Basics With The Experts

John D. England, MD Jun Kimura, MD Vern C. Juel, MD Bassam A. Bassam, MD

AANEM 59th Annual Meeting Orlando, Florida

Copyright © October 2012 American Association of Neuromuscular & Electrodiagnostic Medicine 2621 Superior Drive NW Rochester, MN 55901

Printed by Johnson Printing Company, Inc. 1 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 judgment of the treating physician, such use is medically indicated to treat a patient’s condition. Information regarding the FDA clearance status of a particular device or pharmaceutical may be obtained by reading the product’s package labeling, by contacting a sales representative or legal counsel of the manufacturer of the device or pharmaceutical, or by contacting the FDA at 1-800-638-2041.

2 Basics With The Experts

Table of Contents

Course Committees & Course Objectives 4

Faculty 5

The Evaluation of Polyneuropathy 7 John D. England, MD

Long and Short of Nerve Conduction Studies for Neuropathy 13 Jun Kimura, MD

Repetitive Nerve Stimulation Testing 19 Vern C. Juel, MD

Muscle Cramps and Hyperactivity Syndromes 25 Bassam A. Bassam, MD

CME Questions 31

No one involved in the planning of this CME activity had any relevant financial relationships to disclose. Authors/faculty have nothing to disclose

Chair: John D. England, 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.

3 Objectives

Objectives - Participants will acquire skills to: (1) indicate the laboratory tests which have the highest yield in the evaluation of peripheral neuropathy, (2) identify the NCSs which are most useful in the evaluation of peripheral neuropathy, (3) describe the technique of repetitive nerve stimulation and the differences between pre-synaptic and post-synaptic disorders of NM transmission, and (4) recognize the EMG characteristics, CLINICAL USEFULNESS AND SYNDROMES of nerve and muscle hyperactivity. Target Audience: • Neurologists, physical medicine and rehabilitation and other physicians interested in neuromuscular and electrodiagnostic medicine • Health care professionals involved in the management of patients with neuromuscular diseases • Researchers who are actively involved in the neuromuscular and/or electrodiagnostic research 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 designates this live activity for a maximum of 3.25 AMA PRA Category 1 CreditsTM. If purchased, the AANEM designates this enduring material for a maximum of 5.75 AMA PRA Category 1 CreditsTM. This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Physicians should claim only the credit commensurate with the extent of their participation in the activity. CME for this course is available 10/2012 - 10/2015. CEUs Credit - The AANEM has designated this live activity for a maximum of 3.25 AANEM CEUs. If purchased, the AANEM designates this enduring material for a maximum of 5.75 CEUs.

2011-2012 Course Committee

Shawn J. Bird, MD, Chair Shashi B. Kumar, MD Marcy C. Schlinger, DO Philadelphia, PA Tacoma, WA Bath, MI

Lawrence W. Frank, MD A. Arturo Leis, MD Nizar Souayah, MD Elmhurst, IL Jackson, MS Westfield, NJ

Taylor B. Harrison, MD Benjamin S. Warfel, II, MD Atlanta, GA Lancaster, PA

2011-2012 AANEM President

John C. Kincaid, MD Indianapolis, IN Basics With The Experts

Faculty

John D. England, MD Vern C. Juel, MD Department of Neurology Division of Neurology LSUHSC School of Medicine Duke University School of Medicine New Orleans, Louisiana Durham, North Carolina

Dr. England is the Grace Benson Professor and Chairman of the Dr. Juel completed neurology residency and neuromuscular Department of Neurology at the LSUHSC School of Medicine fellowship training at Duke University Medical Center. He is in New Orleans. He is an author or co-author of more than 200 currently an Associate Professor in the Division of Neurology at publications. He has served on many AANEM committees and Duke where he directs the Neuromuscular Medicine Fellowship was the Secretary-Treasurer from 2005-2008 and the President Program. Dr. Juel is board certified in neurology, clinical from 2009-2010. He is currently the Chairman of the Guidelines neurophysiology, neuromuscular medicine, and electrodiagnostic Development Subcommittee of the American Academy of medicine. He has served on several AANEM committees and Neurology. His major interests are the pathophysiology and has chaired the Graduate Medical Education and Neuromuscular clinical assessment of peripheral neuropathies. Medicine Self-Examination Committees. His areas of academic interest include neuromuscular junction disorders, Jun Kimura, MD chemodenervation for focal dystonia, and neurological education. Department of Neurology University of Iowa Health Care Bassam A. Bassam, MD Iowa City, Iowa Neuromuscular Program and EMG Laboratory University of South Alabama Dr. Kimura received his medical degree from Kyoto University Mobile, Alabama in Japan. He moved to the United States as a Fulbright scholar for residency training in neurology and a fellowship in Dr. Bassam completed residency training in neurology and a electrophysiology at the University of Iowa, where he now serves fellowship in neuromuscular disease at Wayne State University, as Professor of Neurology. He also has taught at the University with additional fellowship training at Mayo Clinic. He is board of Manitoba in Canada, Kyoto University in Japan, and Tiantan certified by the American Board of Psychiatry and Neurology and Hospital in China. Dr. Kimura has more than 500 original the American Board of Electrodiagnostic Medicine (ABEM) and publications, including four editions of his book, Electrodiagnosis is a diplomate in the neuromuscular medicine sub-specialty. Dr. in Diseases of Nerve and Muscle. Dr. Kimura has received Bassam has served on various AANEM committees, including honorary membership from 25 national societies of neurology, chair of the Workshop Committee; he current serves on the ABEM neurophysiology, and rehabilitation medicine. Examination Committee. His academic interests and achievements focus on neuromuscular disorders and electromyography.

5 6 BASICS WITH THE EXPERTS

The Evaluation of Polyneuropathy John D. England, MD The Grace Benson Professor and Head Department of Neurology Louisiana State University Health Sciences Center School of Medicine New Orleans, Louisiana

Amparo Gutierrez, MD Associate Professor Department of Neurology Louisiana State University Health Sciences Center School of Medicine New Orleans, Louisiana

INTRODUCTION The physician should explore for the presence of other medical conditions, medications which the patient takes (including Peripheral neuropathies are common in neurological practice, nonprescription dietary supplements and vitamins), and and there are a variety of clinical presentations. Through a exposure to toxins such as alcohol, heavy metals, and solvents. combination of clinical findings, electrodiagnostic (EDX) It is important to determine the rate of symptom progression, the studies, and laboratory investigations tailored to the individual pattern of symptoms/signs, and the type of fibers (large versus patients’ circumstances, most neuropathies can be categorized small fibers) involved. The most common clinical phenotype is by subtype and etiology. Such classification is important for that of slowly evolving distal sensory loss with varying degrees determining prognosis and treatment. of muscle weakness, and occasionally autonomic symptoms. The most common variety of polyneuropathy is a chronic distal EPIDEMIOLOGY symmetric polyneuropathy.13-16,29 In this type of polyneuropathy, nerve fibers are involved in a “length-dependent” fashion; as The overall prevalence of polyneuropathy is approximately 2,400 such, symptoms usually begin in the toes/distal feet and spread per 100,000 (2.4%) people, but for those older than 55 years centripetally. Sensory symptoms usually precede motor weakness. the prevalence rises to at least 8,000 per 100,000 (8%).13,19,26 Myotatic reflexes are also affected in a length-dependent manner In the developed, world the most common cause of peripheral such that ankle reflexes are depressed or absent prior to the loss neuropathy is diabetes mellitus (DM) and prediabetes.6 A of other reflexes. The clinical picture is usually one of a stocking- community-based study estimated the prevalence of peripheral glove sensory loss, distal wasting and weakness, and depressed neuropathy in patients with type 2 DM to be 26.4%.9 Although or absent myotatic reflexes. This is an easily recognizable entity. not commonly seen in the United States, in some parts of the world, such as Southeast Asia, India, and Africa, leprosy is still a Another form of neuropathy that is frequently encountered major cause of peripheral neuropathy. is a painful small fiber neuropathy.13 These patients typically complain of burning pain, lancinating pain, burning dyesthesias, DIAGNOSIS and sheet intolerance, but at the same time have a feeling of numbness. At onset the symptoms are infrequent or migratory Although the clinical manifestations of a peripheral neuropathy in nature; as time goes by the symptoms usually become more vary widely, most can be categorized into a relatively limited persistent. The symptoms follow a distal to proximal distribution number of possibilities on the basis of a thorough history, focused in most patients. On examination one mainly finds distal loss of neurological examination, and EDX studies.13,14 The approach pin prick and temperature sensibility. These patients often present to the evaluation of the patient with a polyneuropathy should with complaints of chronic pain and the diffuse pain may be so occur in a logical, evidence-based, and sequential manner. severely disabling that it may limit a patient’s overall ability to Historical features are indispensable for an accurate diagnosis. function. 7 THE EVALUATION OF POLYNEUROPATHY Electrodiagnostic studies are sensitive, specific and validated CHRONIC AXONAL POLYNEUROPATHY measures that are very useful in the assessment of peripheral neuropathy.10-12,14-16 Utilizing nerve conduction studies (NCSs) Chronic axonal polyneuropathy is the most common variety of 13-16 one can determine whether the neuropathy is primarily axonal polyneuropathy, and there are many possible causes. The most or demyelinating. This distinction provides a defining branch common is diabetes or prediabetes, and these should be foremost point since each subtype (demyelinating versus axonal) has in the differential diagnosis. A large number of other systemic different etiologies, prognosis, and treatments. Demyelination diseases and metabolic disorders such as nutritional deficiencies, of nerve results in decreased conduction velocities, increased chronic renal failure, chronic liver disease, hypothyroidism, distal latencies, and conduction block. Axonal loss leads to malignancies as well as exogenous intoxications from medications, decreased sensory nerve action potential and compound muscle alcohol misuse, or chemical agents can result in this pattern of action potential amplitudes with relatively normal distal latencies neuropathy. Several varieties of hereditary neuropathy, especially and conduction velocities. Needle electromyography (EMG) the axonal forms of CMT disease (CMT2) can present with this can be useful in detecting active axonal damage, as evidenced pattern of neuropathy. Even after thorough evaluation, no cause by the presence of spontaneous muscle fiber activity at rest is found in 20-25% of chronic polyneuropathy patients. A subset (i.e., fibrillation potentials and positive sharp waves) as well as of these have a predominantly small fiber neuropathy with pain identifying signs of more chronic denervation-reinnervation. and numbness in the feet accompanied by few signs and normal EDX studies. Some of these patients have unsuspected diabetes However, NCSs are often normal in small fiber polyneuropathy, or prediabetes, which can be diagnosed with an elevated fasting in which the large myelinated fibers are preserved. In this type serum glucose, abnormal oral glucose tolerance test (GTT), 6,13,16 of neuropathy skin biopsy with determination of intraepidermal or elevated glycosylated hemoglobin (HgbA1C). Other nerve fiber density or autonomic testing may serve as useful possible causes of small fiber neuropathy include amyloidosis, ancillary diagnostic aids.15 human immunodeficiency virus (HIV) infection, alcohol misuse, microvasculitis, Fabry disease, and several other diseases. Even CHRONIC DEMYELINATING after exclusion of these diseases, a fair number of small fiber POLYNEUROPATHY neuropathies remain idiopathic.

Chronic demyelinating polyneuropathies are either acquired LABORATORY TESTING or genetically determined. Electrodiagnosis can help make this distinction since uniform symmetrical slowing of nerve conduction Laboratory testing should begin by testing for the most common usually indicates a genetically-determined neuropathy, whereas causes of polyneuropathy.13,16 Additional studies are then obtained multifocal slowing and conduction block are usually indicative as necessary to refine the etiology. The majority of studies of acquired neuropathies.13 Most genetically-determined indicate that screening laboratory tests comprised of a complete demyelinating polyneuropathies are variants of Charcot-Marie- blood count, erythrocyte sedimentation rate or C-reactive protein, Tooth (CMT) disease, and about 70-80% of these patients have comprehensive metabolic panel (fasting blood glucose, renal a duplication of peripheral myelin protein-22 (PMP22) gene. function, and liver function), thyroid function tests, serum B12, Most of the others are due to mutations of connexin-32 (Cx32) and serum protein immunofixation electrophoresis are indicated which encodes for the gap junction beta-1 (GJB1) protein or for most patients. The preceding laboratory studies were identified mutations of myelin protein zero (MPZ).13,16 The acquired as useful in a recent evidence-based practice guideline.16 demyelinating polyneuropathies are a heterogeneous group of mostly dysimmune neuropathies. Chronic inflammatory The screening blood test with the highest yield is the blood demyelinating polyradiculoneuropathy is the most common type glucose, consistent with the well-known fact that DM is the of acquired demyelinating polyneuropathy. This neuropathy most common cause of distal symmetrical polyneuropathy.16 is usually primarily motor, affecting both proximal and distal Several studies have highlighted the relatively high prevalence muscles; however, it occasionally presents with predominantly of prediabetes (impaired glucose tolerance) in patients who do sensory symptoms and signs. A related disorder, multifocal motor not fulfill the criteria for definite16,28 DM. Prediabetes can be neuropathy (MMN) usually presents with weakness and atrophy diagnosed by fasting blood glucose, HgbA1C, or a GTT. The oral of muscles in the forearms and hands, and it can be mistaken GTT may be particularly useful in screening patients with a small clinically for motor neuron disease. The EDX hallmark of MMN fiber painful neuropathy of unknown etiology.16 is partial conduction block in motor, but not sensory, fibers. Approximately 10% of patients with acquired demyelinating Vitamin B12 deficiency is frequently seen in patients with polyneuropathy have a serum paraprotein, which is usually an polyneuropathy. The yield of uncovering this deficiency is even immunoglobulin M (IgM). Some have antibodies directed against greater when the metabolites of cobalamin (methylmalonic acid myelin associated glycoprotein (MAG), and they exhibit an EDX or homocysteine) are tested.31,33 A large study demonstrated that pattern characterized by disproportionate prolongation of distal measuring methylmalonic acid is more specific then homocysteine latencies.21 Although most patients with a serum paraprotein for diagnosing vitamin B12 deficiency.33 Methylmalonic acid with have a monoclonal gammopathy of unknown significance, all or without homocysteine should also be checked when B12 is at need evaluation to look for plasmacytoma, amyloidosis, or the lower range of normal (i.e., 200-500 pg/dL) since such patients lymphoreticular malignancy. may really be relatively deficient in vitamin B12.16 Recently, more attention has been drawn to the fact that the oral hypoglycemic agent, metformin, can cause vitamin B12 malabsorption. Some 8 BASICS WITH THE EXPERTS studies indicate that this adverse effect can occur in approximately infectious diseases, recent vaccinations, medications (including 20-30 % of diabetic subjects taking metformin.37 Thus, diabetic dietary supplements and vitamins), or exposure to toxins such patients who take metformin should be screened for vitamin B12 as alcohol, heavy metals or organic solvents (Tables 1 and 2). deficiency. Laboratory testing should then be performed to identify any underlying condition or possible etiology. If there is a suspicion Monoclonal gammopathies are more common in patients with of infection, inflammatory disease, or neoplasm, the cerebrospinal polyneuropathy than in the normal population. IgM monoclonal fluid should be analyzed as well. If chronic heavy metal gammopathies may be associated with autoantibody activity, intoxication is suspected, analysis of the hair or nails should be type I or II cryoglobulinemia, macroglobulinemia, or chronic performed.13 lymphocytic leukemia. GENETIC TESTING Immunoglobulin G (IgG) or immunoglobulin A (IgA) monoclonal gammopathies may be associated with multiple myeloma, POEMS Hereditary neuropathies are an important subtype of (polyneuropathy, organomegaly, endocrinopathy, monoclonal polyneuropathy with a prevalence of 1:2,500 people. Most gammopathy, and skin changes) syndrome, primary amyloidosis, commonly, they present as a hereditary motor and sensory or chronic inflammatory conditions. One study of 279 consecutive neuropathy.25 A comprehensive family history should always be patients with a polyneuropathy of unknown etiology found that obtained in patients with a polyneuropathy. It is important to keep 10% of these patients had a monoclonal gammopathy, a significant in mind that the hereditary neuropathies may exhibit phenotypic increase over that reported in community studies.23 Serum protein variability within families and that spontaneous genetic mutations immunofixation electrophoresis (IFE) is more sensitive than serum do occur. protein electrophoresis (SPEP), especially for detecting small or nonmalignant monoclonal gammopathies.20 The yield of IFE is The majority of genetically-determined polyneuropathies are increased by 10% over routine SPEP for finding a monoclonal variants of CMT disease. The two most common causes of gammopathy; therefore, immunofixation is recommended when hereditary demyelinating polyneuropathy are CMT1A, in which screening for serum monoclonal gammopathy. patients exhibit a duplication of PMP22 gene, and CMTX, caused by mutations of Cx32 (GJB1).38 Axonal forms of CMT are most The history, clinical picture, and features of the EDX studies commonly caused by either mutations of Cx32 (GJB1) resulting in found in the individual patient will determine if additional CMTX or mutations of mitofusin-2 (MFN2) resulting in CMT2.32 laboratory testing beyond the routine is necessary. As noted, an As is evident from the above description, CMTX may manifest important aspect of the history in patients with a chronic axonal as either an axonal or demyelinating neuropathy.4,16 Because of polyneuropathy is inquiry into the presence of other medical the complicated nature and expense of genetic testing for CMT, conditions, symptoms of systemic disease, recent viral or other algorithms to guide such testing have been proposed (Figure).16

Figure. Evaluation of suspected hereditary neuropathies Reprinted and modified with permission from England, Gronseth, Franklin, and colleagues.15 9 THE EVALUATION OF POLYNEUROPATHY method for IENF density determination with good intra- and AUTONOMIC TESTING inter-observer reliability in normal control subjects and patients with a distal symmetrical polyneuropathy.17 In particular, patients Autonomic nervous system dysfunction may be a component of who are suspected of having a predominately small fiber, length- a polyneuropathy. In distal axonal symmetrical polyneuropathies dependent sensory polyneuropathy may benefit from skin biopsy with autonomic involvement, the most common clinical findings with IENF analysis since this test can document a decrease in the are abnormalities of sweating and signs of circulatory instability density of IENFs, thereby helping to confirm the diagnosis of a in the feet.13,15,16 small fiber neuropathy.

Various types of autonomic testing exist and can provide sensitive ETIOLOGIES OF CHRONIC indices of cardiovagal, adrenergic, and postganglionic sudomotor POLYNEUROPATHY function. Heart rate variability is a simple and reliable test of cardiovagal function. It can detect the presence of diabetic Painful Small Fiber Neuropathies polyneuropathy with nearly the same sensitivity as NCSs.11,15 The quantitative sudomotor axon reflex test (QSART) may be used Painful small fiber neuropathies are most likely associated with and can detect distal sudomotor loss with a sensitivity of 75- diabetes, prediabetes, amyloidosis, HIV infection, and alcohol 90%.15 Analysis of available studies on autonomic testing indicate misuse. Fabry and Tangier diseases are two rare inherited disorders that a combination of autonomic reflex screening tests provide which may present with a painful small fiber neuropathy. In one distinct advantages over using a single modality.35 The composite study, hyperlipidemia, especially hypertriglyceridemia, was autonomic scoring scale (CASS)—which includes QSART; reported as a potential risk factor for small fiber neuropathy.18 orthostatic blood pressure; heart rate response to tilt, deep Many cases of small fiber neuropathy remain idiopathic even after breathing, and the Valsalva ratio; and beat-to-beat blood pressure intensive investigation. Neuropathic pain is frequently reported in measurement to phases II and IV of the Valsalva maneuver, patients with sarcoidosis, a multisystemic inflammatory disorder tilt, and deep breathing—provides the highest sensitivity and characterized by the presence of noncaseating granulomas. One specificity for documentation of autonomic dysfunction.15 For study reported that approximately one-third of patients with comprehensive assessment of autonomic function, the performance sarcoidosis complained of burning feet consistent with a small of the full CASS is recommended. However, if the capability to fiber neuropathy.3 perform a complete battery of autonomic testing is not available, most patients can be screened with measurement of orthostatic Chronic Sensory or Sensory-Motor blood pressure and heart rate response to deep breathing using an Neuropathies electrocardiogram to measure R-to-R variability. Chronic sensory or sensory-motor neuropathies constitute the NERVE BIOPSY largest group of polyneuropathies. There are many etiologies for these types of polyneuropathies, including systemic diseases, There is little indication for a nerve biopsy in the usual cases metabolic abnormalities, nutritional deficiencies, and exogenous of chronic distal symmetric polyneuropathy.15 Nerve biopsy toxins. (Tables 1-2) The most prevalent etiologies in the developed should be considered when the diagnosis remains uncertain world are diabetes and prediabetes.6,12,13,28,36 after laboratory and EDX testing have been performed, or Occasionally, a chronic polyneuropathy may be associated with when confirmation of the diagnosis is needed before initiating a serum paraprotein. The associated monoclonal proteins are aggressive therapies. Nerve biopsy can be extremely valuable mostly IgM or IgG. When the monoclonal protein is IgM, there in cases of suspected vasculitic, inflammatory, infectious, or is sometimes binding to MAG resulting in a distally predominant neoplastic diseases. Although these diseases usually present as a demyelinating polyneuropathy.21 Even less frequently there may multifocal neuropathy or a mononeuropathy multiplex, they can be a polyneuropathy associated with IgA or IgG monoclonal rarely present as a symmetrical polyneuropathy.30 gammopathy.

SKIN BIOPSY Clinically overt peripheral nervous system involvement is common in patients with cancer, occurring in 1.7-16% of cases.8 Skin biopsy can be performed in patients with burning, numbness, Chemotherapy-induced nerve damage is the most common cause and pain in whom NCSs are normal. These patients may have of polyneuropathy in patients with cancer. The combination of involvement of the small, somatic, unmyelinated intraepidermal several neurotoxic products, especially in the case of cancer nerve fibers which can be quantified by a skin 15 biopsy. The recurrence, or the association of neurotoxic chemotherapy skin biopsy can also assess the autonomic fibers innervating and radiotherapy, increase the risk of toxic side effects, which sweat glands.34 Skin biopsy is a technique that involves a 3-mm explains some severe neuropathies.2 Malignancies are sometimes punch biopsy of skin taken from standardized sites on the leg. associated with production of specific autoantibodies which The tissue is immunostained with anti-protein-gene-product 9.5 may be associated with polyneuropathy. These neuropathies fall (PGP 9.5) antibodies. Both bright-field immunohistochemistry under the classification of paraneoplastic diseases. Neuropathies and indirect immunofluorescence have established normative associated with anti-Hu antibodies (also known as ANNA-1) values for intraepidermal nerve fiber density.7 Staining with PGP are the most frequent and present mainly as a subacute sensory 9.5 allows for identification and counting of intraepidermal nerve neuropathy.24 Less frequent are neuropathies associated with anti- fibers (IENFs). This technique has been validated as a reliable crossveinless-2 (anti-CV2) (anti-collapsing-response-mediator 10 BASICS WITH THE EXPERTS

Table 1. Different etiologies of axonal polyneuropathies: mixed Table 2. Different etiologies of axonal polyneuropathies: neuropathy types primarily sensory types

TYPEType OFof DISEASES TypeTYPE of OF neuropathy NEUROPATHY CommentsCOMMENTS DISEASES CommentsCOMMENTS NEUROPATHYneuropathy Diabetes mellitus S, SM rarely M Most common May be associated with Renal insufficiency SM Controlled with dialysis Vitamin B12 S Liver disease S or SM Mild myelopathy Porphyria M or SM Rare Acromegaly S Carpal tunnel frequent Malabsorption Deficiency of vitamins E or B12, some Chronic (inflammatory bowel S or SM basis unknown obstructive and short bowel) S Only in severe cases pulmonary Celiac disease S or SM May have autoimmune basis disease Primary sysytemic SM, may have small fiber Most have serum paraprotein, small fiber amyloidosis component with autonomic symptoms Paraneoplastic ganglionitis Involves cutaneous nerves in cold parts of with small cell or breast Leprosy S, SM Carcinoma S the body cancer, positive antibodies Focal or multifocal radiculopathy or Lyme disease S > M neuropathy, facial neuropathy common (Anti-Hu, CV2) HIV infection S > M Connective Mainly lung cancer, positive antibodies Carcinoma SM tissue disease: (anti-Hu, anti-CV2 and anti-Ri) Lymphoma SM systemic IgG, IgA SM lupus, Cryglobulinemia SM Chronic hepatitis C rheumatoid S Systemic manifestations Multiple myeloma S, M, or SM Uncommon DRUGS arthritis, Amiodarone SM Dose related systemic Chloramphenicol SM Rare sclerosis, Chloroquine SM Principle toxicity is myopathy Colchicine S or SM Principle toxicity is myopathy Sjögren’s Dapsone M Prominent arm, hand weakness DRUGS Dichloroacetate SM Delayed onset Panmodal sensory loss, Almitrine S Disulfiram SM After months to years of exposure reversible Ethambutol S Mild and usually reversible Painful, most recover after Hydralazine S > M Pyridoxine antagonist Bortezomib S Interferon-α S, SM Reversible, uncommon drug is stopped Isoniazid SM Pyridoxine antagonist Ethambutol S Mild, reversible Leflunomide S, SM Panmodal Etoposide Metronidazole S or SM Mainly large fiber S Not frequent Misonidazole S or SM Dose related toxicity (VP-16) Nitrofurantoin SM Rapidly progressive Usually inhalational abuse; interferes with Nitrous oxide S vitamin B12 metabolism Inhalational abuse, presents Nucleosides (anti- with ataxia,megaloblastic S > M Painful, limits dose exposure Nitrous oxide S retrovirals) anemia (worsens in Phenytoin S > M Doses > 200 mg/day Severe large fiber sensory; coasting can presence of B12 deficiency) Platinum drugs S occur 2 Taxol S > M Doses > 200 mg/m Platinum Severe large fiber, dose Thalidomide S > M Insensitivity to pain and touch drugs related Onset in hands > feet, autonomic Vinca alkaloids S > M neuropathy Cisplatin Large sensory fiber Less common but also large TOXINS Large fiber neuropathy with diffuse Carboplatin sensory fiber Acrylamide monomer S > M areflexia and ataxia; high doses can cause Acute neurosensory S encephalopathy syndrome with dysesthesias Painful sensory symptoms, prominent Arsenic SM systemic effects; acute intoxication can and cold-induced resemble GBS Oxaliplatin pharyngolaryngeal Alcohol S, SM Panmodal sensory loss dysesthesias, and late Carbon disulphide S > M Sensory symptoms followed by motor Ethylene oxide SM Inhalational exposure cumulative distal large fiber 2 Hexacarbons SM Inhalational abuse (> 540 mg/M ) Primarily motor; arms (wrist drop) > legs; Lead (inorganic) M Pyridoxine S Doses > 200 mg/day occurs with systemic effects Methyl bromide M > S Loss of color vision early Mercury M > S Predominately motor, usually with tremor S = sensory Delayed neuropathy after exposure, Organophosphates M > S myelopathy can be seen Painful sensory neuropathy, alopecia, Thallium S > M systemic effects

CV2 = crossveinless-2, GBS = Guillain Barré syndrome, HIV = human immunodeficiency virus, Ig = immunoglobulin, M = motor, S = sensory

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Novella SP, Inzucchi SE, Goldstein JM. The frequency of undiagnosed and its application in sarcoidosis. Neurology 2009;73:1142-1148. diabetes and impaired glucose tolerance in patients with idiopathic sensory 4. Bort S, Nelis E, Timmerman V, et al. Mutational analysis of the MPZ, neuropathy. Muscle Nerve 2001;24:1229-1231. PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot-Marie- 29. Rosenberg NR, Vermeulen M. Chronic idiopathic axonal polyneuropathy Tooth disease and hereditary neuropathy with liability to pressure palsies. revisited. J Neurol 2004;251:1128-1132. Hum Genet 1997;99:746-754. 30. Said G. Value of nerve biopsy. Lancet 2001;357:1220-1221 5. Briani C,Vitaliani R, Grisold W, et al. Spectrum of paraneoplastic disease 31. Saperstein DS, Wolfe GI, Gronseth GS, et al. Challenges in the identification associated with lymphoma. Neurology 2011;76:705-710. of cobalamin-deficient polyneuropathy. Arch Neurol 2003;60:1296-1301 6. Bril V, England J, Franklin GM, et al. Evidence-based guideline: treatment of 32. Saporta ASD, Sottile SL, Miller LJ et al. Charcot-Marie-Tooth Disease painful diabetic neuropathy. Neurology 2011;76:1758-1765. subtypes and genetic testing strategies. Ann Neurol 2011;69:22-23. 7. Chien HF, Tseng TJ, Lin W, et al. Quantitative pathology of cutaneous nerve 33. Savage DG, Lindenbaum J, Stabler SP, et al. Sensitivity of serum terminal degeneration in the human skin. Acta Neuropathol 2001;102:455- methymalonic acid and total homocysteine determinations for diagnosing 461. cobalamin and folate deficiencies. Am J Med 1994;96:239-246. 8. Croft PB, Wilkinson M. The incidence of carcinomatous neuromyopathy in 34. Sommer C, Lauria G. Skin biopsy in the management of peripheral patients with various types of carcinoma. Brain 1965;88:427-434. neuropathy. Lancet Neurol 2007;6:632-642. 9. Davies M, Brophy S, Williams R, et al. The prevalence, severity and impact 35. Stewart AG, Low PA, Fealey RD. Distal small fiber neuropathy: results of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care of test of sweating and autonomic cardiovascular reflexes. Muscle Nerve 2006;29:1518-1522. 1992;15:661-665. 10. Dyck PJ, Bushek W, Spring EM, et al. Vibratory and cooling detection 36. Sumner CJ, Sheth S, Griffin JW et al. The spectrum of neuropathy in diabetes thresholds compared with other test in diagnosing and staging diabetic and impaired glucose tolerance. Neurology 2003;60:108-111. neuropathy. Diabetes Care 1987;10:432-40. 37. Tomkin GH. Malabsorption of vitamin B12 in diabetic patients treated with 11. Dyck PJ, Karnes JL, O’Brien PC, et al. The Rochester Diabetic Neuropathy phenformin: a comparison with metformin. BMJ 1973;3:673-675. Study: reassessment of test and criteria for diagnosis and staged severity. 38. Wise CA, Garcia CA, Davis SN et al. Molecular analyses of unrelated Neurology 1992;42:1164-1170. Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of 12. Dyck PJ, Thomas PK. Diabetic neuropathy, 2nd ed. Philadelphia: Saunders, the CMT1A duplication. Am J Hum Genet 1993;53-853-863. 1999. p 255-278. 13. England JD, Asbury AK. Peripheral neuropathy. Lancet 2004;363:2151-61. 14. England JD, Gronseth GS, Franklin G, et al. Distal symmetrical polyneuropathy: Definition for clinical research. Muscle Nerve 2005;31:113-123.

12 BASICS WITH THE EXPERTS

Long and Short of Nerve Conduction Studies for Neuropathy

Jun Kimura, MD Professor Department of Neurology University of Iowa Health Care Iowa City, Iowa

Nerve conduction studies (NCSs), as an extension of the clinical distance between stimulating and pickup electrodes, the recorded assessment, help delineate the extent and distribution of the potentials become smaller in amplitude and longer in duration; neural lesion and distinguish two major categories of peripheral and, contrary to the common belief, the area under the waveform nerve disease: demyelination and axonal degeneration. With also diminishes. Thus, proximal stimulation in the axilla or steady improvement and standardization of methods, they have Erb’s point normally gives rise to a very small digital potential become a reliable test not only for precise localization of a compared to a much larger response elicited by distal stimulation lesion but also for accurate characterization of peripheral nerve at the wrist or palm. This discrepancy may lead to a false diagnosis function.20 This discussion will review the fundamental principles of a conduction block (CB) between the proximal and the distal and changing concepts of nerve stimulation techniques and their sites of stimulation.16,30 proper application in the differential diagnosis of peripheral nerve disorders. These considerations generally discourage the use of A phase cancellation results when two waveforms containing automated hand-held nerve conduction devices as a replacement negative and positive phases of comparable size superimpose. of the standard studies.7,35 With short-duration diphasic sensory spikes, a slight physiologic latency difference could line up the positive peaks of the fast PHYSIOLOGIC TEMPORAL DISPERSION fibers with the negative peaks of the slow fibers, canceling both (Figure 1A). In addition to the maximal motor or sensory conduction velocities based on the onset latencies, waveform changes of compound muscle (CMAPs) and sensory nerve action potentials (SNAPs) help estimate the range of the functional units.7,31 This aspect of analysis plays a greater role when studying a peripheral A = axilla, E = elbow, CMAP = compound neuropathy with a focal lesion affecting some axons and sparing muscle action potential, P = palm, others.25,27 In clinical tests of motor and sensory conduction, the SNAP = sensory nerve action potential, size of the recorded response approximately parallels the number W = wrist of excitable fibers. The responses elicited by proximal and distal shocks may vary as the result of physiologic or pathologic Simultaneous recordings of compound muscle action potentials resynchronization among the individual potentials. Figure 1. from the thenar eminence and sensory nerve action potentials from the index finger after stimulation of the median nerve at palm, wrist, elbow, and axilla. Under normal conditions, the impulses of physiologically Progressively more proximal series of stimuli elicited nearly the same muscle slow conducting fibers lag increasingly behind those of fast response but progressively smaller sensory response from the wrist to the conducting fibers over a long conduction path. With increasing axilla. Note a linear change of sensory amplitudes, which usually indicate physiologic temporal dispersion and phase cancellation.21 modified 13 LONG AND SHORT OF NERVE CONDUCTION STUDIES FOR NEUROPATHY This phenomenon alone can reduce the normal SNAP to below 50% in amplitude as well as in area, a conservative figure derived from computation of a small number of nerve fibers.22,35,40 Thus, a major reduction in size of the compound SNAP can result solely from physiologic phase cancellation. In contrast, motor unit action potentials (MUAPs), having a longer duration, superimpose nearly in phase rather than out of phase for the same latency shift (Figure 1B). This accounts for a limited reduction in size of the CMAP by the same temporal dispersion.29 As expected from the term, duration-dependent phase cancellation,21 a physiological temporal dispersion may substantially reduce the amplitude of a short-duration CMAP such as those recorded from intrinsic foot muscles.36 Considering linear changes of amplitude and duration, the area will follow a second order polynormal function of conduction distance provided the area equals amplitude times duration and a constant.12

PATHOLOGIC TEMPORAL DISPERSION

If the latency difference between normal and demyelinating motor fibers reach approximately one-half the duration of a MUAP, as expected in some neuropathies, the CMAP also diminishes dramatically based solely on phase cancellation as predicted by the model described by this author and colleagues.22 This type of pathological phase cancellation reduces the amplitude of muscle response well beyond the usual physiologic limits. This finding Figure 2. A model for duration-dependent phase cancellation between fast commonly seen in acquired and, to a lesser extent, in hereditary (F) and slow (S) conducting sensory (A) and motor (B) fibers. With distal demyelinating neuropathy,4,38 may give rise to a false impression stimulation, two unit discharges summate in phase to produce a potential of motor CB.22,27,34 This phenomenon explains an occasionally twice as large for both sensory and motor responses. With proximal encountered discrepancy between severe reduction in amplitude stimulation, a slight delay of the slow fiber causes phase cancellation for of the CMAP despite relatively normal recruitment of the motor short-duration sensory potentials as the negative peak of the slow fiber (dotted line) superimposes on positive peak of the fast fiber (solid line), units (MUs) and preserved strength. Pathological temporal resulting in a 50% reduction in size of the summated response (A). In dispersion may also abolish a SNAP with proximal stimulation, contrast, despite the same latency shift as sensory potential between fast (F) mimicking a CB, if distal stimulation elicits a relatively normal and slow (S) conducting fibers, long-duration motor unit action potential still response. superimpose nearly in phase (B). Thus, a physiologic temporal dispersion usually alters the size of the muscle action potential only minimally. This Comparison between two responses elicited distally and does not hold true with short-duration muscle responses such as those proximally often fails to differentiate pathological, as opposed recorded from intrinsic foot muscle, which may show substantial reduction to physiological, temporal dispersion because many variables of amplitude by physiologic phase cancellation.21 modified make the commonly held percentage criteria untenable except in entirely standardized studies.24 A simpler, more practical approach relies on a linear relationship seen in physiologic phase cancellation between the latency and the size of the recorded responses.19 This approach has a distinct advantage of not requiring adaptation of any specific recording variables such as inter-electrode spacing, although it calls for segmental stimulation at more than two sites to test the linearity of observed changes (Figures 2, 3). Superimposing consecutive traces often reveals subtle abnormalities which may otherwise escape detection (Figure 4). A nonlinear reduction in amplitude or area, often associated with waveform changes, indicates either a pathological temporal Figure 3. Segmental study of the ulnar nerve in 1-cm increments from dispersion or CB. The distinction between the two possibilities below the elbow (1) to above the elbow (7). (A) A 41-year-old man (left) must in part depend on clinical and needle electromyography with distal ulnar neuropathy had prolonged terminal latency (3.7 ms) with (EMG) findings. Conduction block, but not pathological temporal a normal conduction across the elbow. (B) A 52-year-old woman (right) dispersion, causes muscle weakness and decreased recruitment of with a tardy ulnar palsy showed a normal distal latency with an abrupt drop in amplitude above the elbow (5 to 6 and 6 to 7), indicating a partial MUs with voluntary contraction. conduction block as the cause of weakness. In motor or antidromic NCSs, a nonlinear reduction in amplitude of the proximally-elicited response usually suggests a CB, although it may also result from pathologic temporal dispersion.5,39 Either

14 BASICS WITH THE EXPERTS

Figure 4. A patient with mild ulnar neuropathy at the elbow. Note the segment, signaling a clear abnormality. The large per unit increase nonlinear latency and amplitude shift clearly detected on superimposing in latency more than compensates for the inherent measurement consecutive traces as depicted in the smaller display shown on the right error associated with multiple stimulations in short increments.1,9,15 lower corner. This technique suits best in assessing a possible compressive finding implies the presence of focal demyelination,38 although lesion such as median nerve entrapment in the palm,15,37 ulnar other conditions such as ischemia can cause similar reversible neuropathy at the elbow2,14,26,40 or peroneal nerve compression changes.11 Except for occasional cases of secondary axonal at the knee.13 With stimulation of the median nerve every 1 cm degeneration associated with damage of the myelin sheath, needle across the wrist, the latency increments average 0.16-0.21 ms/ EMG reveals little or no evidence of denervation. In the presence cm from the midpalm to the distal forearm. An abrupt change of partial CB, the MUAP, normal in amplitude and waveform, in waveform nearly always accompanies a sharply localized shows poor recruitment from loss of functional fibers accompanied nonlinear latency increase across the site of compression (Figure by a compensatory rapid firing of the remaining axons. 3), indicating a focal abnormality.15 An excessive latency shift may result from inaccurate advances of the stimulating electrodes INCHING TECHNIQUE FOR SHORT SEGMENT or inadvertent spread of stimulus current activating a more excitable neighboring segment. In questionable cases, studies of Ordinary NCSs suffice to approximate the site of involvement the more proximal and distal segments will clarify the ambiguity. in entrapment neuropathies. More precise localization requires If the observed nonlinear shift results from a focal process, rather inching the stimulus in short increments along the course of the than technical errors, the latencies of successive responses above nerve for isolation of a focal lesion.17,18 In the evaluation of a and below the affected zone must form two parallel lines rather localized pathology such as a compressive neuropathy, inclusion than one (Figure 4). These findings localize a focal lesion within of the unaffected segments in calculation dilutes the effect of the short interval in question encopassed by normal segments abnormalities, lowering the sensitivity of the test. Incremental proximally and distally. stimulation across the shorter segment helps isolate a focal lesion that may otherwise escape detection. Thus, the study of LATE RESPONSE FOR LONG SEGMENT short segments provides better resolution of restricted lesions. Assume a nerve impulse conducting at a rate of 0.2 ms/cm A number of neurophysiological methods supplement the (50 m/s) except for a 1-cm segment where demyelination has conventional techniques for the assessment of longer pathways.8 doubled the conduction time to 0.4 ms/cm. In a 10-cm segment, The selection of such techniques necessarily reflects the normally covered in 2.0 ms, a 0.2-ms increase would amount special orientation of each laboratory. Those of general interest to only a 10% change. This delay, approximately equal to one include the F wave and the H reflex. In assessing a diffuse or standard deviation of any measure, falls well within the normal multisegmental process such as in polyneuropathies, the longer range of variability. The same 0.2-ms increase, however, would the segment under study, the more evident the conduction delay. represent a 100% change in latency if measured over a 1-cm In other words, this approach has an advantage of accumulating

15 LONG AND SHORT OF NERVE CONDUCTION STUDIES FOR NEUROPATHY all the segmental abnormalities, which individually might not where V1 and V2 represent the values of the first and second show a clear deviation from the normal range. For example, if measurements of the pair. The ranges of RIV between −10% to a nerve impulse conducts at a rate of 0.2 ms/cm (50 m/s), a 20% +10% usually indicate a higher precision. increase for a 10-cm segment, would yield an unimpressive delay of only 0.4 ms, whereas this same change for a 100-cm segment Measures having larger inter-individual differences usually show would amount to an easily detectable 4.0 ms. a greater intra-individual variability as well. The calculation of ICC takes this into consideration to partially offset the effects of a In addition, evaluating a longer, as compared to shorter, segment large variability among different subjects. Thus, improves the accuracy of latency and distance measurements because the same absolute difference constitutes a smaller ICC = σs2 / (σs2 + σ∑2) percentage error. In determining the length of a 10-cm nerve segment, values measured over the surface may vary between where σs2 and σ∑2 represent among-subject variance and 9.5 and 10.5 cm. A 1-cm difference constitutes a 10% error, experimental error. The values exceeding 0.9 indicate a reliable leading to the range of calculated conduction velocities of 50-55 measure although, as seen from the formula, this may indicate a large m/s. The same 1-cm difference in measuring a 100-cm segment among subject variance rather than a small experimental error.10 represents only 1% change, or the range of 50-50.5 m/s. Using the same argument, percentage errors in latency measurement also diminish for a longer, as compared to shorter, nerve segment. Consequently, the study of a longer path offers a better sensitivity and accuracy and, as stated below, an improved reproducibility in serial studies.

The author and colleagues conducted a multicenter analysis on inter-trial variability of NCSs to determine the confidence limits of the variations for use in future drug assessments for diabetic polyneuropathy.18,23 All measurements, repeated twice at a time interval of 1-4 weeks, followed a standardized method in the study of 132 healthy subjects (63 males, 69 females) and 172 patients (99 males, 73 females) with diabetic polyneuropathy. In both the control subject and the patient groups, amplitude varied most followed by terminal latency and motor and sensory conduction velocity. In contrast, minimal F-wave latency showed the least change, with the range of variability of only 10% for the study of the median nerve and 11% for the tibial nerve in normal subjects and 12% and 14%, respectively, in patients with diabetic polyneuropathy.

These results support the contention that minimal or mean F-wave latency serves as the most stable and consequently reliable measure for a sequential NCSs of the individual subjects.33 The same does not hold, however, when evaluating single patients Figure 5. Reproducibility of various measures in healthy volunteers against a normal range established in a group of subjects. Here (A) and patients with diabetic neuropathy (B), repeated twice at a time interval of 1-4 weeks to calculate relative inter-trial variations as an index F-wave conduction velocity works better, minimizing the effect of comparison of limb length. Alternatively, the use of nomogram can be used in clinical practice, plotting the latency against the height as a simple, albeit indirect, measure of limb length.28 Any indices based on height, however, have an inherent limitation because limb lengths vary in different individuals with the same height. Similarly, the slope of the regression line in the nomograms, indicating the linear relationships between the latency and height, varies from country to country, reflecting different ethnic body characteristics.32

In this study, two independent indices were used to assess reproducibility: relative intertrial variation (RIV) and intraclass Figure 6. Comparison between the first and the second measures of correlation coefficiency (ICC). Of the two, RIV directly represents median nerve motor conduction velocity (A) and F-wave latency (B). a variation of measurements expressed as the percentages of the Individual values plotting the first study on the abscissa and the second difference between V1 and V2 over the mean value of the two. Thus, study on the ordinate show a greater reproducibility of the F-wave latency compared to the motor nerve conduction velocity. RIV (%) = 100 × (V2 − V1)/0.5(V1 + V2) FWL = F-wave latency, MCV = motor conduction velocity 16 BASICS WITH THE EXPERTS Figure 5 shows the 5th to 95th percentiles of RIV and ICC in both groups whereas, Figure 6 illustrates some examples of the individual data from the patients. The measures showing the range of RIV of less than ∑ 10% included F-wave latency and F-wave conduction velocity of both the median and tibial nerve and sensory conduction velocity of the median nerve. In general, amplitudes showed a greater variation than latencies or nerve conduction velocities. Similarly, ICC exceeded 0.9 for F-wave latency of the median and tibial nerves in both the healthy subjects and the patients. Median nerve SNAPs and median and tibial CMAPs had a large range of RIV despite a high ICC. In these amplitude measurements, a large among-subject variance of the amplitudes made σs2 much greater than σ∑2, leading to a high ICC despite a considerable inter-trial variability.

Although a high ICC indicates a statistical correlation between two measurements,6 it does not necessarily imply a good reproducibility. Thus, to achieve an optimal comparison, a sequential study must exclude any measurements with a wide RIV regardless of ICC values. The calculation of RIV in addition to ICC helps detect the indices with an acceptable degree of reproducibility. In this data, F-wave latencies of the median and tibial nerves qualified as a reliable measure showing a large ICC (> 0.9) with a small RIV (< ± 10%). The main factors contributing to an inter-trial variability include inadequate control of skin temperature, insufficient stimulus intensity, errors in determining the latency and the surface distance, and difficulty in placing Figure 7. The use of a height nomogram serves well as an acceptable recording electrodes exactly at the same place on two separate means to adjust F latencies for the limb length. Latency-height nomograms 3 occasions. The variance in amplitudes likely occured because of show linear relationships for upper and lower limb nerves. The data, based an unavoidable shift in the recording site. on F waves elicited by 32 stimuli in 100 healthy subjects, indicate the need of at least 10 stimuli to determine the mean latency and 15 stimuli for the CLINICAL CONSIDERATION minimal and maximal latencies. Similar to other nerve conduction studies, a cold limb calls for a temperature correction to 32°C by subtracting 4% of A question often posed in regard to the accuracy and sensitivity the measured value per degree to achieve anadjusted latency. of latency or velocity measurements relate to the length of the segment under study. Other factors being equal, the question asked REFERENCES is should one study shorter or longer segments for better results. Although both approaches have merits and demerits, the choice 1. Campbell WW. The value of inching techniques in the diagnosis of focal depends entirely on the pattern of the conduction change. Short nerve lesions. Muscle Nerve 1998;21:1554-1566. segmental approaches uncover a focal lesion involving a very 2. Campbell, WW, Pridgeon, RM, Sahni, KS. Short segment incremental restricted zone better than evaluating across a longer distance, studies in the evaluation of ulnar neuropathy at the elbow. Muscle Nerve which tends to obscure the abnormality. In contrast, studies of 1992;15:1050-1054. a longer segment detect diffuse or multisegmental abnormalities 3. Chaudhry V, Corse A, Freimer ML, Glass JD, Mellits ED, Kuncl RW, et better, increasing sensitivity, and decreasing measurement errors, al. Inter- and intraexaminer reliability of nerve conduction measurements which, in percentage, diminish in proportion to the overall latency in patients with diabetic neuropathy. Neurology 1994;44:1459-1462. and surface distance. The increased accuracy of the techniques 4. Cleland JC, Logigian EL, Thaisetthawatkul P, Herrmann, DN. Dispersion in turn improves the reproducibility of the results. In summary, of the distal compound muscle action potential in chronic inflammatory short distances magnify focal conduction abnormalities despite demyelinating polyneuropathy and carpal tunnel syndrome. Muscle increased measurement error, and long distances, though Nerve 2003;28:189-193. insensitive to focal lesions, provide better yields and reliability 5. Cleland JC, Malik K, Thaisetthawatkul P, Herrmann DN, Logigian, EL. for a diffuse or multisegmental process. The use of height Acute inflammatory polyneuropathy: contribution of a dispersed distal F-wave latency nomogram helps circumvent limb length related compound muscle action potential to electrodiagnosis. Muscle Nerve variability in the clinical practice (Figure 7). 2006;33:771-777. 6. Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton LJ, O’Brien PC, et al. The Rochester Diabetic Neuropathy Study: design, criteria for types of 1991. Neurology 1991;41:799-807. 7. England, JD and Franklin, GM. Automated hand-held nerve conduction devices: raw data, raw interpretations. Muscle Nerve 2011;43:6-8. 8. Fraser JL, Olney, RK. The relative diagnostic sensitivity of different

17 LONG AND SHORT OF NERVE CONDUCTION STUDIES FOR NEUROPATHY

F-wave parameters in various polyneuropathies. Muscle Nerve 29. Olney RK, Budingen HJ, Miller, RG. The effect of temporal dispersion 1992;15:912-918. on compound action potential area in human peripheral nerve. Muscle 9. Geiringer SR. Inching techniques are of limited use. Muscle Nerve Nerve 1987;10:728-733. 1998;21:1557-1559. 30. Olney RK, Miller, RG. Pseudo-conduction block in normal nerves. 10. Herrera E, Camargo DM, Delgad, DC, Salvini, TF. Reliability of Muscle Nerve 1983;6:530. superficial peroneal, sural, and medial plantar nerve conduction studies. 31. Olney RK, Miller, RG. Conduction block in compression neuropathy: Analysis of statistical methods. J Clin Neurophysiol 2009;26:372-379. recognition and quantification. Muscle Nerve 1984;7:662-667. 11. Hömberg V, Reiners K, Toyka, KV. Reversible conduction block in 32. Pan H, Lin J, Chen N, Jian F, Zhang Z, Ding Z, Wang Y, No J, Khoara human ischemic neuropathy after ergotamine abuse. Muscle Nerve N, Kimura MD. Normative data of F-wave measures in China. Clin 1992;15:467-470. Neurophysiol 2012: in press. 12. Johnsen B, Fuglsang-Frederiksen A, de Carvalho M, Labarre-Vila A, Nix 33. Pinheiro DS, Manzano GM, Nobrega, JAM. Reproducibility in W, Schofield I. Amplitude, area and duration of the compound muscle nerve conduction studies and F-wave analysis. Clin Neurophysiol action potential change in different ways over the length of the ulnar 2008;119:2070-2073. nerve. Clin Neurophysiol 2006;117:2085-2092. 34. Rhee EK, England JD, Sumner AJ. A computer simulation of conduction 13. Kanakamedala RV, Hong C-Z. Peroneal nerve entrapment at the block: effects produced by actual block versus interphase cancellation. knee localized by short segment stimulation. Am J Phys Med Rehabil Ann Neurol 1990;28:146-156. 1989;68:116-122. 35. Schmidt K, Chinea NM, Sorenson EJ, Strommen JA, Boon, AJ. Accuracy 14. Kim DH, Kang YK, Hwang M, Jo HS, Kim, KH. Localization of ulnar of diagnoses delivered by an automated hand held nerve conduction neuropathy at the elbow using new stimulator for the inching test. Clin device in comparison to standard electrophysiologic testing in patients Neurophysiol 2004;115:1021-1026. with unilateral leg symptoms. Muscle Nerve 2011;43:9-13. 15. Kimura J. The carpal tunnel syndrome: localization of conduction 36. Schulte-Mattler WJ, Muller T, Georgiadis D, Kornhuber ME, Zierz S. abnormalities within the distal segment of the median nerve. Brain Length dependence of variables associated with temporal dispersion in 1979;102:619-635. human motor nerves. Muscle Nerve 2001;24:527-533. 16. Kimura J. Electrodiagnosis in diseases of nerve and muscle: principles 37. Seror P. Orthodromic inching test in mild carpal tunnel syndrome. Muscle and practices. Philadelphia: FA Davis; 1983. Nerve 1998;21:1206-1208. 17. Kimura J. Principles and pitfalls of nerve conduction studies. Ann Neurol 38. Stanton M, Pannoni V, Lewis RA, Logigian EL, Naguib D, Shy 1984;16:415-429. ME, Cleland J, Herrmann, DN. Dispersion of compound muscle 18. Kimura J. 21st annual Edward H. Lambert Lecture. Facts, fallacies, and action potential in hereditary neuropathies and chronic inflammatory fancies of nerve conduction studies. Muscle Nerve 1997;20:777-787. demyelinating polyneuropathy. Muscle Nerve 34:417-422, 2006. 19. Kimura J. Kugelberg Lecture. Principles and pitfalls of nerve conduction 39. Triggs WJ, Cros D, Gominack SC, Zuniga A, Beric A, Shahani BT, studies. Electroencephologr Clin Neurophysiolsiol 1998;106:470-476. Ropper AH, Roongta, SM. Motor nerve inexcitability in Guillain- 20. Kimura J, ed. Peripheral nerve disease, Vol. 7. In: JR Daube, F Mauguiere, Barré syndrome: the spectrum of distal conduction block and axonal series eds. Handbook of clinical neurophysiology. Amsterdam: Elsevier; degeneration. Brain 1992;115:1291-1302. 2006. 40. Van Aken SFJ, Van Dijk, JG. Two approaches to measure amplitude 21. Kimura J, Machida M, Ishida T, Yamada T, Rodnitzky RL, Kudo Y, changes of the sensory nerve action potential over a length of nerve. Suzuki, S. Relation between size of compound sensory or muscle action Muscle Nerve 2003;27:297-301. potentials and length of nerve segment. Neurology 1986;36:647-652. 41. Visser LH, Beekman R, Franssen, H. Short-segment nerve conduction 22. Kimura J, Sakimura Y, Machida M, Fuchigami Y, Ishida T, Claus D, studies in ulnar neuropathy at the elbow. Muscle Nerve 2005;31:331-338. Kameyama S, Nakazumi Y, Wang J, Yamada, T. Effect of desynchronized inputs on compound sensory and muscle action potentials. Muscle Nerve 1988;11:694-702. 23. Kohara N, Kimura J, Kaji R, Goto Y, Ishii, J. Multicenter analysis on intertrial variability of nerve conduction studies: healthy subjects and patients with diabetic polyneuropathy. In J Kimura, H Shibasaki, eds. Recent advances in clinical neurophysiology. Amsterdam: Elsevier Science BV; 1996. pp 809-815. 24. Lateva ZC, McGill KC, Burgar, CG. Anatomical and electrophysiological determinants of the human thenar compound muscle action potential. Muscle Nerve 1996;19:1457-1468. 25. Lewis RA, Sumner AJ, Brown MJ, Asbury, AK. Multifocal demyelinating neuropathy with persistent conduction block. Neurology 1982;32:958- 964. 26. Miller RG. The cubital tunnel syndrome: diagnosis and precise localization. Ann Neurol 1979;6:56-59. 27. Miller RG, Olney RK. Persistent conduction block in compression neuropathy. Muscle Nerve 1982;5:S154-S156. 28. Nobrega JAMN, Pinheiro DS, Manzano GM, Kimura, J. Various aspects of F wave values in a healthy population. Clin Neurophysiol 2004;115:2336-2342.

18 BASICS WITH THE EXPERTS

Repetitive Nerve Stimulation Testing

Vern C. Juel, MD Associate Professor Division of Neurology Duke University Medical Center Durham, North Carolina

Repetitive nerve stimulation (RNS) studies are essential techniques lung carcinoma. In botulism, however, neurotoxins produced by in the evaluation of potential neuromuscular transmission (NMT) Clostridium botulinum interrupt the presynaptic exocytotic release disorders in the electrodiagnostic (EDX) medicine laboratory. of ACh. Congenital myasthenic syndromes (CMS) may involve Contemporary RNS techniques evolved from the direct motor presynaptic or postsynaptic pathology genetically determined and point electrical stimulation studies of Friedrich Jolly dating often manifest at or around the time of birth. from the late nineteenth century. With repeated stimulation, Jolly observed a progressive reduction in the size of muscle NEUROMUSCULAR JUNCTION ANATOMY contractions in patients with myasthenia gravis (MG).1 In 1941, AND PHYSIOLOGY Harvey and Masland reported decrementing muscle electrical responses in MG patients with repetitive motor nerve stimulation Motor nerves chemically synapse with muscle fibers at the and suggested that the technique could be used diagnostically.2,3 neuromuscular junction (NMJ). Each NMJ is composed of a motor RNS testing software is now a standard component of nearly all nerve terminal, synaptic space, and the highly-folded end-plate contemporary electromyography (EMG) equipment. Despite the region of the skeletal muscle fiber. The neurotransmitter ACh is increased availability of serologic and molecular genetic testing synthesized and stored in vesicles in the motor nerve terminal. for junctional diseases, RNS studies remain vitally important in Each vesicle contains about 6,000-10,000 ACh molecules4 or the timely diagnosis of NMT disorders. one “quantum” of ACh. There are three storage “pools” of ACh: a primary or immediate store in the nerve terminal, a secondary NEUROMUSCULAR TRANSMISSION DISORDERS or mobilization store in the distal motor axon, and a tertiary or reserve store in the motor nerve axon and cell body. The VGCCs Patients with NMT disorders typically exhibit painless and fatigable are clustered in active or release zones of the motor nerve terminal. weakness that increases with exercise. The two most common primary NMT disorders, MG and Lambert-Eaton myasthenic When a motor nerve action potential (NAP) is propagated to the syndrome (LEMS), are acquired and autoimmune. Autoimmune motor nerve terminal, VGCCs in the active zones open to permit MG results from immunological attack on the acetylcholine (ACh) entry of calcium into the nerve terminal. This calcium influx receptor and associated postsynaptic proteins with fluctuating, initiates the process of exocytotic release of ACh via SNARE fatigable weakness in ocular, bulbar, and extremity muscles. In (soluble N-ethylmaleimide-sensitive attachment protein receptor) antibodies against voltage-gated calcium channels (VGCC) on proteins. The released ACh diffuses rapidly across the narrow, presynaptic cholinergic nerve terminals elicit proximal lower 50 nm synaptic cleft to bind with ACh receptors located on the limb weakness, fatigue, and cholinergic autonomic dysfunction. tips of the end-plate folds. Binding of ACh results in the opening LEMS may develop as an organ-specific autoimmune disease of sodium channels with movement of sodium into the muscle or as a paraneoplastic disease related to underlying small cell fiber at the end plate. This sodium influx generates an end-plate

19 REPETITIVE NERVE STIMULATION TESTING potential (EPP). When the EPP amplitude reaches or exceeds release in botulism and LEMS, and by postsynaptic ACh receptor the threshold level, a muscle fiber action potential (MFAP) dysfunction in MG. is generated with spread of depolarization from the end-plate region to both ends of the muscle fiber. The process of excitation- REPETITIVE NERVE STIMULATION TESTING contraction coupling is thereby initiated, and the muscle fiber contracts. Acetylcholinesterase (AChE) attached to the end-plate The negative peak amplitude of the recorded compound muscle basal lamina inactivates ACh by hydrolysis to choline and acetic action potential (CMAP) is a summation of individual MFAPs acid. Choline then undergoes reuptake by the presynaptic nerve following motor or mixed nerve stimulation. When individual terminal for ACh resynthesis. EPP amplitudes fail to reach threshold in response to motor NAPs, fewer MFAPs are generated, and the resulting CMAP amplitude Safety Factor is decreased. Such decremental responses may be observed in all NMT disorders with RNS at low stimulation rates (< 5 Hz). The amount of ACh released and the number and density In presynaptic NMT disorders, high stimulation rates (≥ 10 Hz) of functional ACh receptors at the end plate determine EPP or brief exercise may increase quantal ACh release, causing an amplitude. Under normal circumstances, EPP amplitudes are increased number of EPP amplitudes to reach threshold with a somewhat variable and reach threshold at slightly different times corresponding increase in CMAP amplitude or facilitation. to generate MFAPs. This temporal variability is the main source of neuromuscular jitter, the latency variability in MFAPs following General Recording Technique motor NAPs. Each motor NAP normally elicits release of more ACh than necessary to elicit an EPP with amplitude exceeding RNS testing is performed with the same recording scheme that is threshold for generating a MFAP. The difference between the used for motor nerve conduction studies (NCSs). Surface CMAP actual EPP amplitude and the threshold EPP amplitude is called recordings are performed with the recording electrode (G1) placed the safety factor. The safety factor ensures that each motor NAP over the muscle belly and the reference electrode (G2) typically elicits muscle fiber contraction. When the safety factor is reduced placed over a distal tendon. The low-frequency filter should be in NMT disorders, the time for an EPP to reach threshold may be 10 Hz or less, and the high frequency filter should be 5 kHz or abnormally increased, or the EPP may completely fail to reach higher. With surface stimulation, 0.05 or 0.1 ms stimulus duration threshold in response to a motor NAP. is usually adequate to provide maximal stimulation throughout the RNS procedures. A near-nerve stimulation technique using Factors Affecting Acetylcholine Release a needle stimulating electrode placed close to the nerve allows lower intensity stimulation with improved comfort in biceps With repeated motor nerve firing, two competing factors influence brachii RNS testing and is necessary in masseter RNS testing. quantal ACh release. The first involves depletion of immediate Trains of stimuli are delivered at an intensity of 10-25% above ACh stores. With each NAP, approximately 20% of the primary the level needed to activate all muscle fibers of a motor or or immediate ACh store is released. Motor nerve firing rates of mixed nerve. To minimize recording artifact, the stimulating and greater than 0.1 Hz produce serial decline of ACh quantal release recording electrodes should be well secured, and the joint moved for the first four to five nerve impulses with a corresponding by the muscle being tested should be immobilized. Movement of reduction of EPP amplitudes. Then, secondary ACh stores become stimulating electrodes may cause submaximal nerve stimulation mobilized, and EPP amplitudes stabilize in response to additional and a pseudodecrement. Movement of recording electrodes or of motor NAPs.5 Under normal conditions and because of the safety the limb may cause an abrupt change in the CMAP waveform factor, this decline in EPP amplitude has no impact on NMT. during a train of stimuli.

The second factor influencing quantal ACh release relates to the Stimulation Frequency calcium concentration in the presynaptic nerve terminal. Release of ACh is calcium-dependent, and the probability for quantal Low-frequency stimulation at 2-3 Hz is optimal to demonstrate ACh release is increased with increased presynaptic calcium decremental responses in MG and LEMS, and no more than 5-10 concentration. Calcium is normally removed from the motor nerve stimuli in a train are required.9 High-frequency (> 10 Hz) RNS terminals over 100-200 ms in order to terminate ACh release.6 stimulation should be avoided due to several liabilities including When motor NAPs occur more frequently than every 100 ms (10 patient discomfort, frequent movement artifact, and the presence Hz), presynaptic calcium concentration increases, and ACh release of decremental responses in normal individuals.10 In addition, high is potentiated. This potentiated ACh release persists for 30-60 s frequency RNS often produce pseudofacilitation where the CMAP and is followed 2-5 minutes later by postactivation exhaustion negative peak amplitude increases and duration decreases with with reduced release of ACh with each nerve impulse.7,8 no change in CMAP negative peak area. With pseudofacilitation, CMAP amplitude may increase by 50% in response to high- Therefore, the amount of ACh released with each nerve impulse frequency RNS.10 Pseudofacilitation has been attributed to and the subsequent EPPs reflect the interaction between depletion synchronization of MFAP propagation velocities or muscle of immediate ACh stores and presynaptic calcium concentration. shortening.11 In suspected presynaptic NMT disorders, high- Slow firing rates (less than 5 Hz) reduce the safety factor in frequency RNS can be replaced by 10 s of isometric exercise with all circumstances, and high firing rates (10 Hz or greater) may maximal voluntary contraction (MVC) against resistance applied improve the safety factor if there is a disorder of ACh release. by an examiner. This activation technique serves as the equivalent The safety factor is diminished by reduction of quantal ACh of high-frequency RNS without its associated liabilities.12 High-

20 BASICS WITH THE EXPERTS frequency RNS testing should be reserved for evaluation of a The use of RNS testing in intrinsic hand muscles is straightforward suspected presynaptic NMT disorders where isometric exercise and well tolerated by patients. The abductor digiti quinti manis with MVC cannot be performed as with infants, patients with (ADM) and abductor pollicis brevis (APB) are studied with altered consciousness, and patients with severe paralysis. ulnar and median nerve stimulation at the wrist using the same recording scheme as in ulnar and median motor NCSs. Testing Temperature is performed with the patient supine and the hand supinated. The ADM is easily immobilized with adducted fingers held in place Reduced muscle temperature may improve NMT and reduce with folded towels or tape, while the APB may be immobilized the sensitivity of RNS testing. Hand and foot muscles should be with folded towels held in place by the examiner. warmed to 34-36° C, and this temperature should be maintained throughout RNS testing.13 Proximal limb and cranial muscles do Shoulder and proximal upper limb muscles are more likely not require warming. than hand muscles to demonstrate abnormal decrement in MG, and trapezius RNS recordings are probably the least Activation Methods complicated of these to perform.19 The trapezius is studied with spinal accessory nerve stimulation at the posterior border of Activation methods may increase the sensitivity of RNS testing, the sternocleidomastoid. Testing is performed either with the and exercise may reveal an otherwise undetectable NMT defect. patient supine in a semireclined position or seated in a chair with Postexercise or postactivation exhaustion (PAE) may be observed arms adducted while grasping the chair seat to impede shoulder 2-5 min following 30-60 s of isometric exercise with MVC. In elevation and reduce movement artifact. The active recording some patients, abnormal decrement may only be seen following electrode is placed along the superior border of the trapezius at exercise as PAE,14 though the degree of increased sensitivity the angle between shoulder and neck with the reference electrode to detect abnormal decrement may be small.15 Postexercise or placed on the acromion. Trapezius RNS testing is frequently postactivation facilitation (PAF) following a brief, 10 s exercise abnormal in generalized MG (Figure 2).20 period may be observed in patients with low amplitude CMAPs or with baseline decrement. PAF reflects the unblocking of MFAPs due to increased quantal ACh release. PAF may be very marked in presynaptic NMT disorders such as LEMS where CMAPs may more than double in amplitude after brief exercise (Figure 1). In the past, regional ischemia16 and regional curare infusions17 have been used to enhance decremental responses on RNS testing, though these have been supplanted by single-fiber EMG (SFEMG) which 18 provides superior diagnostic sensitivity in MG. Figure 2. Repetitive nerve stimulation testing at 3 Hz in the trapezius in moderate generalized myasthenia gravis with limb weakness. The compound muscle action potential (CMAP) amplitude decrement is 53% between the first and fourth CMAPs in the series. Used with permission from the author.

Though they have superior diagnostic sensitivity over intrinsic hand muscles in MG, deltoid and biceps brachii RNS testing are technically challenging and often uncomfortable for patients. Deltoid RNS testing is performed with axillary nerve stimulation at Erb’s point in a seated position. Stimulating electrodes must be held firmly behind the clavicle. The active recording electrode is placed over the belly of the deltoid with the reference electrode Figure 1. Compound muscle action potentials (CMAPs) recorded from on the acromion. Immobilization is provided by adduction and the abductor pollicis brevis in Lambert-Eaton myasthenic syndrome at internal rotation of the shoulder so that the tested forearm is placed rest (upper trace) and after 10 s of maximum voluntary contraction (lower over the abdomen. The patient grasps the wrist of the tested limb trace). At rest, the CMAP amplitude is less than 50% of normal, and there with the other hand to minimize movement artifact. It is difficult is more than 500% postactivation facilitation. Used with permission from to fully immobilize the limb, and movement artifact is common. the author. Costimulation of the brachial plexus may also contaminate the recording. Deltoid RNS testing is slightly more sensitive than Muscle Selection testing in the trapezius for decremental responses in MG.21,22

To achieve the highest diagnostic yield, RNS testing should be Biceps brachii RNS testing is performed with musculocutaneous performed in clinically weak muscles wherever feasible. An RNS nerve stimulation in the axilla in a supine position. The recording testing is most easily performed in intrinsic hand muscles, though electrode is placed over the muscle belly with the reference in MG, weakness is typically distributed in ocular, bulbar, and electrode placed distally over the biceps tendon. Surface proximal limb muscles. Accordingly, RNS testing for MG should stimulating electrodes are held firmly against the posterior border include proximal limb or cranial muscles in addition to intrinsic of the short head of the biceps within 2 cm of the anterior axillary hand muscles. In LEMS, at least one hand and one foot muscle fold. Alternatively, a monopolar stimulating needle electrode should be assessed. 21 REPETITIVE NERVE STIMULATION TESTING reduces the stimulus intensity required for maximal nerve between the first and fourth CMAP in a train of low frequency stimulation and improves patient comfort.18 As with deltoid RNS RNS. Decrement is normally less than 8%, and greater than 10% testing, costimulation of local nerves may introduce artifact. The decrement is abnormal.27 arm must be restrained with a padded board or by an examiner to minimize movement artifact.

Anconeus RNS testing is as sensitive as deltoid RNS testing in MG and is better tolerated by patients.23 Testing is performed in either a seated or supine position with the forearm pronated and supported. Surface stimulation of the radial nerve is performed in the lateral intermuscular septum about 1-2 cm proximal to the lateral epicondyle. The active recording electrode is placed about 3 cm distal to the midpoint of a line drawn between the lateral epicondyle and the olecranon. Figure 3. Repetitive nerve stimulation testing at 3 Hz in the abductor In the setting of lower limb weakness, RNS testing in lower limb digiti minimi in Lambert-Eaton myasthenic syndrome demonstrating a muscles may be useful. The extensor digitorum brevis (EDB) saddle or U-shaped series of compound muscle action potential (CMAP) with deep fibular (peroneal) nerve stimulation at the ankle or the waveforms with a nadir in CMAP amplitude with the fourth and fifth CMAPs tibialis anterior with common fibular (peroneal) nerve stimulation of the series (34% amplitude decrement). The sixth, seventh, and eighth CMAP amplitudes are slightly higher, reflecting mobilization of secondary at the fibular head are assessed in the supine position. The active acetylcholine stores. Used with permission from the author. recording electrode is placed over the muscle belly with the reference placed over the lateral portion of the fifth toe for EDB Facilitation testing or over the distal tibialis anterior tendon. The foot may be immobilized by an examiner to minimize movement artifact. Facilitation is ideally elicited with 10 s of isometric MVC in the context of low frequency RNS. A pre-exercise RNS train Facial RNS testing may be recorded in the nasalis or inferior is initially delivered to establish a stable baseline and to assess orbicularis oculi muscles. Nasalis recordings generate a more 24 for decrement. After 10 s of isometric MVC, a second train of monophasic CMAP waveform that facilitates data analysis. RNS is delivered. The amplitude of the first postexercise CMAP The facial nerve is stimulated at the stylomastoid foramen with (CMAPPost) is compared with the first CMAP in a baseline, pre- surface electrodes. Alternatively, a monopolar needle may be used exercise RNS train (CMAPPre) using the formula: to stimulate the zygomatic branch of the facial nerve about 2 cm anterior to the tragus. The active recording electrode is placed % Facilitation = [(CMAPPost − CMAPPre)/ CMAPPre] × 100% over the nasalis or the most inferior aspect of the orbicularis oculi, and the reference electrode is placed at the lateral canthus. Facial Where high frequency RNS testing is required, the initial CMAP RNS testing is often uncomfortable and movement artifact is (CMAP1) and the highest CMAP (CMAPn) in a train are compared common. RNS in facial muscles is more diagnostically sensitive using the formula: than in hand muscles in oculobulbar MG.25 % Facilitation = [(CMAPn − CMAP1)/CMAP1] × 100% Masseter RNS testing is nearly as sensitive as facial RNS testing 26 and better tolerated. The mandibular branch of the trigeminal Amplitude facilitation and area facilitation should be compared nerve is stimulated using a monopolar electrode inserted about 2 to document pseudofacilitation when high frequency RNSs are cm deep at the mandibular notch. The active recording electrode performed. is placed over the masseter with the reference placed just inferior to the angle of the jaw. Quality Control

DATA ANALYSIS There are numerous opportunities for technical error in RNS testing, and rigorous inspection of each train of actual CMAP Decrement waveforms is necessary to prevent reporting error. Stylized bar or stick renderings of CMAPs may not reveal important Decrement is calculated by comparing the initial CMAP amplitude 1 n morphological information. The baseline for each series of (CMAP ) with the lowest CMAP amplitude (CMAP ) elicited by CMAPs should be stable. A shifting or unstable baseline suggests a stimulus train using the formula: limb and/or recording electrode movement. Abrupt changes in

n n 1 1 CMAP morphology or amplitude suggest understimulation related % Decrement = [(CMAP − CMAP )/CMAP ] × 100% to movement of the stimulating electrodes. Pseudofacilitation may follow high frequency RNS or muscle shortening with inadequate With appropriate technique in low frequency RNS, the fourth immobilization. Actual disease generates a regular, orderly or fifth CMAP amplitude will be the lowest due to depletion of decline in CMAP amplitudes by the fourth or fifth stimulus. The immediate ACh stores. With mobilization of secondary ACh maximum decrement is often observed between the first and stores, CMAP amplitudes typically increase slightly after the second CMAPs in a series (Figure 2). Findings from RNS testing fourth stimulation, resulting in a saddle or U-shaped series of should be reproducible after appropriate rest periods. CMAP waveforms (Figure 3). Decrement is typically calculated BASICS WITH THE EXPERTS REPETITIVE NERVE STIMULATION characteristic RNS finding in botulism is persistent PAF that may TESTING IN SPECIFIC NEUROMUSCULAR last for several minutes and the absence of PAE. Mild cases of TRANSMISSION DISORDERS adult botulism may demonstrate normal RNS testing with only mild PAF,33 and significant PAF may only seen in slightly more The RNS testing protocol is tailored to the type of NMT disorder than half of adult cases.32 suggested by the clinical history and examination and the findings on sensory and motor NCS. Drugs used to augment NMT such as 3,4-diaminopyridine or AChE inhibitors, such as pyridostigmine Congenital Myasthenic Syndromes bromide, should be held if medically safe to do so, as they may render RNS testing less sensitive.28 RNS testing in many CMSs may elicit decremental responses to low frequency stimulation. Prolonged low frequency RNS or a Myasthenia Gravis 5-10 min exercise period may be required to elicit a significant decrement in endplate choline acetyltranserase (CHAT) deficiency Studies for MG should utilize 2-3 Hz RNS and assess at least one or CMS with episodic apnea (CMS-EA). Subsequently, PAE may hand and one proximal muscle in the face or shoulder. An initial be prolonged and last as long as 5-10 min.30 train of 5-10 stimuli is administered, and the resulting CMAP responses are inspected. If there is significant decrement, the train Small, repetitive discharges may arise during RNS testing in NMT is repeated after 1 min of rest to demonstrate that the finding is disorders involving increased EPP duration due to prolonged end- reproducible. The tested muscle is then isometrically exercised plate depolarization that exceeds the absolute refractory period of for 30-60 s with MVC. A train of five stimuli is administered the MFAP.34,35 Repetitive discharges are observed in slow channel immediately after the exercise period. Additional trains of five CMS and congenital AChE deficiency. They may also be seen in stimuli are delivered at 30 or 60 s intervals for 5 min to assess acquired NMT disorders including organophosphate intoxication for PAE. and autoimmune MG with high AChE inhibitor doses. Muscle specific tyrosine kinase (MuSK) MG may exhibit significant Decremental responses are most likely to be elicited in proximal cholinergic hypersensitivity with numerous repetitive discharges and bulbar muscles in MG. When present, PAE is observed at with low therapeutic doses of AChE inhibitors.36 2-4 min after 30-60 s of isometric exercise. Sometimes PAF is observed after exercise, but it is generally less than 50%. In a Other Neuromuscular Disorders large cohort of patients with generalized MG, 76% had abnormal RNS findings in a hand or shoulder muscle.11 Decremental responses to low frequency RNS are not unique to primary NMT disorders and may be observed in progressive Lambert-Eaton Myasthenic Syndrome motor neuron disease37,38 and in myotonic disorders.39 Findings from RNS must therefore be interpreted in the full context of The diagnosis of LEMS is suggested by proximal limb weakness clinical history, examination, and other standard EDX testing, with cholinergic autonomic dysfunction and reduced baseline including motor and sensory NCSs and needle EMG. CMAP amplitudes. By contrast to MG, the muscles most likely to exhibit abnormal findings in LEMS are the ADM, APB, and REFERENCES EDB. In order to obtain baseline CMAPs that are not influenced by facilitation, it is essential to rest the muscle being tested for 1. Jolly F. Ueber myasthenia gravis pseudoparalytica. Berliner 5 min before eliciting a baseline CMAP. The muscle should Klinische Wochenschrift 1895;32:1-7. then be activated with MVC for 10 s, relaxed completely, and a 2. Harvey AM, Masland RL. A method for the study of neuromuscular postactivation stimulus given within 5 s. Longer exercise periods transmission in human subjects. Bull Johns Hopkins Hosp deplete ACh stores and blunt facilitation, and PAF is reduced if 1941;68:81-93. the postactivation stimulus is delayed. After 3-5 min of additional 3. Harvey AM, Masland RL. The electromyogram in myasthenia rest, an initial train of 5-10 stimuli with low frequency RNS is gravis. Bull Johns Hopkins Hosp 1941;69:1-13. delivered to establish a decrement. After another 10 s period of 4. Engel AG. The neuromuscular junction. In: Engel AG, Franzini- isometric exercise with MVC, a train of five stimuli is administered Armstrong C, eds. Myology, 3rd ed. New York: McGraw-Hill, within 5 s to confirm PAF with additional stimulus trains given 2004:325-372. at 30-60 s intervals for 5 min to assess for PAE. Although more 5. Stålberg E, Sanders DB. Electrophysiological tests of than 100% PAF following brief exercise or high frequency RNS is neuromuscular transmission. In: Stålberg E, Young RR, eds. Clinical characteristic of LEMS (Figure 1), the most sensitive RNS finding Neurophysiology. London: Butterworths. 1981:88-116. is decrement to low frequency RNS that is observed in at least one 6. Katz B, Miledi R. The role of calcium in neuromuscular facilitation. hand muscle in virtually all patients (Figure 3).29 J Physiol 1968;195:481-492. 7. Magleby KL. Neuromuscular transmission. In: Engel AG, Franzini- Botulism Armstrong C, eds. Myology, 3rd ed. New York: McGraw-Hill, 2004:373-395. In botulism, RNS testing should be performed in clinically 8. Magleby KL. The effect of repetitive stimulation on facilitation of weak muscles since abnormal findings may be confined to transmitter release at the frog neuromuscular junction. J Physiol these muscles.30 Studies in infant botulism may demonstrate 1976;257:449-470. low amplitude resting CMAPs and more than 40% PAF.31,32 The

23 REPETITIVE NERVE STIMULATION TESTING 9. Desmedt JE. The neuromuscular disorder in myasthenia gravis. 24. Ruys-Van Oeyen AE, van Dijk JG. Repetitive nerve stimulation 1. Electrical and mechanical response to nerve stimulation of the nasalis muscle: technique and normal values. Muscle Nerve in hand muscles. In: Desmedt JE, ed. New developments in 2002;26:279-282. electromyography and clinical neurophysiology. Basel: Karger; 25. Niks EH, Badrising UA, Verschuuren JJ, et al. Decremental response 1973. pp 241-304. of the nasalis and hypothenar muscles in myasthenia gravis. Muscle 10. Oh SJ, Eslami N, Nichihira T, et al. Electrophysiological and Nerve 2003;28:236-238. clinical correlation in myasthenia gravis. Trans Am Neurol Assoc 26. Rubin DI, Harper CM, Auger RG. Trigeminal nerve repetitive 1982;12:348-354. stimulation in myasthenia gravis. Muscle Nerve 2004;29:591-596. 11. Stålberg E, Trontelj JV, Sanders DB. Single fiber electromyography 27. Slomic A, Rosenfalck A, Buchthal F. Electrical and mechanical studies in healthy and diseased muscle, 3rd ed. Fiskebäckskil, responses of normal and myasthenic muscle. Brain Res 1968;10:1-78. Sweden: Edshagen Publishing House; 2010. 28. American Association of Electrodiagnostic Medicine Quality 12. Katirji B, Kaminski HJ. Electrodiagnostic approach to the patient Assurance Committee. Practice parameter for repetitive nerve with suspected neuromuscular junction disorder. Neurol Clin N Am stimulation and single fiber EMG evaluation of adults with suspected 2002;20:557-586. myasthenia gravis or Lambert-Eaton myasthenic syndrome: 13. Borenstein S, Desmedt JE. Local cooling in myasthenia. summary statement. Muscle Nerve 2001;24:1236-1238. Improvement of neuromuscular failure. Arch Neurol 1975;32:152-157. 29. Tim RW, Massey JM, Sanders DB. Lambert-Eaton myasthenic 14. Lo YL, Dan YF, Leoh TH, Tan YE, Nurjannah S, Ratnagopal P. syndrome: Electrodiagnostic findings and response to treatment. Effect of exercise on repetitive nerve stimulation studies: New Neurology 2000;54:2176-2178. appraisal of an old technique. J Clin Neurophysiol 2004;21:110-113. 30. Meriggioli MN, Howard JF, Harper CM. Neuromuscular junction 15. Rubin DI, Hentshel K. Is exercise necessary with repetitive nerve disorders: diagnosis and treatment. New York: Marcel Dekker; 2004. stimulation in evaluating patients with suspected myasthenia gravis? 31. Fakadej A, Gutmann L. Prolongation of post-tetanic facilitation in Muscle Nerve 2007;35:103-106. infant botulism. Muscle Nerve 1982;5:727-729. 16. Desmedt JE, Borenstein S. Double-step nerve stimulation test for 32. Cornblath DR, Sladky JT, Sumner AJ. Clinical electrophysiology of myasthenic block: sensitization of postactivation exhaustion by infant botulism. Muscle Nerve 1983;6:448-452. ischemia. Ann Neurol 1977;1:55-64. 33. Cherington M. Electrophysiologic methods as an aid in diagnosis of 17. Horowitz SH, Sivak M. The regional curare test and botulism: a review. Muscle Nerve 1982;5:528-529. electrophysiologic diagnosis of myasthenia gravis: further studies. 34. Engel AG, Ohno K, Sine S. Congenital myasthenic syndromes. In: Muscle Nerve 1978;1:432-434. Engel AG, ed. Myasthenia gravis and myasthenic disorders. New 18. Sanders DB. Clinical neurophysiology of disorders of the York: Oxford University Press; 1999. pp 251-297. neuromuscular junction. J Clin Neurophys 1993;10:167-180. 35. Engel AG. The investigation of congenital myasthenic syndromes. 19. Schumm F, Stohr M. Accesory nerve stimulation in the assessment Ann NY Acad Sci 1993;681:425-434. of myasthenia gravis. Muscle Nerve 1984;7:147-151. 36. Punga A, Flink R, Askmark H, Stalberg EV. Cholinergic 20. Costa J, Evangelista T, Conceição I, de Carvalho M. Repetitive neuromuscular hyperactivity in patients with myasthenia gravis nerve stimulation in myasthenia gravis—relative sensitivity of seropositive for MuSK antibody. Muscle Nerve 2006;34:111-115. different muscles. Clin Neurophys 2004;115:2776-2782. 37. Denys EH, Norris FH. Amyotrophic lateral sclerosis. Impairment of 21. Schady W, MacDermott N. On the choice of muscle in the neuromuscular transmission. Arch Neurol 1979;36:202-205. electrophysiological assessment of myasthenia gravis. Electromyogr 38. Bernstein LP, Antel JP. Motor neuron disease: decremental responses Clin Neurophysiol 1992;32:99-102. to repetitive nerve stimulation. Neurology 1981;31:204-207. 22. Yiannikas C, Sheean GL, King PJL. The relative sensitivities of the 39. Aminoff MJ, Layzer RB, Satya-Murti S, Faden AI. The declining axillar and accessory nerves in the diagnosis of myasthenia gravis. electrical response of muscle to repetitive nerve stimulation in Muscle Nerve 1994;17:561-562. myotonia. Neurology 1977;27:812-816. 23. Kennett RP, Fawcett PR. Repetitive nerve stimulation of anconeus in the assessment of neuromuscular transmission disorders. Electroencephalogr Clin Neurophysiol 1993;89:170-176.

24 BASICS WITH THE EXPERTS

Muscle Cramps and Hyperactivity Syndromes

Bassam A. Bassam, MD Professor of Neurology University of South Alabama Mobile, Alabama

CRAMPS

Cramps are sudden, episodic, involuntary, and painful shortening of a muscle, accompanied by uncomfortable squeezing or contraction, often with a palpable hard knot or muscle hardening, lasting seconds to minutes. Muscle stretching, massage, or contraction of antagonist muscle speeds relief from the cramps; however, cramps have the tendency to recur. Cramps are common, Figure 1. Cramp discharges of a few motor units firing repetitively a high 1,2 with a prevalence range of 40-60%, often benign, encountered frequency rate, appearing similar to an interference pattern. in normal individuals, especially after strenuous exercise or in a hot environment as a result of dehydration. Habitual nocturnal FASCICULATIONS calf cramps also occur in older age groups. However, cramps are among the symptoms of various neuromuscular diseases (NMDs), Fasciculations are random spontaneous, abrupt involuntary such as amyotrophic lateral sclerosis (ALS), various neuropathies, discharges of a given single motor unit (MU) and all of its muscle myopathies, drug-induced, pregnancy, endocrinologic, metabolic, fibers (Figure 2). They have a dull “popping” sound and usually and liver diseases. fire slowly and irregularly (1-3 Hz). Oftentimes they can be missed unless the electrodiagnostic (EDX) physician waits a sufficient A needle electromyography (EMG) examination during the cramp amount of time. Fasciculations may have the morphology of demonstrates involuntary, repetitive firing of a single or multiple a normal MUAP (Figure 2) or an abnormal morphology in profuse motor unit action potential(s) (MUAP[s]) at a high pathological conditions, depending on the MU from which they frequency rate (30-75 Hz) which subside gradually (Figure 1). arise. The origin of fasciculations is anywhere along the lower motor neuron, from the anterior horn cell or its axon, at a point The exact mechanism for muscle cramps origin appears to be at prior to its terminal branches. Fasciculations in isolation are the level of anterior horn cell, terminal axons, or both central and more often benign, especially when confined to a single muscle.3 peripheral motor neurons; it is not primarily a muscle phenomenon. However, they are encountered along with other manifestations Muscle cramps should be differentiated from muscle contractures in various chronic neurogenic diseases, such as radiculopathies, seen in metabolic myopathy or other involuntary neuronal or polyneuropathies, and (especially common) ALS. skeletal muscle overactivity, such as myotonia, neuromyotonia, focal dystonia, or myokymia. Muscle electrical contractures, usually encountered in metabolic myopathy after exercise, do not respond to stretching, last longer periods of time, and typically are electrically silent on needle EMG examination. 25 MUSCLE CRAMPS AND HYPERACTIVITY SYNDROMES Complex repetitive discharges are encountered in a number of chronic neurogenic and myopathic disorders including radiculopathies, neuropathies, and inflammatory and slowly progressive myopathies. They rarely occur in normal muscle, and they likely reflect a residual, inactive old process.

Figure 2. Fasciculations with normal motor unit potential morphology and a slow abrupt firing pattern. Figure 4. Complex repetitive discharges firing repetitively at a 30-40 Hz rate.

DOUBLETS, TRIPLETS, AND MULTIPLETS MYOTONIC DISCHARGES

Motor units normally discharge as single potentials; however, Myotonic discharges are spontaneous, generated by a single MUAPs may discharge spontaneously or voluntarily in bursts muscle fiber, and are in the form of brief spikes or positive waves of two (doublets), three (triplets), or multiple discharges at a frequency range of 20-150 Hz. These discharges are often (multiplets), at short intervals, and variable intra-bursts frequency initiated by needle insertion or movement, with a characteristic (Figure 3). Multiplets are characteristically seen in peripheral increase or decrease of the amplitude and frequency (waxing and nerve hyperexciteability disorders such tetany and hypocalcemia, waning) (Figure 5). The sound of myotonic discharges resembles predominantly in the distal muscles, and occasionally seen in that of a “dive-bomber” or “mooing” sound. Myotonia is typically 4 otherwise normal individuals. Additionally, multiplets are seen in seen in myopathies with clinical myotonia such as myotonic association with fasciculations in chronic neuropathic disorders. dystrophy types 1 and 2, myotonia congenita, and paramyotonia congenita. However, they are also seen in myopathies without clinical myotonia, such as hyperkalemic periodic paralysis, acid maltase deficiency, polymyositis, and a few toxic myopathies. They are seen rarely in severe, chronic neurogenic disorders.4 Myotonic discharges are usually not encountered in normal muscle and, when firing at slow frequency, they can be mistaken as acute denervation.

Figure 3. Triplet and multiplet discharges due to membrane hyperexcitability.

COMPLEX REPETITIVE DISCHARGES Figure 5. Myotonic discharges at a high frequency rate, with characteristic Complex repetitive discharges (CRDs) previously known as waxing and waning amplitude and frequency. “pseudomyotonia or bizarre repetitive discharges” are spontaneous firing of groups of muscle fibers in repeatedly synchronous pattern, at high frequency rates of 20-150 Hz, with an abrupt onset and MYOKYMIC DISCHARGES termination (Figure 4). Single fiber EMG recordings suggest that Myokymia is a rhythmic grouped discharge of a single motor CRDs are initiated by spontaneous firing of a single muscle fiber, unit potential firing spontaneously at a frequency of 5-60 Hz, which ephaptically spreads and depolarizes a variable number in a pattern of repetitive bursts with intervening periods of of adjacent denervated fibers in sequence and creates a recurrent electrical silence, recurring at intervals of 0.5-10 s (Figure circuit of discharges.5 Complex repetitive discharges usually 6). The number of potentials in each burst varies, and it has a maintain identical discharge morphology from one discharge to “marching soldiers”-like sound. Myokymic discharges appear as the next and fire in a regular pattern with a machine-like sound; worm-like quivering or undulating movements in muscles with however, a sudden change of frequency, morphology, or sound may thin overlying subcutaneous tissue, such as the facial muscles. occur as individual fibers may drop or the circuit is overdriven by Myokymic discharges very likely represent depolarization or another denervated muscle fiber. Single fiber EMG shows low jitter ephaptic transmission along demyelinated nerve fibers, and they because CRDs are generated by muscle fibers, and they are not can be provoked by lowering ionized serum calcium. Facial abolished by neuromuscular junction blocking agents. 26 BASICS WITH THE EXPERTS myokymia occurs in multiple sclerosis, brainstem neoplasm, pain secondary to degenerative spine disease. The neurological Guillain-Barré syndrome, and facial neuropathy. Limb myokymia examination was entirely normal, with no muscle weakness or is characteristically seen in radiation-induced nerve damage atrophy, sensory deficit, or reflexes alteration. Basic laboratory or plexopathy, and infrequently in radiculopathy, entrapment studies were all normal, except for mildly elevated serum creatine neuropathy, spinal cord demyelinating lesions, and thyrotoxicosis. kinase (CK)levels. Nerve conduction studies, including motor and sensory components, were all normal. Needle EMG examination of various distal and proximal limb muscles showed a few profuse bursts of MUAPs firing at high frequency rates (25-30 Hz) in the gastrocnemius muscle, (associated with pain) and followed with a few muscle twitches. However, there was no abnormal spontaneous activity or MUAP parameter abnormality.

MUSCLE CRAMPS

Muscle cramps are common, often encountered in healthy persons, especially during exercise or at night, or even at rest; however, they may also signify a variety of neuromuscular and metabolic disorders. They are more common in certain groups: the elderly, Figure 6. Myokymic discharges appearing as rhythmic grouped discharges females more than males, and those who are pregnant. Infrequent in a pattern of repetitive bursts with intervening periods of electrical silence. cramps are reported in up to 95% of healthy individuals, with an estimated weekly prevalence of 35%.8 Muscle cramps are usually painful, and ordinarily are self-limiting within minutes. NEUROMYOTONIC DISCHARGES However, muscles can remain sore for hours or even a few days (NEUROMYOTONIA) after intense cramps, which may cause muscle fiber damage and elevated blood CK levels. Muscle cramps should not be confused Neuromyotonia is very rare spontaneous bursts, or trains of a with muscle spasm, which is a sustained involuntary muscle single MUAP, firing at a very high frequency range of 150-250 contraction, usually nonpainful. Likewise, muscle cramps should Hz for few seconds. These often starts or stop abruptly with a be differentiated from muscle contractures that often cause painful characteristic high-pitched “pinging” sound (Figure 7). The muscular stiffness, typically are electrically silent on needle EMG potential may decrease in amplitude (wanes) due to muscle fiber examination, and usually seen in glycogen storage myopathies, inability to maintain discharges at a very high rate. Neuromyotonic and less frequently in lipid storage or mitochondrial myopathies. discharges are generated by motor neurons, or their axons, likely When evaluating patients with muscle cramps—in addition to the 6 distally. They persist during spinal or general anesthesia, diminish clinical history, the neurological examination, inquiring about by distal nerve block, and abolish by neuromuscular blocking provoking factors as well as other neuromuscular symptoms/ agents. Neuromyotonia is typically seen in disorders of peripheral signs—identifying the involved muscles is very helpful in the nerve hyperexcitability, such as Isaac’s syndrome, as a result of evaluation process. Blood tests, standard EDX studies, and, at 7 a defect in potassium channels in the nerve membrane, and less times, the “ischemic exercise” test may help identify benign from often in extremely chronic neuropathic diseases (poliomyelitis disease-associated muscle cramps. and spinal muscular atrophy) and rare familial cases. Benign nocturnal cramps are extremely painful, sleep disruptive, and usually involve the calf muscles at night or during sleep. They are more common in the elderly population, who are otherwise healthy or may have neuropathy or peripheral vascular disease. Quinine sulfate 300 mg at bedtime is an effective treatment; however, the potential serious toxicity and adverse effects of quinine limits its use.9 Other medications including phenytoin, carbamazepine, and clonazepam are useful alternative treatments. Stretch exercise of the calf muscles for few a minutes before bedtime may reduce nocturnal cramps. Figure 7. Neuromyotonic discharges of a motor unit potential at a very high frequency range with a decrementing amplitude. Heat- and exercise-induced cramps occur in healthy and athletic individuals after strenuous exercise, dehydration, and sweating, Case One and they can be prevented by ingesting electrolyte solution and salt tablets. Leg cramps are known to increase during pregnancy A 62-year-old female presents with 9 months history of frequent for reasons not fully understood. Studies have shown that oral painful, explosive, and palpable knot like contractions of the calf magnesium supplements reduced their frequency and severity.10 muscles at night. She states that they awaken her from sleep, often Chronic renal failure patients undergoing hemodialysis are are terminated by passive leg stretch, and are occasionally followed subject to increased muscle cramps, usually toward the end of the by muscle soreness for few hours, or through the next day. Her session. These can be prevented by intravenous hypertonic saline past medical history includes hypertension and chronic low back or hypertonic glucose solution.11 A high number of patients with

27 MUSCLE CRAMPS AND HYPERACTIVITY SYNDROMES liver cirrhosis experience frequent muscle cramps which increase were reduced, and sensation was intact. He walks with short with the worsening of the disease. Intravenous albumin infusion, shuffling steps, and jerking of the trunk throws him off-balance. taurine, and vitamin E orally decreased the muscle cramps in Extensive laboratory studies were unrevealing. The EDX study these patients.12,13 showed abundant myokymic and neuromyotonic discharges, fasciculations, and variable decrement-increment on 3-5 Hz A number of neuromuscular conditions are associated with frequent RMNS. The patient tested positive for serum VGKC antibodies. muscle cramps, including radiculopathy, polyneuropathy (e.g., chemotherapy-induced neuropathy) and especially ALS. Muscle NEUROMYOTONIA (ISAACS’ SYNDROME) cramps occur in 55% of ALS patients.14 Various myopathies including Becker muscular dystrophy, myoadenalate deaminase Isaacs’ syndrome (IS), also referred to as the acquired deficiency, and metabolic myopathies are often associated with neuromyotonia and continuous muscle fiber activity syndrome, muscle cramps and myalgia. Muscle cramps are a main feature was first described by Issacs in 1961. It is characterized by of spontaneous muscle hyperactivity syndromes including sustained, diffuse MU activity due to hyperactivity of peripheral neuromyotonia (Isaac’s syndrome), stiff-person syndrome (SPS), nerve motor axons.17 The excess MU activity can be abolished and cramp-fasciculation syndrome. by neuromuscular junction block but is not substantially altered by sleep, general or spinal anesthesia, or proximal nerve block. Muscle cramps, fatigue, painless muscle twitches (fasciculations), The syndrome can begin at any age, typically in adolescent or myalgias, and parasthesias, are the main physical complaints adult life, and is characterized clinically by diffuse muscle in patients with benign fasciculation syndrome (BFS). The stiffness and delayed relaxation (pseudomyotonia), widespread neurological examination and EDX studies are normal, except muscle twitching (myokymia and fasciculations), and cramps. for prominent fasciculations on needle EMG examination. None Abnormal posturing is common, often provoked by voluntary of these individuals developed a significant NMD on a longterm activity such as carpopedal spasm despite normal calcium retrospective followup study for 2-32 years.15 A peripheral nerve level, plantar flexion, elbow or wrist twists and flexion, and syndrome with frequent and more disabling muscle cramps, facial grimacing. Muscle aching is usual, but severe myalgia is fasciculations, myokymia, myalgias, stiffness, and exercise uncommon. Nonspecific sensory complaints can be encountered. intolerance is known as cramp-fasciculation syndrome (CFS). Dyspnea, hoarseness, swallowing difficulty, and excessive This was first described by Tahmouch and colleagues in 1991.16 sweating may occur. The patient’s subsequent disability varies The syndrome is not well understood. It can be mild and overlaps from severely disabled to mild complaints, and on occasion IS with BFS, or, in rare cases, can be severe and disabling. Rarely, may present as a focal disorder. Affected individuals with severe CFS is associated with positive antibodies to voltage-gated cases may lose substantial weight during the course of their potassium channels (VGKC) and it overlaps with neuromyotonia. illness. Isaacs’ syndrome may be associated central nervous The neurological examination and EDX studies are usually syndrome manifestations or encephalopathy such as confusion or normal, except for prominent fasciculations and myokymia hallucination, referred to as Morvan syndrome. on needle EMG provoked after discharges on repetitive motor nerve stimulation (RMNS) at a low stimulation rate. The after Physical examination in patients with IS reveals variable stiff discharges are not specific for CFS, and they can be also seen abnormal postures, such as trunk flexion, elbow or wrist flexion, in various primary nerve hyperexcitability with symptoms of shoulder elevation, or plantar flexion of the foot which is often muscle cramps and twitching. Carbamazepine was found to be provoked by strong voluntary contraction. Muscle strength is an effective therapy in treating muscle cramps in both BFS and usually normal, and tendon reflexes can be diminished or absent. CFS.16 Widespread fasciculations and undulating muscle twitching (myokymia) are prominent with a predilection for distal muscles, Case Two particularly in the calf, limb, and facial muscles. Facial grimacing and myokymia are common, and delayed eyes’ opening following A 46-year-old male presents with a 6-month history of progressive forceful eye closure may occur (pseudomyotonia). Most IS shaking, jerking, muscle twitches, and cramps. They were initially cases are sporadic and appear to be an autoimmune disorder, episodic, started in the left hand, and then progressed to involve but some are associated with neoplasms, including small-cell the arms, legs, trunk, and neck, and frequently they worsened carcinoma, thymoma, and Hodgkin’s disease. Familial inherited with voluntary activity. In addition, he reported associated cases of IS with autosomal-dominant inheritance have been mild decreased sensation and parasthesias. He denied prior reported.18 Antibodies directed to VGKCs have been identified infection, exposure to chemicals, or toxic substance. His muscle in the serum and cerebrospinal fluid (CSF), as well as increased twitches, jerking, and painful cramps improved with diazepam, protein and oligoclonal bands in the CSF.19 Association with levetiracetam, and dilaudid. Past medical history was positive for other autoimmune disorders, including myasthenia and systemic coronary artery disease, and he is adopted. Daily he drinks two lupus, has been reported.20 A combination of immunomodulating to three beers which helps with the jerks but he has no history treatments (intravenous immunoglobulin [IVIg], plasmapheresis, of tobacco or illicit drug use. General physical examination was or corticosteroids), coupled with symptomatic treatment to unremarkable, with the exception of a pulse rate of 120. The suppress neuronal hyperactivity (phenytoin, carbamazepine, neurological examination revealed visible emotional distress, baclofen, and gabapentin) seems to be an effective therapy and decreased facial expression, intermittently broken speech by alleviates clinical symptoms.21 In most cases, the IS course is jerks, posturing of arms, frequent muscle twitches, and jerks of chronic, requiring prolonged maintenance therapy; however, the neck and trunk. He has no muscle weakness, tendon reflexes some patients may achieve remission. 28 BASICS WITH THE EXPERTS spontaneous firing of normal-appearing MUAPs that cannot Case Three be voluntarily stopped and can be recorded simultaneously in agonist and antagonist muscle pair. Spontaneous discharges such A 40-year-old female first noted vague neck soreness over the past as myokymia, myotonia, or neuromyotonia are not seen in SPS. 2 years that did not improve with nonsteroidal anti-inflammatory Additional ectrophysiological studies not routinely performed drugs and physical therapy. She then developed increasing soreness that may help support the diagnosis include hyperexcitability and and back stiffness. Over the next few months, she experienced lack of vibration-induced inhibition of the H reflex and enhanced episodes of back, proximal arms, and occasionally legs spasm for blink reflex. An effective treatment of SPS should include a hours, with difficulty to move. These spasms were quite painful. combination of symptomatic and immunomodulating treatments. The episodes would spontaneously remit but are becoming Diazepam is the mainstay symptomatic treatment, often in very increasingly frequent and limiting her mobility. Her neurological high doses (40-100 mg/day). Other gamma aminobutyric acid examination was normal, except for palpable paraspinal muscle enhancing drugs such as baclofen and valproic acid have been tightness, and she walks with very upright hyperlordotic gait; used. Plasma exchange and IVIg therapy has benefited some SPS EDX studies were normal except for continuous firing normal- patients. Intrathecal baclofen and intermittent botulinum toxin appearing MUAPs in the paraspinal muscles, and no maneuvers injection of the paraspinal muscles have been used in patients’ were successful in relaxing these muscles. refractory to standard therapy.30

STIFF-PERSON SYNDROME REFERENCES

Stiff-person syndrome, first described by Moersch and Woltman,22 1. Abdulla AJ, Jones BW, Pearce VR. Leg cramps in the elderly; is characterized by persistent muscular stiffness and painful prevalence, drug and disease associations. Int J Clin Pract reflex spasms. The syndrome is rare, mostly sporadic, occurs in 1999;53:494-496. middle age, and follows a slowly progressive chronic course. 2. Naylor JR, Young JB. A general population survey of rest cramps. Patients with SPS develop a characteristic insidious onset of Age Ageing 1994;23:418-420. increasing proximal and axial musculature muscle stiffness and 3. Layzer RB. The origin of muscle fasciculations and cramps. Muscle superimposed painful muscle spasms. The stiffness typically Nerve 1994;17;1243-1249. begins in the axial trunk and neck muscles, then spreads over time 4. Daube JR, Rubin DI. AANEM monograph #11: Needle to involve proximal limb muscles as well. The spasms are either electromyography. Muscle Nerve 2009;39:244-270. spontaneous or precipitated by movements or auditory, emotional 5. Trontelj JV, Stalberg E. Bizarre repetitive discharges recorded with or tactile stimuli. They can produce enough force to cause osseous single fiber EMG. J Neurol Neurosurg Psychiatry 1983;46:310-316. fractures. The muscle stiffness and spasms in SPS concomitantly 6. Torbergsen T, Stalberg E, Brautaset M. Generator sites for affect agonist and antagonist muscle, can be abolished by general spontaneous activity in neuromyotonia, an EMG study. EEG Clin anesthesia and neuromuscular blocking agents, and are diminished Neurophysiol 1996;101:69-78. during sleep. Some patients have associated autonomic features 7. Hart IK. Acquired neuromyotonia: a new autoantibody-mediated during paroxysms, including diaphoresis, tachycardia, tachypnea, neuronal potassium channelopathy. Am J Med Sci 2000;319-216. fluctuations of blood pressure, and rarely sudden death.23 8. Norris FH, Gasteiger EL, Chatfield PO. An Electromyographic The syndrome is progressive, limits flexibility and mobility study of induced and spontaneous muscle cramps. EEG Clin overtime, and walking becomes laborious with a characteristic Neurophysiol 1957;9:138-147. hyperlordotic gait. However, less commonly SPS may have a 9. Man-Son Hing M, wells G. Metaanalysis of efficacy of quinine limited distribution, confined to limb muscles.24 On the opposite for treatment of nocturnal leg cramps in elederly people. BMJ end, the syndrome may evolve to a progressive encephalomyelitic 1995;310:13-17. disorder with rigidity, myoclonic jerks of the trunk and limbs, and 10. Dahle LO, Berg G, Humar M, et al. The effect of oral painful spasms.25 About 5% of SPS cases have been associated magnesiumsubstitution on pregnancy-induced leg cramps. Am J with malignancy, including Hodgkin’s disease, breast cancer, Obest Gynecol 1995;173:175-180. thymoma, colon, and small-cell cancer of the lung, with the upper 11. Jenkins PG, Dreher WH. Dialysis-induced muscle cramps; treatment limbs predominantly affected.26 A strong family history of cancer with hypertonic saline and theory as to etiology. Trans Amer Soc and predominant upper limbs involvement justify diagnostic Artif Int Organs 1975;21:479-482. studies for an underlying malignancy. 12. Matsuzaki Y, Tanaka N, Osuga T. Is taurine effective for treatment of painful muscle cramps in liver cirrhosis? Am J Gastroenterol There is considerable evidence that SPS is an autoimmune disorder 1993;88:1466-1467. that results in disinhibition of the alpha motor neurons at the spinal 13. Konikoff F, Ben-Amitay G, Halpern Z, et al. Vitamin E and cirrhotic level. Antibodies to glutamic acid decarboxylase are detected in muscle cramps. Isr J Med Sci 1999;27:221-223. up to 80% of SPS cases. Antibodies against amphiphysin in SPS 14. Ganzini L, Johnson WS, Hoffman WF. Correlates of suffering in associated with breast cancer, and antibodies against gephyrin, a amyotrphic lateral sclerosis. Neurology 1999;52:1434-1440. protein associated with inhibitory neurotransmitters, have been 15. Blexrud MD, Windebank AJ, Daube JR. Long-term follow-up of 121 reported.27,28 An increased incidence of diabetes mellitus and patients with begnign fasciculations. Ann Neurol 1993;34:622-625. other autoimmune disorders, such as Hashimoto’s thyroiditis, 16. Tahmouch AJ, Alonso RJ, Tahmouch GP, et al. Cramp-fasciculation pernicious anemia, and myasthenia gravis, have been reported.29 syndrome: a treatable hyperexcitable peripheral nerve disorder. Routine nerve conduction studies in SPS are normal. Needle EMG Neurology 1991;41:1021-1024. of the involved muscles, especially the paraspinal muscles, reveals

29 MUSCLE CRAMPS AND HYPERACTIVITY SYNDROMES 17. Isaacs H. A syndrome of continuous muscle-fiber activity. J Neurol Neurosurg Psychiatry 1961;24:319-325. 18. Auger RG, Daube JR, Gomez MR, et al. Hereditary form of sustained muscle activity of peripheral nerve origin causing generalized myokymia and muscle stiffness. Ann Neurol 1985;15:13-21. 19. Shillito P, Molenaar PC, Vincent A, et al. Acquired neuromyotonia: evidence for autoantibodies directed against K+ channels of peripheral nerves. Ann Neurol 1995;38:714-722. 20. Newsom-Davis J, Mills KR. Immunological associations of acquired neuromyotonia (Isaacs’ Syndrome). Brain 1993;116:453-469. 21. van den Berg P, van Engelen BGM, Boerman RH, et al. Acquired neuromyotonia: superiority of plasma exchange over high dose IVIg. J Neurol 1999;246:623-625. 22. Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm (stiff-man syndrome). Proc Staff Meet Mayo Clin 1956;31:421-427. 23. Goetz CG, Klawans HL. On the mechanism of sudden death in Moersch-Woltman syndrome. Neurology 1983;33:930-932. 24. Brown P, Rothwell JC, Marsden CD. The stiff-leg syndrome. J Neurol Neurosurg Psychiatry 1997;62:31-37. 25. Barker RA, Revesz T, Thom M, et al. Review of 23 patients affected by the stiffman syndrome; clinical subdivision into stiff trunk (man) syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 1998;65:633-640. 26. Evoli A, Lo-Monaco M, Marra R, et al. Multiple paraneoplastic deseases associated with thymoma. Neuromuscull Disord 1999;9:601-603. 27. Solimena M, Folli F, Aparisi R, et al. Autoantibodies to GABA- ergic neurons and pancreatic beta cells in stiff-person syndrome. N Engl J Med 1990;322:1555-1560. 28. Dalakas MC, Fujii M, Li M, et al. The clinical spectrum of anti-GAD antibody-postive patients with stiff person syndrome. Neurology 2000;55:1531-1535. 29. Piccolo G, Cosi V. Stiff-man syndrome, dysimmune disorder, and cancer. Ann Neurol 1989;26(1):105. 30. Davis D, Jabbari B. Significant improvement of stiff-person syndrome after paraspinal injection of botulin toxin A. Mov Disord 1993;8:371-373.

30 BASICS WITH THE EXPERTS

Basics With The Experts CME Questions:

1. Which of the following is the MOST COMMON cause of 7. All of the following may erroneously suggest a conduction polyneuropathy in the developed world? block of the median nerve in the forearm EXCEPT: A. Hypothyroidism. A. Studies during the first few days of neurotmesis. B. Diabetes mellitus. B. Use of submaximal stimulation at the elbow. C. Vitamin B12 deficiency. C. Presence of Martin-Gruber anastomosis. D. Monoclonal gammopathy of unknown significance. D. Failure to recognize pathological temporal dispersion. E. In excitability of the affected segment to externally 2. All of the following are characteristic of a small fiber applied current. polyneuropathy EXCEPT: A. Numbness and loss of pain sensibility in feet. 8. A physiological temporal dispersion of sensory potentials B. Weakness of foot dorsiflexion. results in all of the following EXCEPT: C. Normal sensory nerve conduction studies. A. Phase cancellation between positive and negative peaks. D. Normal tendon reflexes. B. Decreased amplitude measured peak-to-peak. C. Increased duration measured from onset to return to the 3. The MOST COMMON type of Charcot-Marie-Tooth baseline. disease is due to which of the following? D. Linear amplitude changes in proportion to latency. A. Mutations of connexin-32 (Cx-32). E. No change in area under the waveform. B. Mutations of myelin protein zero (MPZ). C. Mutations of mitofusin 2 (MFN2). 9. A complete ischemic lesion in polyarteritis nodosa may D. Duplication of peripheral myelin protein 22 (PMP 22) gene. show “discontinuity conduction block” during which of the following? 4. Most neurotoxic agents cause which of the following types A. The first week. of neuropathy? B. The second week. A. Axonal polyneuropathy. C. The third week. B. Demyelinating polyneuropathy. D. The fourth week. C. Mononeuropathy multiplex. E. None of the above. D. Small fiber polyneuropathy. 10. Clinical weakness arises from which of the following 5. Nerve biopsy is LEAST useful in defining the etiology of combination of results? which of the following types of neuropathy? 1. Axonal degeneration A. Mononeuropathy multiplex. 2. Phase cancellation B. Patchy sensory neuropathy. 3. Conduction block C. Multifocal demyelinating neuropathy. 4. Pathological temporal dispersion D. Distal symmetric polyneuropathy. A. Only1, 2, and 3 are correct. B. Only 1 and 3 are correct. 6. Which of the following measures shows the LARGEST C. Only 2 and 4 are correct. variability from one trial to the next in the same subject? D. Only 4 is correct. A. Amplitude of the compound muscle action E. All are correct. potential (CMAP). B. Distal motor latency. C. F-wave conduction velocity. D. F-wave latency. E. Motor conduction velocity.

31 CME QUESTIONS 11. The saddle or U-shaped contour of a series of compound 16. Needle electromyography of a “cramped” muscle reveals muscle action potential waveforms following low frequency electric silence in which of the following? repetitive nerve stimulation testing reflects which of the A. Neuromyotonia (Isaacs’ syndrome). following? B. Stiff-person syndrome. A. Increased presynaptic calcium concentration. C. Myotonic dystrophy. B. Depletion of primary and mobilization of secondary D. Myophosphorylase deficiency (McArdle’s disease). acetylcholine (ACh) stores. E. Benign cramp. C. Prolonged end-plate depolarization. D. Postactivation facilitation. 17. Neuromyotonia (Isaacs’ syndrome) has been associated with which of the following? 12. High frequency (greater than 10 Hz) repetitive nerve A. Antibodies directed against ACh receptors. stimulation may enhance quantal ACh release by which of B. Antibodies directed against voltage-gated calcium channels. the following? C. Antibodies directed to the presynaptic sodium channels. A. Increasing the rate of choline reuptake. D. Antibodies directed against voltage-gated potassium B. Mobilizing secondary ACh stores. channels. C. Increasing presynaptic calcium concentration. E. Antibodies directed against GM1 ganglioside. D. Reducing the safety factor.

13. High frequency repetitive nerve stimulation testing: 18. Which one of the following is LEAST LIKELY to be seen in A. May elicit pseudofacilitation. muscle disease? B. Is well tolerated by patients. A. Fibrillation potentials. C. Improves movement artifact. B. Complex repetitive discharges. D. Should follow a brief isometric exercise period. C. Positive sharp waves. D. Myotonic discharges. 14. Postactivation facilitation may be sustained in which of the E. Fasciculation potentials. following conditions? A. Myasthenia gravis. 19. Myokymic discharges in limb muscles are MOST LIKELY B. Botulism. seen in which of the following? C. Lambert-Eaton myasthenic syndrome. A. Inflammatory myopathy. D. Amyotrophic lateral sclerosis. B. Post-radiation brachial plexopathy. C. Diabetic polyneuropathy. 15. Which of the following abnormal spontaneous activities is D. Cramp-fasciculation syndrome. generated by a single muscle fiber? E. Axonal degeneration polyneuropathy. A. Myokymic discharges. B. Neuromyotonic discharges. C. Myotonic discharges. D. Muscle cramp discharges. E. Fasciculation potentials.

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