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Neuromuscular Rehabilitation and Electrodiagnosis. 3.
Diseases of Muscles and Neuromuscular Junction
Jeffrey A. St...
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lower back muscle...
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plitude may be reduced in those ...
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   Needle electromyography will r...
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Fig 4. Two-he...
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  1. 1. S18 Neuromuscular Rehabilitation and Electrodiagnosis. 3. Diseases of Muscles and Neuromuscular Junction Jeffrey A. Strommen, MD, Jeffery S. Johns, MD, Chong-Tae Kim, MD, PhD, Faren H. Williams, MD, MS, Lyn D. Weiss, MD, Jay M. Weiss, MD, Ira G. Rashbaum, MD ABSTRACT. Strommen JA, Johns JS, Kim C-T, Williams FH, statins, is the most effective medication for managing elevated Weiss LD, Weiss JM, Rashbaum IG. Neuromuscular rehabil- LDL.4 Recent guidelines5 for cholesterol management define a itation and electrodiagnosis. 3. Diseases of muscles and neu- broad expansion of patients who are at high cardiovascular risk romuscular junction. Arch Phys Med Rehabil 2005;86(3 Suppl for whom statin use might be considered. As statin use be- 1):S18-27. comes more prevalent, understanding its possible side effects This self-directed learning module highlights formation of a and drug interactions becomes more important. differential diagnosis as well as electrodiagnostic evaluation Serious adverse events associated with statins in large ran- for those patients who present with the common complaint of domized controlled trials are relatively rare ( 1%), but include weakness. It is part of the chapter on neuromuscular rehabili- liver enzyme elevation and myopathy.2 The rates of muscular tation and electrodiagnosis in the Self-Directed Physiatric Ed- side effects for statins and placebo were each about 5% in these ucation Program for practitioners and trainees in physical med- studies,6 but these results may underestimate rates in general icine and rehabilitation. This article specifically focuses on the practice.4 common symptoms and typical clinical findings that allow the Inconsistent terminology may make comparisons among clinician to narrow the differential diagnosis. This is followed these studies difficult or impossible. Therefore, the recent Clin- by the diagnostic evaluation, with emphasis on the technical ical Advisory on the Use and Safety of Statins5 provides aspects and interpretation of electrodiagnostic studies. standardization of several definitions: myopathy is any muscle Overall Article Objective: To summarize the clinical pre- complaint; myalgia is muscle aching or weakness without sentation and electrodiagnostic findings in persons with disor- serum creatine kinase (CK) elevations; myositis implies muscle ders of muscle or disorders of the neuromuscular junction. symptoms accompanied by CK elevations; and rhabdomyolysis Key Words: Fatigue; Lambert-Eaton myasthenic syndrome; signifies muscle complaints with CK elevations 10 times the Muscle weakness; Myasthenia gravis; Myotonic dystrophy; upper limits of normal (ULN) with creatinine elevation.3,5 Neuromuscular junction diseases; Polymyositis; Rehabilita- Clinically important myopathy with CK elevations greater tion. than 10 times ULN is estimated to occur in approximately © 2005 by the American Academy of Physical Medicine and 0.1% of patients who receive statin monotherapy. Clinically Rehabilitation important myopathy and rhabdomyolysis have been reported with all statins with an overall death rate of .15 per 1 million 3.1 Clinical Activity: To evaluate and manage a 68-year- prescriptions.2 The death rate for cerivastatin was 16 to 80 old woman with recent coronary stenting who pre- times greater than the other statins, leading to the manufactur- sents with thigh pain and thigh cramping. er’s withdrawal of that medication from the market in August 2001.4 Fatal rhabdomyolysis has been reported for all statins R components ofThis patient likelyAND elevated low-density ISK-FACTOR ASSESSMENT diovascular events. modification are key primary and secondary prevention of car- had except fluvastatin.2 Factors that increase risk for myopathy include advanced age, small body frame or frailty, multisystem disease, multiple medications, perioperative periods, and lipoprotein (LDL) cholesterol and was subsequently placed on higher statin doses.5 a cholesterol-lowering medication in accordance with recently Drug-drug interactions have been suspected in about 50% of published guidelines.1 Multiple studies2,3 have documented the all cases of statin-related rhabdomyolysis, and the list of con- benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase comitant medications and foods that increase the risk of my- inhibitors as a means of reducing both primary and secondary opathy includes fibrates, cyclosporine, niacin, macrolide anti- cardiovascular events, mortality from all causes, cardiovascular biotics, digoxin, protease inhibitors, some antifungals, mortality, and stroke. This class of medications, known as warfarin, verapamil, amiodarone, grapefruit juice, and excess alcohol.2,3 These interactions are thought to be caused by their effects on cytochrome P450 pathways, but may involve addi- From the Department of Physical Medicine and Rehabilitation, Mayo Clinic, tional interactions at the excretion level as a consequence of Rochester, MN (Strommen); Department of Physical Medicine and Rehabilitation, competition for P-glycoproteins, recently recognized cellular Charlotte Institute of Rehabilitation, Charlotte, NC (Johns); Division of Child Devel- membrane drug transport proteins.2 opment and Rehabilitation, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA (Kim); Section of Physical Medicine and Rehabili- Muscle side effects or complaints may occur at any time, but tation, Philadelphia Veterans Administration Medical Center and University of Penn- may be triggered by starting or increasing regular physical sylvania, Philadelphia, PA (Williams); Department of Physical Medicine and Reha- exercise, even after years of asymptomatic statin therapy.5,6 bilitation, Nassau University Medical Center, East Meadow, NY (LD Weiss); Long Exercise in combination with lovastatin has produced greater Island PMR, Levittown, NY (JM Weiss); and Department of Rehabilitation Medicine, New York University Medical Center, New York, NY (Rashbaum). CK elevations than those produced by exercise alone, suggest- No commercial party having a direct financial interest in the results of the research ing exacerbation of skeletal muscle injury by statins.7 Myalgia supporting this article has or will confer a benefit upon the author(s) or upon any or myositis symptoms may include aching, cramping, weak- organization with which the author(s) is/are associated. ness, exhaustion, joint pains, and occasionally mild tempera- Reprint requests to Jeffrey A. Strommen, MD, Mayo Clinic, Dept of PM&R, 2200 First St SW, Rochester, MN 55905, e-mail: strommen.jeffrey@mayo.edu. ture elevations.6,8 Muscle symptoms tend to present in the 0003-9993/05/8603S-9665$30.00/0 pectoralis muscles, quadriceps, and, to a lesser extent, the doi:10.1016/j.apmr.2004.12.005 biceps and abdominal musculature; however, the masseters and Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
  2. 2. DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen S19 lower back muscles may also be involved.6 Although relatively quent follow-up visit, and obtaining a CK level with onset of rare and not statistically higher when compared with placebo in muscle soreness, tenderness, or pain.5 controlled studies, myalgias have been reported to contribute to 6% to 25% of all adverse events associated with statin use, yet 3.2 Clinical Activity: To clarify the cause of continued labeling information reports incidence rates of 1% to 5%.4 The weakness in a 43-year-old man being treated with exact incidence of statin-induced muscle injury may be under- prednisone for polymyositis. estimated because many of the symptoms are not associated with CK elevations and may be incorrectly attributed to other Within the group of inflammatory myopathies, polymyositis etiologies.6 Weakness frequently occurs with clinically impor- is the most commonly encountered, generally presenting with tant myositis and rhabdomyolysis, but can also present with slowly progressive, predominantly proximal weakness. Dys- little or no CK elevation.4 The overall frequency of statin- phagia is common, but other bulbar symptoms are absent, and associated weakness is not reported,4 but a recent study of 4 it lacks a clear, fatigable component that would be seen with patients with normal CK levels found hip abduction strength disorders of neuromuscular transmission. decreased by 10% to 47% and hip flexion strength decreased by In this case scenario, the patient is being treated with corti- 5% to 47%.8 The natural history of muscle side effects of costeroids for the diagnosis of polymyositis and shows pro- statins is uncertain, because the medication is typically with- gressive weakness despite treatment. The potential reasons for drawn with onset of symptoms or CK elevations, resulting in decline include: (1) inadequate treatment of the inflammatory rapid remission of symptoms.6 myopathy; (2) an alternative myopathy or neuropathic condi- Patients should be educated about the signs and symptoms of tion that would not respond to corticosteroids; and (3) a steroid muscle side effects when initiating statins, and the onset of any induced myopathy. Electrodiagnosis serves a crucial role in symptoms should prompt CK measurement.5 Baseline lipid differentiating these processes. profiles, liver function tests, and CK are generally recom- In most inflammatory myopathies, there is destruction of mended.5 Routine laboratory monitoring of CK is of little muscle fibers, resulting in the typical electromyography find- value,5 and normative CK values may not exclude myopathy.3 ings, although these findings may vary enormously, depending Patients who experience muscle symptoms should also be on the severity, distribution, and duration of the disease. The advised to moderate physical activity, especially with combi- major electromyographic changes are caused by segmental nation lipid-lowering therapy.5 injury to and loss of muscle fibers from the motor unit in In severe myopathy, muscle biopsies may find a noninflam- scattered areas of the muscle. Motor unit action potentials matory process with focal degeneration of myocytes and for- (MUAPs) become shorter in duration and lower in amplitude, mation of vacuoles, with evidence of mitochondrial dysfunc- and the amount of this change increases with the severity of the tion including abnormally increased lipid stores and signs of a disease. As muscle fibers are lost from individual motor units, defect in mitochondrial respiratory chain funtion.6,8 Biopsies of the force exerted on activation is reduced. To produce the same patients with myositis have demonstrated polymyositis and force, more motor units must be activated, which can be myolysis.4 Muscle biopsy findings of patients with pain but referred to as rapid or early recruitment. The spotty character of normal CK levels are normal under both light and electron these changes is striking, especially in comparison with other microscopy.6 forms of myopathy. Some areas of muscle may show an If a patient on a statin presents with muscle complaints, with entirely normal MUAP population whereas others show or without CK elevations, other causes, including strenuous marked changes, generally most prominent in proximal mus- exercise or hypothyroidism, must be considered.4,5,7 If a patient cles, especially paraspinal muscles. initially has normal or only moderately elevated CK levels, the Fibrillation potentials are typical, representing muscle fibers statin may be continued with close monitoring of symptoms that have lost innervation from segmental necrosis or fiber and CK levels; however, if symptoms become intolerable or if splitting. They tend to fire at slower rates than those in neuro- the CK level is 10 times the ULN or greater, the statin must be genic disorders. The frequency of fibrillation potentials and the discontinued.4,5 If myositis is present or strongly suspected, the severity of MUAP changes increase with the severity of the statin should be discontinued immediately.5 Early diagnosis myositis and are further modified by the disease duration. and treatment of symptomatic CK elevations, including cessa- Fibrillation potentials become less prominent as the disease tion of drug therapies potentially related to myopathy, can improves with treatment. Chronic myositis shows more exten- prevent progression to rhabdomyolysis.2 Symptoms and CK sive MUAP changes. In some patients MUAPs become mark- levels should resolve completely before reinitiating therapy, at edly polyphasic with time; this occurrence is associated with an a lower dose if possible.5 Asymptomatic elevation of CK at 10 increase in fiber density, suggesting that fibers become rein- times the ULN or greater should also prompt discontinuation of nervated by nerve sprouting within the motor unit. As this the statin.5 Consideration should also be given to discontinua- process progresses, the MUAP can increase in duration and tion of statins before events that may exacerbate muscle injury, develop satellite potentials. Myotonic discharges and complex such as surgical procedures or extreme physical exertion.4 repetitive discharges may also be seen. Prominent abnormal Needle electromyography abnormalities are uncommon in spontaneous activity is characteristic of most active inflamma- statin-induced myopathy, and a normal electromyogram tory myopathies and distinguishes these from most other my- (EMG) does not exclude statin-induced myopathy, because it opathies. However, as with any needle electromyographic primarily affects type II muscle fibers.6 Electromyography is changes, these are not specific and may also occur in other not routinely performed or recommended unless the clinical myopathies such as acid maltase deficiency or after rhabdomy- presentation does not improve with statin discontinuation or if olysis. The electromyographic interpretation of an inflamma- concern exists about other diagnoses. tory myopathy must therefore always include the comment that General recommendations for monitoring statin side effects a limited group of other myopathies may have similar findings, are available.2,5 These include evaluation of muscle symptoms naming those that are most appropriate clinically. Nerve con- and CK level prior to starting a statin, evaluation of muscle duction studies (NCSs) usually show little change in myositis, symptoms 6 to 12 weeks postinitiation and with each subse- although the compound muscle action potential (CMAP) am- Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
  3. 3. S20 DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen plitude may be reduced in those muscles in which there has erations would be myasthenia gravis (MG), multiple sclerosis, been sufficient muscle fiber damage or loss. stroke, multiple cranial neuropathies, myopathy, polyradiculo- The differentiation between a myopathic and neuropathic neuropathy, or a nonorganic disorder. The temporal pattern of condition is relatively straightforward although in very chronic onset in conjunction with the pattern of weakness and associ- myopathies, the progressive reinnervation of regenerated fibers ated sensory symptoms generally makes the clinical diagnosis will produce significant numbers of polyphasic, long duration, more certain. This patient reports absence of sensory symp- high amplitude MUAPs. Observing the recruitment pattern will toms, gradual onset, and increased weakness with activity. generally be helpful in this setting with rapid recruitment noted Physical examination reveals weakness in proximal more than in a myopathy and reduced recruitment in a neuropathic dis- distal muscles, with worsening during repetitive maximal con- order. traction. Reflexes and sensation are normal. The history and One must also consider alternative myopathies that may not examination would strongly suggest MG, with the most unify- be responsive to corticosteroids. This is particularly true of ing clinical feature of fatigable weakness. muscular dystrophies or inclusion body myositis, an increas- Diplopia or ptosis is present in 50% of patients with MG at ingly recognized myopathy. The latter is generally insidious presentation, and eventually 90%. There may be associated onset after the age of 50 years and has a relatively characteristic dysphagia or dyspnea.14,15 Research has identified that this is pattern of weakness involving the quadriceps and tibialis an- an immunologic process: immunoglobulin G antibodies di- terior as well as a predilection for proximal muscles and the rected against the postsynaptic acetylcholine (ACh) receptors long finger flexors.9 Because the condition is chronic, there is are found in 80% to 90% of patients.16 This, in turn, leads to a pattern on needle electromyography of mixed motor unit ultrastructural changes including reduced nerve terminal area, potentials, with long-duration, high-amplitude polyphasic and simplification of the postsynaptic folds with sparse sec- MUAPs as well as typical myopathic potentials. Given the ondary synaptic clefts that are shallow or abnormally wide.14 large MUAPs, this condition can frequently be misdiagnosed With appropriate electrodiagnostic testing, one can usually as a motoneuron disease (MND). When large MUAPs are determine whether the disorder is presynaptic or postsynaptic, found, it is important to search for small MUAPs as well so as define the severity, exclude other neuromuscular conditions, not to mistakenly suggest a diagnosis of MND. and follow the disease course. A clear understanding of the Most commonly, the question is raised to distinguish be- anatomy and neurophysiology of the neuromuscular junction tween ongoing inflammation and steroid myopathies. As dis- (NMJ) is crucial to obtaining and interpreting the electrodiag- tinct from previously described electromyographic findings, nostic data. Despite their complexity, the neuromuscular dis- those with steroid myopathies may still have myopathic orders are among the most understood neurologic conditions, MUAPs from the known underlying polymyositis but will have with clearly defined pathophysiology and histology. The evo- significantly less or no abnormal spontaneous activity. This lution of specialized electrodiagnostic techniques has added to distinction can be difficult, but if compared with previous this understanding and allows accurate diagnosis of most dis- electromyographic findings, the etiology is usually clear. The orders of neuromuscular transmission. clinical distinction can also be difficult, but in steroid myopa- The NMJ is composed of the presynaptic nerve terminal and thies the onset is generally gradual, following a period of clear membrane, the synaptic cleft, and the postsynaptic membrane. response to treatment of the polymyositis. Laboratory evalua- The presynaptic region is responsible for the synthesis, storage, tion can also be helpful, with a further increase in muscle and release of ACh in response to depolarization. Within this enzymes suggesting inadequate treatment of the inflammatory structure are specialized double parallel rows of particles at the myopathy. Serial urine creatine can also be measured, given presynaptic membrane, directly opposite the postsynaptic junc- that increased urine secretion is associated with steroid myop- tional folds. These particles are termed active zones, and rep- athies versus a stable urine level in polymyositis.10 Finally, resent areas of concentrated ACh release. When an action muscle biopsy may be performed. potential arrives, calcium influxes leading to the release of In those treated with corticosteroid for other nonmyopathic several quanta of ACh into the synaptic space, which is com- conditions, the incidence of steroid myopathies varies between posed of the primary cleft and the secondary cleft (junctional 2.4% and 21%.11 The clinical presentation is generally a grad- folds). Approximately 25% to 50% of the ACh is hydrolyzed ual onset of proximal weakness. It is usually not associated by acetylcholinesterase (AChE) that is present in the synaptic with steroid use for less than 4 weeks, is more common with cleft, with the remainder binding to the ACh receptors on the fluorinated glucocorticoids, and is often associated with other postsynaptic membrane. When 2 molecules bind to the recep- steroid effects such as hypertension, hyperglycemia, osteopo- tors, there is a conformational change leading to an influx of rosis, fragile skin, a “buffalo hump,” or electrolyte abnormal- sodium and the generation of an endplate potential with an ities.10 The mechanism of weakness is postulated to be caused amplitude of 40 to 60mV. Because the threshold to depolarize by type II fiber atrophy as a result of impaired muscle and the muscle membrane is only 15 to 25mV, there is 3 to 4 times carbohydrate metabolism.11,12 As the initial MUAPs recruited the depolarization necessary for the development of an action during needle electromyography are type I fibers, electrodiag- potential. This is referred to as the safety factor. Any patho- nostic abnormalities may not be apparent unless the process is logic process that reduces the safety factor will lead to failure very severe. Thus, a normal EMG does not exclude steroid of neuromuscular transmission, which correlates with the clin- myopathy. Treatment in this setting includes dose reductions, ical and electrophysiologic characteristics of these diseases.17 converting to nonfluorinated glucocorticoids, exercise, and Repetitive stimulation is the mainstay of the electrophysi- avoidance of starvation.10,11,13 ologic evaluation of NMJ disorders. In normal physiologic conditions, there is a gradual reduction of the quantal content 3.3 Clinical Activity: To establish an electrodiagnostic because of depletion of the immediately available stores of and treatment plan for a 34-year-old woman with ACh. Although the endplate potential shows a reduction during diplopia and dysphagia. the first several stimuli, the safety factor is several fold higher than threshold, thus, the action potentials continue to be prop- The differential diagnosis of dysphagia is relatively broad, agated in an all-or-nothing fashion with no change in the but, in the setting of diplopia, the primary diagnostic consid- CMAP amplitude. However, in disease states, there may be a Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
  4. 4. DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen S21 In MG, the resting CMAP amplitude is generally normal, although this can be reduced in severe cases. Three phenomena are most important to be aware of in repetitive stimulation: decrement, repair, and postactivation exhaustion. With repeti- tive stimulation, the typical amplitude decrement is a smooth pattern of decline, which becomes maximal at the fourth or fifth response but has the greatest relative reduction between the first and second responses (fig 1). If stimulation were continued past the fifth response, there would be stabilization, presumably associated with mobilization of ACh stores. If the decrement is not smooth or the major decrement does not occur between the first and second responses, this should be attrib- uted to technical factors until proven otherwise (see fig 1). Immediately after brief exercise, there should be at least partial repair of the decrement, characterized by return of the CMAP Fig 1. Two-hertz repetitive stimulation showing (A) a mild decre- to the baseline amplitude of the first response in the train. ment with characteristic pattern; (B) a more severe defect of neu- During the 2 to 4 minutes after exercise, there is postactivation romuscular transmission; (C) a technical error (note the decrement is not smooth with the drop occurring after the second stimulus); exhaustion that will again show a smooth decrement that may and (D) a technical error with fourth response—it must be repeated exceed that at rest (fig 2). A consistent decrement of greater to determine whether the apparent decrement of the previous re- than 10% in 2 nerves with typical repair and postexercise sponses is reproducible. exhaustion is necessary to support the diagnosis.18 In MG, there may be decrement at rest if more severe disease or decrement after exercise (generally 1min) in more mild dis- ease. reduced quantal content or impaired response of the AChE. In The sensitivity of repetitive stimulation is dependent on the this situation, the endplate potential will become subthreshold muscles examined and the degree of clinical weakness. Prox- in some fibers, leading to fewer summated responses, reflected imal muscles tend to show relatively greater involvement, as a reduced CMAP amplitude. This is the main principle possibly caused by warmer core temperature, which destabi- behind interpretation of repetitive stimulation studies. By as- lizes the NMJ (fig 3). Özdemir and Young19 reported that if sessing the baseline values and response to exercise, one can only the abductor digiti minimi (ADM) is examined, the like- characterize the disorder with high diagnostic accuracy. Repet- lihood of obtaining a diagnostic result is 59%. However, the itive stimulation can be technically challenging, potentially deltoid showed abnormalities in 82% and the orbicularis oculi leading to misinterpretation and erroneous diagnosis. A clear in 62.5%. When these muscles and the wrist flexors were understanding and proficiency in use of these techniques is considered together, a positive test was identified in 95% of absolutely essential for accurate interpretation. patients.19 The needle examination generally only shows Fig 2. Two-hertz repetitive stimulation to the ulnar, spi- nal accessory, and facial nerves in MG. Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
  5. 5. S22 DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen Fig 3. Two-hertz repetitive stimulation showing myas- thenia gravis; each tracing represents 4 superimposed responses. Note the signifi- cant decrement with proximal studies as compared with the ulnar nerve. Adapted with permission.17 MUAP variation in weak muscles and, occasionally, a second- tract hyperactivity and increased respiratory secretions. Vari- ary myopathy in more severe or longstanding cases. Single ous immunosuppressants are also used to sustain remissions. fiber is the most sensitive technique, showing abnormalities in The first choice is generally corticosteroids followed by aza- up to 99%, depending on which muscles are examined. The thioprine, cyclophosphamide, and cyclosporine. All of these technique, however, is relatively nonspecific in that significant carry the risk of immunosuppression and may increase the risk jitter and blocking can be seen in other disorders, particularly of malignancy, but are generally effective in sustaining remis- more rapidly progressive neurogenic disorders such as MND.20 sions. Mycophenolate mofetil (CellCept) and methotrexate are Finally, the acetylcholine antibody titer is abnormal in approx- also being evaluated and used for treatment. Finally, plasma- imately 90% of patients with MG.16,21 A normal antibody titer, pheresis is an effective short-term therapy for severe weakness however, does not exclude MG, because the sensitivity in those especially in the setting of a recent exacerbation or to offset the with pure ocular symptoms is only 65%. worsening that can be seen with the initiation of corticoste- In this case, there was no significant decrement to 2-Hz repetitive stimulation when recorded over the ADM, but there roids. Because there is an association between thymoma and was a consistent pattern of decrement with at least partial repair MG, thymectomy may be indicated for those who are under the when recorded over the trapezius muscle and a facial muscle age of 60 years and have generalized weakness and for persons (see fig 2). The neurologic examination revealed no abnormal with a thymoma.15 spontaneous activity and varying MUAP morphology of the same MUAP without other morphologic changes primarily in 3.4 Clinical Activity: To coordinate the electrodiagnostic proximal muscles. The electrodiagnostic testing in conjunction and treatment protocol for a 23-year-old man with with positive ACh receptor antibodies would confirm the di- weakness of the hands and feet, and difficulty with agnosis of MG. grasp relaxation. The initial pharmacologic management of MG is with cho- linesterase inhibitors such as pyridostigmine bromide (Mesti- The history of difficulty with grasp relaxation is character- non) or neostigmine methylsulfate (Prostigmin), the former istic of a myotonic disorder, and the presence of clinical beginning at doses of 15 to 60mg every 4 to 6 hours, with the weakness would suggest a disorder with both myotonia and a dosage and dosage interval gradually increased to maximal myopathy. The potential etiology of myotonia is relatively response. The most common side effects are gastrointestinal broad but with other clinical features, such as weakness and, Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
  6. 6. DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen S23 Table 1: Clinical and Electrophysiologic Characteristics of the Common Myotonic Disorders Characteristic Myotonic Dystrophy Myotonia Congenita Paramyotonia Congenita PROMM Inheritance type Autosomal dominant Autosomal dominant Autosomal dominant Autosomal (Thomsen’s), dominant Autosomal recessive (Becker’s) Weakness pattern Distal initially, generalized late, Generally no weakness, Generally none Proximal “Hatchet face” muscle hypertrophy, “Herculean” Extramuscular features Frontal balding, testicular None None Cataracts atrophy, DM, cataracts, cardiac arrhythmias, dysphagia, alveolar, hypoventilation, cognitive Myotonia pattern Distally/grip More generalized Distally predominant Proximal Exercise effect Reduced myotonia Reduced myotonia Reduced myotonia Reduced myotonia weakness Cold sensitivity Increased myotonia Increased myotonia Increased myotonia, Usually not severe weakness worsened CMAP May be low Normal Normal at rest Normal RNS pattern Rest Decrement Decrement May decrement No decrement Brief exercise Decreased CMAP Decreased CMAP Abrupt fall in CMAP No change Cooling No change No change Falls to zero with No change cooling Needle exam findings May have discharges None With cooling Occasional small Fibrillation potentials Small, polyphasics Normal Normal Scattered MUAPs Distally predominant Faster, shorter, diffuse Diffuse No clear change Myotonia Increased mytonia Increased mytonia Electric No clear change Cooling Reduced myotonia Reduced myotonia silence/paralysis Exercise Increases myotonia Postexercise fibrillation potentials Abbreviations: DM, diabetes mellitus; PROMM, proximal myotonic myopathy; RNS, repetitive nerve stimulation. more important the pattern of weakness, the differential diag- Most myotonic disorders have a relatively typical response nosis can be narrowed (appendix 1). to repetitive stimulation characterized by a decremental re- Electrophysiologically, myotonic discharges are characterized sponse at rest that is very similar to that seen in NMJ disorders by a waxing and waning of amplitude and frequency that is often but differs physiologically in that it is likely caused by mem- described as a “dive bomber.” They are regular in rhythm but vary brane inactivation.23,24 There is also a repair after brief exer- in frequency between 2 and 100Hz and are generally triggered by cise, but, in contrast to NMJ disorders, there is a clear reduction needle movement, percussion, or muscle contraction.22 When of the CMAP amplitude immediately after exercise. This phe- sustained and of higher frequency, the discharges are easily iden- nomenon is seen in most myotonic disorders except proximal tified, but when slow, they may be mistaken for fibrillation po- myotonic myopathy, which, in conjunction with the proximal tentials. Myotonia varies with temperature, increasing with cool- pattern of weakness, is a characteristic that distinguishes this ing and decreasing with warming as well as with muscle activity; disorder.25 the exception is in paramyotonia congenital, in which the response Prolonged exercise has a variable effect on the CMAP to temperature is just the opposite. They may take either positive amplitudes, depending on the condition, and is especially or spike waveforms, depending on how the needle electrode is useful in distinguishing paramyotonia congenita from other positioned in relation to the muscle fiber. disorders. In paramyotonia congenita, as well as in periodic In this scenario, there is clear weakness in addition to the paralysis, paresis can be induced with prolonged exercise myotonia, which reinforces the suspicion of a distally pre- (5min), characterized by a reduction of the CMAP amplitude dominant myopathy, most likely myotonic dystrophy (ap- of more than 40% over 20 to 40 minutes.23 Finally, muscle pendix 2). Electrodiagnostic testing is important to better cooling will have variable effects, depending on the condi- define the degree and pattern of myotonia as well as to tion. Although cooling increases myotonia in all these con- define whether there is an associated myopathy. Addition- ditions, only paramyotonia congenital features prominent ally, specialized techniques, such as repetitive stimulation, and prolonged weakness after cooling. During moderate response to cooling, or response to exercise, will generally cooling, intense fibrillation potentials may occur before all confirm the diagnosis. Table 1 describes the clinical and activity ceases. The pathophysiologic basis of this phenom- electrophysiologic abnormalities of the most common myo- enon with cooling is an altered sodium conductance with or tonic disorders. without a change in chloride conductance. Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
  7. 7. S24 DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen Needle electromyography will reveal short-duration, Residency Review Committee of the Accreditation Council for polyphasic MUAPs with rapid (early) recruitment in myotonic Graduate Medical Education.30 dystrophy, and is the most reliable electromyographic criterion It is vital for the insurance carrier to understand that these for differentiating this disorder from myotonia congenita. Ma- factors are important because “the electrodiagnostic consulta- jor changes in MUAPs are not seen in myotonia congenita, but tion is actually an extension of the neurologic portion of the the MUAP amplitude may gradually decrease with repeated physical examination.”28 Unlike many radiologic or laboratory firing. It must be reemphasized, however, that myotonic dis- tests, electrodiagnostic testing must be individualized to fit the charges are not specific for these conditions, because similar specific clinical circumstances. The test is interpreted in real findings can be seen in the other conditions as well (see time, and, frequently, the results of specific parts of the test will appendix 1). Electrodiagnostic testing will generally lead to the dictate which nerves and muscles are tested next. For these reasons the test must be designed, performed, and interpreted correct diagnosis. Genetic testing will generally confirm the by a physician with expertise in electrodiagnosis. diagnosis. Under certain circumstances, the physiatrist may directly Currently, there is no scientifically proven pharmacologic supervise a technician to perform portions of the examination, treatment to increase muscle strength in myotonic dystrophy. with the physician deciding which nerves to study and that Clinical myotonia can be treated with agents such as phenytoin, physician must be available to confirm the results. mexiletine, acetazolamide, tocainide, carbamazapine, or lam- While NCSs can be reviewed after the study, the needle otrigine, but many of these can have untoward cardiac effects electromyography portion of the study cannot be delegated and and probably should be avoided in myotonic dystrophy.26 They should be performed entirely by the physician. It is impossible may be of more benefit in myotonia congenita or other chan- to capture all of the information from an electromyography nelopathies that may present with cramps. Education on exer- study on a printout or recording, and many study interpreta- cise and avoidance of cold is key to treatment. Use of appro- tions are based on the electrodiagnostic experience and knowl- priate orthosis and gait aids can assist ambulation. The patient edge of the electrodiagnostic consultant. Judgments about from should be instructed on stretching, particularly muscles of the which muscle the tip of the needle is recording and whether the lower extremities that cross 2 joints. Dysphagia is relatively muscle is at rest or voluntarily contracting can only be made in common and careful screening with appropriate aspiration pre- person. cautions and dietary modification may be necessary. Pulmo- In addition to the technical and educational factors that nary function tests should be followed with the possible need physiatrists possess, there are additional attributes that make for noninvasive ventilatory assistance as well as serial electro- them uniquely qualified to perform electrodiagnostic studies in cardiograms, given the association with cardiac conduction a workers’ compensation setting. Physiatrists diagnose NMDs defects. Because myotonic dystrophies are an inherited disor- and have extensive experience in the musculoskeletal condi- der, assistance with family planning decisions is important. tions that can mimic neurologic disorders. For example, they can help evaluate whether shoulder weakness is caused by a 3.5 Educational Activity: You are a physiatrist seeking musculoskeletal disorder or a root, plexus, or peripheral nerve enrollment to perform electrodiagnostic studies from lesion. The specialty of PM&R emphasizes functional restora- a workers’ compensation carrier. Explain your tion, and, occasionally, the physiatrist may try various thera- unique qualifications to perform such studies. peutic interventions prior to performing electrodiagnostic test- ing, because a positive therapeutic response may have both Physiatrists are uniquely qualified to perform electrodiag- diagnostic and therapeutic value. nostic studies. Unfortunately, despite years of effort on the part For example, when a patient presents with anterolateral thigh of physiatric associations, a lack of knowledge persists in the dysesthesias without weakness, possibly from lateral femoral health insurance carrier industry about physiatry and the diag- cutaneous nerve entrapment, a corticosteroid injection initially, nostic potential of electrodiagnostic studies. with symptom resolution postinjection, would have similar As a physiatrist seeking enrollment with a carrier, one diagnostic value to electrodiagnostic testing. More important, it should explain that electrodiagnostic consultations are medical would provide pain relief and functional restoration. consultations and should be performed only by physicians with In summary, the physiatrist must explain to the insurance expertise in this area. One should prepare an information carrier that he/she possesses the education, training, knowl- packet for the carrier, including the American Association of edge, and experience that are specifically required to perform Electrodiagnostic Medicine’s publications27,28 on educational electrodiagnostic studies in the workers’ compensation area. requirements for the practice of electrodiagnostic medicine. The physiatrist can illustrate the exceptional qualifications he/ The electrodiagnostic medicine consultant should be a physi- she has, and cite numerous position statements from recog- cian who has specialized training in the diagnosis and treatment nized medical groups to help educate the carrier in its choice of neurologic diseases and neuromuscular disorders (NMDs). among the medical specialties. He/she must also be an expert in the application of particular neurophysiologic techniques unique to the study of these dis- 3.6 Clinical Activity: To formulate a clinical and electro- orders. This type of training is provided during the residency or diagnostic evaluation for a 66-year-old female smoker fellowship programs of physicians who specialize in physical with difficulty climbing stairs. medicine and rehabilitation (physiatrists) or in neurology (neu- rologists).29 The clinical complaint of weakness is very common, with a In most PM&R residencies, the resident is required to per- differential diagnosis that includes NMDs, musculoskeletal form a minimum of 200 supervised studies and to attend formal disorders, deconditioning, or cardiopulmonary diseases. The lectures on multiple electrodiagnostic topics. On completion of most common NMDs in this age group would be myopathies, a physical medicine and rehabilitation residency program, the lumbosacral radiculopathies, MND, or disorders of neuromus- physician has gained training in the basic sciences necessary to cular transmission. Obtaining an accurate history and physical understand neurophysiology and has had clinical experience in examination will generally narrow the differential diagnosis electrodiagnosis, as well. This training is a requirement of the and help focus the electrodiagnostic evaluation. On further Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
  8. 8. DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen S25 Fig 4. Two-hertz repetitive stimulation to the ulnar and femoral nerves in a 66-year- old patient with Eaton-Lam- bert myasthenic syndrome. Adapted with permission.17 questioning, this patient reports a lack of sensory symptoms, amplitude, represents the summated activity of all muscle fi- and physical examination shows no fasciculations and rela- bers stimulated. If the endplate potentials in some of these tively greater weakness in proximal muscle groups of the limbs fibers fail to reach threshold, the summated CMAP will be of but no weakness in bulbar muscles. This would make radicu- lower amplitude and area. This pattern correlates with the lopathies unlikely. Further, on examination, deep tendon re- clinical complaints of weakness and with the electrodiagnostic flexes are found to be absent, making MND less likely. finding of blocking, which is manifested on needle electromyo- As an extension of the neurologic examination, electrodiag- graphy as MUAP variation. Repetitive stimulation at 2 to 3Hz nostic testing is especially critical for those disorders that will lead to a decrement in the CMAP amplitude. Immediately present with weakness, particularly in this setting where clin- after brief exercise, there should be at least partial repair of the ical examination cannot clearly determine the cause. With decrement, characterized by return of the CMAP to the base- appropriate electrodiagnostic testing, one can determine line amplitude of the first response. In a presynaptic disorder whether the process is myopathic, neuropathic, or related to an such as Lambert-Eaton myasthenic syndrome, exercise will NMJ disorder, which can be further defined as to whether the lead to a significant CMAP facilitation. Although this syn- process is presynaptic or postsynaptic. A clear understanding drome is the most common presynaptic disorder, this pattern of of the anatomy and neurophysiology of the NMJ is crucial to findings could also be seen, to a lesser degree, with botulism. obtaining and interpreting the electrodiagnostic data. The Lambert et al31 initially described this syndrome in 1956 in reader is encouraged to refer to neurophysiology texts for more 3 patients with malignant tumors in the chest. Its typical extensive review. clinical characteristic is weakness that is predominantly prox- In this case (fig 4), baseline repetitive stimulation at rest imal but with significantly less bulbar involvement than myas- recorded over the first dorsal interosseous muscle revealed a thenia gravis. Deep tendon reflexes are markedly reduced or low amplitude CMAP with decrement of 20% between the first absent throughout. Muscle strength is potentiated by exercise, and fourth responses. Brief (10-s) exercise led to a significant as are reflexes, which distinguishes this from a postsynaptic increase of the CMAP to 2 times its baseline value, a 200% deficit where there is clearly fatigable weakness and relative facilitation (or 100% increment). This pattern of facilitation, to preservation of reflexes (table 2). There may also be significant a much greater degree, was reproduced when recorded over the dysautonomia characterized by dry eyes and dry mouth as well rectus femoris with percutaneous femoral nerve stimulation. as occasional sensory involvement. Constitutional symptoms Median and sural sensory NCSs were normal. Needle exami- are common, because the disease is associated with malignancy nation revealed varying motor unit potentials but no abnormal in 60% to 70% of cases (most commonly small cell lung spontaneous activity. cancer) and with connective tissue diseases, especially in wom- Three terms are particularly important in assessing NMJ en.32 disorders: endplate potential, blocking, and repair. The under- The electrophysiologic abnormalities can be predicted by the lying mechanism of all neuromuscular junction disorders is a pathophysiology, which features a reduced endplate potential, reduced safety factor leading to failure of an endplate potential because of impaired quantal release of ACh from the presyn- to produce an action potential in some muscle fibers. In elec- aptic terminal in response to a nerve impulse. This phenome- trodiagnostic testing, this can be readily assessed by evaluating non was supported by freeze-fracture studies that revealed a the CMAP at rest and can be further classified based on the marked decrease in active zones and active zone particles per response to exercise. The CMAP area, and to a lesser extent the unit area, suggesting that the presynaptic release sites are the Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
  9. 9. S26 DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen Table 2: Differentiating Characteristics of MG and Eaton-Lambert Myasthenic Syndrome Characteristics MG Eaton-Lambert Myasthenic Syndrome Clinical finding Limb weakness Proximally predominant Proximal but more diffuse Bulbar weakness Common Less common Repetitive contraction Fatigable Potentiates strength Sensory Normal May be involved Reflexes Normal Reduced, potentiated with exercise Dysautonomia Absent Present Pathophysiology Site Postsynaptic Presynaptic Antibody Acetylcholine receptor P/Q-type voltage-gated calcium channel Repetitive nerve stimulation Baseline CMAP Normal Reduced Decrement at rest None at rest if mild Usually Brief exercise (10s) Repair if decrement at rest Facilitation 1 minute exercise Repair if decrement at rest May miss facilitation 2–5 min postexercise Postexercise exhaustion Postexercise exhaustion Needle electromyography Fibrillation potentials Rare unless severe Rare unless severe MUAPs Varying (more at higher rates) Varying (less at higher rates) Occasionally myopathic Occasionally myopathic targets of the pathologic process.33 It was experimentally im- APPENDIX 1: CONDITIONS THAT MAY HAVE plicated by Lennon and Lambert32 that there was a tumor- MYOTONIC DISCHARGES associated, voltage-gated, calcium-channel, autoimmunizing stimulus. The antibody binding to calcium channels leads to Myotonic dystrophy (Steinert’s)* inhibited entry of calcium into the nerve terminal, with conse- Myotonia congenita* quent reduced quantal release, a subthreshold endplate poten- Thomsen’s (autosomal dominant) tial, and resultant clinical weakness. Brief exercise or repetitive Becker’s (autosomal recessive) stimulation at rates of 30 to 50Hz leads to flooding of the Paramyotonia (von Eulenberg)* presynaptic terminal with calcium, resulting in potentiation of Chondrodystrophic myotonia (Schwartz-Jampel)* the quantal content with a significant increase in the endplate potential, correlating with improvement in strength on repeti- Acid maltase deficiency tive contraction.33 This is the principle of electrodiagnostic Inflammatory myopathies testing in which the endplate potential is significantly reduced Proximal myotonic myopathy during stimulation at rest and falls further below the safety Statin myopathy factor during slow rate repetitive stimulation leading to a Amyloid decremental response of the CMAPs. Brief exercise, then, Hyperkalemic periodic paralysis leads to facilitation of the response, generally regarded as diagnostic if there is a doubling of the response in at least 2 Normokalemic periodic paralysis nerve-muscle pairs.17,34 In contrast to MG, these abnormalities Hypokalemic periodic paralysis in Lambert-Eaton myasthenic syndrome are more prominent in Hypothyroid myopathy distal muscles (abductor digiti quinti, abductor pollicis brevis, Potassium sensitive myotonia extensor digitorum brevis) than in proximal muscles such as Centronuclear myopathy the trapezius.35 Recording over the rectus femoris with percu- Chronic neurogenic disorders (rarely) taneous femoral nerve stimulation may also be helpful as in this Drugs (eg, clofibrate, diazocholesterol, 2, 4 D) case. Table 2 outlines the clinical and electrophysiologic fea- tures that can help distinguish MG from Lambert-Eaton myas- Paraneoplastic syndromes thenic syndrome. The evaluation of possible Lambert-Eaton myasthenic syn- *Clinical myotonia. drome consists of neoplastic search including computerized tomography of the chest and abdomen, as well as gynecologic APPENDIX 2: MYOPATHIES WITH evaluation and breast examination/mammography in women. DISTAL WEAKNESS Serum antibody testing will reveal antibodies to P/Q-type volt- Late adult 1 (Welander’s) age-gated calcium channels in more than 90% of patients.36 Late adult 2 (Markesbury/Udd) Treatment generally involves removal of the tumor, which will reverse the process in most cases. Pyridostigmine bromide Early adult 1 (Nonaka)-IBM2, distal myopathy with rimmed (Mestinon), which acts as a cholinesterase inhibitor, is gener- vacuoles-GNE mutations ally not helpful, but preliminary studies using 3,4 diaminopy- Early adult 2 (Miyoshi) rimidine, which increases channel opening time by blocking Early adult 3 (Laing) potassium channel conductance, has proved beneficial.37 Myofibrillar (Desmin) Arch Phys Med Rehabil Vol 86, Suppl 1, March 2005
  10. 10. DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen S27 Myotonic dystrophy of repetitive nerve stimulation and single fiber EMG in the Fascioscapulohumeral dystrophy, and other scapuloperoneal electrodiagnostic evaluation of patients with suspected patterns myasthenia gravis or Lambert-Eaton myasthenic syndrome. Oculopharyngeal muscular dystrophy Muscle Nerve 2001;24:1239-47. Inclusion body myositis 19. Özdemir C, Young RR. The results to be expected from electrical Debranching enzyme deficiency testing in the diagnosis of myasthenia gravis. Ann N Y Acad Sci 1976;274:203-22. Nemaline, acid maltase 20. Sanders DB, Stalber EV. AAEM Minimonograph #25: single- Central core fiber electromyography. Muscle Nerve 1996;19:1069-83. Centronuclear 21. Kelly JJ, Daube JR, Lennon VA, Howard FM Jr, Younge BR. References The laboratory diagnosis of mild myasthenia gravis. Ann Neurol 1. Expert Panel on Detection, Evaluation, and Treatment of High 1982;12:238-42. Blood Cholesterol in Adults. Executive Summary of the Third 22. Daube JR. AAEM Minimonograph #11: needle examination in Report of the National Cholesterol Education Program (NCEP) clinical electromyography. Muscle Nerve 1991;14:685-700. Expert Panel on Detection, Evaluation, and Treatment of High 23. Kuntzer T, Flocard F, Kohler A, et al. Exercise test in muscle Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA channelopathies and other muscle disorders. Muscle Nerve 2000; 2001;285:2486-97. 23:1089-94. *2. Ballantyne CM, Corsini A, Davidson MH, et al. Risk for myop- 24. Aminoff MJ, Layzer RB, Satya-Murti S, Faden AI. The declining athy with statin therapy in high-risk patients. Arch Intern Med electrical response of muscle to repetitive nerve stimulation in 2003;163:553-64. myotonia. Neurology 1977;27:812-6. 3. Gotto AM Jr. Risks and benefits of continued aggressive statin 25. Sander HW, Scelsa SN, Conigliari MR, Chokroverty S. The therapy. Clin Cardiol 2003;26(4 Suppl 3):III3-12. short exercise test is normal in proximal myotonic myopathy. *4. Thompson PD, Clarkson P, Karas RH. Statin-associated myop- Clin Neurophysiol 2000;111:362-6. athy. JAMA 2003;289:1681-90. 26. Amato AA, Dumitru D. Hereditary myopathies. In: Dumitru DD, *5. Pasternak RC, Smith SC, Bairey-Merz CN, et al. ACC/AHA/ Amato AA, Awart M, editors. Electrodiagnostic medicine. 2nd NHLBI clinical advisory on the use and safety of statins. J Am ed. Philadelphia: Hanley & Belfus; 2002. p 1265-370. Coll Cardiol 2002;40:567-72. 27. Who is qualified to practice electrodiagnostic medicine? Position 6. Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statement. Muscle Nerve 1999;22(Suppl 8):S263-5. statins. J Cardiovasc Pharmacol 2002;40:163-71. 28. Qualifications of physiatrists to perform electrodiagnostic studies. 7. Thompson PD, Zmuda JM, Domalik LJ, Zimet RJ, Staggers J, Position statement. American Association of Electrodiagnostic Guyton JR. 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