2007 AANEM Course H

AANEM 54thAnnual MeetingPhoenix, Arizona

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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

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2007 COURSE H AANEM 54th Annual Meeting

Phoenix, Arizona

Copyright © October 2007 American Association of Neuromuscular & Electrodiagnostic Medicine

2621 Superior Drive NW Rochester, MN 55901

Printed by Johnson Printing ComPany, inC.

Steve R. Geiringer, MDRobert A. Werner, MD, MS

P. James B. Dyck, MDPeter D. Donofrio, MDZachary Simmons, MDLisa S. Krivickas, MD

Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine

Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine

Faculty

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Steve R. Geiringer, MDClinical ProfessorDepartment of Physical Medicine and RehabilitationWayne State UniversityWestland, MichiganDr. Geiringer graduated from medical school and physical medicine and rehabilitation (PMR) residency training at the University of Michigan Medical School in Ann Arbor. He spent 9 years as faculty there before moving to the Wayne State University School of Medicine in 1991, where he remains as a clinical professor. Dr. Geiringer’s solo clinical practice is devoted to acute and subacute musculoskeletal medicine and electrodi-agnostic medicine. He is a director of the American Board of PMR, and the chair of its Credentials Committee. He also serves as the chair of the Medical Education committee for the American Academy of PMR, which oversees all educational efforts of that organization. Dr. Geiringer’s hand-book, Anatomic Localization in Needle Electromyography, is used worldwide, and he has lectured extensively on that and other topics comprising the realm of his practice.

Robert A. Werner, MD, MSProfessorDepartment of Physical Medicine and RehabilitationAnn Arbor VA Medical CenterAnn Arbor, MichiganDr. Werner is a professor in the Department of Physical Medicine and 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 physi-cal 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.

P. James B. Dyck, MDAssociate ProfessorDepartment of NeurologyMayo Clinic College of MedicineRochester, MinnesotaDr. Dyck is a consultant in neurology at Mayo Clinic Rochester, and is an associate professor of neurology at the Mayo Clinic College of Medicine. Dr. Dyck received his medical degree from the University of Minnesota; performed a neurology residency at Washington University in St. Louis; and performed peripheral nerve, electromyography (EMG), and research fellowships at the Mayo Clinic, where he he joined the neurology faculty in 1999. Dr. Dyck is Director of the Peripheral Nerve Neuromuscular Pathology Laboratory; the head of the peripheral nerve section; and a board member of the United Council of Neurologic Subspecialties. He re-ceives research support from a National Institute of Neurological Disorders and Stroke grant. His main research interest has focused on the histopa-thology of nerve in diabetic and nondiabetic lumbosacral radiculoplexus 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 approach, Dr. Dyck has pioneered the use of high-resolution magnetic resonance imaging to identify focal or multifocal nerve lesions in proximal nerves (nerve root, plexus, or proximal nerve), that are then biopsied to identify the histopathology. This targeted fascicular nerve biopsy approach improves the physician’s ability to detect, characterize, and treat focal nerve lesions of proximal nerves and represents a major new advance in diagnosis and management.

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.

Peter D. Donofrio, MDProfessorDepartment of NeurologyChiefNeuromuscular SectionVanderbilt UniversityNashville, TennesseeDr. Donofrio is a graduate of The Ohio State University School of Medicine. He completed a medicine residency at Good Samaritan Hospital in Cincinnati, Ohio, and a neurology residency and neuro-muscular fellowship at the University of Michigan. After several years on the faculty at the University of Michigan, he moved to Wake Forest University where he remained for 20 years before moving to Vanderbilt University Medical Center in 2006. He is Professor of Neurology and Chief of the Neuromuscular Section, the EMG Laboratory, the Muscular Dystrophy Aassociation Clinic, and the Amyolateral Sclerosis (ALS) Clinic at Vanderbilt. His research interests included clinical trials in ALS, inflam-matory neuropathies, and electrodiagnosis of peripheral neuropathy. Dr. Donofrio has served on the Board of Directors of the AANEM and is currently President-elect of the organization.

Zachary Simmons, MDProfessorDepartment of NeurologyPenn State UniversityDirectorNeuromuscular Program and Clinical Neurophysiology LaboratoryPenn State Hershey Medical CenterHershey, PennsylvaniaDr. 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, cogni-tive 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 Examination Committee.

Lisa S. Krivickas, MDAssociate ProfessorDepartment of Physical Medicine and RehabilitationHarvard Medical SchoolBoston, MassachusettsDr. Krivickas is Associate Professor of Physical Medicine and Rehabilitation (PMR) at Harvard Medical School, Associate Chief of PMR at Massachusetts General Hospital, and Director of EMG at Spaulding Rehabilitation Hospital. She received her medical degree from Harvard Medical School. She completed a residency in PMR at the University of Medicine and Dentistry, New Jersey, New Jersey Medical School and Kessler Institute of Rehabilitation, and a fellowship in EMG and neuromuscular disease at the Cleveland Clinic. Dr. Krivickas’ current research involves the study of muscle physiology in neuromuscular disor-ders and aging, investigation of new electrophysiologic techniques for the assessment of neuromuscular disorders, and clinical trials for amyotrophic lateral sclerosis, and other neuromuscular diseases. She is a director on the American Board of Electrodiagnostic Medicine and a member of the Neuromuscular Medicine Examination Committee of the American Board of Psychiatry and Neurology. In 2006, she received the Young Academician Award from the Association of Academic Physiatrists.

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Authors had nothing to disclose.

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 indi-cated 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.

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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 1Steve R. Geiringer, MD

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

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

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

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

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

Activity and Faculty Evaluation 33

CME Self-Assessment Test 35

Objectives—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.

Prerequis ite—This course is designed as an educational opportunity for residents, fellows, and practicing clinical EDX physi-cians 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.

AccreditAtiOn stAtement—The AANEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians.

cme credit—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

A. Extremely

B. Somewhat

C. Very Little

D. Not at all

It is important that the CME activity:

1. Address my most pressing questions.

2. Address competencies identified by my specialty.

3. Provide fair and balanced content.

4. Provide clear evidence to support content.

5. Include opportunities to learn interactively from faculty and par-ticipants.

6. Provide me with supporting materials or tools for my office (re-minders, patient materials, etc.).

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.

Pre-activity Questions

BEFORE YOU BEGIN THIS ACTIVITYWe 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:

Fill

in an

swer

s here

Instructions for filling out

your parSCORE sheet

Using a #2 pencil, fill in your answers beginning with ques-tion #1.

After completion of this activity, go to the back of the book and fill in your answers beginning with ques-tion #10.

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

viii

Thomas Hyatt Brannagan, III, MDNew York, New York

Brian A. Crum, MDRochester, Minnesota

Erick A. Grana, MDTampa, Florida

Subhadra Nori, MDBronx, New York

Thomas Y.C. Pang, MDChicago, Illinois

T. Darrell Thomas, MDKnoxville, Tennessee

Simon Zimnowodzki, MDChicago, Illinois

Sasa Zivkovic, MDPittsburgh, Pennsylvania

2006-2007 AANEM PRESIDENT

Kathryn A. Stolp, MD, MSRochester, Minnesota

2006-2007 AANEM COURSE COMMITTEE

Anthony E. Chiodo, MD, ChairAnn Arbor, Michigan

INTRODUCTION

It is commonly held knowledge that carpal tunnel syndrome (CTS) is the most prevalent of all entrapment neuropathies. It is by far the most common condition encountered by electrodiagnostic (EDX) physicians across the country, and any argument otherwise would be widely seen as nonsense.

It is also universally accepted that there are myriad intrinsic predis-posing factors for CTS. Chief among these are pregnancy, obesity, smoking, diabetes, female gender, and being a postmenopausal woman. None of these predisposing factors would appear to be in dispute.

Based on informal conversations among peers, a thorough literature review, and this author’s 25 years of experience with electrodiagno-sis in the realm of musculoskeletal medicine, it is widely accepted that CTS is often related to ergonomic and exposure factors in the work place. These include forceful gripping, direct pressure applied to the carpal ligament area at the heel of the palm, vibration expo-sure, and exposure to cold temperatures, especially when one or any combination of the above occurs in repetitive fashion.

Why, then, is there a debate about whether CTS is work-related? This author has seen reports from “defense” physicians who are typically part of an independent medical evaluation that attempt to make the counterargument. The most common tack is to dem-onstrate, through the use of nerve conduction studies (NCSs), that a worker with median entrapment symptoms on one side only has bilateral electrical abnormalities. Using this line of reasoning, the patient has a preexisting, nonwork-related condition on both sides. If the patient’s CTS is in fact work-related, as the defense physician

would conclude, the nonsymptomatic hand would show normal NCS results.

The flaw in this argument also should be common knowledge. It is well known that the entrapment syndrome is often unilaterally symptomatic. Up to 80% of contralateral hands will show conduc-tion abnormalities; however, in nearly all cases, the dominant hand becomes symptomatic. In this author’s experience, the exceptional cases arise because the nondominant hand happens to be doing the lion’s share of the offending activity that led to the CTS. An inher-ent component of this is the difference between an entrapment neuropathy that one can detect with careful NCSs and a clinically relevant syndrome.

RELEVANCE OF WORK-RELATEDNESS

Why does it matter whether or not CTS is actually related to work activities? There are several important reasons; the first is how to treat it. There are different treatment recommendations depending on the patient’s work activities, but if the CTS was not work-re-lated, there would be no need for work modifications (e.g., impact gloves or restricted duty). Treatment responsibility is another factor. The Worker’s Compensation system would not be responsible for the patient’s CTS if there were no relationship between CTS and the patient’s work. Instead, the patient’s sickness and accident insurance would be responsible. However, in some jurisdictions, the line is blurred. For example, in Michigan, if an employee with preexisting CTS and a history of diabetes has their CTS ag-gravated by work activities, the employer is responsible for 100% of the treatment until the employee returns to preinjury baseline. Financially, if an employee required time off from work for CTS

Carpal Tunnel Syndrome Usually Is Occupationally Related

Steve R. Geiringer, MDClinical Professor

Department of Physical Medicine and RehabilitationWayne State University

Westland, Michigan

treatment, he or she would not be eligible (in typical scenarios) for extensive (if any) medical and/or lost wage benefits if the CTS was not work-related. Finally, if the patient’s CTS was not work-related, this author speculates there would be little incentive for employers to study the ergonomics of offending jobs, tools, or postures in order to prevent the condition.

LITERATURE REVIEW

As of June 2007, there were more than 6000 articles found on a PubMed literature search conducted for “carpal tunnel syndrome” (no limits were attached to this search). After adding search limits for the “English language” and “human studies only”, 75% of those articles remained. After adding the criterion of a random-ized, controlled trial, only 158 articles remained. The remaining 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 techniques that correlated best with surgical outcomes, and the use of different anesthetics, corticosteroids, and/or the number of injections of each of these materials.

What will not be found is even one article categorized as random-ized and controlled that pertains to whether CTS is work-related. When searching for “carpal tunnel syndrome work-related,” five articles are found and none address the primary issue of work-relatedness. The only two that come close compare the ergonomics of different handles for dental tools.

When one searches for “CTS work-related” and limits on the type of article are removed, 183 articles result. All anecdotal and case reports were then removed, as well as all publications that did not directly address the issue currently under debate—which unfortu-nately comprised the great majority. The outcome was 20 articles; some were prospective in design, some had controls, and none were randomized or blinded.1-7,9-17,19-22

Even this relatively small sample of articles led to some interesting observations. For example, within these articles, the inclusion of patients as having verifiable CTS was based on: having had surgical release; EDX testing (approximately 5 of the 21 articles); physical 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 employer; or a combination of all of these factors (distressingly seldom).

Most of these articles started with an assumption, i.e., that it was a “given” that CTS is work-related. So much for Cochrane criteria; it is no wonder that careful research design is not found in this cohort of articles. The conclusions included that CTS is correlated with: number of years worked; repetitiveness of the job; vibration exposure; working full-time compared with part-time; ergonomic factors; and the “workload.”

One article that studied dental hygienists21 was equivocal about whether the CTS diagnosed was work-related. The other 19 articles

concluded, most with no uncertainty, that in some patients CTS is definitely work-related. Of course, there might also be personal or intrinsic factors, as noted earlier. These studies included the fol-lowing occupations:

Video-display terminal operators•Clerical•Television assembly•Auto assembly•Manufacturing/assembly•Grocery workers•Typists •Meat/fish processors•Operators of orbital sanders•Cashiers •Dental hygienists•

Apart from the 20 citations just covered, 2 articles8,18 raised doubt about the otherwise widely accepted conclusion that CTS can arise from job factors. Both of these articles were published by Australian authors in the Australia New Zealand Journal of Surgery. One article is single-authored by a medicolegal consultant who is clear about his preconceived notion that CTS only arises from personal factors.18 The first author of the other article8 is a government employee in New South Wales. The only work factor he allows as a factor leading to CTS is prolonged exposure to extreme cold, as with butchers. Otherwise, he concludes that resources are inap-propriately allocated, because no other work factors are primary causes of CTS. He does allow that the other job components men-tioned earlier could be the “last straw” in the course of CTS, but it never occurs without some predisposing factor that is personal in nature.

What follows is a passage from the abstract of one of the articles in support of CTS having work-related causes: “CTS is common in the industrial setting, but there are still some advocates who argue that CTS is not a work-related problem.” It concludes with “CTS has both work-related and personal risk factors.” This thoughtful, useful article19 takes a common-sense, understandable, and defensi-ble approach, that while there are certainly personal contributors, it is quite clear that there are offending work-related factors as well.

SUMMARY

What has this exercise taught us? First, any attempt to identify literature that applies careful research criteria to the question of the work-relatedness of CTS fails. There simply are no such studies, at least none that incorporate all or most of the design features this author would like to see.

Having said that, consensus of expert opinion does qualify as one level of “evidence.” Nineteen of the 20 articles reviewed in this search concluded that CTS can be related to work factors, although not exclusively so. The lone dissenter was only equivocal—not negative—on that question. The other articles lean more toward “opinion pieces” or editorials that reflect the “conventional wisdom”

2 CTS Usually is Occupationally Related AANEM Course

dictated by the authors’ employment situations. Overall, there is no disputing that expert consensus exists here: while personal factors are also pertinent, CTS is definitely work-related.

REFERENCES

1. Abbas MA, Afifi AA, Zhang ZW, Kraus JF. Meta-analysis of pub-lished studies of work-related carpal tunnel syndrome. Int J Occup Environ Health 1998;4:160-167.

2. Abbas MF, Faris RH, Harber PI, Mishriky AM, El-Shahaly HA, Waheeb YH, Kraus JF. Worksite and personal factors associated with carpal tunnel syndrome in an Egyptian electronics assembly factory. Int J Occup Environ Health 2001;7:31-26.

3. Bekkelund SI, Pierre-Jerome C, Torbergsen T, Ingebrigtsen T. Impact of occupational variables in carpal tunnel syndrome. Acta Neurol Scand 2001;103:193-197.

4. Bonfiglioli R, Mattioli S, Fiorentini C, Graziosi F, Curti S, Violante FS. Relationship between repetitive work and the prevalence of carpal tunnel syndrome in part-time and full-time female supermar-ket cashiers: a quasi-experimental study. Int Arch Occup Environ Health 2007;80:248-253.

5. Bonfiglioli R, Mattioli S, Spagnolo MR, Violante FS. Course of symptoms and median nerve conduction values in workers perform-ing repetitive jobs at risk for carpal tunnel syndrome. Occup Med (Lond) 2006;56:115-121.

6. Bovensi M, Della Vedova A, Nataletti P, Alessandrini B, Poian T. Work-related disorders of the upper limb in female workers using orbital sanders. Int Arch Occup Environ Health 2005;78:303-310.

7. Davis L, Wellman H, Punnett L. Surveillance of work-related carpal tunnel syndrome in Massachusetts, 1992-1997: a report from the Massachusetts Sentinel Event Notification System for Occupational Risks (SENSOR). Am J Ind Med 2001;39:58-71.

8. Falkiner S, Myers S. When exactly can carpal tunnel syndrome be considered work-related? ANZ J Surg 2002;72:204-209.

9. Gell N, Werner RA, Franzblau A Ulin SS, Armstrong TJ. A longi-tudinal study of industrial and clerical workers: incidence of carpal tunnel syndrome and assessment of risk factors. J Occup Rehabil 2005;15:47-55.

10. Giersiepen K, Eberle A, Pohlabein H. Gender differences in carpal tunnel syndrome? Occupational and non-occupational risk factors in 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.

12. Lam N, Thurston A. Association of obesity, gender, age and occupa-tion with carpal tunnel syndrome. ANZ J Surg 1998;68:190-193.

13. Latko WA, Armstrong TJ, Franzblau A, Ulin SS, Werner RA, Albers JW. Cross-sectional study of the relationship between work and the prevalence of upper limb musculoskeletal disorders. Am J Ind Med 1999;36:248-259.

14. Matias AC, Salvendy G, Kuczek T. Predictive models of carpal tunnel syndrome causation among VDT operators. Ergonomics 1998;41:213-216.

15. Melchior M, Roquelaure Y, Evanoff B, Chastang JF, Ha C, Imbernon E, and colleagues. Why are manual workers at high risk of upper limb disorders? The role of physical work factors in a random sample of workers in France (the Pays de la Loire study). Occup Environ Med 2006;63:754-761.

16. Nordstrom DL, Vierkant RA, DeStefano F, Layde PM. Risk factors for carpal tunnel syndrome in a general population. Occup Environ Med 1997;54:734-740.

17. Roquelaure Y, Ha C, Leclerc A, Touranchet A, Sauteron M, Melchior M, and colleagues. Epidemiologic surveillance of upper-extremity musculoskeletal disorders in the working population. Arthritis Rheum 2006;55:765-778.

18. Stapleton MJ. Occupation and carpal tunnel syndrome. ANZ J Surg 2006;76:494-496.

19. Werner RA. Evaluation of work-related carpal tunnel syndrome. J Occup Rehabil 2006;16:207-222.

20. Werner RA, Franzblau A, Gell N, Hartigan AG, Ebersole M, Armstrong TJ. Incidence of carpal tunnel syndrome among auto-mobile assembly workers and assessment of risk factors. J Occup Environ Med 2005;47:1044-1050.

21. Werner RA, Hamann C, Franzblau A, Rodgers PA. Prevalence of carpal tunnel syndrome and upper extremity tendinitis among dental hygienists. J Dent Hyg 2002;76:126-132.

22. Yagev Y, Carel RS, Yagev R. Assessment of work-related risk factors for carpal tunnel syndrome. Isr Med Assoc J 2001;3:569-571.

AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 3

4 AANEM Course

NON WORK-RELATED RISK FACTORS AND CTS

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 growing numbers of investigators in Europe, Japan, and the United States are reporting associations between nonbiomechanical aspects of work and CTS.

To fully understand the etiology of musculoskeletal disorders, it is important to examine physical and health-related factors intrinsic to the individual worker in addition to work-related biomechanical and nonbiomechanical factors. For example, age, obesity, chronic 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-sonal characteristics of the worker, and the relative strength of the biomechanical versus personal characteristics.

Personal Factors

There are many personal co-factors that have been related to the development of CTS (Table 1). Obesity (body mass index [BMI]), square wrist configuration, small carpal canal area, diabetes, as well as several other connective tissue disorders and poor general fitness have all been associated with higher prevalence of CTS. The ulti-mate mechanism of injury is likely ischemia; therefore, anything that influences the health of the vascular system may compromise the soft tissues (e.g., nerve, muscle, and tendon).

Several investigators have suggested that CTS is a primary result of health habits and lifestyle and secondary to biomechanical stress.40-

45,58,59 Of the numerous personal co-factors reported, only a few have demonstrated a statistical significant association. In instances where the relative risk has been determined, attempts at modeling the disease based upon these factors have only explained a small percentage of the variance. The same limitation can be stated re-garding the strength of work-related factors. When modeling the incidence of CTS using both ergonomic and nonwork-related risk factors, the studies have not demonstrated a significant ergonomic risk factor. Those studies that have demonstrated a significant work-related factor have consistently demonstrated that nonwork-related factors explain an overwhelming majority of the variance in the model.

5

Carpal Tunnel Syndrome is Usually Not Occupationally Related

Robert A. Werner, MD, MSChief

Department of Physical Medicine and RehabilitationAnn Arbor VAMC

University of Michigan Health SystemAnn Arbor, Michigan

Table 1 Nonbiomechanical Risk Factors for Carpal Tunnel Syndrome

Medical Conditions: diabetes, rheumatoid arthritis, thyroid disease, connective tissue disorders, vitamin B6 deficiency, pregnancyBody Mass Index: Weight, StatureGenderWrist dimension/Anatomical size and shape of the carpal canalAgeGeneral conditioning: strength, aerobic conditioningGenetics

The National Academy of Science reviewed the epidemiologic evidence that nonmechanical factors were associated with CTS and found strong epidemiologic evidence for a positive associa-tion between the development of CTS and increasing age, certain medical conditions, higher BMI, and gender. Other factors were less well-established (e.g., genetics, general conditioning, psycho-logical issues, and wrist dimension).20

Systemic Disorders

Many systemic disorders place an individual at higher risk for the development of soft tissue injuries. Diabetes and rheumatoid arthritis are the most obvious risk factors affecting the develop-ment of overuse syndromes.2,4,54,55 Rheumatoid arthritis patients, as well as those with other connective tissue disorders, are at higher 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 other compression mononeuropathies.2,54 Stevens and colleagues54 calculated a standardized morbidity ratio for rheumatoid arthritis (3.6), diabetes (2.3), and pregnancy (2.5). Thyroid disease and kidney disease also have many connective tissue side effects placing the individual at higher risk for nerve injuries. Thyroid disease may also lead to muscle disease. Systemic disease causes the nerves to be more susceptible to compression and ischemia. The biologic plau-sibility of this association is high and the association is strong, but these disorders affect a small percentage of active workers. Atcheson and colleagues4 suggest that these disorders are more common among workers diagnosed with CTS compared to other cumulative trauma disorders and may be under-recognized in the industrial setting. The studies reviewed in this area use a methodology based upon population-based data or large cross-sectional data. There is little bias associated with sample selection and the statistics are ap-propriate for the sample.

Vitamin B6

In 1973, Ellis and Presley17-19 suggested an association between vitamin B6 deficiency and CTS. Over the next two decades, several additional reports appeared which suggest that this association is causal in many cases. The impact of these studies on physician understanding and treatment of CTS is substantial. Vitamin defi-ciency is mentioned in a prominent textbook of occupational medi-cine34 as a possible CTS risk factor, implying that such deficiency contributes to CTS among workers.

Unfortunately, the studies which demonstrate an association between vitamin B6 status and CTS usually include small numbers of non-randomly selected subjects, frequently rely on nonstandard or entirely subjective measures of outcome, and occasionally suffer from serious design flaws. Recent prospective and population-based 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 are without the selection bias of earlier studies and use appropriate statistical analysis. The recent study by Keniston and colleagues33 suggesting a relationship between vitamin B6 deficiency, vitamin C, and CTS (among women but not men) has methodological as well as statistical flaws.24

The biologic plausibility is moderate. However, the strength of the relationship is weak, except in severe vitamin B6 deficiency (which is rare). The cross-sectional studies of active workers and population-based studies are sound enough to claim that there is not a significant relationship between B6 levels and CTS.

Pregnancy/Gynecologic History

Pregnancy is considered an independent risk factor (estimated RR of 2.5) for the development of CTS due to increased vasculature and interstitial fluids.30,36,52,54 These studies have adequate sample size and statistical analysis. This is a strong association with strong biologic plausibility. Fortunately, this condition is time-limited and there is usually resolution of symptoms at the end of the pregnancy or shortly thereafter.

Both the use of oral contraceptives and gynecologic surgery have been hypothesized as risk factors for CTS based on epidemio-logical data, but this has not been consistently identified as a risk factor.11,14,51 The biological significance and rationale for this is not well-established, although increased interstitial fluid as a result of hormonal changes is a suggested mechanism. This is a weak as-sociation with modest biologic plausibility. These studies are large cross-sectional studies with statistically significant findings in some of the studies, but the clinical significance is low.

Body Mass Index

Several investigators have reported that individuals with CTS were heavier and shorter than the general population. Cannon and col-leagues11 noted that 27% of individuals (8 of 30) with CTS were obese compared to 12% (11 of 90) in a control population; this difference did not reach statistical significance. Dieck and Kelsey15 found an increased prevalence of CTS within an adult female population among individuals with short stature, greater weight, and recent weight gain. The BMI was significantly higher in the CTS group (27 kg/m2 versus 25 kg/m2, p = 0.01). Vessey and col-leagues57 found that the risk for CTS among obese women was double that of slender women.

Within an industrial population, Nathan and colleagues45 demon-strated that a higher BMI was associated with a higher prevalence of median mononeuropathy. They found a relative risk of 4.1 for obese individuals compared to slender individuals. This relation-ship was more pronounced in men (RR=5.1) than in women (RR=2.7). This study did have a number of methodological flaws of which the most prominent was an analysis by the number of hands instead of by the number of patients in the study. The findings of Werner and colleagues58,60 support the hypothesis that individuals with a higher BMI are at increased risk for CTS.

In terms of obesity, the pathophysiology that would explain this relationship is not well understood. Letz and Gerr28 found the same relationship between obesity and slow conduction of the median nerve across the wrist in a large population-based study, but an inverse relationship was found between obesity and other periph-eral nerve measures. The conduction velocity of the peroneal, sural,

6 CTS Usually is Not Occupationally Related AANEM Course

and ulnar nerves all tended to improve among subjects who were more obese whereas only the median sensory nerve across the wrist demonstrated slowing. The finding that BMI is correlated with the median but not ulnar sensory distal latencies suggest that the condition of obesity affects the nerves differently. The additional finding that the difference in the latencies is more strongly corre-lated with BMI than the median latency alone further supports this contention. This large cross-sectional study of Vietnam veterans has greater validity due to the large sample size (more than 6000) and the uniformity in electrodiagnostic testing.

If a causal relationship between obesity and a slowing of median conduction across the wrist exists, it may relate to increased fatty tissue within the carpal canal or to increased hydrostatic pres-sure throughout the carpal canal in obese individuals compared to normal or slender individuals. The median nerve at the wrist is more compartmentalized than the ulnar, peroneal, or sural nerves and may be subjected to compression due to fatty build-up within the carpal canal among obese individuals. Conversely, heavier individuals may simply place more mechanical stress on their hands and wrists and thus place the median nerve at higher risk as opposed to some intrinsic change within the carpal canal. The possible association between obesity and the development of early type II diabetes may be a confounder, but is not related to the workers’ report of diabetes. Alternatively, thinner subjects may be a surrogate of a person’s overall conditioning which may in turn influence the performance of the median nerve. Thinner subjects may be healthier and thus their nerves are healthier and perform better when tested. Their thinness is not the important issue, health is the issue but they may be go hand in hand. There is a very strong association between obesity and the health of the median nerve. The more obese the patient, the worse the nerve function. There appears to be a strong dose-response relation-ship between obesity and nerve function: when one goes up, the other closely follows. Studies on obesity and median nerve health are either case control or large cross-sectional studies with sound statistical analysis. The biologic plausibility is still under question. Whether this is based upon biomechanical or metabolic factors is not known. The pathophysiology that would explain this relation-ship is not well understood. Although this is a strong relationship with an apparent dose-response effect, this factor at best explains only a small portion of the variance (less than 8%) related to the diagnosis of CTS or electrodiagnostic abnormalities involving the median nerve.41,45,58,60 Despite the small amount of the variance explained by obesity, the addition of work-related factors did not substantially improve the model. Nathan and colleagues41,42 did not find any significant work-related factor in their model while Werner and colleagues60 found some independent ergonomic risk factors. However, these factors contributed little to the strength of the model.

Gender

Gender has been suggested as an independent risk factor for the development of CTS.5,8,32,47,48,55,56 This risk factor is not well ex-plained although historically women had a higher use of the health care system and this may represent another spectrum of higher use.

The finding that women were more likely to have a higher prevalence of CTS than men is supported by population-based studies54,55 but differs from the worker compensation-based data on CTS reported by Franklin and colleagues.23 In the workplace, the risk for women is only 10%-20% higher than men as opposed to 300% reported in population-based studies (Franklin and col-leagues23; and Werner and colleagues60). It was believed that the carpal canal was smaller in women thus exposing them to more compression of the median nerve. Further investigation of carpal canal dimension among women has not demonstrated any relation-ship between CTS and canal dimensions (as discussed below).

Wrist Size and Carpal Tunnel Syndrome

A narrow carpal canal, a squarer shape of the wrist, and a smaller sized hand have all been associated with a higher prevalence of CTS.9,27,31,39,61 This is a moderately strong association with high biologic plausibility.

Several studies have demonstrated a relationship between a more square shaped wrist and a finding of median mononeuropathy at the wrist,31,49 but this relationship was not confirmed by other studies.60 The relationship described by Radecki49 was in a clinic population of referred patients while the population studied by Werner and colleagues60 was a random selection of active workers, regardless of symptoms. The pathophysiology of this association, if it exists, has not been demonstrated. A squarer wrist has not been associated with a smaller cross-sectional area although this mecha-nism has been proposed. This is a relatively weak association with poor biologic plausibility.

Anomalous muscles extending into the carpal canal have been reported as etiologies for CTS.6,7,10,12,46 Muscle variants implicated include the muscle bellies of the flexor superficialis, palmaris longus, lumbrical muscles, abductor digiti quinti, and the acces-sory palmaris longus muscle. These are rare occurrences and do not account for the typical person with CTS. Likewise, there are other space-occupying lesions such as lipoma, haemangioma, synovial sarcoma, tendon sheath fibroma, ganglion, or calcified mass that have been reported as etiologies of CTS, but these are also rare oc-currences. This is a strong association with high biologic plausibil-ity but again represents a rare anatomical variant.6,46

Aging and Carpal Tunnel Syndrome

Increasing age has consistently been associated with slowing of the median nerve across the wrist and the incidence of CTS.16,35,45,53,58 These studies have consistently demonstrated a strong association with high biologic plausibility. Tissue repair declines with aging and may be the basis for this relationship.

General Fitness

There has been an association between lower exercise levels and a higher prevalence of CTS as well as slowing of the median nerve across the carpal canal.43 Most studies demonstrate a close cor-relation between poor general fitness with higher BMI, alcohol/tobacco use, and age of the patient. Even when general fitness is

AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 7

identified as a significant independent factor, it only accounts for a small component of the variance (3% or less). However, this is as large an influence as most ergonomic factors have shown.43 The association between general fitness and CTS is modest, but it is still stronger than most independent ergonomic risk factors.

Genetics

There are a limited number of studies that explore the relationship between specific genetic markers and the incidence of CTS.13,50 It is clear that genetics plays a role in the risks associated with gender, obesity, carpal canal size, and several connective tissue disorders, but apart from these relationships, the role of genetics in the etiology of CTS is not well-established. Radecki50 demonstrated a higher prevalence of carpal canal surgery or clinical history of CTS among family members with a documented slowing of the median nerve at the wrist compared to the families of other pa-tients without slowing of the median nerve. There were 27% of subjects with a documented median mononeuropathy who had a positive family history of CTS compared to 13% without evidence of median mononeuropathy (p<0.001). The familial occurrence of CTS has usually been reported as one or two families involving two or three generations. An autosomal dominant inheritance has been postulated. The mechanism for a hereditary etiology for CTS is unclear, but may relate to a thicker carpal tunnel ligament, smaller carpal canal or altered geometry, or it may be related to obesity. Although the sample sizes in these studies are relatively small, the relationship is robust and suggests a strong association. More study is necessary to establish the strength of the relationship.

Longitudinal Studies

There are few longitudinal studies that have assessed work and personal attributes as they relate to the development of CTS.26,29,40,41,42,59 In 1984, Nathan and colleagues40,41,42 initiated a prospective study of factors associated with research-defined CTS in 471 industrial workers. They assessed the medical history, lifestyle factors, and job tasks. The CTS case status was based on 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 increased risk of CTS. There were 256 still in the study by 1998 and 166 participants were successfully reexamined in 2001-2002. An analysis of baseline risk factors showed that fewer repetitive tasks at work, female gender, and greater relative weight were asso-ciated with any occurrence of CTS during follow-up. In an analysis of aggregate risk factor scores from the 1994 to 1995 study, only greater relative weight and female gender were associated with CTS in the 2001 to 2002 follow-up study. Although obesity and gender are consistent predictors of CTS, workplace demands appear to bear an uncertain relationship to CTS.

Gell and colleagues26 followed workers in five different industrial and clerical settings over an extended period of time to identify factors which may influence the onset of CTS. The purpose of the study was to evaluate incidence of CTS and to create a predic-

tive model of factors that play a role in the development of CTS. This prospective longitudinal study followed 432 workers over 5.4 years. Incident cases were defined as workers who had no prior history of CTS at baseline testing and who were diagnosed with CTS during the follow-up period or at the follow-up screening. Based on logistic regression, significant predictors for CTS in-cluded a baseline prolongation of the median-ulnar peak latency difference, a history of wrist/hand/finger tendonitis, a history of numbness, tingling, burning, and/or pain in the hand, and work above the action level of the “peak force and hand activity level” threshold limit value (TLV) (as defined by the American Congress of Government Industrial Hygienists).1 The majority of the vari-ance explained came from the nonwork-related risk factors. The peak force/hand activity level threshold explained a minimum of the model variance.

Werner and colleagues59 reported a longitudinal study of workers from an auto assembly plant in the southern United States. Of the 1700 assembly plant workers, 475 agreed to participate in the study, but only 279 subjects completed the initial detailed symptom questionnaire and sensory nerve conduction studies. There were 189 workers who completed the 13-month follow-up evaluation. This study identified diabetes as a significant predictor of new onset CTS. Several prior cross-sectional studies had demonstrated a threefold increase in CTS among diabetics both in the workplace and the general population. They found a 6.5-fold increase in inci-dent CTS cases among diabetics. This study demonstrated that an obese person (i.e., BMI=30) was 2.5 times more likely to develop CTS compared to person with a normal person (BMI=25) even when controlling for diabetes. They found a fourfold increase in the risk of CTS among female workers, but the 95% confidence interval included 1.0 and therefore was not statistically significant, although the trend was in the same direction as previous studies. They did not find that hand repetition or force were significant predictors. Elbow posture was a significant risk factor although the proportion of the variance explained by this variable was nominal, i.e., the nonmechanical factors, were much more prominent in predicting incident cases of CTS.

CONCLUSION

The nonbiomechanical risk factors for developing CTS are the most predictive factors in determining who will develop CTS. Biomechanical factors may also play a role but it is a minor role compared to the personal factors. The only factor that has demon-strated a dose-response relationship is obesity (i.e., the more there is, the more likely the problem). The mechanism of all the personal factors may not be understood, but its impact is measurable and it is profound.

REFERENCES

1. 2002 Threshold Limit Values for Chemical Substances and Physical Agents in the Work Environment. ACGIH Worldwide; 2002.

8 CTS Usually is Not Occupationally Related AANEM Course

2. Albers JW, Brown MB, Sima AA, Greene DA. Frequency of median mononeuropathy in patients with mild diabetic neuropathy in the early diabetes intervention trial. Muscle Nerve 1996;19:140-146.

3. Amadio PC. Pyridoxine as an adjunct in the treatment of carpal tunnel syndrome. J Hand Surg 1985;10:237-241.

4. Atcheson SG, Ward JR, Lowe W. Concurrent medical disease in work-related carpal tunnel syndrome. Arch Intern Med 1998;158:1506-1512.

5. Atisook R, Benjapibal M, Sunsaneevithayakul P, Roongpisuthipong A. Carpal tunnel syndrome during pregnancy: prevalence and blood level of pyridoxine. J Med Assoc Thai 1995;78:410-414.

6. Backhouse KM, Churchill-Davidson D. Anomalous palmaris longus muscle producing carpal tunnel-like compression. Hand 1975;7:22-24.

7. Bauer JM, Trusell JJ. Palmaris profundus causing carpal tunnel syn-drome. Orthopedics 1992;15:1348-1350.

8. Björkqvist SE, Lang AH, Punnonen R, Rauramo L. Carpal tunnel syndrome in ovariectomized women. Acta Obstet Gynecol Scand 1977;56:127-130.

9. Bleecker ML, Bohlman M, Moreland R, Tipton A. Carpal tunnel syndrome: role of carpal canal size. Neurology 1985;35:1599-1604.

10. Brown FE, Morgan GJ, Taylor T, O’Connor GT. Coexistence of muscle anomalies and rheumatoid arthritis in patients with carpal tunnel syndrome. Clin Exp Rheumatol 1984;2:297-302.

11. Cannon LJ, Bernacki EJ, Walter SD. Personal and occupational factors associated with carpal tunnel syndrome. J Occup Med 1981;23:255-258.

12. Cobb TK, An KN, Cooney WP, Berger RA. Lumbrical muscle incursion into the carpal tunnel during finger flexion. J Hand Surg 1994;4:434-438.

13. Danta G. Familial carpal tunnel syndrome with onset in childhood. J Neurol Neurosurg Psychiatry 1975;38:350-355.

14. de Krom MC, Kester AD, Knipschild PG, Spaans F. Risk factors for carpal tunnel syndrome. Am J Epidemiol 1990;132:1102-1110.

15. Dieck GS, Kelsey JL. An epidemiologic study of the carpal tunnel syndrome in an adult female population. Prev Med 1985;14:63-69.

16. Dyck PJ, Litchy WJ, Lehman KA, Hokanson JL, Low PA, O'Brien PC. Variables influencing neuropathic endpoints: the Rochester dia-betic neuropathy study of healthy subjects. Neurology 1995;45:1115-1121.

17. Ellis J, Folkers K, Watanabe T, Kaji M, Saji S, Caldwell JW, and col-leagues. Clinical results of a cross-over treatment with pyridoxine and placebo of the carpal tunnel syndrome. J Clin Nutr 1979;32:2046-2070.

18. Ellis JM, Folkers K, Levy M, Shizukuishi S, Lewandowski J, Nishii S, and colleagues. Response to vitamin B6 deficiency and the carpal tunnel syndrome to pyridoxine. Proc Natl Acad Sci USA 1982;79:7494-7498.

19. Ellis JM, Folkers K, Levy M, Takemura K, Shizukuishi S, Ulrich R, Harrison P. Therapy with vitamin B6 with and without surgery for treatment of patients having the idiopathic carpal tunnel syndrome. Res Commun Chem Pathol Pharmacol 1981;33:331-344.

20. Faucett J, Werner RA. Non-biomechanical factors potentially affect-ing musculoskeletal disorders. Washington DC: National Academy Press; 1999. p 175-199.

21. Folkers K, Ellis J, Watanabe T, Saji S, Kaji M. Biomechanical evidence for a deficiency of vitamin B6 in the carpal tunnel syndrome based on a crossover clinical study. Proc Natl Acad Sci USA 1978;75:3410-3412.

22. Folkers K, Willis R, Takemura K. Biochemical correlations of a de-ficiency in vitamin B6, the carpal tunnel syndrome and the Chinese restaurant syndrome. Int Commun Sys J Med 1985;9:441.

23. Franklin GM, Haug J, Heyer N, Checkoway H, Peck N. Occupational carpal tunnel syndrome in Washington state, 1984-1988. Am J Public Health 1991;81:741-746.

24. Franzblau A, Rock CL, Werner RA, Albers JW. Vitamin B6, vitamin C, and carpal tunnel syndrome. J Occup Environ Med 1998;40:305-309.

25. Franzblau A, Rock CL, Werner RA, Albers JW, Kelly MP, Johnston E. The relationship of vitamin B6 to median nerve function and carpal tunnel syndrome among active industrial workers. J Occup Env Med 1996;38:485-491.

26. Gell N, Werner RA, Franzblau A, Ulin SS, Armstrong TJ. A longi-tudinal study of industrial and clerical workers: incidence of carpal tunnel syndrome and assessment of risk factors. J Occup Rehabil 2005;15:47-55.

27. Gelmers H. Primary carpal tunnel stenosis as a cause of entrapment of the median nerve. Acta Neurochir 1981;55:317-320.

28. Gerr F, Letz R. Risk factors for carpal tunnel syndrome in industry: blaming the victim? J Occup Med 1992;34:1117-1119.

29. Gerr F, Marcus M, Ensor C, Kleinbaum D, Cohen S, Edwards A, Gentry E, Ortiz D, Monteilh C. A prospective study of computer users: I. Study design and incidence of musculoskeletal symptoms and disorders. Am J Ind Med 2002;41:221-235.

30. Gould JS, Wissinger A. Carpal tunnel syndrome in pregnancy. South Med J 1978;71:144-145.

31. Johnson EW, Gatens T, Poindexter D, Bowers D. Wrist dimensions: correlation with median sensory latencies. Arch Phys Med Rehabil 1983;64:556-557.

32. Kendall D. Aetiology, diagnosis, and treatment of paraesthesia in the hands. Br Med J 1960;2:1633-1640.

33. Keniston RC, Nathan PA, Leklem JE, Lockwood RS. Vitamin B6, vitamin C, and carpal tunnel syndrome. A cross-sectional study of 441 adults. J Occup Environ Med 1997;39:949-959.

34. Keyserling WM, Armstrong TJ. Ergonomics. In Rom WN, editor. Environmental and occupational medicine, 2nd edition. Boston: Little-Brown; 1992.

35. Letz R, Gerr F. Covariates of human peripheral nerve function: I. nerve conduction velocity and amplitude. Neurotoxicol and Teratol 1994;16:95-104.

36. Massey EW. Carpal tunnel syndrome in pregnancy. Obstet Gynecol Surg 1978;33:145-147.

37. Mesgaradeh M, Schneck CD, Bonakdarpour A, Mitra A, Conaway D. Carpal tunnel: MR imaging part II. Carpal tunnel syndrome. Radiology 1989;171:749-754.

38. McCann VJ, Davis RE. Carpal tunnel syndrome, diabetes and pyri-doxal. Aust NZJ Med 1978;8:638-640.

39. Nakamichi K, Tachibana S. Small hand as a risk factor for idiopathic carpal tunnel syndrome. Muscle Nerve 1995;18:664-666.

40. Nathan P, Keniston RC, Myers LD, Meadows KD, Lockwood RS. Natural history of median nerve sensory conduction in industry: relationship to symptoms and carpal tunnel syndrome in 558 hands over 11 years. Muscle Nerve 1998;21:711-721.

41. Nathan P, Meadows KD, Istvan JA. Predictors of carpal tunnel syndrome: an 11-year study of industrial workers. J Hand Surg Am 2002;27:644-651.

42. Nathan PA, Istvan JA, Meadows KD. A longitudinal study of pre-dictors of research-defined carpal tunnel syndrome in industrial workers: findings at 17 years. J Hand Surg Br 2005;30:593-598.

43. Nathan PA, Keniston RC. Carpal tunnel syndrome and its relation to general physical condition. Hand Clin 1993;9:253-261.

44. Nathan PA, Keniston RC, Lockwood RS, Meadows KD. Tobacco, caffeine, alcohol, and carpal tunnel syndrome in American indus-try. A cross-sectional study of 1464 workers. J Occup Env Med 1996;38:290-298.

AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 9

45. Nathan PA, Keniston RC, Myers LD, Meadows KD. Obesity as a risk factor for slowing of sensory conduction of the median nerve in industry. A cross-sectional and longitudinal study involving 429 workers. J Occup Med 1992;34:379-383.

46. Neviaser RJ. Flexor digitorum superficialis indicis and carpal tunnel syndrome. Hand 1974;6:155-156.

47. Phalen G. The carpal tunnel syndrome: clinical evaluation of 598 hands. Clin Orthop Relat Res 1972;83:29-40.

48. Phillips RS. Carpal tunnel syndrome as a manifestation of systemic disease. Ann Rheum Dis 1967;26:59-63.

49. Radecki P. A gender specific wrist ratio and the likelihood of a median nerve abnormality at the carpal tunnel. Am J Phys Med Rehabil 1994;73:157-162.

50. Radecki P. The familial occurrence of carpal tunnel syndrome. Muscle Nerve 1994;17:325-330.

51. Sabour M, Fadel H. The carpal tunnel syndrome: a new complication ascribed to the pill. Am J Obstet Gynecol 1970;107:1265-1267.

52. Soferman N, Weissman SL, Haimov M. Acroparesthesias in preg-nancy. Am J Obstet Gynecol 1964;89:528-531.

53. Stetson DS, Albers JW, Silverstein BA, Wolfe RA. Effects of age, sex, and anthropometric factors on nerve conduction measures. Muscle Nerve 1992;15:1095-1104.

54. Stevens JC, Beard CM, O’Fallon WM, Kurland LT. Conditions as-sociated with carpal tunnel syndrome. Mayo Clin Proc 1992;67:541-548.

55. Stevens JC, Sun S, Beard CM, O’Fallon WM, Kurland LT. Carpal tunnel syndrome in Rochester, Minnesota, 1961-1980. Neurology 1988;38:134-138.

56. Tanzer R. The carpal tunnel syndrome. J Bone Joint Surg Am 1959;41:626-634.

57. Vessey MP, Villard-Mackintosh L, Yeates D. Epidemiology of carpal tunnel syndrome in women of childbearing age. Findings in a large cohort study. Int J Epidemiol 1990;19:655-659.

58. Werner R, Albers JW, Franzblau A, Armstrong TJ. The relationship between body mass index and the diagnosis of carpal tunnel syn-drome. Muscle Nerve 1994;17:632-636.

59. Werner R, Franzblau A, Gell N, Hartigan AG, Ebersole M, Armstrong TJ. Incidence of carpal tunnel syndrome among auto assembly workers and assessment of risk factors. J Occup Environ Med 2005;47:1044-1050.

60. Werner RA, Albers JW, Franzblau A, Armstrong TJ. The influence of body mass index and work activity in determining the prevalence of median mononeuropathy at the wrist. J Occup Environ Med 1997;54:268-271.

61. Winn FJ, Habes DJ. Carpal tunnel area as a risk factor for carpal tunnel syndrome. Muscle Nerve 1990;13:254-258.

10 CTS Usually is Not Occupationally Related AANEM Course

11

INTRODUCTION

Over the past 40 years, nerve biopsies have been one of the main tools used by physicians in evaluating patients with peripheral neu-ropathies. However with improvements in laboratory, radiographic, and electrophysiological evaluations and the introduction of quan-titative sensory and autonomic testing, the need for nerve biopsy has been on the decline. Furthermore, with a better understanding of disease pathophysiology, it has become clear that biopsies are not needed in some classes of neuropathies (such as inherited neu-ropathies) or in others (even if treatable) can be recognized by the disease characteristics (such as chronic inflammatory demyelinat-ing polyneuropathy). These observations and trends have led some neuromuscular experts to question if there is still an ongoing need for nerve biopsy at all.8

BACKGROUND

The use of nerve biopsy is relatively recent. German neuropatholo-gists as early as the 1800s introduced ways of looking at autopsy nerve specimens. During the mid-20th century, an occasional nerve biopsy was performed, but it was not until the 1960s that Dr. Peter J. Dyck (Mayo Clinic, Rochester, MN) and Dr. P. K. Thomas (Guy’s Hospital, London, UK) systematically introduced the technique of nerve biopsy. Traditionally, nerve biopsy of a cutaneous nerve or a skin sensory nerve is performed. The main reasons these nerves are selectively used is because they are purely sensory and when they are taken the patient has no motor deficit and only a limited sensory deficit. Originally, Dr. Peter J. Dyck often used the greater auricular nerve in the posterior part of the neck for most of his biopsies. However, because most neuropathies are length-dependent processes and since the longest nerves in the

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 that the postoperative sensory disturbance in the lower extremity was less bothersome than that of the posterior neck and back of the ear. Consequently, he switched to using the sural nerve slightly proximal to the ankle as the standard site for nerve biopsy. Others have argued that the superficial peroneal nerve may be preferable because it lies near the peronei muscles and, therefore, a nerve and muscle biopsy can be taken simultaneously.2 This strategy is often useful when there is high suspicion of necrotizing vasculitis (when two tissues can be sampled instead of one). Nevertheless, the pre-ferred site of routine nerve biopsy in the Mayo Clinic laboratory has remained the sural nerve.

The sural nerve is a pure sensory nerve and biopsy of this nerve does create some sensory deficits; however, if the cases are appro-priately selected these side effects are acceptable. In one series, 1 year after biopsy 60% of patients report no symptoms, 30% had intermittent symptoms which ultimately resolved, and 10% had a greater amount of pain or paresthesia.3 New sensory symptoms are more likely if the patient had a detectable sural response on nerve conduction studies (NCSs) prior to biopsy.6 Overall it is a well-tolerated procedure, and usually should be taken from a sensory distribution that is already significantly affected by the underlying neuropathy and so few additional symptoms or signs will be created by the biopsy itself.

The diagnostic yield of cutaneous sensory nerve biopsies has also been studied. Argov and colleagues performed a retrospective analysis of 120 patients with peripheral neuropathy who were evaluated in their electrodiagnostic clinic, and found that in 48% of patients, a diagnosis was reached without the performance of a sural nerve biopsy. In the patients who were biopsied, 38% of the

Nerve Biopsy Often is a Helpful Diagnostic Procedure

P. James B. Dyck, MDAssociate Professor

Department of NeurologyJennifer A. Tracy, MD

Mayo Clinic College of MedicineRochester, Minnesota

12 Nerve Biopsy Often is a Helpful Diagnostic Procedure AANEM Course

biopsies yielded diagnostic or important contributory findings. It was concluded overall that the management of 50% of the biopsied patients was favorably affected by the histological findings.1 Oh reviewed 385 cases in which sural nerve biopsies were performed over a 15-year period. He found that in 45% of the cases, clini-cally helpful or relevant information was added by the biopsy, and a specific diagnosis was obtained in 24% of patients as a result of the biopsy.7

The difficulty with interpreting this type of data is that clearly the yield of nerve biopsy is heavily dependent upon the selection of ap-propriate patients for biopsy as well as selection of an appropriate nerve to biopsy. Care must be taken in extrapolating the results of any such study without undertaking an analysis of these selection criteria. It is the author’s opinion that the vast majority of patients with peripheral neuropathy do not need a nerve biopsy; however, in selected circumstances, this procedure can provide very impor-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.

SITE OF BIOPSY

The use of the sural nerve as the predominant site for nerve biopsy certainly does have limitations. If the underlying disease is only a motor process, using a cutaneous sensory nerve will not provide useful information. Similarly, if the disorder is multifocal or predominantly proximal, the sural nerve may not be involved. Therefore, the evaluating physician needs to be sure that the nerve biopsied is clinically involved. Results of NCSs and needle elec-tromyography (EMG), as well as clinical findings, are helpful in this determination. Consequently, the sural nerve should not just be used as the site of nerve biopsy in an automatic fashion. Biopsy sites need to be considered on a case-by-case basis and the most appropriate nerve needs to be selected when performing a nerve biopsy. For example, chronic inflammatory sensory polyradicul-opathy is an inflammatory demyelinating neuropathy selectively involving the sensory root, and a sural nerve biopsy would be normal, whereas a sensory rootlet biopsy would show onion-bulbs and macrophages.9

Before performing a nerve biopsy, it should be deteremined that it is, in fact, a justifiable procedure. For example in most cases of small fiber neuropathy, the damage to small fibers is not sufficient enough to warrant treatment with prednisone, cyclophosphamide, and other immunosuppressive drugs. Consequently, even if a mi-crovasculitis is suspected as the underlying cause of a small fiber neuropathy, in general a nerve biopsy should not be performed because systemic vasculitis with only mild small fiber involvement would not be treated. When deciding to perform a biopsy, the physician has to ensure that the neuropathy is sufficiently severe to justify the side effects of potential treatment. In general, a physician is performing a nerve biopsy to make a diagnosis of the underlying process, but alsomay perform a nerve biopsy to see if that process is still active and needs ongoing treatment. For example, diabetic lumbosacral radiculoplexus neuropathy is caused by microvasculitis

and ischemic injury to nerve. In the past, this author would biopsy most cases that were suspected diabetic lumbosacral radiculoplexus neuropathies. However now that the underlying pathology of the disease is better understood, if a case appears to be straightforward and the patitent is in the early stages of the disease, the patient is usually treated without a nerve biopsy. However, in longstanding cases of diabetic lumbosacral radiculoplexus neuropathy, it may be difficult to know if the disease is still active or if the patient is suffering from the residual nerve damage from the microvasculitis. A nerve biopsy may be performed in such a patient. The purpose of the biopsy is not as much to make a diagnosis of the underlying condition as it is to discover whether the microvasculitis is active. In these cases, if there was active evidence of microvasculitis, the patient would likely be treated; if inflammation was not seen, then there would be less likelihood of treatment. Consequently, one major use of nerve biopsy is to judge disease activity and the neces-sity of treatment.

SELECTING PATIENTS TO BIOPSY

One of the most important questions to ask is which patients should undergo nerve biopsy. Unlike many muscle diseases in which muscle biopsy is needed to diagnose the type of myopathy, most cases of peripheral neuropathy do not need to have a nerve biopsy performed. It should be the exception rather than the rule. Patients should undergo a thorough workup for their neuropathy before nerve biopsy is considered or performed. This includes a neurologic history, a neurologic examination, NCSs and needle EMG, quantitative sensory studies, autonomic reflex screen, labo-ratory evaluations for potential underlying causes of neuropathy, and, in some cases, spinal fluid evaluation. In general, it is only after these evaluations have been performed that nerve biopsy should be considered. There are, of course, exceptions.

A nerve biopsy should not be performed just because the evaluating physician does not know the cause of the neuropathy. It is common that a thorough evaluation does not elucidate an underlying cause. This is especially the case in small fiber neuropathies. In spite of not having a diagnosis, most of these patients should not undergo nerve biopsy. Frequently, a physician will order a thyroid function study, a fasting blood sugar, heavy metals, and an Athena antibody panel; and if these tests are negative, often the next step will be to perform a nerve biopsy. There needs to be a better indication for performing a nerve biopsy than that the evaluating physician does not know what to do next. When deciding whether or not to perform a nerve biopsy, several important criteria emerge.

Perhaps the most important criterion for determining whether or not to perform a nerve biopsy is that a suspected diagnosis can only be reached by having a pathological nerve biopsy specimen. In this case, the physician is considering a specific diagnosis in which pathological/histological nerve material is needed. Such diagnoses include necrotizing vasculitis, amyloidosis, sarcoidosis, leprosy, lymphoma, metastatic tumor, and others. Before ordering a biopsy for these conditions, the physician needs to consider their likeli-hood in a particular patient.

AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 13

Another important issue to consider when performing a nerve biopsy is whether the potential side effects of the nerve biopsy are outweighed by the potential gain. Part of this question is judging the severity of the neuropathy. Since immune causes are one of the major side effects in neuropathy, the physician might decide that the potential side effects of immunotherapy (cyclophosphamide, steroids, etc.) are worse than the neuropathy itself. Another issue in deciding whether to perform a nerve biopsy is the temporal course. If the neuropathy is rapidly worsening and is of a severe character, this is a more compelling reason to perform a nerve biopsy. In general, motor deficits are more disabling than sensory deficits. If the patient is rapidly weakening, this is a more compelling reason to perform a nerve biopsy than if the patient is just experiencing some tingling or numbness. Again, remember that when perform-ing a sural nerve biopsy, only sensory nerve tissue is obtained and not motor tissue.

INFORMATION GAINED BY NERVE BIOPSIES

Nerve biopsies give information about the nerve fibers themselves and also about the interstitium surrounding them. Since nerves are valuable tissue that re-grow slowly, once they are cut, as much in-formation as possible should be obtained. Consequently, physicians should perform multiple preparations on nerve tissue received. These include teased fiber preparations, which can be exceedingly helpful in analyzing abnormalities that occur in a patchy manner along the length of a nerve fiber (i.e., segmental demyelination). Other myelin abnormalities can be assessed, such as tomaculae, as well as the rate of axonal degeneration and empty nerve strands. Many of these abnormalities are better seen in longitudinal prepara-tions than in cross-section, but still are best seen on teased fibers.

Paraffin sections are obtained (both cross-section and longitudi-nal), with hematoxylin and eosin stain, Luxol Fast Blue Periodic Acid Schiff (LFB-PAS), and trichrome stains. Congo red and methyl violet slides are prepared primarily to assess for amyloid. Epoxy preparations stained with methyl blue are ideal for assessing density of myelinated fibers and the different fiber populations (large myelinated, small myelinated and maybe unmyelinated). The author’s routine immunohistochemistry preparations are leukocyte common antigen, (cd45) and kp-1 (macrophage preparation) (cd68). Further studies are based upon suspicion for particular disease entities, either by clinical/laboratory grounds, or by results obtained from the tissue preparations already assessed (e.g., smooth muscle actin for suspected microvasculitis, S-100 for assessment of onion bulbs, tumor markers for various suspected neoplasms). Electron microscopy can be performed for evaluation of abnormali-ties of small myelinated and unmyelinated fibers as well as axonal inclusions and a host of other entities. Overall, there is a tremen-dous amount of information potentially obtainable from nerve biopsy, provided an appropriately affected nerve is obtained, and the appropriate stains and preparations are performed for suspected disease entities.

When writing biopsy reports, two diagnoses should be listed. The first diagnosis should describe the neuropathic abnormalities, whereas the second diagnosis should describe the interstitial abnor-malities. In most cases, the primary reason to obtain a nerve biopsy is not to learn about neuropathic abnormalities. In fact, significant information about neuropathic abnormalities should already be known based on the neurologic history, neurologic examination, and physiological studies including NCSs, EMG, quantitative sen-sation, quantitative autonomic and thermoregulatory sweat tests. For instance, the distinction between a demyelinating neuropathy and an axonal neuropathy can usually be inferred from the electro-physiological studies; nerve biopsy is not necessary to determine if there is demyelination.

In contrast, the main reason to perform a nerve biopsy is to under-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 most important group of disorders in which interstitial abnormali-ties are searched are the inflammatory/immune neuropathies. The inflammatory neuropathies are among the most treatable causes of peripheral neuropathies. It is important to have pathological evidence of inflammation to help tailor treatment, because many of the available treatments have significant side effects, they may need to be administered long term, and they are often very expen-sive. The inflammatory neuropathies include necrotizing vasculitis, inflammatory demyelination, granulomatous (such as sarcoidosis), sometimes paraneoplastic, and others. Another interstitial abnor-mality that is very important to recognize is amyloidosis. Tumor infiltration of nerve needs to be recognized, and biopsy can often be useful to address issues of tumor recurrence versus radiation change (more relevant for proximal nerve biopsies).

The importance of adequate understanding of interstitial abnor-malities is why whole rather than fascicular distal cutaneous (sural) nerve biopsies are preferred. Whole biopsies generally include gen-erous interstitium to analyze for diagnostic and potentially treatable abnormalities. Occasionally there are neuropathic abnormalities that are diagnostic of underlying neuropathy like amyloidosis, sar-coidosis, necrotizing vasculitis, perineurioma, etc. In most cases of peripheral neuropathy, however, the pathological findings suggest an underlying process, but are not diagnostic of one. Often these suggestive findings are inflammatory infiltrates.

When performing a nerve biopsy, three different compartments within the nerve are reviewed (endoneurium, perineurium, and epineurium). The endoneurium historically was thought of as only the nerve fibers themselves, but references to the endoneurium in this manuscript include all the tissue within the confines of the perineurium, including microvessels, Schwann cells, fibroblasts, and the actual nerve fibers. The perineurium is the lining around the fascicles and is made up of perineurial cells and some microves-sels. It is the smallest of the three components and contributes 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 blood vessels of different sizes. Most of the inflammation seen in neuropathies is in the epineurium, but other areas of inflamma-tion, if found, have important pathologic significance as well. (For example, inflammation of the perineurium is frequently seen in sarcoidosis.)

The information obtained from a nerve biopsy and electrophysi-ological studies is not the same. They provide complementary information rather than redundant information. When perform-ing electrophysiological studies, the information gathered is about many nerves, both motor and sensory, over widespread areas of the body. This makes it less likely to miss a pathologically affected site, which can be a problem with the small sample size of a nerve biopsy. A nerve biopsy assesses a very small area but it provides much more information about that particular sampled area within the nerve than electrophysiological studies. Usually the informa-tion is only about a sensory nerve, given that is typically what is biopsied. In contrast to the electrophysiology studies that only look at the largest myelinated nerve fibers, nerve biopsies supplies infor-mation about large myelinated fibers, small myelinated fibers and unmyelinated fibers. Consequently, nerve biopsies provide more information about different fiber populations than electrophysi-ological studies. Also, NCSs provide pathophysiological data that is inferred, whereas nerve pathology shows the direct evidence of the neuropathic abnormalities as well as interstitial abnormalities. The examining physician needs to remember that different information is being gathered from these evaluations.

TARGETED FASCICULAR NERVE BIOPSY

One of the new, exciting aspects of nerve biopsies is the use of targeted fascicular nerve biopsy, a very important advancement in the use of nerve pathology. In the past, physicians have typically not been able to specifically target nerve biopsies because of an in-ability to image nerves well enough. Occasionally, this author has performed some targeted biopsies through the use of electrophysi-ological abnormalities. An example is in multifocal motor neuropa-thy with conduction block where the nerve is sampled at the site of conduction block by using intraoperative monitoring. However, until recently, this author has mostly performed distal cutaneous nerve biopsies in length-dependent peripheral neuropathies. In general, the distal segments of the sural nerve will show more pa-thology than the proximal segments. This was shown by the work of Dr. Peter J. Dyck on uremic neuropathy and Friedreich’s ataxia.4 Consequently, biopsying the distal segment of nerves in length-dependent processes is recommended.

However, in some neuropathic conditions, the process is not a length-dependent, symmetrical process, but rather a multifocal process that often involves proximal nerves. There has always been a concern about the risk of biopsying proximal nerves because of the potential neuropathic deficits since most proximal nerves are mixed motor and sensory nerves. A technique to sample some, but not all, of a nerve (fascicular nerve biopsy) was introduced by Dr. Peter J. Dyck and colleagues in the 1960s. The authors describe re-moving one or two fascicles of the nerve and leaving the rest of the

nerve intact.5 This technique was mostly used on distal cutaneous nerves since, until recently, there were no good method of targeting proximal nerves.

Over the last several years, there has been considerable advance-ment in the ability of magnetic resonance imaging (MRI) and ultrasound to look at nerves. This author has developed a special practice at the Mayo Clinic with a peripheral nerve neurologist, a radiologist with special expertise in viewing nerves, a peripheral nerve neurosurgeon expert in performing fascicular nerve biopsies, and a peripheral nerve pathology laboratory expert in preparing and interpreting nerve pathology. This has been a great benefit because many patients are evaluated with focal neuropathies involv-ing the brachial plexus, lumbosacral plexus, and other individual nerves including sciatic, ulnar, and median and roots. These cases are evaluated with special attention to the involved proximal nerve segments with high-powered imaging techniques (3-Tesla MRI). Through this integrated practice a general idea about the location of a clinical problem based on neurologic history and examination can be formed. The radiologist can then further refine this local-ization by examining the identified nerves in great detail with the use of high-resolution MRI. In general, these MRI scans are best for identifying a lesion and giving a limited differential diagnosis However, by themselves they are not diagnostic of the disease process and pathological specimens are still needed. With the in-formation provided by the MRI, the peripheral nerve neurosurgeon can perform a targeted fascicular nerve biopsy and remove a fascicle 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 periph-eral nerve laboratory, and special preparations are made to evaluate it further and to diagnose the cause of the focal neuropathy.

With this integrated approach, this author and colleagues have performed approximately 150 nerve biopsies over the last 4 or 5 years. A diagnostic rate of the underlying process was determined in 84% of the patients in the series. In these patients, targeted fascicular nerve biopsy from proximal nerves versus blind distal cu-taneous nerve biopsy, there is a highly significant increased rate of diagnostic findings from the proximal fascicular nerve biopsy (84% positive) versus from the distal nerve (33% positive). Consequently, this technique of targeted fascicular biopsy has become an im-portant clinical tool. These diagnoses often are also potentially treatable conditions that would have otherwise gone undiagnosed; this makes a real difference to the patients. The morbidity of the procedure has been low. Only patients with with problematic defi-cits are biopsied, and therefore all of these patients have neurologic impairment before surgery. Little new weakness or sensory loss has been caused by the procedure. It is not uncommon for patients to develop some transient pain and numbness but this is usually short-lived and the patient returns to baseline. This technique has been a major success.

The conditions that have been diagnosed through these types of approaches include inflammatory, immune conditions such as focal inflammatory demyelinating lesions, granulomatous lesions, sarcoi-dosis, and necrotizing vasculitis. Many different types of tumors have also been seen. Some of these tumors are benign tumors, like perineurioma. Schwannoma and neurofibroma have been less

common. Malignant tumors such as lymphoma and metastatic breast and prostate cancer to the nerves have been identified. In ad-dition, focal amyloid infiltration of the nerve (amyloidoma), as well as vascular malformations in the nerve, and some infection of the nerve such as leprosy has been seen. Overall, approximately 75% of the conditions diagnosed have been treatable.

Recently some neuropathologists have concluded that the use of nerve biopsy has become a dying art and they argue that with the availability of other laboratory and noninvasive techniques, nerve biopsy will no longer be needed. This does not seem to be the case at all. There are, in fact, more varied ways to perform nerve biop-sies and to make diagnoses where physicians were not able to do so in the past. Through the use of targeted fascicular nerve biopsies, many patients who previously would not have received a nerve biopsy, may now be biopsied and their neuropathies diagnosed. Because of the specialized expertise required for these biopsies, they should be performed at centers that have extensive experience with these techniques. In order to perform these targeted fascicu-lar nerve biopsies, four criteria need to be met. There must be a: (1) physician with special expertise in peripheral nerve disorders, (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 in processing peripheral nerve.

CONCLUSIONS

Peripheral nerve biopsies are still an important technique in evalu-ating people with peripheral neuropathies. Nerve biopsy should only be used in a minority of patients with neuropathy. It is very valuable in conditions such as necrotizing vasculitis, amyloidosis, lymphoma, metastatic tumor, perineurioma, inflammatory demy-elination, and other conditions. Nerve biopsy should be performed mostly in academic centers and not at the local level. An option for those physicians not in an academic center is to have the nerve tissue harvested locally and then processed and interpreted at an academic center. An important point to remember is that if a physician is going to perform a nerve biopsy, a nerve is being cut and valuable tissue is being destroyed. It is important to ensure that as much information as possible is obtained from the biopsy. Consequently, it is not sufficient just to obtain paraffin sections and nothing more. The following tests should be performed in the nerve biopsy: (1) Teased fiber preparations (so one can judge the different patho-logic abnormalities of individual nerve fibers); (2) paraffin sec-tions with stains including hematoxylin and eosin; (3) LFB-PAS, trichrome and amyloid stains (Congo Red and methyl violet);

(4) semithin epoxy sections looking at the ultrastructural features of the nerve, and potentially electron microscopy if needed; and (5) immunohistochemical preparations including CD45 (lympho-cytes) and CD68 (macrophages) and more should be performed as necessary. Finally, it is imperative to have colleagues in general pathology with whom one can confer for issues of malignancy (es-pecially hematological) and other in areas of pathology.

In conclusion, the practice of nerve pathology is still a vital com-ponent of the evaluation of patients with peripheral neuropathies. Nerve biopsies should not be performed in most patients with neuropathies, and when performed, need to be carefully selected. However, nerve pathology still is the only way to assess the inter-stitium and diagnose many disorders (especially the inflammatory and immune disorders) and still is an invaluable tool in diagnosing and treating patients with neuropathy. With improved imaging, new techniques of using nerve biopsy (targeted fascicular biopsy) have become apparent and are a vital tool for the physician.

Supported in part by a grant obtained from the National Institute of Neurological Disease and Stroke (NINDS 36797).

REFERENCES

1. Argov Z, Steiner I, Soffer D. The yield of sural nerve biopsy in the evaluation of peripheral neuropathies. Acta Neurol Scand 1989;79:243-245.

2. Collins MP, Mendell JR, Periquet MI, Sahenk Z, Amato AA, Gronseth GS, and colleagues. Superficial peroneal nerve/peroneus brevis muscle biopsy in vasculitic neuropathy. Neurology 2000;55:636-643.

3. Dyck PJ, Dyck PJB, Engelstad J. Pathologic alterations of nerves. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy, 4th edition, volume 1. Philadelphia: Elsevier; 2005. p 733-830.

4. Dyck PJ, Johnson WJ, Lambert EH, O’Brien PC. Segmental demyeli-nation secondary to axonal degeneration in uremic neuropathy. Mayo Clin Proc 1971;46:400-431.

5. Dyck PJ, Lofgren EP. Method of fascicular biopsy of human periph-eral nerve for electrophysiologic and histologic study. Mayo Clin Proc 1966;41:778-784.

6. Gabriel CM, Howard R, Kinsella N, Lucas S, McColl I, Saldanha G, and colleagues. Prospective study of the usefulness of sural nerve biopsy. J Neurol Neurosurg Psychiatry 2000;69:442-446.

7. Oh SJ. Diagnostic usefulness and limitations of the sural nerve biopsy. Yonsei Medical Journal 1990;31:1-26.

8. Pleasure DE. Dwindling indications for sural nerve biopsy. Arch Neurol 2007;64:935-936.

9. Sinnreich M, Klein CJ, Daube JR, Engelstad J, Spinner RJ, Dyck PJ. Chronic immune sensory polyradiculopathy: a possibly treatable sensory ataxia. Neurology 2004;63:1662-1669.

AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 15

16 AANEM Course

17

The results from a biopsy of a peripheral nerve can influence the treatment of a patient only if the condition identified is amenable to a therapy. This presentation will argue that most treatable neu-ropathies can be diagnosed without tissue verification. In their textbook on pathology of peripheral nerve, Asbury and Johnson recommended nerve biopsy whenever one of the following dis-orders is considered: amyloidosis, leprosy, conditions producing palpable nerves, and in pediatric illnesses such a metachromatic leukodystrophy, Krabbe’s disease, and ataxia-telangiectasia.2 The authors believed that nerve biopsy was least helpful in acute or subacute distal symmetric polyneuropathies due to presumed meta-bolic disorders or toxins.2

It is the perception of most clinicians that the yield of nerve biopsy is low for influencing the management of patients with neuropa-thy. The results are often nonspecific, leaving the physician with no additional useful information and the patient may be left with residual pain and numbness. Said, writing in a manuscript on the indications and usefulness of nerve biopsy, agreed with the poor yield of nerve biopsies when performed in unselected patients.14

From his perspective, nerve biopsies should be obtained to identify a specific cause rather than to define the presence or absence of a neuropathy.14 He recommended a nerve biopsy for patients with suspected vasculitis, diabetic patients with focal or multifocal neu-ropathies, amyloidosis, leprosy, and only rarely in acquired demy-elinating polyneuropathies.14 Biopsy should be considered in select patients with inherited neuropathies only when genetic testing failed to identify a defect. Oh made similar recommendations for nerve biopsy and included on his list: hypertrophic neuropathy, inflammatory neuropathy, ischemic neuropathy, metachromatic leukodystrophy, sarcoidosis, and giant axonal dystrophy.11 He expressed his opinion that nerve biopsy is clearly indicated in two

groups: patients with suspected vasculitis and in patients with a clinically significant peripheral neuropathy of unknown cause.11

Even though the results of nerve biopsy can be helpful in influenc-ing patient management, many interpretations are non-specific and fail to offer further direction in the evaluation of an idiopathic neuropathy. Lubec and colleagues retrospectively reviewed the medical records of 171 inpatients whose final diagnosis was pe-ripheral neuropathy.10 They determined that noninvasive testing was sufficient to identify the underlying etiology of the neuropathy in 114 patients (83%). A biopsy of the nerve and/or gastrocnemius muscle was conducted in 27 patients. Twenty one of the patients underwent both a nerve and muscle biopsy. In three patients, vas-culitis was diagnosed. In the 24 remaining patients, the biopsies were nonspecific. In a prospective study of the usefulness of sural nerve biopsy in 50 consecutive patients with neuropathy, Gabriel and colleagues showed that the nerve biopsy results changed the diagnosis in 7 of the 50 patients.6 In 35 patients, the biopsy simply confirmed the suspected diagnosis and in 8 patients the biopsy results were nonspecific. An independent neurologist involved in the study determined that the biopsy either changed or was helpful in guiding the patient’s management in 60% of the cases. The authors did not explain how this relatively high percentage was derived nor the specifics of the term “helpful.”

It is customarily taught that nerve biopsy is most helpful when a vasculitis is considered in the differential diagnosis. Vasculitis commonly presents as a mononeuritis multiple or a multifocal asymmetric process, so patients who present in this manner are ap-propriate candidates for nerve biopsy unless an accurate diagnosis can be made in a noninvasive way. Nevertheless, the yield of nerve biopsy in patients with suspected vasculitis is not impressive. Vital

Nerve Biopsy Rarely is a Helpful Diagnostic Procedure

Peter D. Donofrio, MDProfessor

Department of NeurologyChief, Neuromuscular Section

Director of the EMG LaboratoryVanderbilt University Medical Center

Nashville, Tennessee

18 Nerve Biopsy Rarely is Helpful AANEM Course

and colleagues performed a 16-year retrospective study of 202 cases with suspected vasculitis.21 A necrotizing vasculitis was found in nerve only in 16 patients, in muscle in 19 patients, and in nerve and muscle in 25 patients. A granulomatous vasculitis was detected in one patient. Thus, nerve biopsy showed a necrolyzing vasculitis in only 20% of the 202 patients. If one included the pathologic findings of microvasculitis, this percentage increased from 20 to 29%. In an additional 12% of patients, the nerve biopsy was in-terpreted as “probably vasculitis.” Performance of a muscle biopsy improved the chances of making the diagnosis of vasculitis by 27%, a percentage approximate to the yield of the nerve biopsies. Claussen and her colleagues published more impressive results from 115 nerve and muscle biopsies collected over 20 years at the University of Alabama.5 Her results differed significantly from Vital’s. The diagnostic sensitivity of nerve biopsy in patients with suspected vasculitis was 39% whereas the yield from muscle tissue was only 17%. Not surprisingly, the highest diagnostic yield (73%) of nerve biopsy was observed in patients with clinical evidence of a myopathy and neuropathy and known rheumatologic disease. Abnormal sural nerve conduction was highly correlated with an abnormal nerve biopsy, an encouraging result for those who use nerve conduction studies (NCSs) to select nerves for biopsy.

The surgical literature portrays a less optimistic picture of the usefulness of nerve biopsy. Rappaport and colleagues reported the results of sural nerve biopsy in 60 patients undergoing biopsy.12 Vasculitis was suspected in 29 patients, yet the nerve biopsy showed confirmatory findings in only 6 of 29 patients. Almost half of the patients remained undiagnosed after the biopsy. The authors em-phasized their complication rate of 27%. Six patients developed wound infections, seven patients had delayed wound healing, and three patients progressed to chronic pain in the distribution of the sural nerve. The authors judged the complication rate to be signifi-cant and suggested the need for strict criteria to select patients for sural nerve biopsy. In another report from a surgery journal, Ruth and colleagues reported their results and adverse effects from 67 pa-tients who underwent a nerve biopsy.13 In cases of polyneuropathy of unknown etiology, a definitive diagnosis was made in only 24% of patients and lead to therapy in 19% of patients. Follow-up of the patients over time (a mean of 24 months) found chronic pain in the distribution of the sural nerve in 30% of patients, dysesthesias in 47%, and persistent sensory loss in 72% of patients. Approximately 50% of patients stated that they would not submit to the biopsy again. Based on their data and experience, the authors proposed that nerve biopsy should only be recommended for cases of sus-pected inflammatory, collagenous, immunologic, and hereditary neuropathies.13

Sural nerve biopsy is sometimes ordered in patients who are consid-ered to have chronic inflammatory demyelinating polyneuropathy (CIDP), yet the diagnosis is not supported by NCSs. The rationale for obtaining the biopsy is to document focal demyelination and inflammation that would support the diagnosis of CIDP in the absence of nerve conduction abnormalities. Bosboom and col-leagues looked at the diagnostic value of sural nerve demyelination in CIDP.4 Using several parameters for measuring nerve demyeli-nation and remyelination, he compared the sural nerve biopsy of 21 patients with CIDP to those of 13 patients with a chronic idio-

pathic axonal polyneuropathy (CIAP) and to 6 autopsy controls. To assess demyelination and remyelination, the authors analyzed the number of onion bulbs using the g ratio, the myelinated nerve fiber density, the number of clusters, and endoneurial area. Considerable overlap was found between abnormalities in CIDP and CIAP pa-tients. The authors found no difference in demyelinating features between patients with CIDP and CIAP. Based on their results, the authors concluded that limited diagnostic value exists in perform-ing nerve biopsies to substantiate the diagnosis of CIDP.

Other authors have reported impressive nerve biopsy findings sup-porting the diagnosis of CIDP in patients whose NCSs were more in keeping with a chronic axon loss neuropathy. Vallat and col-leagues described 8 patients whose nerve biopsies were indicative of CIDP and whose electrophysiological results did not meet criteria for the diagnosis.20 Five of the eight patients responded favorable to immunotherapy. The authors proposed that CIDP should be suspected if the electrophysiological examination shows subtle ab-normalities suggestive of demyelination.

Nerve biopsy is often recommended to establish or eliminate the diagnosis of amyloidosis. Based on recent publications, a nerve biopsy should not be necessary in most cases of suspected amyloi-dosis because of the high yield of a bone marrow biopsy and ab-dominal fat pad aspiration for identifying amyloid deposits. Data from the Mayo Clinic has shown that amyloid deposits will be detected in approximately 90% of patients with amyloidosis who undergo either a bone marrow biopsy or fat pad aspirate.7 Nerve biopsy for amyloidosis should be recommended only for those patients in whom the diagnosis of amyloidosis remains a strong possibility after biopsies of other tissues are unrevealing. In another study from the Mayo Clinic, Andrews and colleagues demonstrated the complete lack of yield of subcutaneous fat aspirates in patients with isolated neuropathy and who did not have any family history, clinical history, or laboratory findings suggestive of systemic amy-loidosis.1

Before the prevalence of genetic testing and its application to inherited neuropathies, nerve biopsy played a role in identifying onion bulb formation, a pathologic process formed by recurrent demyelination and remyelination of peripheral nerve. In light of the impressive advancements in molecular genetics, genetic testing is the more appropriate first step in making the diagnosis of an inherited neuropathy. Unfortunately, the choice of genetic tests to order and where to send the specimen is almost as bewilder-ing as the choice to proceed to a nerve biopsy. A recent review of the website of gene tests (www.genetests.org) and several publica-tions disclosed an overwhelming number of genetic abnormalities that clinically present as the phenotype of Charcot-Marie-Tooth (CMT) disease.3,9 Presently, there are 6 different genetic abnormali-ties for CMT Type 1 (Type 1A through F), 15 for CMT Type 2 (Type 2 A1 through 2L), 8 for CMT Type 4 (Type 4 A through H) and 5 for CMT Type X (Type X 1 through 5). Outside of the category of CMT, there are numerous genetic abnormalities for congenital hypomyelinating neuropathy, for hereditary neuropathy with propensity to pressure palsies, the distal hereditary motor neu-ropathies, the hereditary sensory and/or autonomic neuropathies, 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 without tissue confirmation. In mononeuritis multiplex, the nerve biopsy is often required to identify defects of the vasa nervorum, abnormal deposits, and inflammation. Vasculitis is the most common cause of mononeuritis multiplex and its consideration is one of the main indications for performing the nerve biopsy. Table 1 lists the differential diagnosis of mononeuritis multiplex.

Although the sural nerve is the most common nerve to be sampled for pathologic analysis, the superficial peroneal nerve and the radial nerve can be biopsied if the clinical examination shows greater involvement of those respective nerve distributions. Combining the nerve biopsy with a muscle biopsy in the same region as well as the use of electrophysiology can increase diagnostic sensitivity 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 on a nerve that was physiologically affected, the percentage in-creased to 61%. If the gastrocnemius muscle was denervated by electromyography, the yield of combined nerve and muscle useful-ness increased to 73%.

Some authors have advocated the use of nerve biopsy in patients with diabetes who have asymmetric, multifocal, or proximal neu-ropathies. Nerve biopsy can be useful in diabetes to rule out a superimposed cause of neuropathy such as CIDP. In some medical centers, nerves in the region of the lumbosacral plexus are biopsied to substantiate pathology. Said and his group reported inflamma-tory nerve lesions in the intermediate cutaneous nerve of the thigh, a sensory branch of the anterior division of the femoral nerve, in four patients with proximal diabetic neuropathy.15 Ironically, the biopsy results did not influence treatment as the patients improved quickly and spontaneously after the biopsy; i.e., one patient became pain-free the day after his biopsy and the other three within 1 week. As a general rule, nerve biopsy in diabetics with the common distal symmetric sensory and motor neuropathy is unhelpful and may be dangerous given the propensity of diabetic patients to heal slowly and develop infection. As Sima expressed in his manuscript on the utility of nerve biopsy in diabetes, “nerve biopsy is an invasive pro-cedure associated with extremely high costs of analysis that will not provide any information in addition to what can be obtained from carefully performed electrophysiological measurements.”19

Suspected sarcoidosis is often listed as one of the indications for nerve biopsy. Surprisingly, muscle biopsy is as helpful in document-ing noncaseating granulomas as nerve biopsy. In one study, muscle was affected in 10 of 11 patients who had granulomas in their nerve biopsy specimens.16 Silverstein and Sitzbach report that 60% of patients with sarcoidosis will have muscle involvement whereas less than 1% will have nerve affected.18

Another indication often cited for nerve biopsy is Hanson disease or leprosy. In the majority of patients with leprosy, the diagnosis of peripheral neuropathy can by made by the clinical presentation in

an endemic area, characteristic skin lesions, and the identification of acid fast bacilli from a skin smear or skin biopsy. In the rare instance of suspected leprosy in an endemic area in the absence of typical skin lesions and negative skin biopsy, a biopsy of a sural, superficial peroneal, or radial nerve near the area of sensory deficit may show the caseating necrotizing granulomatous neuropathy as-sociated with leprosy.

Metachromatic leukodystrophy (MLD) is a condition in which analysis of blood leukocytes and cultured skin fibroblasts should be tested before biopsy of a peripheral nerve is contemplated. Other testing that may obviate the need for nerve biopsy in MLD include spinal fluid analysis, brain MRI, NCSs, and neurocognitive testing. Nerve biopsy is also rarely needed to substantiate the diagnosis of Krabbe’s disease. Once again, blood leukocytes and cultured skin fibroblasts can be used to measure the activity of galactosylceramide beta-galactosidase (GALC) which will be very low in patients with Krabbe’s disease. Testing of cerebrospinal fluid for an el-evated protein, brain magnetic resonance imaging, brain magnetic resonance spectroscopy, electroencephalography, and NCSs can be implemented before a nerve biopsy is ordered.

Fabry disease results from a deficiency of alpha-galactosidase A. This enzyme can be measured in plasma, serum, leukocytes, tissue biopsy, and cultured skin fibroblasts in lieu of performing a nerve biopsy. If the disease is further suspected, DNA analysis can be requested for alpha-Gal A gene sequencing, and brain magnetic resonance imaging can be ordered to evaluate the patient for isch-emic lesions associated with the disease.

Nerve biopsy is indicated for the very rare presentation of lym-phoma infiltrating nerve (neurolymphomatosis), which is most commonly seen in non-Hodgkin’s lymphoma.8

Table 2 lists the author’s indications for nerve biopsy when all other means of establishing the diagnosis have been exhausted. Some of the disorders commonly listed as indications for nerve biopsy by other authors, such as inherited neuropathy and amyloidosis, are

Table 1 Differential diagnosis for mononeuritis multiplex

Churg-Strauss angiitis CryoglobulinemiaDiabetes Giant cell arteritisHIV Infection Hypersensitivity vasculitisIschemia LeprosyParaneoplastic Periarteritis nodosumRheumatoid arthritis Systemic lupus erythematosusSarcoidosis Necrotizing vasculitisWegener’s granulomatosis Waldenstrom’s macroglobulinemia

HIV = human immunodeficiency virus

20 Nerve Biopsy Rarely is Helpful AANEM Course

not listed because of the high probability of making the diagnosis after less invasive testing. With the advances in epidural nerve analysis through skin biopsy, the need for sural nerve biopsy to document a small fiber neuropathy will be diminished.

In summary, nerve biopsy results are often unhelpful because of the nonspecific way in which nerve responds to disease. Vasculitis remains the most common indication for nerve biopsy, especially in patients who do not have active manifestations of a connective tissue disorder. If a nerve biopsy is needed, electrophysiology should be used to identify the nerves most likely to yield a diagnosis. In almost all patients, an adjacent muscle should be sampled at the same time the nerve undergoes biopsy, preferably a muscle which is abnormal by the needle examination. The clinician ordering testing for possible vasculitis should keep in mind that a higher positive tissue yield will be obtained if the superficial peroneal nerve and adjacent muscle are biopsied in lieu of the sural nerve biopsy alone. Nerve biopsy should only be performed at medical centers that have extensive experience performing the studies, use the proper stains, and have neuropathologists who have expertise in interpreting the nerve tissue. In most situations, adequate nerve should be obtained to prepare the tissue for plastic embedding, frozen sections, teased fibers dissection, immunostaining, electronmicroscopy, and paraf-fin sections. Adequate tissue should be obtained to allow the nerve to be cut into multiple sections for analysis as abnormalities may not be present in all sections of the nerve.

REFERENCES

1. Andrews TR, Colon-Otero G, Calamai KT, and colleagues. Utility of subcutaneous fat aspiration for diagnosing amyloidosis in patients with isolated peripheral neuropathy. Mayo Clin Proc 2002;77:1278-1290.

2. Asbury AK, Johnson PC. Pathology of peripheral nerve, volume 9: major problems in pathology. Philadelphia: WB Saunders; 1978.

3. Berciano J, Combarros O. Hereditary neuropathies. Curr Opin Neuro 2003;16:613-622.

4. Bosboom WMJ, van den Berg LH, Franssen H, and colleagues Diagnostic value of sural nerve demyelination in chronic inflamma-tory demyelinating polyneuropathy. Brain 2001;124:2427-2438.

5. Claussen G, Thomas TD, Goyce C, and colleagues. Diagnostic value of nerve and muscle biopsy in suspected vasculitis cases. J Clin Neuromusc Dis 2000;1:117-123.

6. Gabriel CM, Howard R, Kinsella N, and colleagues. Prospective study of the usefulness of sural nerve biopsy, J Neurol Neurosurg Psychiatry 2000;69:442-446.

7. Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis: recognition, con-firmation, prognosis, and therapy. Mayo Clin Proc 1999;74:490-494.

8. Kelly JJ, Karcher DS. Lymphoma and peripheral neuropathy: a clini-cal 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-thies. J Neurol 2002;249:1629-1650.

10. Lubec D, Mullbacher W, Finsterer J, Mamoli B. Diagnostic work-up in peripheral neuropathy: an analysis of 171 cases. Postgrad Med J 1999;75:723-727.

11. Oh, SJ. Diagnostic usefulness and limitations of the sural nerve biopsy. Yonsei Med J 1990;31:1-31.

12. Rappaport WD, Valente J, Hunter GC, and colleagues. Clinical utilization and complications of sural nerve biopsy. Am J Surg 1993;166:252-256.

13. Ruth A, Schulmeyer FJ, Roesch M, and colleagues. Diagnostic and therapeutic value due to suspected diagnosis, long-term complica-tions, and indication for sural nerve biopsy. Clin Neurol Neurosurg 2005;107:214-217.

14. Said G. Indications and usefulness of nerve biopsy. Arch Neurol 2002;59:1532-1535.

15. Said G, Elgrably F, Lacroix C, and colleagues. Painful proximal diabetic neuropathy: inflammatory nerve lesions and spontaneous favorable outcome. Ann Neurol 1997:41:762-770.

16. Said G, Lacroix C, Plante-Bordeneuve V, and colleagues. Nerve granulomas and vasculitis in sarcoid peripheral neuropathy: a clinico-pathological study of 11 patients. Brain 2002;125:264-275.

17. Sanchez J, Coll-Canti J, Ariza A, and colleagues. Neuropathy due to necrotizing vasculitis: a study of the clinical anatomy, neurophysi-ological characteristics, and clinical course of the disorder in 27 pa-tients. Rev Neurol 2001;33:1033-1036.

18. Silverstein A, Siltzbach LE. Muscle involvement in sarcoidosis. Arch Neurol 1969;21:235-241.

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-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 biopsy in the diagnosis of vasculitic neuropathy. A 16-year retro-spective study of 202 cases, J Peripheral Nervous System, 2006, 11: 20-29.

Table 2 Indications for Nerve Biopsy

VasculitisHanson disease (leprosy)Metachromatic leukodystrophyFabry diseaseKrabbe’s diseaseGiant axonal neuropathyPolyglucosan body diseaseTumor infiltration Small fiber neuropathy

INTRODUCTION

As an extension of the clinical examination, electrodiagnostic (EDX) studies (i.e., nerve conduction studies [NCSs] and needle electromyography [EMG]) often are part of the diagnostic evalua-tion of patients in whom neuromuscular disease is suspected, but in whom the neurological examination is normal. Such patients may have subjective sensory disturbances, fatigue, or symptoms of weakness which are not supported by the examination. Others have pain for which a neurological basis is suspected. In some pa-tients, strength and other aspects of the neurological examination are clearly normal, and the patient is eventually identified via EDX testing as having a clear but mild or early case of a neurological disorder. In other patients, accurate assessment of strength may be challenging because pain and fatigue prevent the examiner from determining whether strength is normal or mildly impaired. Some such patients are found to have abnormal EDX examinations, and eventually are identified as having clear neurological disorders. Others have no abnormal findings on EDX testing but meet clini-cal criteria for fibromyalgia or other non-neurological disorders. Still other patients have normal EDX studies and no identifiable disease. EDX studies are of tremendous value in helping to make such distinctions.

PATIENTS IN WHOM THE NEUROLOGICAL EXAMINATION IS RELIABLE AND NORMAL

Carpal Tunnel Syndrome Without Clear Localizing Features

Although carpal tunnel syndrome (CTS) is a common condition associated with nocturnal pain and paresthesias in a median distri-bution with features on the neurological examination which make diagnosis straightforward (e.g., thenar atrophy and sensory loss in a median nerve distribution), CTS may be associated with sensory disturbances or pain outside of the median nerve distribution, and with a normal neurological examination. In such cases, EDX studies may facilitate diagnosis. In one series of 100 patients with electrodiagnostically verified CTS in 159 hands who lacked other conditions likely to produce upper extremity symptoms (radiculop-athy, plexopathy, other entrapment neuropathies, polyneuropathy, etc.), the ring finger was affected by sensory symptoms in 83% of hands, and the little finger in 56.6%. Interestingly, the little finger was the most affected digit in 2.5% of hands, and the ring finger in 3.8%. Paresthesias or pain were reported proximal to the wrist in 36.5% of hands. Pain in the neck was seen in 0.6%, pain in the shoulder in 6.3%, and pain in the upper arm in 7.5% of hands.34

Electrodiagnostic Studies Generally are Helpful in the Evaluation of

Patients With Weakness and Normal Neurological Examinations

Zachary Simmons, MDProfessor

Department of NeurologyPenn State University

Penn State Hershey Medical CenterHershey, Pennsylvania

21

Another series found 46% of patients with pain in the forearm or higher,21 while yet another group reported symptoms present in the forearm in 50%, at the elbow in 45%, and at the shoulder in 27%.19 A large series of 1039 patients with CTS involving 1528 upper limbs found pain in a distribution which did not involve the hand in 18.5% and paresthesias without involvement of the hand in 1.9%.27

Fasciculations

Spontaneous fasciculations are noted by 70% of healthy medical personnel.30 Needle EMG is a valuable tool, in conjunction with the clinical examination, to differentiate benign fasciculations from early neuromuscular disease when patients present with normal strength. A useful study from Mayo Clinic identified 121 persons diagnosed as having benign fasciculations.2 Presenting symptoms included muscle twitching or fasciculation, generalized fatigue, cramps or spasms, paresthesias, myalgias, concern about amyo-trophic lateral sclerosis (ALS), and muscle stiffness. All had normal neurological examinations and EDX studies which demonstrated no evidence of motor neuron disease (MND) except for fascicula-tion potentials. Over a follow-up period which ranged from 2 to 32 years (mean 7.2), none developed MND. As has been pointed out, it is extremely rare for individuals who ultimately are found to have ALS to present with fasciculations only. Two such patients who initially presented with normal strength are reported in the literature, but a careful reading of the reports reveals that needle EMG examinations distinguish these individuals from those with “benign fasciculations.” One patient reported muscle fasciculations and cramps for 3 years. Examination revealed normal strength and reflexes. Needle EMG revealed not only fasciculation poten-tials, but also fibrillation potentials and positive sharp waves in several muscles. The patient developed weakness associated with muscle atrophy a year later, eventually resulting in the diagnosis of MND.13 Another report describes a 72-year-old man with gen-eralized muscle fasciculation potentials and cramps. Examination revealed widespread fasciculations and muscle cramps evoked by moderate exercise. Strength, reflexes, and sensation were normal. Needle EMG examination revealed not only diffuse fasciculation potentials, but also a few complex motor unit action potentials (MUAPs) in the anterior tibialis muscles bilaterally and a few fibril-lation potentials in the right tibialis anterior muscle. The patient developed clear features of MND over the next year.7 It is clear that when patients present with fasciculations and normal neuro-logical examinations, an EMG which is completely normal except for fasciculation potentials makes it highly unlikely that MND will develop. However, subtle abnormalities on the needle EMG examination are a very sensitive indicator of early MND, and such patients require careful follow-up.

Cramp-Fasciculation Syndrome

Muscle aches, cramps, and exercise intolerance are common symp-toms in a neuromuscular clinic, and approximately one-third of these patients are found to have a specific muscle abnormality after comprehensive evaluation.25 A syndrome has been described featuring patients with muscle cramps and aching in leg muscles

and sometimes in arm muscles, all of whom had normal strength, reflexes, and sensation. Some had fasciculations or myokymia on clinical examination. Repetitive stimulation studies of motor nerves at various frequencies (0.5, 1, 2, and 5 Hz) produced after-discharges. Needle examination was normal except for fasciculation potentials. Carbamazepine provided symptomatic relief in some. These patients have been classified as having a cramp-fasciculation syndrome. Needle EMG studies provided a diagnosis despite normal neurological examinations.38

Lambert-Eaton Myasthenic Syndrome

Most patients with Lambert-Eaton myasthenic syndrome (LEMS) present with proximal lower extremity weakness. However, this may be difficult to objectively document. As muscle strength is augmented initially by continuing to attempt to contract against resistance (until fatigue sets in), the examiner may conclude that strength is normal or near normal. So, the examiner must grade the initial strength of contraction, not the grade after several seconds of maintaining the contraction.10,22 In addition, one-third of patients note muscle aching and stiffness, which makes objective identifica-tion of weakness even more difficult because of the “breakaway” component exhibited by many patients on manual muscle testing. Add to this the fact that ocular and bulbar symptoms are much less common in LEMS than in myasthenia gravis, and the clini-cian is confronted with patients whose chief complaint is fatigue and weakness, but whose examinations may seem inconsistent and which lack the characteristic ocular and bulbar findings which raise the index of suspicion for myasthenia gravis. Electrodiagnostically, LEMS patients demonstrate low compound muscle action po-tential (CMAP) amplitudes which increase dramatically after 10 seconds of isometric exercise or with rapid (20-50 Hz) repetitive stimulation.10 Thus, EDX testing may provide very useful objective data on such patients.

Early Motor Neuron Disease

Motor neuron loss begins before clinical weakness in patients with ALS. Collateral sprouting permits reinnervation to keep up with denervation early in the disease course. In such muscles, CMAP amplitudes and twitch tensions remain normal until motor unit loss reaches 50%-80%, because collateral reinnervation keeps up with denervation up to this point, preventing loss of function. Thus, strength is unaffected despite significant disease progression.23,36 However, needle examination will demonstrate abnormalities.12

Myotonic Dystrophy

Myotonic dystrophy type 1 (DM1) is caused by an unstable expan-sion of a CTG trinucleotide repeat in the 3’ untranslated region of 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 repeats are associated with DM1. There is a relationship between the size of the repeat expansion and the clinical severity and age of onset of the disease. Repeat expansions of less than 100 are gener-ally associated with mild disease and a later age of onset of symp-toms. Young patients may have normal neurological examinations

22 EDX Studies are Helpful in Weakness With Normal Neurological Exams AANEM Course

but have myotonic discharges on needle EMG examination.15,18 Thus, EDX studies can identify patients with myotonic dystrophy in the presymptomatic stage. Such patients often seek medical at-tention because their child has been diagnosed with DM1. The parents may both be asymptomatic, but one is found to have myotonic discharges on needle EMG examination despite normal strength, overall normal function, and minimal to no signs of clini-cal myotonia. Similarly, a patient with DM2 has been described who had an elevated serum creatine kinase (CK) level but was asymptomatic and had a normal neurological examination. Muscle biopsy showed findings consistent with myotonic dystrophy, and Deoxyribonucleic acid (DNA) testing confirmed the presence of a CCTG repeat expansion in the ZNF9 gene consistent with type 2 myotonic dystrophy.24 Although EMG studies were not described, they would be useful in identifying myotonic dystrophy in this patient, similar to the studies’ utility in identifying abnormalities in patients who carry the deletion for Becker muscular dystrophy and present with normal strength and an elevated serum CK level.

Inflammatory Myopathy

Abnormalities may be seen on needle examination in muscles which demonstrate normal strength or in which strength cannot be adequately assessed. There is a rough correlation between muscle strength (determined by manual muscle testing) and the amount of fibrillation potentials and positive sharp waves, indicating that weaker muscles with a Medical Research Council score of less than 4 will have more fibrillation potentials and positive sharp waves 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 and positive sharp waves. The amount of abnormal spontaneous activity is determined by the status of the muscle fibers in the vicin-ity of the EMG needle. Inflammatory myopathy can be a patchy process, particularly in mild or early cases. Such patients may de-scribe weakness, but strength may be normal to the examiner, and the serum CK level may be only mildly elevated. The needle exami-nation may appear normal in many muscles, but a careful needle examination usually will identify some muscles with abnormal spontaneous activity or with MUAPs and recruitment consistent with a myopathy. The sensitivity of EMG for the diagnosis of in-flammatory myopathy is said to be 80%-90%, although this varies depending on the stage of the disease and the muscles tested.4 For example, a recent series found that no patients with acute polymyo-sitis or dermatomyositis (onset within 6 months of testing) or with inclusion body myositis had a normal EMG study.3

Dystrophinopathies

The deletions associated with Becker muscular dystrophy may produce clinical syndromes which are not associated with any weakness. These include myalgias, cramps, rhabdomyolysis, and cardiomyopathy.

Myalgias and cramps: A 33-year-old man has been described who was a member of a family in which several individuals had myalgias and cramps. On his examination, he had normal strength. Needle

EMG demonstrated MUAP amplitudes, durations, and recruit-ment which were consistent with myopathy. He and several other male family members, also with normal strength, had markedly elevated serum CK levels (CK 2000-3000 in the patient, 1,458-12,270 in other affected individuals). DNA analysis revealed a deletion in the dystrophin gene.17 Similarly, 4 patients have been described in another family with exertional myalgias, normal strength or minimal weakness, and serum CK levels which varied from normal to 2000 U/L. Needle EMG demonstrated small, poly-phasic MUAPs in some family members. DNA testing revealed a deletion in the dystrophin gene.16

Exercise-induced myalgias and rhabdomyolysis: A 9-year-old boy has been reported with exercise-induced muscle pain and two episodes of myoglobinuria. Neurological examination was normal. Needle EMG revealed low-amplitude polyphasic MUAPs, inter-preted as being consistent with a myopathy. He was found to have a deletion in the dystrophin gene.9

Cardiomyopathy: A 40-year-old man with severe congestive heart failure was diagnosed with a dilated cardiomyopathy at age 32. His serum CK level was 8000 U/L. Strength was normal. The needle EMG examination demonstrated low-amplitude polyphasic MUAPs, interpreted as being consistent with a diffuse myopathic pattern. On DNA testing, he was found to have a deletion in the dystrophin gene.28 One of the members of the family described above with myalgias, cramps, and normal strength had a cardio-myopathy as well.16

PATIENTS IN WHOM THE NEUROLOGICAL EXAMINATION IS LIMITED

Although manual muscle testing is in theory a simple and accurate test for weakness, the determination of “normal” strength may chal-lenging. In such situations, EDX testing is of great value.

Examination Limited by Poor Effort

It may be the examiner’s impression that strength is normal and that the patient is not producing a full effort against resistance. There are many reasons for this. One of the most common is pain, which is also a very common reason for referral for EDX testing. Other reasons include secondary gain (disability, sympathy), or inability to cooperate (e.g., a child or a mentally retarded adult). Often these patients are characterized as having “break-away” or “give-away” weakness, meaning that they do not sustain an effort against resistance, but rather produce a brief effort against the examiner’s force, followed by a marked decrease in effort and collapse of the limb. The examiner may believe that strength is normal briefly, but he or she cannot be certain, and the patient’s perception is that of weakness. The needle EMG examination may demonstrate abnor-malities of spontaneous activity which indicate acute or subacute denervation, or may indicate changes in motor unit amplitude and morphology indicative of chronic neurogenic or myopathic changes. Also important is the ability of the EDX physician to assess recruitment and activation. Recruitment is defined as “the

AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 23

successive activation of the same and additional motor units with increasing strength of voluntary muscle contraction.”1 In contrast, activation simply refers to the process of MUAP firing.1,29 Reduced activation indicates a central nervous system process, such as poor effort. Reduced recruitment or early recruitment are indicators of abnormalities of the peripheral nervous system, and characteristi-cally indicate neurogenic or myopathic disorders respectively. Thus, the needle EMG examination is a sensitive tool for detecting subtle neurogenic or myopathic disease.

Radiculopathy

Although it is a common diagnosis, the clinical assessment of ra-diculopathy may be challenging. Because virtually all limb muscles are innervated by several nerve roots, radiculopathy which produces relatively mild axonal loss and affects only one nerve root level may not produce significant weakness at that level to be unequivocally detectable on strength testing, particularly if the patient also has pain which limits effort. A thorough needle EMG examination may help to clarify the diagnosis. Care must be taken to examine several muscles with overlapping innervation for two reasons: (1) the individual’s innervation my differ from the “standard” in-nervation, and (2) only a small number of nerve root fibers to a particular muscle may be compromised. However, a needle exami-nation which is carefully planned and carried out is a sensitive way of detecting even mild radiculopathy.

Examination Limited by Extremely Strong Premorbid Status

Patients who are extremely strong at baseline and who now perceive that they are weaker pose a great challenge to the clinician. The standard manual muscle test may not demonstrate weakness, but such testing is limited by the examiner’s strength and by knowledge of the preexisting strength of the patient, and therefore may not be adequate for identifying early and mild loss of strength in such a patient. EDX testing is of great value in such cases. Low-amplitude CMAPs may indicate axon loss, myopathy, or a postsynaptic defect of neuromuscular transmission such as LEMS. The needle EMG examination is a sensitive method of detecting subtle denervation which may not be sufficient to produce detectable weakness on examination. Repetitive stimulation studies permit identification of disorders of neuromuscular transmission.

Fibromyalgia

Arguably one of the most disliked diagnoses because of its rela-tive subjectivity, fibromyalgia is nonetheless frequently diagnosed because of the common occurrence of symptoms that fit the diagnosis. The American College of Rheumatology has defined fi-bromyalgia as occurring in patients with a history of chronic wide-spread pain involving all four quadrants of the axial skeleton, and the presence of 9 of 18 tender points on physical examination.37 These individuals may have many other symptoms, including weakness, paresthesias, headache, affective disorders, temporoman-dibular joint syndrome, weight fluctuations, night sweats, sleep disturbances, irritable bowel syndrome, cognitive difficulties, dizzi-ness, esophageal dysmotility, noncardiac chest pain, and dyspnea.6

Unfortunately, there are no biologic markers which permit defini-tive diagnosis of this condition. One important role served by EDX studies in these patients is to exclude diseases of muscle and of the neuromuscular junction as factors causing weakness, fatigue, and muscle pain. A normal needle examination is helpful for excluding a wide variety of neuromuscular diseases including myopathies and dystrophies. Repetitive stimulation studies are useful for excluding disorders of neuromuscular transmission and should be performed on these patients because of their prominent fatigue.

Paresthesias are reported in 26% to 84% of patients with fibromyalgia.20,32,38 NCSs can be helpful in assessing paresthesias in these patients in two important ways. The paresthesias may be part of the fibromyalgia syndrome, in which case normal studies are helpful in the same manner as normal needle examinations or repetitive stimulation studies. However, some patients with fibro-myalgia have entrapment neuropathies which may not be identi-fied without EDX studies. CTS was identified by EDX studies in 10% of patients with fibromyalgia in one series and in 15% in another.11,31

Chronic Fatigue Syndrome

The Centers for Disease Control defines chronic fatigue syndrome as being characterized by unexplained persistent or relapsing chronic fatigue of new or definite onset (not lifelong), not the result of ongoing exertion, not substantially alleviated by rest, and resulting in substantial reduction in previous activities. There also must be four or more of the following symptoms, all of which must have persisted or recurred during 6 or more months of illness and must not have predated the fatigue: (1) self-reported impair-ment in short-term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social or personal activities; (2) sore throat; (3) tender cervical or axillary lymph nodes; (4) muscle pain, multi-joint pain without joint swelling or redness; (5) headaches of a new type, pattern, or severity; (6) unrefreshing sleep; and (7) postexertional malaise lasting more than 24 hours.14 The estimated prevalence is 0.4%-1% of the population.8 Like fibromyalgia, this condition has no biologic markers to aid in its identification. EDX studies are expected to be normal, but play a role similar to that described for fibromyalgia. Because fatigue is the major symptom, repetitive stimulation studies performed before and after exercise are impor-tant to rule out a presynaptic or postsynaptic disorder of neuro-muscular transmission. The needle examination serves to exclude a myopathic disorder. NCSs are extremely useful both for excluding an underlying neurogenic disorder and for identifying atypical pre-sentations of entrapment neuropathies such as CTS.

SPECIAL ELECTROMYOGRAPHY TECHNIQUES

There are special EMG techniques which may be useful for patients in whom the standard EDX methods do not provide clear diagnos-tic information. These span the broad field of quantitative EMG, including quantitative analysis of the MUAP, interference pattern analysis, turns and amplitude analysis, and decomposition.26 Two special techniques merit particular attention.

24 EDX Studies are Helpful in Weakness With Normal Neurological Exams AANEM Course

Single-fiber Electromyography

Single-fiber EMG studies may demonstrate abnormal jitter in LEMS, myasthenia gravis, or congenital defects of neuromuscular transmission. Single-fiber EMG also may demonstrate abnormal fiber density. Fiber density generally is increased in neuropathies and in myopathies, being particularly high in dystrophies and in chronic neuropathies.26,33

Motor Unit Number Estimation

Motor unit number estimation (MUNE) can detect motor neuron loss in muscles not clinically weakened. In such muscles, CMAP amplitudes and twitch tensions remain normal until motor unit loss reaches 50%-80%. This is because collateral reinnervation keeps up with denervation up to this point, preventing loss of func-tion. MUNE shows abnormalities, however.23 MUNE is also useful for longitudinal follow-up. In patients with slowly progressive ALS, the rate of change per month was found to be greater for thenar MUNE than for a variety of other techniques, including thenar CMAP amplitude, grip strength, total manual muscle testing score, Appel ALS rating scale, and forced vital capacity.12 In all patients with ALS, the rate of change in MUNE was greater than the rate of change in manual muscle testing and forced vital capacity.12

CONCLUSION

EDX testing generally provides clinically useful information on patients who have neurological examinations which are clearly normal or likely normal, but challenging to accurately assess. While not all of these patients will be found to have neurological disease, even negative testing can have clinical utility. Most of the informa-tion necessary to the clinician can be obtained by standard NCSs, repetitive stimulation studies, and needle EMG, but some special tests add useful information in selected cases.

REFERENCES

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2. Blexrud MD, Windebank AJ, Daube JR. Long-term follow-up of 121 patients with benign fasciculations. Ann Neurol 1993;34:622-625.

3. Blijham PJ, Hengstman GJ, Hama-Amin AD, van Engelen BG, Zwarts MJ. Needle electromyographic findings in 98 patients with myositis. Eur Neurol 2006;55:183-188.

4. Blijham PJ, Hengstman GJ, Ter Laak HJ, Van Engelen BG, Zwarts MJ. Muscle-fiber conduction velocity and electromyography as di-agnostic tools in patients with suspected inflammatory myopathy: a prospective study. Muscle Nerve 2004;29:46-50.

5. Buchthal F. Fibrillations: clinical electrophysiology. In: Culp WJ, Ochoa J, editors. Abnormal nerves and muscle generators. New York: Oxford University Press; 1982. p 632-662.

6. Clauw DJ. Fibromyalgia. In: Ruddy S, Harris ED, Sledge CB, editors. Kelly’s textbook of rheumatology, 6th edition. Philadelphia: WB Saunders; 2001. p 417-427.

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9. Doriguzzi C, Palmucci L, Mongini T, Chiado-Piat L, Restagno G, Ferrone M. Exercise intolerance and recurrent myoglobinuria as the only expression of Xp21 Becker type muscular dystrophy. J Neurol 1993;240:269-271.

10. Dumitru D, Amato AA. Neuromuscular junction disorders. In: Dumitru D, Amato AA, Zwarts M, editors. Electrodiagnostic medi-cine, 2nd edition. Philadelphia: Hanley & Belfus; 2002. p 1127-1227.

11. Ersoz M. Nerve conduction tests in patients with fibromyalgia: com-parison with normal controls. Rheumatol Int 2003;23:166-170.

12. Felice KJ. A longitudinal study comparing thenar motor unit number estimates to other quantitative tests in patients with amyotrophic lateral sclerosis. Muscle Nerve 1997;20:179-185.

13. Fleet WS, Watson RT. From benign fasciculations and cramps to motor neuron disease. Neurology 1986;36:997-998.

14. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994;121:953-959.

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16. Gold R, Kress W, Meurers B, Meng G, Reichmann H, Muller CR. Becker muscular dystrophy: detection of unusual disease courses by combined approach to dystrophin analysis. Muscle Nerve 1992;15:214-218.

17. Gospe SM, Lazaro RP, Lava NS, Grootscholten PM, Scott MO, Fischbeck KH. Familial-X-linked myalgia and cramps: a nonprogres-sive myopathy associated with a deletion in the dystrophin gene. Neurology 1989;39:1277-1280.

18. Harper PS, Monckton DG. Myotonic dystrophy. In: Engel AG, Franzini-Armstrong C, editors. Myology, 3rd edition. New York: McGraw-Hill; 2004. p 1039-1076.

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21. Loong SC. The carpal tunnel syndrome: a clinical and electrophysi-ological study of 250 patients. Clin Exp Neurol 1977;14:51-65.

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23. McComas AJ. Motor unit estimation: methods, results, and present status. Muscle Nerve 1991;14:585-597.

24. Merlini L, Sabatelli P, Columbaro M, Bonifazi E, Pisani V, Massa R, Novelli G. Hyper-CK-emia as the sole manifestation of myotonic dystrophy type 2. Muscle Nerve 2005;31:764-767.

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26. Nandekar SD, Stalberg EV, Sanders DB. Quantitative EMG. In: Dumitru D, Amato AA, Zwarts M, editors. Electrodiagnostic medi-cine, 2nd edition. Philadelphia: Hanley & Belfus; 2002. p 293-356.

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28. Palmucci L, Doriguzzi C, Mongini T, Chiado-Piat L, Restagno G, Carbonara A, Paolillo V. Dilating cardiomyopathy as the expression of Xp21 Becker type muscular dystrophy. J Neurol Sci 1992;111:218-221.

AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 25

26 EDX Studies are Helpful in Weakness With Normal Neurological Exams AANEM Course

29. Preston DC, Shapiro BE. Electromyography and neuromuscular disorders, 2nd edition. Philadelphia: Elsevier; 2005. p 223.

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One of the most common presenting complaints in the neuromus-cular clinic is weakness. To the physician, weakness means a lack of muscular force or power production. To the patient, the term weak-ness may be used to describe a number of problems that impair mo-bility including lack of strength, poor muscular endurance, fatigue, and even vertigo. Thus, the first task of the physician evaluating a patient with weakness is to determine specifically what are the pa-tient’s symptoms. True muscle weakness, which can be detected by manual muscle testing, may be produced by central or peripheral nervous system pathology. However, many patients who complain of generalized weakness, fatigue, or lack of muscular endurance have normal muscle strength on neurologic examination and have a nonneurologic explanation for their symptoms. It is useful to divide these patients into two groups; (1) those who complain of pain or myalgia in addition to weakness, and (2) those who do not experience pain. Table 1 provides a differential diagnosis for each of these two groups of patients. Some of the more common of these nonneurologic causes of weakness will be discussed.

Patients with any of the diagnoses listed in Table 1, other than some of the subtle neuromuscular disorders, will have a normal electrodi-agnostic (EDX) study. Thus, EDX evaluation is not warranted in most patients with complaints of weakness but normal neurologic examinations.

In a recent study,7 only 2% of patients complaining of myalgias with a normal neurologic examination had muscle pathology on biopsy; by extrapolation, one would expect very few of these patients to have EDX abnormalities. However, one must keep in mind that up to 40% of motor neurons must be lost for weakness to be detectable on manual muscle testing.19 Thus, in a very strong, physically fit individual it may be difficult to detect subtle weakness due to evolving neuromuscular disease with manual muscle testing. An EDX study may be warranted in a young, physically fit individ-ual who appears to have normal strength, but reports a decline in functional capacity, i.e., cannot carry a child or lift as much weight in the gym. This individual could have very early motor neuron

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

Neurologic Examinations

Lisa S. Krivickas, MDAssociate Professor

Department of Physical Medicine and RehabilitationHarvard Medical SchoolBoston, Massachusetts

27

disease or a neuromuscular junction disorder. A serum creatine kinase that is elevated in the preceding scenario may also suggest the need for EDX testing to look for myopathy. On the other hand, several forms of myopathy have normal EDX studies when they are mild or in their early stages; these include the mitochondrial dis-orders, common metabolic myopathies such as myophosphorylase deficiency (McArdle’s disease) and carnitine palmitoyl transferase II deficiency, and steroid myopathy.

MEDICAL WORK-UP OF WEAKNESS WITH NORMAL NEUROLOGIC EXAMINATION

Patients who complain of weakness but have a normal neurologic exam warrant a medical work up to rule out many of the etiologies listed in Table 1. This should include a thorough physical examina-tion with attention to age-appropriate screening procedures such as mammography and colonoscopy. In addition, medications should be reviewed to look for possible iatrogenic causes of fatigue and lack of muscular endurance. Suggested laboratory testing includes a complete blood cell count, thyroid screen, sedimentation rate, and cortisol level. If there is suspicion of cardiac or pulmonary dysfunc-tion as a contributing factor to the symptoms, a cardiac stress test, echocardiogram, or pulmonary function tests might be performed.

Symptoms suggestive of sleep apnea should prompt a sleep study. The entities to be discussed below are primarily diagnoses of exclu-sion.

Myofascial Pain Syndrome

Myofascial pain is a muscle-related pain disorder associated with 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 consecutively seen patients at a comprehensive pain center.9 Many of these patients also complain of weakness in affected muscles.

The most commonly accepted hypothesis regarding the pathophys-iology of trigger point related pain suggests that abnormally active motor endplates release excessive acetylcholine producing a con-stant state of myofibril contraction. Prolonged contraction causes local tissue hypoxia with edema, and if not reversed, leads to the development of ischemic muscle pain.14 Trigger points do not have any abnormal histologic findings, and EDX of muscle affected by myofascial pain is normal.

The pain of trigger points is typically described as dull, deep, and aching with a stereotypical referral pattern. For example, when the

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 PainlessMyofascial pain syndrome Systemic illnessFibromyalgia AnemiaChronic fatigue syndrome Cancer or post cancer fatiguePolymyalgia rheumatica Pulmonary diseaseSubtle 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

trapezius muscle is involved, the pain is usually localized to the suprascapular region with referral into the upper neck as well as to the parietooccipital and periorbital areas. The intensity of pain can change from day to day and is typically exacerbated by maintenance of static postures, repetitive movement, stress, lack of sleep, and nu-tritional imbalance. Patients may also complain of decreased range of motion, local tenderness, and some dysaesthesias.

On physical examination, the physician is able to locally palpate a taut and tender muscle band which reproduces the patient’s typical pattern of referred pain when an appropriate amount of pressure is applied. A local twitch response is elicited by manually snapping the trigger point. The involved region may exhibit decreased range of motion and some pain-related local muscle weakness.

Treatment consists of reassurance regarding the benign nature of this disorder, use of analgesics, physical therapy incorporating myo-fascial release techniques and modalities, a home exercise program, and trigger point injections and/or acupuncture.

Fibromyalgia

Fibromyalgia is a chronic and complex pain syndrome. Patients typically complain of diffuse body pain frequently involving the spinal region. They may also complain of diffuse weakness because their pain limits function and results in deconditioning. Whereas myofascial pain may involve only one or two regions of the body, the pain of fibromyalgia is widespread and accompanied by mul-tiple tender points, which differ from trigger points in their lack of the typical trigger point pain referral pattern. Epidemiologic studies show that approximately 2% of the United States popula-tion and 6%-10% of patients seen in the average medical practice carry this diagnosis.4,20 Women are affected more frequently than men with initial onset of symptoms in the second or third decade of life. Given the lack of objective clinical findings, the diagnosis of fibromyalgia can be delayed for many years leading to un-necessary medical treatments and unfortunate desperation on the patient’s part. Possible predisposing factors and triggers include physical trauma, psychological stress, and a history of physical or sexual abuse. Genetic predisposition may also play a role in the development of this condition.15 Altered central processing of no-ciceptive stimuli leading to heightened pain response is thought to be the main pathophysiologic mechanism of fibromyalgia. Spinal fluid abnormalities such as abnormal elevation of substance P and decreased levels of excitatory amino acids, as well as systemic deficiency of serotonin, have also been postulated as causative factors.16,17,18 A number of other chronic conditions are frequently associated with fibromyalgia. These include chronic fatigue, sleep disturbance, myofascial pain, irritable bladder syndrome, irritable bowel syndrome, and cognitive dysfunction.

Patients typically present with constant, frequently debilitating, bilateral, widespread pain with an axial predisposition. The pain is usually exacerbated by physical activity, stress, lack of sleep, and cold and damp weather. The patient might complain of generalized

weakness, daily fatigue, muscle and joint stiffness, and generalized muscle tenderness. Other frequent symptoms include unrefreshed sleep, depressed mood, anxiety, urinary frequency, irritable bowel, and multiple chemical sensitivities. On physical examination pa-tients may have decreased spinal range of motion, pronounced pain behavior, psychomotor retardation, slowed mentation, and a relative degree of somnolence. Generalized tactile allodynia is a pathognomonic finding in fibromyalgia, and tenderness of at least 11 of 18 designated tender points tends to support the diagnosis. Giveway weakness is commonly observed; however, neurological examination is typically normal.

Diagnostically, imaging and laboratory studies are used to rule out other musculoskeletal conditions or systemic disorders such as hypothyroidism, myopathy, rheumatic disease, and electrolyte or nutrient abnormalities. Referral for a sleep study is recommended if a serious sleep disorder, such as sleep apnea or restless legs syn-drome, is suspected.

Treatment is similar to that for myofascial pain. It should include education, stress reduction and relaxation, and a physical therapy program that emphasizes aerobic activity or exercise. Useful medi-cations include low-dose tricyclic anti-depressants or selective sero-tonin reuptake inhibitors to normalize sleep and reduce pain, and simple analgesics such as nonsteroidal anti-inflammatory drugs and acetaminophen.

Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is a group of nonspecific symp-toms, and there is much debate regarding whether it is a specific disease entity or merely a syndrome with multiple etiologies. A formal definition of the syndrome was proposed in 1994 by an international panel of experts.10 The defining criteria are (1) severe chronic fatigue for more than 6 months with no known explana-tion, and (2) at least four of the following symptoms: short term memory impairment, sore throat, tender lymph nodes, muscle pain/ fibromyalgia-like symptoms, joint pain, new headache, unre-freshing sleep, and postexertional malaise for more than 24 hours. Many patients also report generalized muscle weakness or fatigue. The diagnosis is one of exclusion. CFS is more common in women than men, and the prevalence is as high as 1 per 10,000 in the United States population.5

The etiology of CFS is unclear. Viral causes and immune system dysfunction have been postulated as pathogenic factors, but this has not been supported by scientific studies. There is preliminary evidence suggesting elevation of cytokine levels, relative hypoadren-alism or relative orthostatic hypotension as etiologic factors, but these theories require further investigation.

Treatment is symptomatic and includes moderate exercise, a healthy diet, vitamin supplementation, counseling, and stress reduction. Nonsteroidal anti-inflammatory drugs and low-dose tricyclic anti-depressants are useful for pain and myalgia. A systematic review of

AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 29

the literature found a median full recovery rate of only 5%, but 40% of patients improved over time; 8%-30% returned to work in the studies assessing this variable.3

Polymyalgia Rheumatica

Polymyalgia rheumatica (PMR) is a rheumatologic syndrome of unknown etiology that may produce neck and trunk pain. The disease typically develops in patients 50 years of age and older and evolves over the course of 4-8 weeks. The diagnosis is primarily clinical, but suggested diagnostic criteria include: (1) aching and morning stiffness lasting greater than 30 minutes and involving at least two of the following regions - neck, shoulder girdle, or pelvic girdle; (2) age greater than 50; (3) erythrocyte sedimentation rate greater than 40; (4) duration of symptoms greater than 1 month; and (5) no other disease present.6 Patients have a normal neurologic examination without significant muscle weakness. Diseases that need to be excluded from the differential diagnosis include various forms of arthritis, viral myalgia, fibromyalgia, polymyositis, hypo-thyroidism, depression, and occult malignancy or infection.13 Once a diagnosis of PMR has been made, it is important to also rule out temporal arteritis which approximately 15% of patients with PMR develop. Temporal arteritis, when untreated, can produce 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.

Conversion Disorders and Malingering

A small percentage of patients who complain of weakness and have normal neurologic examinations have medically unexplained 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 listed as part of the somatoform disorder group.2 It is also known as Hysterical Neurosis – Conversion type. Patients with this diagnosis have neurologic symptoms which may include gait disorders, limb paralysis, and paraplegia or tetraplegia. In contrast to patients who are malingering, their symptoms are not intentionally produced, and they have no voluntary control over them. In one recent study, a surprising 35% of new referrals to the neurology service met DSM-IV criteria for somatoform disorder,8 and this was more common in outpatients than in inpatients. The etiology of conver-sion disorders is not well understood, but early childhood abuse and stress are thought to play a role.1

The treatment of conversion disorder is often best carried out on an inpatient rehabilitation unit. It should include behavior modifica-tion, psychotherapy, and physical therapy.11 The degree of recovery is quite variable. In general, the longer the duration of symptoms, the less likely full recovery is to occur. In a series of 30 patients

admitted to a rehabilitation hospital in Israel with paralysis ranging from monoplegia to tetraplegia, 27% had full recovery, 27% had partial recovery, and 46% remained unchanged.12

In contrast to the patient with a conversion disorder, the malin-gerer consciously feigns weakness for the purpose of secondary gain (compensation for motor vehicle accident, release from work or jail, discharge from the army, etc.). In these patients, the symptoms and degree of weakness may fluctuate depending upon who is observing the patient.

“Therapeutic Electrodiagnosis” in Patients With Normal Neurologic Examination

With the exception of possible poor motor unit activation, the EDX study will be normal in patients with myofascial pain syndrome, fibromyalgia, chronic fatigue syndrome, PMR, and conversion dis-orders. However, in some of these patients the performance of the EDX study does have therapeutic value. Performing the study and explaining the results as one performs the test may help to convince patients that they do not have nerve or muscle pathology. This, in turn, may facilitate their participation in a multidisciplinary reha-bilitation program designed to improve function.

ACKNOWLEDGEMENT

I would like to thank Dr. Alec Meleger for his assistance with writing the sections on myofascial pain and fibromyalgia. These sec-tions are adapted from Meleger AL, Krivickas LS. Musculoskeletal disorders. Neurol Clin 2007;25:419-438.

REFERENCES

1. Allet J, Allet R. Somatoform disorders in neurologic practice. Curr Opin Psychiatry 2006;19:413-420.

2. American Psychiatric Association. Diagnostic and statistical manual of mental disorder, 4th edition. Washington, DC: American Psychiatric Association; 1994.

3. Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med 2005;55:20-31.

4. Campbell S, Clark S, Tindall E, Forehand M, Bennett R. Clinical char-acteristics of fibrositis. I: a blinded, controlled study of symptoms and tender points. Arthritis Rheum 1983;26:817-824.

5. Dawson D. Chronic fatigue syndrome. In: Katirji B, Kaminski H, Preston D, Ruff R, Shapiro B, editors. Neuromuscular disorders in clinical practice. Boston, MA: Butterworth Heinemann; 2002. p 1376-1382.

6. Deal C. Polymyalgia Rheumatica. In: Katirji B, Kaminski H, Preston D, Ruff R, Shapiro B, editors. Neuromuscular disorders in clinical practice. Boston: Butterworth Heinemann; 2002. p 1369-1375.

30 EDX Studies are Not Helpful in Weakness with Normal Neurological Exams AANEM Course

AANEM Course Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine 31

7. Filosto M, Tonin P, Vattemi G, Bertolasi L, Simonati A, Rizzuto N, Tomelleri G. The role of muscle biopsy in investigating isolated muscle pain. Neurology 2007;68:181-186.

8. Fink P, Hansen MS, Sondergaard L. Somatoform disorders among first-time referrals to a neurology service. Psychosomatics 2005;46:540-548.

9. Fishbain D, Goldberg M, Meagher R, Steele R, Rosomoff H. Male and female chronic pain patients categorized by DSM-III psychiatric diagnostic criteria. Pain 1986;26:181-197.

10. Fukuda K, Straus S, Hickie I, Sharpe M, Dobbins J, Komaroff A, the International Chronic Fatigue Syndrome Study Group. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994;121:953-959.

11. Heruti R, Levy A, Adunski A, Ohry A. Conversion motor pa-ralysis disorder: overview and rehabilitation model. Spinal Cord 2002;40:327-334.

12. Heruti R, Reznik J, Adunski A, Levy A, Weingarden H, Ohry A. Conversion motor paralysis disorder: analysis of 34 consecutive referrals. Spinal Cord 2002;40:335-340.

13. Hunder G. Polymyalgia rheumatica: pinning down an elusive syn-drome. 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.

15. Offenbaecher M, Bondy B, de Jonge S, Glatzeder K, Kruger M, Schoeps P, Ackenheil M. Possible association of fibromyalgia with a polymorphism in the serotonin tansporter gene regulatory region. Arthritis Rheum 1999;42:2482-2488.

16. Russell I, Vaereroy H, Javors M, Nyberg F. Cerebrospinal fluid bio-genic amine metabolites in fibromyalgia/ fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum 1992;35:550-556.

17. Russell I, Orr M, Littman B, Vipraio G, Alboukrek D, Michalek J, Lopez Y, MacKillip F. Elevated cerebrospinal fluid levels of sub-stance P in patients with the fibromyalgia syndrome. Arthritis Rheum 1994;37:1593-1601.

18. Russell I. Neurochemical pathogenesis of fibromyalgia syndrome. J Musculoskel Pain 1996;4:61-92.

19. Sharrard W. The distribution of the permanent paralysis in the lower limb in poliomyelitis; a clinical and pathological study. J Bone Joint Surg (Br) 1955;37:540-558.

20. Wolfe F, Ross K, Anderson J, Russill I, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 1995;38:19-28.

32 AANEM Course

AANEM Course 33

AFTER COMPLETION OF THIS ACTIVITYCrossfire: Debates in Neuromuscular and Electrodiagnostic Medicine

ACTIVITY AND FACULTY EVALUATIONOn 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.

11. Addressed competencies identified by my specialty.

12. Provided fair and balanced content.

13. Provided clear evidence to support content.

14. Included opportunities to learn interactively from faculty and participants.

15. Provided me with supporting materials or tools for my office (re-minders, patient materials, etc.).

16. Included opportunities to solve patient cases.

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?

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?A. Definitely will change. B. Possibly will change. C. Definitely will not change.

Written comments can be provided on page 37.

Fill

in an

swer

s here

Instructions for filling out

your parSCORE sheet

Using a #2 pencil, fill in your answers beginning with #10:

Leave the completed form at the table out-side your session.

34 Activity and Faculty Evaluation AANEM Course

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

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

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

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

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

27. Did you perceive any commercial bias in Dr. Dyck’s presentation?A. Yes.B. No.

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

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

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

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

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

33. Did you perceive any commercial bias in Dr. Krivickas’ presenta-tion?A. Yes.B. No.

Crossfire: Controversies in Neuromuscular and Electrodiagnostic Medicine

CME SELF-ASSESSMENT TEST

Select the ONE best answer for each question.

AANEM Course 35

34. Which risk factor for carpal tunnel syndrome (CTS) has been demonstrated to have a dose-response relationship?A. Hand repetition.B. Diabetes.C. Obesity.D. Height.

35. Which of the following risk factors for CTS has the weakest evi-dence to support it?A. Obesity.B. Vitamin B6 level.C. Age.D. Gender.

36. Genetics has not been demonstrated to play a role in idiopathic CTS.A. True.B. False.

37. Which of the following medical disorders is not related to a higher risk for the development of CTS?A. Diabetes.B. Rheumatoid arthritis.C. Acromegaly.D. None of the above.

38. The ability to predict who will develop carpal tunnel disease is:A. Terrible (0-5% of the variance is explained).B. Poor (8-17% of the variance explained).C. Fair (22-30% of the variance explained).D. Reasonable (35-45% of the variance explained).

39. The positive yield of an unguided sural nerve biopsy in patients with suspected vasculitis is? A. 20%.B. 40%.C. 60%.D. 80%.

40. Noninvasive testing can determine the cause of peripheral neu-ropathy in what percentage of patients?A. 20%.B. 40%.C. 60%.D. 80%.

41. Which of the following disorders is not a common cause of mononeuritis multiplex?A. Churg-Strauss angiitis.B. Periarteritis nodosum.C. Sarcoidosis.D. Alcoholism.

42. To make the diagnosis of sarcoidosis, which of the following tissue biopsies is as likely to yield noncaseating granulomas as a nerve biopsy?A. Bone marrow.B. Muscle.C. Skin.D. Endocardium.

43. Nerve biopsy can be put to good use to diagnose all of the follow-ing disorders except:A. Vasculitis.B. Leprosy.C. Polyglucosan body disease.D. Diabetic distal polyneuropathy.

44. Fasciculations:A. Are usually the only presenting syndrome in amyotrophic

lateral sclerosis (ALS).B. Are noted by most healthy medical personnel.C. Cannot be a benign finding.D. Usually indicate disease if the needle electromyography is

otherwise normal.

36 CME Self-Assessment Test AANEM Course

45. In patients with a normal neurological examination, electrodi-agnostic (EDX) studies may be helpful in diagnosing all of the following except:A. CTS.B. Lambert-Eaton myasthenic syndrome (LEMS).C. Motor neuron disease (MND).D. Normal pressure hydrocephalus.

46. A cardiomyopathy, a normal neurological examination, and an abnormal EDX study may be the presenting features of:A. Becker muscular dystrophy.B. LEMS.C. Benign fasciculations.D. MND.

47. Individuals with no neurological disease in whom muscle strength testing is limited by pain may demonstrate:A. Reduced recruitment.B. Reduced activation.C. Fibrillation potentials.D. Large amplitude motor unit action potentials.

48. The rate of change of which of the following is most sensitive for detecting changes in patients with slowly-progressive ALS?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 weak-ness to be detectable on manual muscle testing?A. 10%.B. 20%.C. 40%.D. 60%.

50. Trigger points may be caused by:A. Focal denervation of muscle.B. Muscle fiber necrosis.C. Spasticity.D. Excessive motor end-plate activity.

51. A diagnosis of fibromyalgia requires: A. Presence of trigger points.B. Presence of tender points.C. Sleep disturbance.D. Exercise intolerance.

52. What is the best treatment for polymyalgia rheumatica?A. Amitryptiline.B. Aerobic exercise.C. Low-dose prednisone.D. High-dose prednisone.

53. A patient who feigns weakness to obtain release from work is best described as having:A. A conversion disorder.B. Hysterical neurosis.C. Somatoform disorder.D. Malingering disorder.

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.

AANEM Course 37

American Association of Neuromuscular & Electrodiagnostic Medicine

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