Neuromuscular Rehabilitation and Electrodiagnosis. 3. Diseases of Muscles and Neuromuscular Junction

Transcription

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, Weiss LD, Weiss JM, Rashbaum IG. Neuromuscular rehabilitation and electrodiagnosis. 3. Diseases of muscles and neuromuscular junction. Arch Phys Med Rehabil 2005;86(3 Suppl 1):S This self-directed learning module highlights formation of a differential diagnosis as well as electrodiagnostic evaluation for those patients who present with the common complaint of weakness. It is part of the chapter on neuromuscular rehabilitation and electrodiagnosis in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on the common symptoms and typical clinical findings that allow the clinician to narrow the differential diagnosis. This is followed by the diagnostic evaluation, with emphasis on the technical aspects and interpretation of electrodiagnostic studies. Overall Article Objective: To summarize the clinical presentation and electrodiagnostic findings in persons with disorders of muscle or disorders of the neuromuscular junction. Key Words: Fatigue; Lambert-Eaton myasthenic syndrome; Muscle weakness; Myasthenia gravis; Myotonic dystrophy; Neuromuscular junction diseases; Polymyositis; Rehabilitation by the American Academy of Physical Medicine and Rehabilitation 3.1 Clinical Activity: To evaluate and manage a 68-yearold woman with recent coronary stenting who presents with thigh pain and thigh cramping. RISK-FACTOR ASSESSMENT AND modification are key components of primary and secondary prevention of cardiovascular events. This patient likely had elevated low-density lipoprotein (LDL) cholesterol and was subsequently placed on a cholesterol-lowering medication in accordance with recently published guidelines. 1 Multiple studies 2,3 have documented the benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors as a means of reducing both primary and secondary cardiovascular events, mortality from all causes, cardiovascular mortality, and stroke. This class of medications, known as From the Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN (Strommen); Department of Physical Medicine and Rehabilitation, Charlotte Institute of Rehabilitation, Charlotte, NC (Johns); Division of Child Development and Rehabilitation, Children s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA (Kim); Section of Physical Medicine and Rehabilitation, Philadelphia Veterans Administration Medical Center and University of Pennsylvania, Philadelphia, PA (Williams); Department of Physical Medicine and Rehabilitation, Nassau University Medical Center, East Meadow, NY (LD Weiss); Long Island PMR, Levittown, NY (JM Weiss); and Department of Rehabilitation Medicine, New York University Medical Center, New York, NY (Rashbaum). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Jeffrey A. Strommen, MD, Mayo Clinic, Dept of PM&R, 2200 First St SW, Rochester, MN 55905, strommen.jeffrey@mayo.edu /05/8603S-9665$30.00/0 doi: /j.apmr statins, is the most effective medication for managing elevated LDL. 4 Recent guidelines 5 for cholesterol management define a broad expansion of patients who are at high cardiovascular risk for whom statin use might be considered. As statin use becomes more prevalent, understanding its possible side effects and drug interactions becomes more important. Serious adverse events associated with statins in large randomized controlled trials are relatively rare ( 1%), but include liver enzyme elevation and myopathy. 2 The rates of muscular side effects for statins and placebo were each about 5% in these studies, 6 but these results may underestimate rates in general practice. 4 Inconsistent terminology may make comparisons among these studies difficult or impossible. Therefore, the recent Clinical Advisory on the Use and Safety of Statins 5 provides standardization of several definitions: myopathy is any muscle complaint; myalgia is muscle aching or weakness without serum creatine kinase (CK) elevations; myositis implies muscle symptoms accompanied by CK elevations; and rhabdomyolysis signifies muscle complaints with CK elevations 10 times the upper limits of normal (ULN) with creatinine elevation. 3,5 Clinically important myopathy with CK elevations greater than 10 times ULN is estimated to occur in approximately 0.1% of patients who receive statin monotherapy. Clinically important myopathy and rhabdomyolysis have been reported with all statins with an overall death rate of.15 per 1 million prescriptions. 2 The death rate for cerivastatin was 16 to 80 times greater than the other statins, leading to the manufacturer s withdrawal of that medication from the market in August Fatal rhabdomyolysis has been reported for all statins except fluvastatin. 2 Factors that increase risk for myopathy include advanced age, small body frame or frailty, multisystem disease, multiple medications, perioperative periods, and higher statin doses. 5 Drug-drug interactions have been suspected in about 50% of all cases of statin-related rhabdomyolysis, and the list of concomitant medications and foods that increase the risk of myopathy includes fibrates, cyclosporine, niacin, macrolide antibiotics, digoxin, protease inhibitors, some antifungals, 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 additional interactions at the excretion level as a consequence of competition for P-glycoproteins, recently recognized cellular membrane drug transport proteins. 2 Muscle side effects or complaints may occur at any time, but may be triggered by starting or increasing regular physical exercise, even after years of asymptomatic statin therapy. 5,6 Exercise in combination with lovastatin has produced greater CK elevations than those produced by exercise alone, suggesting exacerbation of skeletal muscle injury by statins. 7 Myalgia or myositis symptoms may include aching, cramping, weakness, exhaustion, joint pains, and occasionally mild temperature elevations. 6,8 Muscle symptoms tend to present in the pectoralis muscles, quadriceps, and, to a lesser extent, the biceps and abdominal musculature; however, the masseters and

2 DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen S19 lower back muscles may also be involved. 6 Although relatively rare and not statistically higher when compared with placebo in controlled studies, myalgias have been reported to contribute to 6% to 25% of all adverse events associated with statin use, yet labeling information reports incidence rates of 1% to 5%. 4 The exact incidence of statin-induced muscle injury may be underestimated because many of the symptoms are not associated with CK elevations and may be incorrectly attributed to other etiologies. 6 Weakness frequently occurs with clinically important myositis and rhabdomyolysis, but can also present with little or no CK elevation. 4 The overall frequency of statinassociated weakness is not reported, 4 but a recent study of 4 patients with normal CK levels found hip abduction strength decreased by 10% to 47% and hip flexion strength decreased by 5% to 47%. 8 The natural history of muscle side effects of statins is uncertain, because the medication is typically withdrawn with onset of symptoms or CK elevations, resulting in rapid remission of symptoms. 6 Patients should be educated about the signs and symptoms of muscle side effects when initiating statins, and the onset of any symptoms should prompt CK measurement. 5 Baseline lipid profiles, liver function tests, and CK are generally recommended. 5 Routine laboratory monitoring of CK is of little value, 5 and normative CK values may not exclude myopathy. 3 Patients who experience muscle symptoms should also be advised to moderate physical activity, especially with combination lipid-lowering therapy. 5 In severe myopathy, muscle biopsies may find a noninflammatory process with focal degeneration of myocytes and formation of vacuoles, with evidence of mitochondrial dysfunction including abnormally increased lipid stores and signs of a defect in mitochondrial respiratory chain funtion. 6,8 Biopsies of patients with myositis have demonstrated polymyositis and myolysis. 4 Muscle biopsy findings of patients with pain but normal CK levels are normal under both light and electron microscopy. 6 If a patient on a statin presents with muscle complaints, with or without CK elevations, other causes, including strenuous exercise or hypothyroidism, must be considered. 4,5,7 If a patient initially has normal or only moderately elevated CK levels, the statin may be continued with close monitoring of symptoms and CK levels; however, if symptoms become intolerable or if the CK level is 10 times the ULN or greater, the statin must be discontinued. 4,5 If myositis is present or strongly suspected, the statin should be discontinued immediately. 5 Early diagnosis and treatment of symptomatic CK elevations, including cessation of drug therapies potentially related to myopathy, can prevent progression to rhabdomyolysis. 2 Symptoms and CK levels should resolve completely before reinitiating therapy, at a lower dose if possible. 5 Asymptomatic elevation of CK at 10 times the ULN or greater should also prompt discontinuation of the statin. 5 Consideration should also be given to discontinuation of statins before events that may exacerbate muscle injury, such as surgical procedures or extreme physical exertion. 4 Needle electromyography abnormalities are uncommon in statin-induced myopathy, and a normal electromyogram (EMG) does not exclude statin-induced myopathy, because it primarily affects type II muscle fibers. 6 Electromyography is not routinely performed or recommended unless the clinical presentation does not improve with statin discontinuation or if concern exists about other diagnoses. General recommendations for monitoring statin side effects are available. 2,5 These include evaluation of muscle symptoms and CK level prior to starting a statin, evaluation of muscle symptoms 6 to 12 weeks postinitiation and with each subsequent follow-up visit, and obtaining a CK level with onset of muscle soreness, tenderness, or pain Clinical Activity: To clarify the cause of continued weakness in a 43-year-old man being treated with prednisone for polymyositis. Within the group of inflammatory myopathies, polymyositis is the most commonly encountered, generally presenting with slowly progressive, predominantly proximal weakness. Dysphagia is common, but other bulbar symptoms are absent, and it lacks a clear, fatigable component that would be seen with disorders of neuromuscular transmission. In this case scenario, the patient is being treated with corticosteroids for the diagnosis of polymyositis and shows progressive weakness despite treatment. The potential reasons for decline include: (1) inadequate treatment of the inflammatory myopathy; (2) an alternative myopathy or neuropathic condition that would not respond to corticosteroids; and (3) a steroid induced myopathy. Electrodiagnosis serves a crucial role in differentiating these processes. In most inflammatory myopathies, there is destruction of muscle fibers, resulting in the typical electromyography findings, although these findings may vary enormously, depending on the severity, distribution, and duration of the disease. The major electromyographic changes are caused by segmental injury to and loss of muscle fibers from the motor unit in scattered areas of the muscle. Motor unit action potentials (MUAPs) become shorter in duration and lower in amplitude, and the amount of this change increases with the severity of the disease. As muscle fibers are lost from individual motor units, the force exerted on activation is reduced. To produce the same force, more motor units must be activated, which can be referred to as rapid or early recruitment. The spotty character of these changes is striking, especially in comparison with other forms of myopathy. Some areas of muscle may show an entirely normal MUAP population whereas others show marked changes, generally most prominent in proximal muscles, especially paraspinal muscles. Fibrillation potentials are typical, representing muscle fibers that have lost innervation from segmental necrosis or fiber splitting. They tend to fire at slower rates than those in neurogenic disorders. The frequency of fibrillation potentials and the severity of MUAP changes increase with the severity of the myositis and are further modified by the disease duration. Fibrillation potentials become less prominent as the disease improves with treatment. Chronic myositis shows more extensive MUAP changes. In some patients MUAPs become markedly polyphasic with time; this occurrence is associated with an increase in fiber density, suggesting that fibers become reinnervated by nerve sprouting within the motor unit. As this process progresses, the MUAP can increase in duration and develop satellite potentials. Myotonic discharges and complex repetitive discharges may also be seen. Prominent abnormal spontaneous activity is characteristic of most active inflammatory myopathies and distinguishes these from most other myopathies. However, as with any needle electromyographic changes, these are not specific and may also occur in other myopathies such as acid maltase deficiency or after rhabdomyolysis. The electromyographic interpretation of an inflammatory myopathy must therefore always include the comment that a limited group of other myopathies may have similar findings, naming those that are most appropriate clinically. Nerve conduction studies (NCSs) usually show little change in myositis, although the compound muscle action potential (CMAP) am-

3 S20 DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen plitude may be reduced in those muscles in which there has been sufficient muscle fiber damage or loss. The differentiation between a myopathic and neuropathic condition is relatively straightforward although in very chronic myopathies, the progressive reinnervation of regenerated fibers will produce significant numbers of polyphasic, long duration, high amplitude MUAPs. Observing the recruitment pattern will generally be helpful in this setting with rapid recruitment noted in a myopathy and reduced recruitment in a neuropathic disorder. One must also consider alternative myopathies that may not be responsive to corticosteroids. This is particularly true of muscular dystrophies or inclusion body myositis, an increasingly recognized myopathy. The latter is generally insidious onset after the age of 50 years and has a relatively characteristic pattern of weakness involving the quadriceps and tibialis anterior as well as a predilection for proximal muscles and the long finger flexors. 9 Because the condition is chronic, there is a pattern on needle electromyography of mixed motor unit potentials, with long-duration, high-amplitude polyphasic MUAPs as well as typical myopathic potentials. Given the large MUAPs, this condition can frequently be misdiagnosed as a motoneuron disease (MND). When large MUAPs are found, it is important to search for small MUAPs as well so as not to mistakenly suggest a diagnosis of MND. Most commonly, the question is raised to distinguish between ongoing inflammation and steroid myopathies. As distinct from previously described electromyographic findings, those with steroid myopathies may still have myopathic MUAPs from the known underlying polymyositis but will have significantly less or no abnormal spontaneous activity. This distinction can be difficult, but if compared with previous electromyographic findings, the etiology is usually clear. The clinical distinction can also be difficult, but in steroid myopathies the onset is generally gradual, following a period of clear response to treatment of the polymyositis. Laboratory evaluation can also be helpful, with a further increase in muscle enzymes suggesting inadequate treatment of the inflammatory myopathy. Serial urine creatine can also be measured, given that increased urine secretion is associated with steroid myopathies versus a stable urine level in polymyositis. 10 Finally, muscle biopsy may be performed. In those treated with corticosteroid for other nonmyopathic conditions, the incidence of steroid myopathies varies between 2.4% and 21%. 11 The clinical presentation is generally a gradual onset of proximal weakness. It is usually not associated with steroid use for less than 4 weeks, is more common with fluorinated glucocorticoids, and is often associated with other steroid effects such as hypertension, hyperglycemia, osteoporosis, fragile skin, a buffalo hump, or electrolyte abnormalities. 10 The mechanism of weakness is postulated to be caused by type II fiber atrophy as a result of impaired muscle and carbohydrate metabolism. 11,12 As the initial MUAPs recruited during needle electromyography are type I fibers, electrodiagnostic abnormalities may not be apparent unless the process is very severe. Thus, a normal EMG does not exclude steroid myopathy. Treatment in this setting includes dose reductions, converting to nonfluorinated glucocorticoids, exercise, and avoidance of starvation. 10,11, Clinical Activity: To establish an electrodiagnostic and treatment plan for a 34-year-old woman with diplopia and dysphagia. The differential diagnosis of dysphagia is relatively broad, but, in the setting of diplopia, the primary diagnostic considerations would be myasthenia gravis (MG), multiple sclerosis, stroke, multiple cranial neuropathies, myopathy, polyradiculoneuropathy, or a nonorganic disorder. The temporal pattern of onset in conjunction with the pattern of weakness and associated sensory symptoms generally makes the clinical diagnosis more certain. This patient reports absence of sensory symptoms, gradual onset, and increased weakness with activity. Physical examination reveals weakness in proximal more than distal muscles, with worsening during repetitive maximal contraction. Reflexes and sensation are normal. The history and examination would strongly suggest MG, with the most unifying clinical feature of fatigable weakness. Diplopia or ptosis is present in 50% of patients with MG at presentation, and eventually 90%. There may be associated dysphagia or dyspnea. 14,15 Research has identified that this is an immunologic process: immunoglobulin G antibodies directed against the postsynaptic acetylcholine (ACh) receptors are found in 80% to 90% of patients. 16 This, in turn, leads to ultrastructural changes including reduced nerve terminal area, and simplification of the postsynaptic folds with sparse secondary synaptic clefts that are shallow or abnormally wide. 14 With appropriate electrodiagnostic testing, one can usually determine whether the disorder is presynaptic or postsynaptic, define the severity, exclude other neuromuscular conditions, and follow the disease course. A clear understanding of the anatomy and neurophysiology of the neuromuscular junction (NMJ) is crucial to obtaining and interpreting the electrodiagnostic data. Despite their complexity, the neuromuscular disorders are among the most understood neurologic conditions, with clearly defined pathophysiology and histology. The evolution of specialized electrodiagnostic techniques has added to this understanding and allows accurate diagnosis of most disorders of neuromuscular transmission. The NMJ is composed of the presynaptic nerve terminal and membrane, the synaptic cleft, and the postsynaptic membrane. The presynaptic region is responsible for the synthesis, storage, and release of ACh in response to depolarization. Within this structure are specialized double parallel rows of particles at the presynaptic membrane, directly opposite the postsynaptic junctional folds. These particles are termed active zones, and represent areas of concentrated ACh release. When an action potential arrives, calcium influxes leading to the release of several quanta of ACh into the synaptic space, which is composed of the primary cleft and the secondary cleft (junctional folds). Approximately 25% to 50% of the ACh is hydrolyzed by acetylcholinesterase (AChE) that is present in the synaptic cleft, with the remainder binding to the ACh receptors on the postsynaptic membrane. When 2 molecules bind to the receptors, there is a conformational change leading to an influx of sodium and the generation of an endplate potential with an amplitude of 40 to 60mV. Because the threshold to depolarize the muscle membrane is only 15 to 25mV, there is 3 to 4 times the depolarization necessary for the development of an action potential. This is referred to as the safety factor. Any pathologic process that reduces the safety factor will lead to failure of neuromuscular transmission, which correlates with the clinical and electrophysiologic characteristics of these diseases. 17 Repetitive stimulation is the mainstay of the electrophysiologic evaluation of NMJ disorders. In normal physiologic conditions, there is a gradual reduction of the quantal content because of depletion of the immediately available stores of ACh. Although the endplate potential shows a reduction during the first several stimuli, the safety factor is several fold higher than threshold, thus, the action potentials continue to be propagated in an all-or-nothing fashion with no change in the CMAP amplitude. However, in disease states, there may be a

4 DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen S21 Fig 1. Two-hertz repetitive stimulation showing (A) a mild decrement with characteristic pattern; (B) a more severe defect of neuromuscular transmission; (C) a technical error (note the decrement is not smooth with the drop occurring after the second stimulus); and (D) a technical error with fourth response it must be repeated to determine whether the apparent decrement of the previous responses is reproducible. reduced quantal content or impaired response of the AChE. In this situation, the endplate potential will become subthreshold in some fibers, leading to fewer summated responses, reflected as a reduced CMAP amplitude. This is the main principle behind interpretation of repetitive stimulation studies. By assessing the baseline values and response to exercise, one can characterize the disorder with high diagnostic accuracy. Repetitive stimulation can be technically challenging, potentially leading to misinterpretation and erroneous diagnosis. A clear understanding and proficiency in use of these techniques is absolutely essential for accurate interpretation. 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 repetitive 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 attributed 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 to the baseline amplitude of the first response in the train. During the 2 to 4 minutes after exercise, there is postactivation exhaustion that will again show a smooth decrement that may exceed that at rest (fig 2). A consistent decrement of greater than 10% in 2 nerves with typical repair and postexercise 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 disease. The sensitivity of repetitive stimulation is dependent on the muscles examined and the degree of clinical weakness. Proximal muscles tend to show relatively greater involvement, possibly caused by warmer core temperature, which destabilizes the NMJ (fig 3). Özdemir and Young 19 reported that if only the abductor digiti minimi (ADM) is examined, the likelihood of obtaining a diagnostic result is 59%. However, the deltoid showed abnormalities in 82% and the orbicularis oculi in 62.5%. When these muscles and the wrist flexors were considered together, a positive test was identified in 95% of patients. 19 The needle examination generally only shows Fig 2. Two-hertz repetitive stimulation to the ulnar, spinal accessory, and facial nerves in MG.

5 S22 DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen Fig 3. Two-hertz repetitive stimulation showing myasthenia gravis; each tracing represents 4 superimposed responses. Note the significant decrement with proximal studies as compared with the ulnar nerve. Adapted with permission. 17 MUAP variation in weak muscles and, occasionally, a secondary myopathy in more severe or longstanding cases. Single fiber is the most sensitive technique, showing abnormalities in up to 99%, depending on which muscles are examined. The technique, however, is relatively nonspecific in that significant jitter and blocking can be seen in other disorders, particularly more rapidly progressive neurogenic disorders such as MND. 20 Finally, the acetylcholine antibody titer is abnormal in approximately 90% of patients with MG. 16,21 A normal antibody titer, however, does not exclude MG, because the sensitivity in those with pure ocular symptoms is only 65%. In this case, there was no significant decrement to 2-Hz repetitive stimulation when recorded over the ADM, but there was a consistent pattern of decrement with at least partial repair when recorded over the trapezius muscle and a facial muscle (see fig 2). The neurologic examination revealed no abnormal spontaneous activity and varying MUAP morphology of the same MUAP without other morphologic changes primarily in proximal muscles. The electrodiagnostic testing in conjunction with positive ACh receptor antibodies would confirm the diagnosis of MG. The initial pharmacologic management of MG is with cholinesterase inhibitors such as pyridostigmine bromide (Mestinon) or neostigmine methylsulfate (Prostigmin), the former beginning at doses of 15 to 60mg every 4 to 6 hours, with the dosage and dosage interval gradually increased to maximal response. The most common side effects are gastrointestinal tract hyperactivity and increased respiratory secretions. Various immunosuppressants are also used to sustain remissions. The first choice is generally corticosteroids followed by azathioprine, cyclophosphamide, and cyclosporine. All of these carry the risk of immunosuppression and may increase the risk of malignancy, but are generally effective in sustaining remissions. Mycophenolate mofetil (CellCept) and methotrexate are also being evaluated and used for treatment. Finally, plasmapheresis is an effective short-term therapy for severe weakness especially in the setting of a recent exacerbation or to offset the worsening that can be seen with the initiation of corticosteroids. Because there is an association between thymoma and MG, thymectomy may be indicated for those who are under the age of 60 years and have generalized weakness and for persons with a thymoma Clinical Activity: To coordinate the electrodiagnostic and treatment protocol for a 23-year-old man with weakness of the hands and feet, and difficulty with grasp relaxation. The history of difficulty with grasp relaxation is characteristic of a myotonic disorder, and the presence of clinical weakness would suggest a disorder with both myotonia and a myopathy. The potential etiology of myotonia is relatively broad but with other clinical features, such as weakness and,

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 (Thomsen s), Autosomal recessive (Becker s) Weakness pattern Extramuscular features Distal initially, generalized late, Hatchet face Frontal balding, testicular atrophy, DM, cataracts, cardiac arrhythmias, dysphagia, alveolar, hypoventilation, cognitive Autosomal dominant Autosomal dominant Generally no weakness, muscle hypertrophy, Herculean Generally none Proximal None None Cataracts 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, severe weakness Usually not 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 Fibrillation potentials MUAPs Myotonia Cooling Exercise May have discharges Small, polyphasics Distally predominant Increased mytonia Reduced myotonia None Normal Faster, shorter, diffuse Increased mytonia Reduced myotonia With cooling Normal Diffuse Electric silence/paralysis Increases myotonia Postexercise fibrillation potentials Occasional small Scattered No clear change No clear change Abbreviations: DM, diabetes mellitus; PROMM, proximal myotonic myopathy; RNS, repetitive nerve stimulation. more important the pattern of weakness, the differential diagnosis can be narrowed (appendix 1). Electrophysiologically, myotonic discharges are characterized by a waxing and waning of amplitude and frequency that is often described as a dive bomber. They are regular in rhythm but vary in frequency between 2 and 100Hz and are generally triggered by needle movement, percussion, or muscle contraction. 22 When sustained and of higher frequency, the discharges are easily identified, but when slow, they may be mistaken for fibrillation potentials. Myotonia varies with temperature, increasing with cooling and decreasing with warming as well as with muscle activity; the exception is in paramyotonia congenital, in which the response to temperature is just the opposite. They may take either positive or spike waveforms, depending on how the needle electrode is positioned in relation to the muscle fiber. In this scenario, there is clear weakness in addition to the myotonia, which reinforces the suspicion of a distally predominant myopathy, most likely myotonic dystrophy (appendix 2). Electrodiagnostic testing is important to better define the degree and pattern of myotonia as well as to define whether there is an associated myopathy. Additionally, specialized techniques, such as repetitive stimulation, response to cooling, or response to exercise, will generally confirm the diagnosis. Table 1 describes the clinical and electrophysiologic abnormalities of the most common myotonic disorders. Most myotonic disorders have a relatively typical response to repetitive stimulation characterized by a decremental response at rest that is very similar to that seen in NMJ disorders but differs physiologically in that it is likely caused by membrane inactivation. 23,24 There is also a repair after brief exercise, but, in contrast to NMJ disorders, there is a clear reduction of the CMAP amplitude immediately after exercise. This phenomenon is seen in most myotonic disorders except proximal myotonic myopathy, which, in conjunction with the proximal pattern of weakness, is a characteristic that distinguishes this disorder. 25 Prolonged exercise has a variable effect on the CMAP amplitudes, depending on the condition, and is especially useful in distinguishing paramyotonia congenita from other disorders. In paramyotonia congenita, as well as in periodic paralysis, paresis can be induced with prolonged exercise (5min), characterized by a reduction of the CMAP amplitude of more than 40% over 20 to 40 minutes. 23 Finally, muscle cooling will have variable effects, depending on the condition. Although cooling increases myotonia in all these conditions, only paramyotonia congenital features prominent and prolonged weakness after cooling. During moderate cooling, intense fibrillation potentials may occur before all activity ceases. The pathophysiologic basis of this phenomenon with cooling is an altered sodium conductance with or without a change in chloride conductance.

7 S24 DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen Needle electromyography will reveal short-duration, polyphasic MUAPs with rapid (early) recruitment in myotonic dystrophy, and is the most reliable electromyographic criterion for differentiating this disorder from myotonia congenita. Major changes in MUAPs are not seen in myotonia congenita, but the MUAP amplitude may gradually decrease with repeated firing. It must be reemphasized, however, that myotonic discharges are not specific for these conditions, because similar findings can be seen in the other conditions as well (see appendix 1). Electrodiagnostic testing will generally lead to the correct diagnosis. Genetic testing will generally confirm the diagnosis. Currently, there is no scientifically proven pharmacologic treatment to increase muscle strength in myotonic dystrophy. Clinical myotonia can be treated with agents such as phenytoin, mexiletine, acetazolamide, tocainide, carbamazapine, or lamotrigine, but many of these can have untoward cardiac effects and probably should be avoided in myotonic dystrophy. 26 They may be of more benefit in myotonia congenita or other channelopathies that may present with cramps. Education on exercise and avoidance of cold is key to treatment. Use of appropriate orthosis and gait aids can assist ambulation. The patient should be instructed on stretching, particularly muscles of the lower extremities that cross 2 joints. Dysphagia is relatively common and careful screening with appropriate aspiration precautions and dietary modification may be necessary. Pulmonary function tests should be followed with the possible need for noninvasive ventilatory assistance as well as serial electrocardiograms, given the association with cardiac conduction defects. Because myotonic dystrophies are an inherited disorder, assistance with family planning decisions is important. 3.5 Educational Activity: You are a physiatrist seeking enrollment to perform electrodiagnostic studies from a workers compensation carrier. Explain your unique qualifications to perform such studies. Physiatrists are uniquely qualified to perform electrodiagnostic studies. Unfortunately, despite years of effort on the part of physiatric associations, a lack of knowledge persists in the health insurance carrier industry about physiatry and the diagnostic potential of electrodiagnostic studies. As a physiatrist seeking enrollment with a carrier, one should explain that electrodiagnostic consultations are medical consultations and should be performed only by physicians with expertise in this area. One should prepare an information packet for the carrier, including the American Association of Electrodiagnostic Medicine s publications 27,28 on educational requirements for the practice of electrodiagnostic medicine. The electrodiagnostic medicine consultant should be a physician who has specialized training in the diagnosis and treatment of neurologic diseases and neuromuscular disorders (NMDs). He/she must also be an expert in the application of particular neurophysiologic techniques unique to the study of these disorders. This type of training is provided during the residency or fellowship programs of physicians who specialize in physical medicine and rehabilitation (physiatrists) or in neurology (neurologists). 29 In most PM&R residencies, the resident is required to perform a minimum of 200 supervised studies and to attend formal lectures on multiple electrodiagnostic topics. On completion of a physical medicine and rehabilitation residency program, the physician has gained training in the basic sciences necessary to understand neurophysiology and has had clinical experience in electrodiagnosis, as well. This training is a requirement of the Residency Review Committee of the Accreditation Council for Graduate Medical Education. 30 It is vital for the insurance carrier to understand that these factors are important because the electrodiagnostic consultation is actually an extension of the neurologic portion of the physical examination. 28 Unlike many radiologic or laboratory tests, electrodiagnostic testing must be individualized to fit the specific clinical circumstances. The test is interpreted in real time, and, frequently, the results of specific parts of the test will dictate which nerves and muscles are tested next. For these reasons the test must be designed, performed, and interpreted by a physician with expertise in electrodiagnosis. Under certain circumstances, the physiatrist may directly supervise a technician to perform portions of the examination, with the physician deciding which nerves to study and that physician must be available to confirm the results. While NCSs can be reviewed after the study, the needle electromyography portion of the study cannot be delegated and should be performed entirely by the physician. It is impossible to capture all of the information from an electromyography study on a printout or recording, and many study interpretations are based on the electrodiagnostic experience and knowledge of the electrodiagnostic consultant. Judgments about from which muscle the tip of the needle is recording and whether the muscle is at rest or voluntarily contracting can only be made in person. In addition to the technical and educational factors that physiatrists possess, there are additional attributes that make them uniquely qualified to perform electrodiagnostic studies in a workers compensation setting. Physiatrists diagnose NMDs and have extensive experience in the musculoskeletal conditions that can mimic neurologic disorders. For example, they can help evaluate whether shoulder weakness is caused by a musculoskeletal disorder or a root, plexus, or peripheral nerve lesion. The specialty of PM&R emphasizes functional restoration, and, occasionally, the physiatrist may try various therapeutic interventions prior to performing electrodiagnostic testing, because a positive therapeutic response may have both diagnostic and therapeutic value. For example, when a patient presents with anterolateral thigh dysesthesias without weakness, possibly from lateral femoral cutaneous nerve entrapment, a corticosteroid injection initially, with symptom resolution postinjection, would have similar diagnostic value to electrodiagnostic testing. More important, it would provide pain relief and functional restoration. In summary, the physiatrist must explain to the insurance carrier that he/she possesses the education, training, knowledge, and experience that are specifically required to perform electrodiagnostic studies in the workers compensation area. The physiatrist can illustrate the exceptional qualifications he/ she has, and cite numerous position statements from recognized medical groups to help educate the carrier in its choice among the medical specialties. 3.6 Clinical Activity: To formulate a clinical and electrodiagnostic evaluation for a 66-year-old female smoker with difficulty climbing stairs. The clinical complaint of weakness is very common, with a differential diagnosis that includes NMDs, musculoskeletal disorders, deconditioning, or cardiopulmonary diseases. The most common NMDs in this age group would be myopathies, lumbosacral radiculopathies, MND, or disorders of neuromuscular transmission. Obtaining an accurate history and physical examination will generally narrow the differential diagnosis and help focus the electrodiagnostic evaluation. On further

8 DISEASES OF MUSCLES AND NEUROMUSCULAR JUNCTION, Strommen S25 Fig 4. Two-hertz repetitive stimulation to the ulnar and femoral nerves in a 66-yearold patient with Eaton-Lambert myasthenic syndrome. Adapted with permission. 17 questioning, this patient reports a lack of sensory symptoms, and physical examination shows no fasciculations and relatively greater weakness in proximal muscle groups of the limbs but no weakness in bulbar muscles. This would make radiculopathies unlikely. Further, on examination, deep tendon reflexes are found to be absent, making MND less likely. As an extension of the neurologic examination, electrodiagnostic testing is especially critical for those disorders that present with weakness, particularly in this setting where clinical examination cannot clearly determine the cause. With appropriate electrodiagnostic testing, one can determine whether the process is myopathic, neuropathic, or related to an NMJ disorder, which can be further defined as to whether the process is presynaptic or postsynaptic. A clear understanding of the anatomy and neurophysiology of the NMJ is crucial to obtaining and interpreting the electrodiagnostic data. The reader is encouraged to refer to neurophysiology texts for more extensive review. In this case (fig 4), baseline repetitive stimulation at rest recorded over the first dorsal interosseous muscle revealed a low amplitude CMAP with decrement of 20% between the first and fourth responses. Brief (10-s) exercise led to a significant increase of the CMAP to 2 times its baseline value, a 200% facilitation (or 100% increment). This pattern of facilitation, to a much greater degree, was reproduced when recorded over the rectus femoris with percutaneous femoral nerve stimulation. Median and sural sensory NCSs were normal. Needle examination revealed varying motor unit potentials but no abnormal spontaneous activity. Three terms are particularly important in assessing NMJ disorders: endplate potential, blocking, and repair. The underlying mechanism of all neuromuscular junction disorders is a reduced safety factor leading to failure of an endplate potential to produce an action potential in some muscle fibers. In electrodiagnostic testing, this can be readily assessed by evaluating the CMAP at rest and can be further classified based on the response to exercise. The CMAP area, and to a lesser extent the amplitude, represents the summated activity of all muscle fibers stimulated. If the endplate potentials in some of these fibers fail to reach threshold, the summated CMAP will be of lower amplitude and area. This pattern correlates with the clinical complaints of weakness and with the electrodiagnostic finding of blocking, which is manifested on needle electromyography as MUAP variation. Repetitive stimulation at 2 to 3Hz will lead to a decrement in the CMAP amplitude. Immediately after brief exercise, there should be at least partial repair of the decrement, characterized by return of the CMAP to the baseline amplitude of the first response. In a presynaptic disorder such as Lambert-Eaton myasthenic syndrome, exercise will lead to a significant CMAP facilitation. Although this syndrome is the most common presynaptic disorder, this pattern of findings could also be seen, to a lesser degree, with botulism. Lambert et al 31 initially described this syndrome in 1956 in 3 patients with malignant tumors in the chest. Its typical clinical characteristic is weakness that is predominantly proximal but with significantly less bulbar involvement than myasthenia gravis. Deep tendon reflexes are markedly reduced or absent throughout. Muscle strength is potentiated by exercise, as are reflexes, which distinguishes this from a postsynaptic deficit where there is clearly fatigable weakness and relative preservation of reflexes (table 2). There may also be significant dysautonomia characterized by dry eyes and dry mouth as well as occasional sensory involvement. Constitutional symptoms are common, because the disease is associated with malignancy in 60% to 70% of cases (most commonly small cell lung cancer) and with connective tissue diseases, especially in women. 32 The electrophysiologic abnormalities can be predicted by the pathophysiology, which features a reduced endplate potential, because of impaired quantal release of ACh from the presynaptic terminal in response to a nerve impulse. This phenomenon was supported by freeze-fracture studies that revealed a marked decrease in active zones and active zone particles per unit area, suggesting that the presynaptic release sites are the

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) Occasionally myopathic Varying (less at higher rates) Occasionally myopathic targets of the pathologic process. 33 It was experimentally implicated by Lennon and Lambert 32 that there was a tumorassociated, voltage-gated, calcium-channel, autoimmunizing stimulus. The antibody binding to calcium channels leads to inhibited entry of calcium into the nerve terminal, with consequent reduced quantal release, a subthreshold endplate potential, and resultant clinical weakness. Brief exercise or repetitive stimulation at rates of 30 to 50Hz leads to flooding of the presynaptic terminal with calcium, resulting in potentiation of the quantal content with a significant increase in the endplate potential, correlating with improvement in strength on repetitive contraction. 33 This is the principle of electrodiagnostic testing in which the endplate potential is significantly reduced during stimulation at rest and falls further below the safety factor during slow rate repetitive stimulation leading to a decremental response of the CMAPs. Brief exercise, then, leads to facilitation of the response, generally regarded as diagnostic if there is a doubling of the response in at least 2 nerve-muscle pairs. 17,34 In contrast to MG, these abnormalities in Lambert-Eaton myasthenic syndrome are more prominent in distal muscles (abductor digiti quinti, abductor pollicis brevis, extensor digitorum brevis) than in proximal muscles such as the trapezius. 35 Recording over the rectus femoris with percutaneous femoral nerve stimulation may also be helpful as in this case. Table 2 outlines the clinical and electrophysiologic features that can help distinguish MG from Lambert-Eaton myasthenic syndrome. The evaluation of possible Lambert-Eaton myasthenic syndrome consists of neoplastic search including computerized tomography of the chest and abdomen, as well as gynecologic evaluation and breast examination/mammography in women. Serum antibody testing will reveal antibodies to P/Q-type voltage-gated calcium channels in more than 90% of patients. 36 Treatment generally involves removal of the tumor, which will reverse the process in most cases. Pyridostigmine bromide (Mestinon), which acts as a cholinesterase inhibitor, is generally not helpful, but preliminary studies using 3,4 diaminopyrimidine, which increases channel opening time by blocking potassium channel conductance, has proved beneficial. 37 APPENDIX 1: CONDITIONS THAT MAY HAVE MYOTONIC DISCHARGES Myotonic dystrophy (Steinert s)* Myotonia congenita* Thomsen s (autosomal dominant) Becker s (autosomal recessive) Paramyotonia (von Eulenberg)* Chondrodystrophic myotonia (Schwartz-Jampel)* Acid maltase deficiency Inflammatory myopathies Proximal myotonic myopathy Statin myopathy Amyloid Hyperkalemic periodic paralysis Normokalemic periodic paralysis Hypokalemic periodic paralysis Hypothyroid myopathy Potassium sensitive myotonia Centronuclear myopathy Chronic neurogenic disorders (rarely) Drugs (eg, clofibrate, diazocholesterol, 2, 4 D) Paraneoplastic syndromes *Clinical myotonia. APPENDIX 2: MYOPATHIES WITH DISTAL WEAKNESS Late adult 1 (Welander s) Late adult 2 (Markesbury/Udd) Early adult 1 (Nonaka)-IBM2, distal myopathy with rimmed vacuoles-gne mutations Early adult 2 (Miyoshi) Early adult 3 (Laing) Myofibrillar (Desmin)

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