopsy. J Neurol Neurosurg Psychiatry 2000;69:442-446. it is not sufficient just to obtain paraffin sections and nothing 7. Oh SJ. Diagnostic usefulness and limitations of the sural nerve biopsy. Yonsei Medical Journal 1990;31:1-26. more. The following tests should be performed in the nerve biopsy: 8. Pleasure DE. Dwindling indications for sural nerve biopsy. Arch (1) Teased fiber preparations (so one can judge the different patho- Neurol 2007;64:935-936. logic abnormalities of individual nerve fibers); (2) paraffin sec- 9. Sinnreich M, Klein CJ, Daube JR, Engelstad J, Spinner RJ, Dyck tions with stains including hematoxylin and eosin; (3) LFB-PAS, PJ. Chronic immune sensory polyradiculopathy: a possibly treatable trichrome and amyloid stains (Congo Red and methyl violet); sensory ataxia. Neurology 2004;63:1662-1669. 16 AANEM Course 17

Nerve Biopsy Rarely is a Helpful Diagnostic Procedure

Peter D. Donofrio, MD Professor Department of Neurology Chief, Neuromuscular Section Director of the EMG Laboratory Vanderbilt University Medical Center Nashville, Tennessee

The results from a biopsy of a peripheral nerve can influence the groups: patients with suspected vasculitis and in patients with a treatment of a patient only if the condition identified is amenable clinically significant peripheral neuropathy of unknown cause.11 to a therapy. This presentation will argue that most treatable neuropathies can be diagnosed without tissue verification. In their Even though the results of nerve biopsy can be helpful in influenc- textbook on pathology of peripheral nerve, Asbury and Johnson ing patient management, many interpretations are non-specific recommended nerve biopsy whenever one of the following dis- and fail to offer further direction in the evaluation of an idiopathic orders is considered: amyloidosis, leprosy, conditions producing neuropathy. Lubec and colleagues retrospectively reviewed the palpable nerves, and in pediatric illnesses such a metachromatic medical records of 171 inpatients whose final diagnosis was pe- leukodystrophy, Krabbe’s disease, and ataxia-telangiectasia.2 The ripheral neuropathy.10 They determined that noninvasive testing authors believed that nerve biopsy was least helpful in acute or was sufficient to identify the underlying etiology of the neuropathy subacute distal symmetric polyneuropathies due to presumed meta- in 114 patients (83%). A biopsy of the nerve and/or gastrocnemius bolic disorders or toxins.2 muscle was conducted in 27 patients. Twenty one of the patients underwent both a nerve and muscle biopsy. In three patients, vas- It is the perception of most clinicians that the yield of nerve biopsy culitis was diagnosed. In the 24 remaining patients, the biopsies is low for influencing the management of patients with neuropa- were nonspecific. In a prospective study of the usefulness of sural thy. The results are often nonspecific, leaving the physician with nerve biopsy in 50 consecutive patients with neuropathy, Gabriel no additional useful information and the patient may be left with and colleagues showed that the nerve biopsy results changed the residual pain and numbness. Said, writing in a manuscript on the diagnosis in 7 of the 50 patients.6 In 35 patients, the biopsy simply indications and usefulness of nerve biopsy, agreed with the poor confirmed the suspected diagnosis and in 8 patients the biopsy yield of nerve biopsies when performed in unselected patients.14 results were nonspecific. An independent neurologist involved in From his perspective, nerve biopsies should be obtained to identify the study determined that the biopsy either changed or was helpful a specific cause rather than to define the presence or absence of a in guiding the patient’s management in 60% of the cases. The neuropathy.14 He recommended a nerve biopsy for patients with authors did not explain how this relatively high percentage was suspected vasculitis, diabetic patients with focal or multifocal neu- derived nor the specifics of the term “helpful.” ropathies, amyloidosis, leprosy, and only rarely in acquired demyelinating polyneuropathies.14 Biopsy should be considered in select It is customarily taught that nerve biopsy is most helpful when patients with inherited neuropathies only when genetic testing a vasculitis is considered in the differential diagnosis. Vasculitis failed to identify a defect. Oh made similar recommendations for commonly presents as a mononeuritis multiple or a multifocal nerve biopsy and included on his list: hypertrophic neuropathy, asymmetric process, so patients who present in this manner are ap- inflammatory neuropathy, ischemic neuropathy, metachromatic propriate candidates for nerve biopsy unless an accurate diagnosis leukodystrophy, sarcoidosis, and giant axonal dystrophy.11 He can be made in a noninvasive way. Nevertheless, the yield of nerve expressed his opinion that nerve biopsy is clearly indicated in two biopsy in patients with suspected vasculitis is not impressive. Vital 18 Nerve Biopsy Rarely is Helpful AANEM Course and colleagues performed a 16-year retrospective study of 202 cases pathic axonal polyneuropathy (CIAP) and to 6 autopsy controls. To with suspected vasculitis.21 A necrotizing vasculitis was found in assess demyelination and remyelination, the authors analyzed the nerve only in 16 patients, in muscle in 19 patients, and in nerve number of onion bulbs using the g ratio, the myelinated nerve fiber and muscle in 25 patients. A granulomatous vasculitis was detected density, the number of clusters, and endoneurial area. Considerable in one patient. Thus, nerve biopsy showed a necrolyzing vasculitis overlap was found between abnormalities in CIDP and CIAP pain only 20% of the 202 patients. If one included the pathologic tients. The authors found no difference in demyelinating features findings of microvasculitis, this percentage increased from 20 to between patients with CIDP and CIAP. Based on their results, the 29%. In an additional 12% of patients, the nerve biopsy was in- authors concluded that limited diagnostic value exists in perform- terpreted as “probably vasculitis.” Performance of a muscle biopsy ing nerve biopsies to substantiate the diagnosis of CIDP. improved the chances of making the diagnosis of vasculitis by 27%, a percentage approximate to the yield of the nerve biopsies. Other authors have reported impressive nerve biopsy findings sup- Claussen and her colleagues published more impressive results porting the diagnosis of CIDP in patients whose NCSs were more from 115 nerve and muscle biopsies collected over 20 years at the in keeping with a chronic axon loss neuropathy. Vallat and col- University of Alabama.5 Her results differed significantly from leagues described 8 patients whose nerve biopsies were indicative of Vital’s. The diagnostic sensitivity of nerve biopsy in patients with CIDP and whose electrophysiological results did not meet criteria suspected vasculitis was 39% whereas the yield from muscle tissue for the diagnosis.20 Five of the eight patients responded favorable was only 17%. Not surprisingly, the highest diagnostic yield (73%) to immunotherapy. The authors proposed that CIDP should be of nerve biopsy was observed in patients with clinical evidence of suspected if the electrophysiological examination shows subtle ab- a myopathy and neuropathy and known rheumatologic disease. normalities suggestive of demyelination. Abnormal sural nerve conduction was highly correlated with an abnormal nerve biopsy, an encouraging result for those who use Nerve biopsy is often recommended to establish or eliminate the nerve conduction studies (NCSs) to select nerves for biopsy. diagnosis of amyloidosis. Based on recent publications, a nerve biopsy should not be necessary in most cases of suspected amyloi- The surgical literature portrays a less optimistic picture of the dosis because of the high yield of a bone marrow biopsy and ab- usefulness of nerve biopsy. Rappaport and colleagues reported the dominal fat pad aspiration for identifying amyloid deposits. Data results of sural nerve biopsy in 60 patients undergoing biopsy.12 from the Mayo Clinic has shown that amyloid deposits will be Vasculitis was suspected in 29 patients, yet the nerve biopsy showed detected in approximately 90% of patients with amyloidosis who confirmatory findings in only 6 of 29 patients. Almost half of the undergo either a bone marrow biopsy or fat pad aspirate.7 Nerve patients remained undiagnosed after the biopsy. The authors em- biopsy for amyloidosis should be recommended only for those phasized their complication rate of 27%. Six patients developed patients in whom the diagnosis of amyloidosis remains a strong wound infections, seven patients had delayed wound healing, and possibility after biopsies of other tissues are unrevealing. In another three patients progressed to chronic pain in the distribution of the study from the Mayo Clinic, Andrews and colleagues demonstrated sural nerve. The authors judged the complication rate to be signifi- the complete lack of yield of subcutaneous fat aspirates in patients cant and suggested the need for strict criteria to select patients for with isolated neuropathy and who did not have any family history, sural nerve biopsy. In another report from a surgery journal, Ruth clinical history, or laboratory findings suggestive of systemic amy- and colleagues reported their results and adverse effects from 67 pa- loidosis.1 tients who underwent a nerve biopsy.13 In cases of polyneuropathy of unknown etiology, a definitive diagnosis was made in only 24% Before the prevalence of genetic testing and its application to of patients and lead to therapy in 19% of patients. Follow-up of the inherited neuropathies, nerve biopsy played a role in identifying patients over time (a mean of 24 months) found chronic pain in the onion bulb formation, a pathologic process formed by recurrent distribution of the sural nerve in 30% of patients, dysesthesias in demyelination and remyelination of peripheral nerve. In light of 47%, and persistent sensory loss in 72% of patients. Approximately the impressive advancements in molecular genetics, genetic testing 50% of patients stated that they would not submit to the biopsy is the more appropriate first step in making the diagnosis of an again. Based on their data and experience, the authors proposed inherited neuropathy. Unfortunately, the choice of genetic tests that nerve biopsy should only be recommended for cases of sus- to order and where to send the specimen is almost as bewilder- pected inflammatory, collagenous, immunologic, and hereditary ing as the choice to proceed to a nerve biopsy. A recent review of neuropathies.13 the website of gene tests (www.genetests.org) and several publications disclosed an overwhelming number of genetic abnormalities Sural nerve biopsy is sometimes ordered in patients who are consid- that clinically present as the phenotype of Charcot-Marie-Tooth ered to have chronic inflammatory demyelinating polyneuropathy (CMT) disease.3,9 Presently, there are 6 different genetic abnormali- (CIDP), yet the diagnosis is not supported by NCSs. The rationale ties for CMT Type 1 (Type 1A through F), 15 for CMT Type 2 for obtaining the biopsy is to document focal demyelination and (Type 2 A1 through 2L), 8 for CMT Type 4 (Type 4 A through inflammation that would support the diagnosis of CIDP in the H) and 5 for CMT Type X (Type X 1 through 5). Outside of the absence of nerve conduction abnormalities. Bosboom and col- category of CMT, there are numerous genetic abnormalities for leagues looked at the diagnostic value of sural nerve demyelination congenital hypomyelinating neuropathy, for hereditary neuropathy in CIDP.4 Using several parameters for measuring nerve demyeli- with propensity to pressure palsies, the distal hereditary motor neu- nation and remyelination, he compared the sural nerve biopsy of ropathies, the hereditary sensory and/or autonomic neuropathies, 21 patients with CIDP to those of 13 patients with a chronic idio- the hereditary focal neuropathies, and giant axon neuropathy. AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 19

Mononeuritis multiplex is one of the most common indications for performing a nerve biopsy unless the precise diagnosis is known Table 1 Differential diagnosis for mononeuritis multiplex without tissue confirmation. In mononeuritis multiplex, the nerve biopsy is often required to identify defects of the vasa nervorum, Churg-Strauss angiitis Cryoglobulinemia abnormal deposits, and inflammation. Vasculitis is the most common cause of mononeuritis multiplex and its consideration is Diabetes Giant cell arteritis one of the main indications for performing the nerve biopsy. Table HIV Infection Hypersensitivity vasculitis 1 lists the differential diagnosis of mononeuritis multiplex. Ischemia Leprosy Paraneoplastic Periarteritis nodosum Although the sural nerve is the most common nerve to be sampled for pathologic analysis, the superficial peroneal nerve and the radial Rheumatoid arthritis Systemic lupus erythematosus nerve can be biopsied if the clinical examination shows greater Sarcoidosis Necrotizing vasculitis involvement of those respective nerve distributions. Combining Wegener’s granulomatosis Waldenstrom’s macroglobulinemia the nerve biopsy with a muscle biopsy in the same region as well as the use of electrophysiology can increase diagnostic sensitivity HIV = human immunodeficiency virus greatly. Sanchez and colleagues reported their results in 26 patients with necrotizing vasculitis and neuropathy.17 Approximately half of their patients has periarteritis nodosum. The sural nerve biopsy confirmed the diagnosis in 20% of patients, but when performed an endemic area, characteristic skin lesions, and the identification on a nerve that was physiologically affected, the percentage in- of acid fast bacilli from a skin smear or skin biopsy. In the rare creased to 61%. If the gastrocnemius muscle was denervated by instance of suspected leprosy in an endemic area in the absence of electromyography, the yield of combined nerve and muscle useful- typical skin lesions and negative skin biopsy, a biopsy of a sural, ness increased to 73%. superficial peroneal, or radial nerve near the area of sensory deficit may show the caseating necrotizing granulomatous neuropathy as- Some authors have advocated the use of nerve biopsy in patients sociated with leprosy. with diabetes who have asymmetric, multifocal, or proximal neuropathies. Nerve biopsy can be useful in diabetes to rule out a Metachromatic leukodystrophy (MLD) is a condition in which superimposed cause of neuropathy such as CIDP. In some medical analysis of blood leukocytes and cultured skin fibroblasts should be centers, nerves in the region of the lumbosacral plexus are biopsied tested before biopsy of a peripheral nerve is contemplated. Other to substantiate pathology. Said and his group reported inflamma- testing that may obviate the need for nerve biopsy in MLD include tory nerve lesions in the intermediate cutaneous nerve of the thigh, spinal fluid analysis, brain MRI, NCSs, and neurocognitive testing. a sensory branch of the anterior division of the femoral nerve, in Nerve biopsy is also rarely needed to substantiate the diagnosis of four patients with proximal diabetic neuropathy.15 Ironically, the Krabbe’s disease. Once again, blood leukocytes and cultured skin biopsy results did not influence treatment as the patients improved fibroblasts can be used to measure the activity of galactosylceramide quickly and spontaneously after the biopsy; i.e., one patient became beta-galactosidase (GALC) which will be very low in patients pain-free the day after his biopsy and the other three within 1 week. with Krabbe’s disease. Testing of cerebrospinal fluid for an el- As a general rule, nerve biopsy in diabetics with the common distal evated protein, brain magnetic resonance imaging, brain magnetic symmetric sensory and motor neuropathy is unhelpful and may be resonance spectroscopy, electroencephalography, and NCSs can be dangerous given the propensity of diabetic patients to heal slowly implemented before a nerve biopsy is ordered. and develop infection. As Sima expressed in his manuscript on the utility of nerve biopsy in diabetes, “nerve biopsy is an invasive pro- Fabry disease results from a deficiency of alpha-galactosidase A. cedure associated with extremely high costs of analysis that will not This enzyme can be measured in plasma, serum, leukocytes, tissue provide any information in addition to what can be obtained from biopsy, and cultured skin fibroblasts in lieu of performing a nerve carefully performed electrophysiological measurements.”19 biopsy. If the disease is further suspected, DNA analysis can be requested for alpha-Gal A gene sequencing, and brain magnetic Suspected sarcoidosis is often listed as one of the indications for resonance imaging can be ordered to evaluate the patient for isch- nerve biopsy. Surprisingly, muscle biopsy is as helpful in document- emic lesions associated with the disease. ing noncaseating granulomas as nerve biopsy. In one study, muscle was affected in 10 of 11 patients who had granulomas in their nerve Nerve biopsy is indicated for the very rare presentation of lym- biopsy specimens.16 Silverstein and Sitzbach report that 60% of phoma infiltrating nerve (neurolymphomatosis), which is most patients with sarcoidosis will have muscle involvement whereas less commonly seen in non-Hodgkin’s lymphoma.8 than 1% will have nerve affected.18 Table 2 lists the author’s indications for nerve biopsy when all other Another indication often cited for nerve biopsy is Hanson disease means of establishing the diagnosis have been exhausted. Some of or leprosy. In the majority of patients with leprosy, the diagnosis of the disorders commonly listed as indications for nerve biopsy by peripheral neuropathy can by made by the clinical presentation in other authors, such as inherited neuropathy and amyloidosis, are 20 Nerve Biopsy Rarely is Helpful AANEM Course

2. Asbury AK, Johnson PC. Pathology of peripheral nerve, volume 9: Table 2 Indications for Nerve Biopsy major problems in pathology. Philadelphia: WB Saunders; 1978. 3. Berciano J, Combarros O. Hereditary neuropathies. Curr Opin Neuro 2003;16:613-622. Vasculitis 4. Bosboom WMJ, van den Berg LH, Franssen H, and colleagues Hanson disease (leprosy) Diagnostic value of sural nerve demyelination in chronic inflamma- Metachromatic leukodystrophy tory demyelinating polyneuropathy. Brain 2001;124:2427-2438. 5. Claussen G, Thomas TD, Goyce C, and colleagues. Diagnostic value Fabry disease of nerve and muscle biopsy in suspected vasculitis cases. J Clin Krabbe’s disease Neuromusc Dis 2000;1:117-123. 6. Gabriel CM, Howard R, Kinsella N, and colleagues. Prospective Giant axonal neuropathy study of the usefulness of sural nerve biopsy, J Neurol Neurosurg Polyglucosan body disease Psychiatry 2000;69:442-446. Tumor infiltration 7. Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis: recognition, confirmation, prognosis, and therapy. Mayo Clin Proc 1999;74:490-494. Small fiber neuropathy 8. Kelly JJ, Karcher DS. Lymphoma and peripheral neuropathy: a clinical review. Muscle Nerve 2005;31:301-313. 9. Kuhlenbaumer G, Young P, Hunermund G, and colleagues. Clinical features and molecular genetics of hereditary peripheral neuropa- not listed because of the high probability of making the diagnosis thies. J Neurol 2002;249:1629-1650. after less invasive testing. With the advances in epidural nerve 10. Lubec D, Mullbacher W, Finsterer J, Mamoli B. Diagnostic work-up analysis through skin biopsy, the need for sural nerve biopsy to in peripheral neuropathy: an analysis of 171 cases. Postgrad Med J document a small fiber neuropathy will be diminished. 1999;75:723-727. 11. Oh, SJ. Diagnostic usefulness and limitations of the sural nerve In summary, nerve biopsy results are often unhelpful because of biopsy. Yonsei Med J 1990;31:1-31. the nonspecific way in which nerve responds to disease. Vasculitis 12. Rappaport WD, Valente J, Hunter GC, and colleagues. Clinical utilization and complications of sural nerve biopsy. Am J Surg remains the most common indication for nerve biopsy, especially 1993;166:252-256. in patients who do not have active manifestations of a connective 13. Ruth A, Schulmeyer FJ, Roesch M, and colleagues. Diagnostic and tissue disorder. If a nerve biopsy is needed, electrophysiology should therapeutic value due to suspected diagnosis, long-term complica- be used to identify the nerves most likely to yield a diagnosis. In tions, and indication for sural nerve biopsy. Clin Neurol Neurosurg almost all patients, an adjacent muscle should be sampled at the 2005;107:214-217. same time the nerve undergoes biopsy, preferably a muscle which is 14. Said G. Indications and usefulness of nerve biopsy. Arch Neurol abnormal by the needle examination. The clinician ordering testing 2002;59:1532-1535. for possible vasculitis should keep in mind that a higher positive 15. Said G, Elgrably F, Lacroix C, and colleagues. Painful proximal tissue yield will be obtained if the superficial peroneal nerve and diabetic neuropathy: inflammatory nerve lesions and spontaneous adjacent muscle are biopsied in lieu of the sural nerve biopsy alone. favorable outcome. Ann Neurol 1997:41:762-770. Nerve biopsy should only be performed at medical centers that have 16. Said G, Lacroix C, Plante-Bordeneuve V, and colleagues. Nerve granulomas and vasculitis in sarcoid peripheral neuropathy: a clinico- extensive experience performing the studies, use the proper stains, pathological study of 11 patients. Brain 2002;125:264-275. and have neuropathologists who have expertise in interpreting the 17. Sanchez J, Coll-Canti J, Ariza A, and colleagues. Neuropathy due to nerve tissue. In most situations, adequate nerve should be obtained necrotizing vasculitis: a study of the clinical anatomy, neurophysi- to prepare the tissue for plastic embedding, frozen sections, teased ological characteristics, and clinical course of the disorder in 27 pa- fibers dissection, immunostaining, electronmicroscopy, and paraf- tients. Rev Neurol 2001;33:1033-1036. fin sections. Adequate tissue should be obtained to allow the nerve 18. Silverstein A, Siltzbach LE. Muscle involvement in sarcoidosis. Arch to be cut into multiple sections for analysis as abnormalities may Neurol 1969;21:235-241. not be present in all sections of the nerve. 19. Sima AA. Diabetic neuropathy-the utility of nerve biopsy, Electroencephalogr Clin Neurophysiol 1999;50:525-533. 20. Vallat, J-M, Tabaraud F, Magy L, et al. Diagnostic value of nerve biopsy for atypical chronic inflammatory demyelinating polyneurop- REFERENCES athy: Evaluation of eight cases, Muscle & Nerve 2003:27: 478-485. 21. Vital C, Vital A, Canron M-H, et al. Combined nerve and muscle 1. Andrews TR, Colon-Otero G, Calamai KT, and colleagues. Utility biopsy in the diagnosis of vasculitic neuropathy. A 16-year retro- of subcutaneous fat aspiration for diagnosing amyloidosis in patients spective study of 202 cases, J Peripheral Nervous System, 2006, 11: with isolated peripheral neuropathy. Mayo Clin Proc 2002;77:1278- 20-29. 1290. 21

Electrodiagnostic Studies Generally are Helpful in the Evaluation of Patients With Weakness and Normal Neurological Examinations

Zachary Simmons, MD Professor Department of Neurology Penn State University Penn State Hershey Medical Center Hershey, Pennsylvania

INTRODUCTION PATIENTS IN WHOM THE NEUROLOGICAL EXAMINATION IS RELIABLE AND NORMAL As an extension of the clinical examination, electrodiagnostic (EDX) studies (i.e., nerve conduction studies [NCSs] and needle Carpal Tunnel Syndrome Without Clear Localizing electromyography [EMG]) often are part of the diagnostic evalua- Features tion of patients in whom neuromuscular disease is suspected, but in whom the neurological examination is normal. Such patients Although carpal tunnel syndrome (CTS) is a common condition may have subjective sensory disturbances, fatigue, or symptoms associated with nocturnal pain and paresthesias in a median distri- of weakness which are not supported by the examination. Others bution with features on the neurological examination which make have pain for which a neurological basis is suspected. In some pa- diagnosis straightforward (e.g., thenar atrophy and sensory loss in tients, strength and other aspects of the neurological examination a median nerve distribution), CTS may be associated with sensory are clearly normal, and the patient is eventually identified via EDX disturbances or pain outside of the median nerve distribution, testing as having a clear but mild or early case of a neurological and with a normal neurological examination. In such cases, EDX disorder. In other patients, accurate assessment of strength may be studies may facilitate diagnosis. In one series of 100 patients with challenging because pain and fatigue prevent the examiner from electrodiagnostically verified CTS in 159 hands who lacked other determining whether strength is normal or mildly impaired. Some conditions likely to produce upper extremity symptoms (radiculop- such patients are found to have abnormal EDX examinations, and athy, plexopathy, other entrapment neuropathies, polyneuropathy, eventually are identified as having clear neurological disorders. etc.), the ring finger was affected by sensory symptoms in 83% of Others have no abnormal findings on EDX testing but meet clini- hands, and the little finger in 56.6%. Interestingly, the little finger cal criteria for fibromyalgia or other non-neurological disorders. was the most affected digit in 2.5% of hands, and the ring finger Still other patients have normal EDX studies and no identifiable in 3.8%. Paresthesias or pain were reported proximal to the wrist disease. EDX studies are of tremendous value in helping to make in 36.5% of hands. Pain in the neck was seen in 0.6%, pain in the such distinctions. shoulder in 6.3%, and pain in the upper arm in 7.5% of hands.34 22 EDX Studies are Helpful in Weakness With Normal Neurological Exams AANEM Course

Another series found 46% of patients with pain in the forearm or and sometimes in arm muscles, all of whom had normal strength, higher,21 while yet another group reported symptoms present in reflexes, and sensation. Some had fasciculations or myokymia the forearm in 50%, at the elbow in 45%, and at the shoulder in on clinical examination. Repetitive stimulation studies of motor 27%.19 A large series of 1039 patients with CTS involving 1528 nerves at various frequencies (0.5, 1, 2, and 5 Hz) produced after- upper limbs found pain in a distribution which did not involve the discharges. Needle examination was normal except for fasciculation hand in 18.5% and paresthesias without involvement of the hand potentials. Carbamazepine provided symptomatic relief in some. in 1.9%.27 These patients have been classified as having a cramp-fasciculation syndrome. Needle EMG studies provided a diagnosis despite Fasciculations normal neurological examinations.38

Spontaneous fasciculations are noted by 70% of healthy medical Lambert-Eaton Myasthenic Syndrome personnel.30 Needle EMG is a valuable tool, in conjunction with the clinical examination, to differentiate benign fasciculations from Most patients with Lambert-Eaton myasthenic syndrome (LEMS) early neuromuscular disease when patients present with normal present with proximal lower extremity weakness. However, this strength. A useful study from Mayo Clinic identified 121 persons may be difficult to objectively document. As muscle strength is diagnosed as having benign fasciculations.2 Presenting symptoms augmented initially by continuing to attempt to contract against included muscle twitching or fasciculation, generalized fatigue, resistance (until fatigue sets in), the examiner may conclude that cramps or spasms, paresthesias, myalgias, concern about amyo- strength is normal or near normal. So, the examiner must grade the trophic lateral sclerosis (ALS), and muscle stiffness. All had normal initial strength of contraction, not the grade after several seconds of neurological examinations and EDX studies which demonstrated maintaining the contraction.10,22 In addition, one-third of patients no evidence of motor neuron disease (MND) except for fascicula- note muscle aching and stiffness, which makes objective identification potentials. Over a follow-up period which ranged from 2 to tion of weakness even more difficult because of the “breakaway” 32 years (mean 7.2), none developed MND. As has been pointed component exhibited by many patients on manual muscle testing. out, it is extremely rare for individuals who ultimately are found Add to this the fact that ocular and bulbar symptoms are much to have ALS to present with fasciculations only. Two such patients less common in LEMS than in myasthenia gravis, and the clini- who initially presented with normal strength are reported in the cian is confronted with patients whose chief complaint is fatigue literature, but a careful reading of the reports reveals that needle and weakness, but whose examinations may seem inconsistent and EMG examinations distinguish these individuals from those with which lack the characteristic ocular and bulbar findings which raise “benign fasciculations.” One patient reported muscle fasciculations the index of suspicion for myasthenia gravis. Electrodiagnostically, and cramps for 3 years. Examination revealed normal strength LEMS patients demonstrate low compound muscle action po- and reflexes. Needle EMG revealed not only fasciculation poten- tential (CMAP) amplitudes which increase dramatically after 10 tials, but also fibrillation potentials and positive sharp waves in seconds of isometric exercise or with rapid (20-50 Hz) repetitive several muscles. The patient developed weakness associated with stimulation.10 Thus, EDX testing may provide very useful objective muscle atrophy a year later, eventually resulting in the diagnosis data on such patients. of MND.13 Another report describes a 72-year-old man with generalized muscle fasciculation potentials and cramps. Examination Early Motor Neuron Disease revealed widespread fasciculations and muscle cramps evoked by moderate exercise. Strength, reflexes, and sensation were normal. Motor neuron loss begins before clinical weakness in patients with Needle EMG examination revealed not only diffuse fasciculation ALS. Collateral sprouting permits reinnervation to keep up with potentials, but also a few complex motor unit action potentials denervation early in the disease course. In such muscles, CMAP (MUAPs) in the anterior tibialis muscles bilaterally and a few fibril- amplitudes and twitch tensions remain normal until motor unit loss lation potentials in the right tibialis anterior muscle. The patient reaches 50%-80%, because collateral reinnervation keeps up with developed clear features of MND over the next year.7 It is clear denervation up to this point, preventing loss of function. Thus, that when patients present with fasciculations and normal neuro- strength is unaffected despite significant disease progression.23,36 logical examinations, an EMG which is completely normal except However, needle examination will demonstrate abnormalities.12 for fasciculation potentials makes it highly unlikely that MND will develop. However, subtle abnormalities on the needle EMG Myotonic Dystrophy examination are a very sensitive indicator of early MND, and such patients require careful follow-up. Myotonic dystrophy type 1 (DM1) is caused by an unstable expansion of a CTG trinucleotide repeat in the 3’ untranslated region of Cramp-Fasciculation Syndrome the DMPK gene on chromosome 19q13.2-q13.3.18 The normal gene has 5 to 36 CTC repeats. Alleles with more than 50 CTG Muscle aches, cramps, and exercise intolerance are common symp- repeats are associated with DM1. There is a relationship between toms in a neuromuscular clinic, and approximately one-third of the size of the repeat expansion and the clinical severity and age of these patients are found to have a specific muscle abnormality onset of the disease. Repeat expansions of less than 100 are gener- after comprehensive evaluation.25 A syndrome has been described ally associated with mild disease and a later age of onset of symp- featuring patients with muscle cramps and aching in leg muscles toms. Young patients may have normal neurological examinations AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 23 but have myotonic discharges on needle EMG examination.15,18 EMG demonstrated MUAP amplitudes, durations, and recruit- Thus, EDX studies can identify patients with myotonic dystrophy ment which were consistent with myopathy. He and several other in the presymptomatic stage. Such patients often seek medical at- male family members, also with normal strength, had markedly tention because their child has been diagnosed with DM1. The elevated serum CK levels (CK 2000-3000 in the patient, 1,458- parents may both be asymptomatic, but one is found to have 12,270 in other affected individuals). DNA analysis revealed a myotonic discharges on needle EMG examination despite normal deletion in the dystrophin gene.17 Similarly, 4 patients have been strength, overall normal function, and minimal to no signs of clini- described in another family with exertional myalgias, normal cal myotonia. Similarly, a patient with DM2 has been described strength or minimal weakness, and serum CK levels which varied who had an elevated serum creatine kinase (CK) level but was from normal to 2000 U/L. Needle EMG demonstrated small, poly- asymptomatic and had a normal neurological examination. Muscle phasic MUAPs in some family members. DNA testing revealed a biopsy showed findings consistent with myotonic dystrophy, and deletion in the dystrophin gene.16 Deoxyribonucleic acid (DNA) testing confirmed the presence of a CCTG repeat expansion in the ZNF9 gene consistent with type 2 Exercise-induced myalgias and rhabdomyolysis: A 9-year-old boy myotonic dystrophy.24 Although EMG studies were not described, has been reported with exercise-induced muscle pain and two they would be useful in identifying myotonic dystrophy in this episodes of myoglobinuria. Neurological examination was normal. patient, similar to the studies’ utility in identifying abnormalities in Needle EMG revealed low-amplitude polyphasic MUAPs, inter- patients who carry the deletion for Becker muscular dystrophy and preted as being consistent with a myopathy. He was found to have present with normal strength and an elevated serum CK level. a deletion in the dystrophin gene.9

Inflammatory Myopathy Cardiomyopathy: A 40-year-old man with severe congestive heart failure was diagnosed with a dilated cardiomyopathy at age 32. Abnormalities may be seen on needle examination in muscles His serum CK level was 8000 U/L. Strength was normal. The which demonstrate normal strength or in which strength cannot needle EMG examination demonstrated low-amplitude polyphasic be adequately assessed. There is a rough correlation between muscle MUAPs, interpreted as being consistent with a diffuse myopathic strength (determined by manual muscle testing) and the amount pattern. On DNA testing, he was found to have a deletion in the of fibrillation potentials and positive sharp waves, indicating that dystrophin gene.28 One of the members of the family described weaker muscles with a Medical Research Council score of less than above with myalgias, cramps, and normal strength had a cardio- 4 will have more fibrillation potentials and positive sharp waves myopathy as well.16 than those with a grade of 4+ or higher.5 However, the relationship is a general one, and two muscles with the same strength by manual muscle testing may have different amounts of fibrillation potentials PATIENTS IN WHOM THE NEUROLOGICAL EXAMINATION and positive sharp waves. The amount of abnormal spontaneous IS LIMITED activity is determined by the status of the muscle fibers in the vicin- ity of the EMG needle. Inflammatory myopathy can be a patchy Although manual muscle testing is in theory a simple and accurate process, particularly in mild or early cases. Such patients may de- test for weakness, the determination of “normal” strength may chal- scribe weakness, but strength may be normal to the examiner, and lenging. In such situations, EDX testing is of great value. the serum CK level may be only mildly elevated. The needle examination may appear normal in many muscles, but a careful needle Examination Limited by Poor Effort examination usually will identify some muscles with abnormal spontaneous activity or with MUAPs and recruitment consistent It may be the examiner’s impression that strength is normal and that with a myopathy. The sensitivity of EMG for the diagnosis of in- the patient is not producing a full effort against resistance. There flammatory myopathy is said to be 80%-90%, although this varies are many reasons for this. One of the most common is pain, which depending on the stage of the disease and the muscles tested.4 For is also a very common reason for referral for EDX testing. Other example, a recent series found that no patients with acute polymyo- reasons include secondary gain (disability, sympathy), or inability sitis or dermatomyositis (onset within 6 months of testing) or with to cooperate (e.g., a child or a mentally retarded adult). Often inclusion body myositis had a normal EMG study.3 these patients are characterized as having “break-away” or “give- away” weakness, meaning that they do not sustain an effort against Dystrophinopathies resistance, but rather produce a brief effort against the examiner’s force, followed by a marked decrease in effort and collapse of the The deletions associated with Becker muscular dystrophy may limb. The examiner may believe that strength is normal briefly, but produce clinical syndromes which are not associated with any he or she cannot be certain, and the patient’s perception is that of weakness. These include myalgias, cramps, rhabdomyolysis, and weakness. The needle EMG examination may demonstrate abnor- cardiomyopathy. malities of spontaneous activity which indicate acute or subacute denervation, or may indicate changes in motor unit amplitude Myalgias and cramps: A 33-year-old man has been described who and morphology indicative of chronic neurogenic or myopathic was a member of a family in which several individuals had myalgias changes. Also important is the ability of the EDX physician to and cramps. On his examination, he had normal strength. Needle assess recruitment and activation. Recruitment is defined as “the 24 EDX Studies are Helpful in Weakness With Normal Neurological Exams AANEM Course successive activation of the same and additional motor units with Unfortunately, there are no biologic markers which permit defini- increasing strength of voluntary muscle contraction.”1 In contrast, tive diagnosis of this condition. One important role served by EDX activation simply refers to the process of MUAP firing.1,29 Reduced studies in these patients is to exclude diseases of muscle and of the activation indicates a central nervous system process, such as poor neuromuscular junction as factors causing weakness, fatigue, and effort. Reduced recruitment or early recruitment are indicators of muscle pain. A normal needle examination is helpful for excluding abnormalities of the peripheral nervous system, and characteristi- a wide variety of neuromuscular diseases including myopathies and cally indicate neurogenic or myopathic disorders respectively. Thus, dystrophies. Repetitive stimulation studies are useful for excluding the needle EMG examination is a sensitive tool for detecting subtle disorders of neuromuscular transmission and should be performed neurogenic or myopathic disease. on these patients because of their prominent fatigue.

Radiculopathy Paresthesias are reported in 26% to 84% of patients with fibromyalgia.20,32,38 NCSs can be helpful in assessing paresthesias Although it is a common diagnosis, the clinical assessment of ra- in these patients in two important ways. The paresthesias may be diculopathy may be challenging. Because virtually all limb muscles part of the fibromyalgia syndrome, in which case normal studies are innervated by several nerve roots, radiculopathy which produces are helpful in the same manner as normal needle examinations or relatively mild axonal loss and affects only one nerve root level may repetitive stimulation studies. However, some patients with fibro- not produce significant weakness at that level to be unequivocally myalgia have entrapment neuropathies which may not be identi- detectable on strength testing, particularly if the patient also has fied without EDX studies. CTS was identified by EDX studies pain which limits effort. A thorough needle EMG examination in 10% of patients with fibromyalgia in one series and in 15% in may help to clarify the diagnosis. Care must be taken to examine another.11,31 several muscles with overlapping innervation for two reasons: (1) the individual’s innervation my differ from the “standard” in- Chronic Fatigue Syndrome nervation, and (2) only a small number of nerve root fibers to a particular muscle may be compromised. However, a needle exami- The Centers for Disease Control defines chronic fatigue syndrome nation which is carefully planned and carried out is a sensitive way as being characterized by unexplained persistent or relapsing of detecting even mild radiculopathy. chronic fatigue of new or definite onset (not lifelong), not the result of ongoing exertion, not substantially alleviated by rest, and Examination Limited by Extremely Strong Premorbid resulting in substantial reduction in previous activities. There also Status must be four or more of the following symptoms, all of which must have persisted or recurred during 6 or more months of illness Patients who are extremely strong at baseline and who now perceive and must not have predated the fatigue: (1) self-reported impair- that they are weaker pose a great challenge to the clinician. The ment in short-term memory or concentration severe enough to standard manual muscle test may not demonstrate weakness, but cause substantial reduction in previous levels of occupational, such testing is limited by the examiner’s strength and by knowledge educational, social or personal activities; (2) sore throat; (3) tender of the preexisting strength of the patient, and therefore may not be cervical or axillary lymph nodes; (4) muscle pain, multi-joint pain adequate for identifying early and mild loss of strength in such a without joint swelling or redness; (5) headaches of a new type, patient. EDX testing is of great value in such cases. Low-amplitude pattern, or severity; (6) unrefreshing sleep; and (7) postexertional CMAPs may indicate axon loss, myopathy, or a postsynaptic defect malaise lasting more than 24 hours.14 The estimated prevalence is of neuromuscular transmission such as LEMS. The needle EMG 0.4%-1% of the population.8 Like fibromyalgia, this condition has examination is a sensitive method of detecting subtle denervation no biologic markers to aid in its identification. EDX studies are which may not be sufficient to produce detectable weakness on expected to be normal, but play a role similar to that described examination. Repetitive stimulation studies permit identification for fibromyalgia. Because fatigue is the major symptom, repetitive of disorders of neuromuscular transmission. stimulation studies performed before and after exercise are important to rule out a presynaptic or postsynaptic disorder of neuro- Fibromyalgia muscular transmission. The needle examination serves to exclude a myopathic disorder. NCSs are extremely useful both for excluding Arguably one of the most disliked diagnoses because of its rela- an underlying neurogenic disorder and for identifying atypical pre- tive subjectivity, fibromyalgia is nonetheless frequently diagnosed sentations of entrapment neuropathies such as CTS. because of the common occurrence of symptoms that fit the diagnosis. The American College of Rheumatology has defined fibromyalgia as occurring in patients with a history of chronic wide- SPECIAL ELECTROMYOGRAPHY TECHNIQUES spread pain involving all four quadrants of the axial skeleton, and the presence of 9 of 18 tender points on physical examination.37 There are special EMG techniques which may be useful for patients These individuals may have many other symptoms, including in whom the standard EDX methods do not provide clear diagnos- weakness, paresthesias, headache, affective disorders, temporoman- tic information. These span the broad field of quantitative EMG, dibular joint syndrome, weight fluctuations, night sweats, sleep including quantitative analysis of the MUAP, interference pattern disturbances, irritable bowel syndrome, cognitive difficulties, dizzi- analysis, turns and amplitude analysis, and decomposition.26 Two ness, esophageal dysmotility, noncardiac chest pain, and dyspnea.6 special techniques merit particular attention. AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 25

Single-fiber Electromyography 7. de Carvalho M, Swash M. Cramps, muscle pain, and fasciculations: not always benign? Neurology 2004;63:721-723. 8. Devanur LD, Kerr JR. Chronic fatigue syndrome. J Clin Virol Single-fiber EMG studies may demonstrate abnormal jitter in 2006;37:139-150. LEMS, myasthenia gravis, or congenital defects of neuromuscular 9. Doriguzzi C, Palmucci L, Mongini T, Chiado-Piat L, Restagno G, transmission. Single-fiber EMG also may demonstrate abnormal Ferrone M. Exercise intolerance and recurrent myoglobinuria as the fiber density. Fiber density generally is increased in neuropathies only expression of Xp21 Becker type muscular dystrophy. J Neurol and in myopathies, being particularly high in dystrophies and in 1993;240:269-271. chronic neuropathies.26,33 10. Dumitru D, Amato AA. Neuromuscular junction disorders. In: Dumitru D, Amato AA, Zwarts M, editors. Electrodiagnostic medi- Motor Unit Number Estimation cine, 2nd edition. Philadelphia: Hanley & Belfus; 2002. p 1127-1227. 11. Ersoz M. Nerve conduction tests in patients with fibromyalgia: comparison with normal controls. Rheumatol Int 2003;23:166-170. Motor unit number estimation (MUNE) can detect motor neuron 12. Felice KJ. A longitudinal study comparing thenar motor unit number loss in muscles not clinically weakened. In such muscles, CMAP estimates to other quantitative tests in patients with amyotrophic amplitudes and twitch tensions remain normal until motor unit lateral sclerosis. Muscle Nerve 1997;20:179-185. loss reaches 50%-80%. This is because collateral reinnervation 13. Fleet WS, Watson RT. From benign fasciculations and cramps to keeps up with denervation up to this point, preventing loss of func- motor neuron disease. Neurology 1986;36:997-998. tion. MUNE shows abnormalities, however.23 MUNE is also useful 14. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff for longitudinal follow-up. In patients with slowly progressive ALS, A. The chronic fatigue syndrome: a comprehensive approach to its the rate of change per month was found to be greater for thenar definition and study. Ann Intern Med 1994;121:953-959. MUNE than for a variety of other techniques, including thenar 15. Gharehbaghi-Schnell EB, Finsterer J, Korschineck I, Mamoli B, CMAP amplitude, grip strength, total manual muscle testing score, Binder BR. Genotype-pheontype correlation in myotonic dystrophy. Appel ALS rating scale, and forced vital capacity.12 In all patients Clin Genet 1998;53:20-26. 16. Gold R, Kress W, Meurers B, Meng G, Reichmann H, Muller with ALS, the rate of change in MUNE was greater than the rate of 12 CR. Becker muscular dystrophy: detection of unusual disease change in manual muscle testing and forced vital capacity. courses by combined approach to dystrophin analysis. Muscle Nerve 1992;15:214-218. 17. Gospe SM, Lazaro RP, Lava NS, Grootscholten PM, Scott MO, CONCLUSION Fischbeck KH. Familial-X-linked myalgia and cramps: a nonprogres- sive myopathy associated with a deletion in the dystrophin gene. EDX testing generally provides clinically useful information on Neurology 1989;39:1277-1280. patients who have neurological examinations which are clearly 18. Harper PS, Monckton DG. Myotonic dystrophy. In: Engel AG, normal or likely normal, but challenging to accurately assess. While Franzini-Armstrong C, editors. Myology, 3rd edition. New York: not all of these patients will be found to have neurological disease, McGraw-Hill; 2004. p 1039-1076. even negative testing can have clinical utility. Most of the informa- 19. Jackson DA, Clifford JC. Electrodiagnosis of mild carpal tunnel syndrome. Arch Phys Med Rehabil 1989;70:199-204. tion necessary to the clinician can be obtained by standard NCSs, 20. Leavitt F, Katz RS, Golden HE. Comparison of pain properties repetitive stimulation studies, and needle EMG, but some special in fibromyalgia patients and rheumatold arthritis patients. Arthritis tests add useful information in selected cases. Rheum 1986;29:775-781. 21. Loong SC. The carpal tunnel syndrome: a clinical and electrophysiological study of 250 patients. Clin Exp Neurol 1977;14:51-65. REFERENCES 22. Maddison P, Newsom-Davis J. Lambert-Eaton myasthenic syndrome. In: Katirji B, Kaminski HJ, Preston DC, Ruff RL, Shapiro 1. American Association of Electrodiagnostic Medicine glossary of BE, editors. Neuromuscular disorders in clinical practice. Boston: terms in electrodiagnostic medicine. Muscle Nerve 2001;24:S1-S50. Butterworth-Heinemann; 2002. p 931-941. 2. Blexrud MD, Windebank AJ, Daube JR. Long-term follow-up of 23. McComas AJ. Motor unit estimation: methods, results, and present 121 patients with benign fasciculations. Ann Neurol 1993;34:622- status. Muscle Nerve 1991;14:585-597. 625. 24. Merlini L, Sabatelli P, Columbaro M, Bonifazi E, Pisani V, Massa R, 3. Blijham PJ, Hengstman GJ, Hama-Amin AD, van Engelen BG, Novelli G. Hyper-CK-emia as the sole manifestation of myotonic Zwarts MJ. Needle electromyographic findings in 98 patients with dystrophy type 2. Muscle Nerve 2005;31:764-767. myositis. Eur Neurol 2006;55:183-188. 25. Mills KR, Edwards RH. Investigative strategies for muscle pain. J 4. Blijham PJ, Hengstman GJ, Ter Laak HJ, Van Engelen BG, Zwarts Neurol Sci 1983;58:73-78. MJ. Muscle-fiber conduction velocity and electromyography as di- 26. Nandekar SD, Stalberg EV, Sanders DB. Quantitative EMG. In: agnostic tools in patients with suspected inflammatory myopathy: a Dumitru D, Amato AA, Zwarts M, editors. Electrodiagnostic medi- prospective study. Muscle Nerve 2004;29:46-50. cine, 2nd edition. Philadelphia: Hanley & Belfus; 2002. p 293-356. 5. Buchthal F. Fibrillations: clinical electrophysiology. In: Culp WJ, 27. Nora DB, Becker J, Ehlers JA, Gomes I. Clinical features of 1039 pa- Ochoa J, editors. Abnormal nerves and muscle generators. New tients with neurophysiological diagnosis of carpal tunnel syndrome. York: Oxford University Press; 1982. p 632-662. Clin Neurol Neurosurg 2004;107:64-69. 6. Clauw DJ. Fibromyalgia. In: Ruddy S, Harris ED, Sledge CB, editors. 28. Palmucci L, Doriguzzi C, Mongini T, Chiado-Piat L, Restagno G, Kelly’s textbook of rheumatology, 6th edition. Philadelphia: WB Carbonara A, Paolillo V. Dilating cardiomyopathy as the expression Saunders; 2001. p 417-427. of Xp21 Becker type muscular dystrophy. J Neurol Sci 1992;111:218- 221. 26 EDX Studies are Helpful in Weakness With Normal Neurological Exams AANEM Course

29. Preston DC, Shapiro BE. Electromyography and neuromuscular 35. Tahmoush AJ, Alonso RJ, Tahmoush GP, Heiman-Patterson TD. disorders, 2nd edition. Philadelphia: Elsevier; 2005. p 223. Cramp-fasciculation syndrome: a treatable hyperexcitable peripheral 30. Reed DM, Kurland LT. Muscle fasciculations in a healthy population. nerve disorder. Neurology 1991;41:1021-1024. Arch Neurol 1963;9:363-367. 36. Wohlfart G. Collateral regeneration from residual motor nerve fibers 31. Sarmer S, Yavuzer G, Kucukdeveci A, Ergin S. Prevalence of carpal in amyotrophic lateral sclerosis. Neurology 1957;7:124-134. tunnel syndrome in patients with fibromyalgia. Rheumatol Int 37. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, 2002;22:68-70. Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, et 32. Simms RW, Goldenberg DL. Symptoms mimicking neurologic dis- al. The American College of Rheumatology 1990 Criteria for the orders in fibromyalgia syndrome. J Rheumatol 1988;15:1271-1273. Classification of Fibromyalgia. Report of the Multicenter Criteria 33. Stalberg E, Trontelj JV. Single fiber electromyography: studies in Committee. Arthritis Rheum 1990;33:160-172. healthy and diseased muscle, 2nd edition. New York: Raven Press; 38. Yunus M, Masi AT, Calabro JJ. Primary fibromyalgia: clinical study of 1994. 50 patients with matched normal controls. Semin Arthritis Rheum 34. Stevens JC, Smith BE, Weaver AL, Bosch EP, Deen HG, Wilkens JA. 1983;26:817-824. Symptoms of 100 patients with electromyographically verified carpal tunnel syndrome. Muscle Nerve 1999;22:1448-1456. 27

Electrodiagnostic Studies Generally are Not Helpful in the Evaluation of Patients With Weakness and Normal Neurologic Examinations

Lisa S. Krivickas, MD Associate Professor Department of Physical Medicine and Rehabilitation Harvard Medical School Boston, Massachusetts

One of the most common presenting complaints in the neuromus- Patients with any of the diagnoses listed in Table 1, other than some cular clinic is weakness. To the physician, weakness means a lack of of the subtle neuromuscular disorders, will have a normal electrodi- muscular force or power production. To the patient, the term weak- agnostic (EDX) study. Thus, EDX evaluation is not warranted in ness may be used to describe a number of problems that impair mo- most patients with complaints of weakness but normal neurologic bility including lack of strength, poor muscular endurance, fatigue, examinations. and even vertigo. Thus, the first task of the physician evaluating a patient with weakness is to determine specifically what are the pa- In a recent study,7 only 2% of patients complaining of myalgias tient’s symptoms. True muscle weakness, which can be detected by with a normal neurologic examination had muscle pathology manual muscle testing, may be produced by central or peripheral on biopsy; by extrapolation, one would expect very few of these nervous system pathology. However, many patients who complain patients to have EDX abnormalities. However, one must keep in of generalized weakness, fatigue, or lack of muscular endurance mind that up to 40% of motor neurons must be lost for weakness have normal muscle strength on neurologic examination and have to be detectable on manual muscle testing.19 Thus, in a very strong, a nonneurologic explanation for their symptoms. It is useful to physically fit individual it may be difficult to detect subtle weakness divide these patients into two groups; (1) those who complain of due to evolving neuromuscular disease with manual muscle testing. pain or myalgia in addition to weakness, and (2) those who do not An EDX study may be warranted in a young, physically fit individ- experience pain. Table 1 provides a differential diagnosis for each of ual who appears to have normal strength, but reports a decline in these two groups of patients. Some of the more common of these functional capacity, i.e., cannot carry a child or lift as much weight nonneurologic causes of weakness will be discussed. in the gym. This individual could have very early motor neuron 28 EDX Studies are Not Helpful in Weakness With Normal Neurological Exams AANEM Course

Table 1 Causes of perceived weakness in patients with normal neurologic examinations

Painful Painless Myofascial pain syndrome Systemic illness Fibromyalgia Anemia Chronic fatigue syndrome Cancer or post cancer fatigue Polymyalgia rheumatica Pulmonary disease Subtle neuromuscular disease Cardiac disease Proximal myotonic myopathy (PROMM) Hypo- or hyper-thyroidism Mitochondrial disorder with exercise intolerance Adrenal insufficiency or Cushings disease Metabolic myopathy Chronic infection (human immunodeficiency virus, hepatitis, mononucleosis) Deconditioning Depression, chronic anxiety Medication side effect (calcium channel blocker, beta blocker, anti-epileptic, tricyclic anti-depressant) Sleep disorders Conversion disorder, Malingering Subtle neuromuscular disease Mild myopathy Early motor neuron disease Neuromuscular junction disorder Mitochondrial disease

disease or a neuromuscular junction disorder. A serum creatine Symptoms suggestive of sleep apnea should prompt a sleep study. kinase that is elevated in the preceding scenario may also suggest The entities to be discussed below are primarily diagnoses of exclu- the need for EDX testing to look for myopathy. On the other hand, sion. several forms of myopathy have normal EDX studies when they are mild or in their early stages; these include the mitochondrial dis- Myofascial Pain Syndrome orders, common metabolic myopathies such as myophosphorylase deficiency (McArdle’s disease) and carnitine palmitoyl transferase II Myofascial pain is a muscle-related pain disorder associated with deficiency, and steroid myopathy. the local formation of trigger points. It is fairly common in the general population and almost ubiquitous among chronic pain suf- ferers with at least one study showing a prevalence of 85% among Medical Work-up of Weakness With Normal consecutively seen patients at a comprehensive pain center.9 Many Neurologic Examination of these patients also complain of weakness in affected muscles.

Patients who complain of weakness but have a normal neurologic The most commonly accepted hypothesis regarding the pathophys- exam warrant a medical work up to rule out many of the etiologies iology of trigger point related pain suggests that abnormally active listed in Table 1. This should include a thorough physical examina- motor endplates release excessive acetylcholine producing a con- tion with attention to age-appropriate screening procedures such as stant state of myofibril contraction. Prolonged contraction causes mammography and colonoscopy. In addition, medications should local tissue hypoxia with edema, and if not reversed, leads to the be reviewed to look for possible iatrogenic causes of fatigue and development of ischemic muscle pain.14 Trigger points do not have lack of muscular endurance. Suggested laboratory testing includes a any abnormal histologic findings, and EDX of muscle affected by complete blood cell count, thyroid screen, sedimentation rate, and myofascial pain is normal. cortisol level. If there is suspicion of cardiac or pulmonary dysfunction as a contributing factor to the symptoms, a cardiac stress test, The pain of trigger points is typically described as dull, deep, and echocardiogram, or pulmonary function tests might be performed. aching with a stereotypical referral pattern. For example, when the AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 29 trapezius muscle is involved, the pain is usually localized to the weakness, daily fatigue, muscle and joint stiffness, and generalized suprascapular region with referral into the upper neck as well as to muscle tenderness. Other frequent symptoms include unrefreshed the parietooccipital and periorbital areas. The intensity of pain can sleep, depressed mood, anxiety, urinary frequency, irritable bowel, change from day to day and is typically exacerbated by maintenance and multiple chemical sensitivities. On physical examination pa- of static postures, repetitive movement, stress, lack of sleep, and nu- tients may have decreased spinal range of motion, pronounced tritional imbalance. Patients may also complain of decreased range pain behavior, psychomotor retardation, slowed mentation, and of motion, local tenderness, and some dysaesthesias. a relative degree of somnolence. Generalized tactile allodynia is a pathognomonic finding in fibromyalgia, and tenderness of at least On physical examination, the physician is able to locally palpate a 11 of 18 designated tender points tends to support the diagnosis. taut and tender muscle band which reproduces the patient’s typical Giveway weakness is commonly observed; however, neurological pattern of referred pain when an appropriate amount of pressure is examination is typically normal. applied. A local twitch response is elicited by manually snapping the trigger point. The involved region may exhibit decreased range Diagnostically, imaging and laboratory studies are used to rule of motion and some pain-related local muscle weakness. out other musculoskeletal conditions or systemic disorders such as hypothyroidism, myopathy, rheumatic disease, and electrolyte or Treatment consists of reassurance regarding the benign nature of nutrient abnormalities. Referral for a sleep study is recommended this disorder, use of analgesics, physical therapy incorporating myo- if a serious sleep disorder, such as sleep apnea or restless legs syn- fascial release techniques and modalities, a home exercise program, drome, is suspected. and trigger point injections and/or acupuncture. Treatment is similar to that for myofascial pain. It should include Fibromyalgia education, stress reduction and relaxation, and a physical therapy program that emphasizes aerobic activity or exercise. Useful medi- Fibromyalgia is a chronic and complex pain syndrome. Patients cations include low-dose tricyclic anti-depressants or selective sero- typically complain of diffuse body pain frequently involving the tonin reuptake inhibitors to normalize sleep and reduce pain, and spinal region. They may also complain of diffuse weakness because simple analgesics such as nonsteroidal anti-inflammatory drugs and their pain limits function and results in deconditioning. Whereas acetaminophen. myofascial pain may involve only one or two regions of the body, the pain of fibromyalgia is widespread and accompanied by mul- Chronic Fatigue Syndrome tiple tender points, which differ from trigger points in their lack of the typical trigger point pain referral pattern. Epidemiologic Chronic fatigue syndrome (CFS) is a group of nonspecific symp- studies show that approximately 2% of the United States popula- toms, and there is much debate regarding whether it is a specific tion and 6%-10% of patients seen in the average medical practice disease entity or merely a syndrome with multiple etiologies. A carry this diagnosis.4,20 Women are affected more frequently than formal definition of the syndrome was proposed in 1994 by an men with initial onset of symptoms in the second or third decade international panel of experts.10 The defining criteria are (1) severe of life. Given the lack of objective clinical findings, the diagnosis chronic fatigue for more than 6 months with no known explana- of fibromyalgia can be delayed for many years leading to un- tion, and (2) at least four of the following symptoms: short term necessary medical treatments and unfortunate desperation on the memory impairment, sore throat, tender lymph nodes, muscle patient’s part. Possible predisposing factors and triggers include pain/ fibromyalgia-like symptoms, joint pain, new headache, unre- physical trauma, psychological stress, and a history of physical or freshing sleep, and postexertional malaise for more than 24 hours. sexual abuse. Genetic predisposition may also play a role in the Many patients also report generalized muscle weakness or fatigue. development of this condition.15 Altered central processing of no- The diagnosis is one of exclusion. CFS is more common in women ciceptive stimuli leading to heightened pain response is thought to than men, and the prevalence is as high as 1 per 10,000 in the be the main pathophysiologic mechanism of fibromyalgia. Spinal United States population.5 fluid abnormalities such as abnormal elevation of substance P and decreased levels of excitatory amino acids, as well as systemic The etiology of CFS is unclear. Viral causes and immune system deficiency of serotonin, have also been postulated as causative dysfunction have been postulated as pathogenic factors, but this factors.16,17,18 A number of other chronic conditions are frequently has not been supported by scientific studies. There is preliminary associated with fibromyalgia. These include chronic fatigue, sleep evidence suggesting elevation of cytokine levels, relative hypoadren- disturbance, myofascial pain, irritable bladder syndrome, irritable alism or relative orthostatic hypotension as etiologic factors, but bowel syndrome, and cognitive dysfunction. these theories require further investigation.

Patients typically present with constant, frequently debilitating, Treatment is symptomatic and includes moderate exercise, a healthy bilateral, widespread pain with an axial predisposition. The pain diet, vitamin supplementation, counseling, and stress reduction. is usually exacerbated by physical activity, stress, lack of sleep, and Nonsteroidal anti-inflammatory drugs and low-dose tricyclic anti- cold and damp weather. The patient might complain of generalized depressants are useful for pain and myalgia. A systematic review of 30 EDX Studies are Not Helpful in Weakness with Normal Neurological Exams AANEM Course the literature found a median full recovery rate of only 5%, but admitted to a rehabilitation hospital in Israel with paralysis ranging 40% of patients improved over time; 8%-30% returned to work in from monoplegia to tetraplegia, 27% had full recovery, 27% had the studies assessing this variable.3 partial recovery, and 46% remained unchanged.12

Polymyalgia Rheumatica In contrast to the patient with a conversion disorder, the malin- gerer consciously feigns weakness for the purpose of secondary gain Polymyalgia rheumatica (PMR) is a rheumatologic syndrome of (compensation for motor vehicle accident, release from work or jail, unknown etiology that may produce neck and trunk pain. The discharge from the army, etc.). In these patients, the symptoms and disease typically develops in patients 50 years of age and older and degree of weakness may fluctuate depending upon who is observing evolves over the course of 4-8 weeks. The diagnosis is primarily the patient. clinical, but suggested diagnostic criteria include: (1) aching and morning stiffness lasting greater than 30 minutes and involving at “Therapeutic Electrodiagnosis” in Patients With Normal least two of the following regions - neck, shoulder girdle, or pelvic Neurologic Examination girdle; (2) age greater than 50; (3) erythrocyte sedimentation rate greater than 40; (4) duration of symptoms greater than 1 month; With the exception of possible poor motor unit activation, the EDX and (5) no other disease present.6 Patients have a normal neurologic study will be normal in patients with myofascial pain syndrome, examination without significant muscle weakness. Diseases that fibromyalgia, chronic fatigue syndrome, PMR, and conversion dis- need to be excluded from the differential diagnosis include various orders. However, in some of these patients the performance of the forms of arthritis, viral myalgia, fibromyalgia, polymyositis, hypo- EDX study does have therapeutic value. Performing the study and thyroidism, depression, and occult malignancy or infection.13 Once explaining the results as one performs the test may help to convince a diagnosis of PMR has been made, it is important to also rule patients that they do not have nerve or muscle pathology. This, in out temporal arteritis which approximately 15% of patients with turn, may facilitate their participation in a multidisciplinary reha- PMR develop. Temporal arteritis, when untreated, can produce bilitation program designed to improve function. visual loss. PMR is quite treatable and responds well to low-dose oral steroids (10-20 mg/day of prednisone). If it is associated with temporal arteritis, higher doses of steroids are required. Acknowledgement

Conversion Disorders and Malingering I would like to thank Dr. Alec Meleger for his assistance with writing the sections on myofascial pain and fibromyalgia. These sec- A small percentage of patients who complain of weakness and tions are adapted from Meleger AL, Krivickas LS. Musculoskeletal have normal neurologic examinations have medically unexplained disorders. Neurol Clin 2007;25:419-438. symptoms and will fall into the category of either a conversion disorder or malingering. In the Diagnostic and Statistical Manual for Mental Disorders, 4th Edition (DSM-IV), conversion disorder is References listed as part of the somatoform disorder group.2 It is also known as Hysterical Neurosis – Conversion type. Patients with this diagnosis 1. Allet J, Allet R. Somatoform disorders in neurologic practice. Curr have neurologic symptoms which may include gait disorders, limb Opin Psychiatry 2006;19:413-420. paralysis, and paraplegia or tetraplegia. In contrast to patients who 2. American Psychiatric Association. Diagnostic and statistical manual of are malingering, their symptoms are not intentionally produced, mental disorder, 4th edition. Washington, DC: American Psychiatric and they have no voluntary control over them. In one recent Association; 1994. study, a surprising 35% of new referrals to the neurology service 3. Cairns R, Hotopf M. A systematic review describing the prognosis met DSM-IV criteria for somatoform disorder,8 and this was more of chronic fatigue syndrome. Occup Med 2005;55:20-31. 4. Campbell S, Clark S, Tindall E, Forehand M, Bennett R. Clinical char- common in outpatients than in inpatients. The etiology of conver- acteristics of fibrositis. I: a blinded, controlled study of symptoms sion disorders is not well understood, but early childhood abuse 1 and tender points. Arthritis Rheum 1983;26:817-824. and stress are thought to play a role. 5. Dawson D. Chronic fatigue syndrome. In: Katirji B, Kaminski H, Preston D, Ruff R, Shapiro B, editors. Neuromuscular disorders The treatment of conversion disorder is often best carried out on an in clinical practice. Boston, MA: Butterworth Heinemann; 2002. p inpatient rehabilitation unit. It should include behavior modifica- 1376-1382. tion, psychotherapy, and physical therapy.11 The degree of recovery 6. Deal C. Polymyalgia Rheumatica. In: Katirji B, Kaminski H, Preston is quite variable. In general, the longer the duration of symptoms, D, Ruff R, Shapiro B, editors. Neuromuscular disorders in clinical the less likely full recovery is to occur. In a series of 30 patients practice. Boston: Butterworth Heinemann; 2002. p 1369-1375. AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 31

7. Filosto M, Tonin P, Vattemi G, Bertolasi L, Simonati A, Rizzuto 15. Offenbaecher M, Bondy B, de Jonge S, Glatzeder K, Kruger M, N, Tomelleri G. The role of muscle biopsy in investigating isolated Schoeps P, Ackenheil M. Possible association of fibromyalgia with muscle pain. Neurology 2007;68:181-186. a polymorphism in the serotonin tansporter gene regulatory region. 8. Fink P, Hansen MS, Sondergaard L. Somatoform disorders Arthritis Rheum 1999;42:2482-2488. among first-time referrals to a neurology service. Psychosomatics 16. Russell I, Vaereroy H, Javors M, Nyberg F. Cerebrospinal fluid bio- 2005;46:540-548. genic amine metabolites in fibromyalgia/ fibrositis syndrome and 9. Fishbain D, Goldberg M, Meagher R, Steele R, Rosomoff H. Male rheumatoid arthritis. Arthritis Rheum 1992;35:550-556. and female chronic pain patients categorized by DSM-III psychiatric 17. Russell I, Orr M, Littman B, Vipraio G, Alboukrek D, Michalek J, diagnostic criteria. Pain 1986;26:181-197. Lopez Y, MacKillip F. Elevated cerebrospinal fluid levels of sub- 10. Fukuda K, Straus S, Hickie I, Sharpe M, Dobbins J, Komaroff A, the stance P in patients with the fibromyalgia syndrome. Arthritis Rheum International Chronic Fatigue Syndrome Study Group. The chronic 1994;37:1593-1601. fatigue syndrome: a comprehensive approach to its definition and 18. Russell I. Neurochemical pathogenesis of fibromyalgia syndrome. J study. Ann Intern Med 1994;121:953-959. Musculoskel Pain 1996;4:61-92. 11. Heruti R, Levy A, Adunski A, Ohry A. Conversion motor pa- 19. Sharrard W. The distribution of the permanent paralysis in the lower ralysis disorder: overview and rehabilitation model. Spinal Cord limb in poliomyelitis; a clinical and pathological study. J Bone Joint 2002;40:327-334. Surg (Br) 1955;37:540-558. 12. Heruti R, Reznik J, Adunski A, Levy A, Weingarden H, Ohry A. 20. Wolfe F, Ross K, Anderson J, Russill I, Hebert L. The prevalence and Conversion motor paralysis disorder: analysis of 34 consecutive characteristics of fibromyalgia in the general population. Arthritis referrals. Spinal Cord 2002;40:335-340. Rheum 1995;38:19-28. 13. Hunder G. Polymyalgia rheumatica: pinning down an elusive syndrome. Contemp Intern Med 1997;9:9-15. 14. Mense S, Simons D, Russell I. Muscle Pain: Understanding its nature, diagnosis, and treatment. Baltimore: Lippincott Williams and Wilkins; 2001. 32 AANEM Course AANEM Course 33

AFTER COMPLETION OF THIS ACTIVITY

Crossfire: Debates in Neuromuscular and Electrodiagnostic Medicine ACTIVITY AND FACULTY EVALUATION

On the Scantron Sheet provided rate how well you perceived the activity to have met your expectations using the following scale for questions 10-19. For questions 20 and beyond, use the scale provided under the question.

A. Extremely

B. Somewhat

C. Very Little

D. Not at all

This CME activity:

10. Addressed my most pressing questions. Instructions for 11. Addressed competencies identified by my specialty. filling out your parSCORE 12. Provided fair and balanced content. sheet

13. Provided clear evidence to support content. Using a #2 pencil, 14. Included opportunities to learn interactively from faculty and fill in your answers participants. beginning with #10:

15. Provided me with supporting materials or tools for my office (re- Leave the completed minders, patient materials, etc.). form at the table out- 16. Included opportunities to solve patient cases. side your session.

17. Translated trial data to patients I see in my practice.

18 Addressed barriers to my optimal patient management.

19. Improved my knowledge/ability in the objectives outlined? Fill in answers here Fill in answers

20. Will you incorporate new elements presented in this educational session into your practice to improve patient care? A. Already do this. B. Yes. C. No. D. Not applicable to my patients.

21. After attending this session, do you expect your management strategies in this clinical area to change within the next 6 months? Written comments can be provided on page 37. A. Definitely will change. B. Possibly will change. C. Definitely will not change. 34 Activity and Faculty Evaluation AANEM Course

22. How would you rate the quality of instruction received during 28. How would you rate the quality of instruction received during Dr. Geiringer’s presentation? Dr. Donofrio’s presentation? A. Best possible. A. Best possible. B. Good. B. Good. C. Average. C. Average. D. Poor. D. Poor. E. Worst possible. E. Worst possible.

23. Did you perceive any commercial bias in Dr. Geiringer’s presenta- 29. Did you perceive any commercial bias in Dr. Donofrio’s presentation? tion? A. Yes. A. Yes. B. No. B. No.

24. How would you rate the quality of instruction received during 30. How would you rate the quality of instruction received during Dr. Werner’s presentation? Dr. Simmons’ presentation? A. Best possible. A. Best possible. B. Good. B. Good. C. Average. C. Average. D. Poor. D. Poor. E. Worst possible. E. Worst possible.

25. Did you perceive any commercial bias in Dr. Werner’s presenta- 31. Did you perceive any commercial bias in Dr. Simmons’ presentation? tion? A. Yes. A. Yes. B. No. B. No.

26. How would you rate the quality of instruction received during 32. How would you rate the quality of instruction received during Dr. Dyck’s presentation? Dr. Krivickas’ presentation? A. Best possible. A. Best possible. B. Good. B. Good. C. Average. C. Average. D. Poor. D. Poor. E. Worst possible. E. Worst possible.

27. Did you perceive any commercial bias in Dr. Dyck’s presentation? 33. Did you perceive any commercial bias in Dr. Krivickas’ presenta- A. Yes. tion? B. No. A. Yes. B. No. AANEM Course 35

Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine

CME SELF-ASSESSMENT TEST

Select the ONE best answer for each question.

34. Which risk factor for carpal tunnel syndrome (CTS) has been 40. Noninvasive testing can determine the cause of peripheral neu- demonstrated to have a dose-response relationship? ropathy in what percentage of patients? A. Hand repetition. A. 20%. B. Diabetes. B. 40%. C. Obesity. C. 60%. D. Height. D. 80%.

35. Which of the following risk factors for CTS has the weakest evi- 41. Which of the following disorders is not a common cause of dence to support it? mononeuritis multiplex? A. Obesity. A. Churg-Strauss angiitis.

B. Vitamin B6 level. B. Periarteritis nodosum. C. Age. C. Sarcoidosis. D. Gender. D. Alcoholism.

36. Genetics has not been demonstrated to play a role in idiopathic 42. To make the diagnosis of sarcoidosis, which of the following tissue CTS. biopsies is as likely to yield noncaseating granulomas as a nerve A. True. biopsy? B. False. A. Bone marrow. B. Muscle. 37. Which of the following medical disorders is not related to a higher C. Skin. risk for the development of CTS? D. Endocardium. A. Diabetes. B. Rheumatoid arthritis. 43. Nerve biopsy can be put to good use to diagnose all of the follow- C. Acromegaly. ing disorders except: D. None of the above. A. Vasculitis. B. Leprosy. 38. The ability to predict who will develop carpal tunnel disease is: C. Polyglucosan body disease. A. Terrible (0-5% of the variance is explained). D. Diabetic distal polyneuropathy. B. Poor (8-17% of the variance explained). C. Fair (22-30% of the variance explained). 44. Fasciculations: D. Reasonable (35-45% of the variance explained). A. Are usually the only presenting syndrome in amyotrophic lateral sclerosis (ALS). 39. The positive yield of an unguided sural nerve biopsy in patients B. Are noted by most healthy medical personnel. with suspected vasculitis is? C. Cannot be a benign finding. A. 20%. D. Usually indicate disease if the needle electromyography is B. 40%. otherwise normal. C. 60%. D. 80%. 36 CME Self-Assessment Test AANEM Course

45. In patients with a normal neurological examination, electrodi- 50. Trigger points may be caused by: agnostic (EDX) studies may be helpful in diagnosing all of the A. Focal denervation of muscle. following except: B. Muscle fiber necrosis. A. CTS. C. Spasticity. B. Lambert-Eaton myasthenic syndrome (LEMS). D. Excessive motor end-plate activity. C. Motor neuron disease (MND). D. Normal pressure hydrocephalus. 51. A diagnosis of fibromyalgia requires: A. Presence of trigger points. 46. A cardiomyopathy, a normal neurological examination, and an B. Presence of tender points. abnormal EDX study may be the presenting features of: C. Sleep disturbance. A. Becker muscular dystrophy. D. Exercise intolerance. B. LEMS. C. Benign fasciculations. 52. What is the best treatment for polymyalgia rheumatica? D. MND. A. Amitryptiline. B. Aerobic exercise. 47. Individuals with no neurological disease in whom muscle strength C. Low-dose prednisone. testing is limited by pain may demonstrate: D. High-dose prednisone. A. Reduced recruitment. B. Reduced activation. 53. A patient who feigns weakness to obtain release from work is best C. Fibrillation potentials. described as having: D. Large amplitude motor unit action potentials. A. A conversion disorder. B. Hysterical neurosis. 48. The rate of change of which of the following is most sensitive for C. Somatoform disorder. detecting changes in patients with slowly-progressive ALS? D. Malingering disorder. A. Compound muscle action potential amplitude. B. Grip strength. C. Motor unit number estimation. D. Manual muscle testing.

49. What percentage of motor neurons must be lost for muscle weakness to be detectable on manual muscle testing? A. 10%. B. 20%. C. 40%. D. 60%. AANEM Course 37

COMMENTS

Write out any additional comments about specific courses or the plenary session (please indicate which), and list suggestions for topics and speakers for future meetings. Leave at the AANEM Registration and Information Center or mail to the AANEM Executive Office at 2621 Superior Drive NW, Rochester, MN 55901. Other AANEM Learning Opportunities PRINT ONLINE Course Handouts Podcasts Workshop Handouts Teleconferences CD-ROMs Case Studies Case Reports Coding and Billing Videotapes Invited Reviews Brochures Practice Guidelines Monographs TPSAEs

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