Neuromuscular Junction Disorders

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34 Neuromuscular Junction Disorders

Disorders affecting the neuromuscular junction (NMJ) are among the most interesting and rewarding seen in the electromyography (EMG) laboratory. These disorders are generally pure motor syndromes that usually preferentially affect proximal, bulbar, or extraocular muscles. They are confused occasionally with myopathies. With knowledge of normal NMJ physiology (see Chapter 6), most of the abnormalities affecting the NMJ can be differentiated using a combination of nerve conduction studies, repetitive stimulation, exercise testing, and needle EMG.

NMJ disorders can be classified into immune-mediated, toxic or metabolic, and congenital syndromes (Box 34–1). They usually are distinguished by their clinical and electrophysiologic findings (Tables 34–1 and 34–2). All are uncommon, but among them, myasthenia gravis (MG) and Lambert–Eaton myasthenic syndrome (LEMS) are the disorders most often encountered in the EMG laboratory. Both are immune-mediated disorders. In MG the autoimmune attack is postsynaptic; in LEMS the presynaptic membrane is the target of attack. Every electromyographer must understand the electrophysiology of these disorders so that appropriate electrodiagnostic tests can be applied and the correct diagnosis not overlooked.

Myasthenia Gravis

MG, the best understood of all the autoimmune diseases, is caused by an immunoglobulin G (IgG)-directed attack on the NMJ, aimed specifically at the nicotinic acetylcholine (ACH) receptor in the vast majority of cases. The role of these anti-acetylcholine receptor antibodies as the cause of MG has been proved through a variety of experimental steps: (1) antibodies are present in the serum of most patients with MG; (2) antibodies passively transferred to animals produce experimental myasthenia; (3) removal of antibodies allows recovery; and (4) immunization of animals with ACH receptors produces antibodies and can provoke an autoimmune disease that closely resembles the naturally occurring disease.

The mechanism of antibody damage to the ACH receptor and postsynaptic membrane involves several steps. First, binding of the antibody to the receptor can directly block the binding of ACH. Second, there is a complement-directed attack, with destruction of the ACH receptor and postjunctional folds. Last, antibody binding can result in an increase in the normal removal of ACH receptors from the postsynaptic membrane (modulation). Thus, although the amount of ACH released is normal, there is reduced binding of ACH to the ACH receptor, resulting in a smaller endplate potential and a reduced safety factor of NMJ transmission.

A subset of patients with MG clinically (approximately 8–15%) will not demonstrate antibodies to ACHR (so-called “seronegative” cases). In this subset, however, approximately 40–50% will have an antibody to muscle-specific tyrosine kinase (MuSK). MuSK is a surface receptor that is involved in the clustering of ACHRs during development.

Clinical

Patients with MG present with muscle fatigue and weakness. Because the disorder is limited to the NMJ, there is no abnormality of mental state or sensory or autonomic function. Myasthenic weakness characteristically affects the extraocular, bulbar or proximal limb muscles. Eye findings are the most common, with ptosis and extraocular muscle weakness occurring in more than 50% of patients at the time of presentation and developing in more than 90% of patients sometime during their illness. Extraocular weakness frequently begins asymmetrically, with one eye involved and the other spared. A very small degree of extraocular weakness is experienced by the patient as visual blurring or double vision. Myasthenic weakness has been known to mimic third, fourth, and sixth nerve palsies and, rarely, an intranuclear ophthalmoplegia. Unlike true third nerve palsies, however, MG never affects pupillary function. Fixed extraocular muscle weakness may occur late in the illness, especially if untreated.

Bulbar muscle weakness is next most common after extraocular weakness. This may result in difficulty swallowing, chewing, and speaking. Patients may develop fatigability and weakness of mastication, with the inability to keep the jaw closed after chewing. Myasthenic speech is nasal (from weakness of the soft palate) and slurred (from weakness of the tongue, lips, and face) but without any difficulty with fluency. Weakness of the soft palate may also result in nasal regurgitation (i.e., liquid coming out the nose when drinking). When myasthenic patients develop limb weakness, it usually is symmetric and proximal. Patients note difficulty getting up from chairs, going up and down stairs, reaching with their arms, or holding up their head. Rare patients present with an isolated limb-girdle form of MG and never develop eye movement or bulbar muscle weakness. It is these patients who are most often misdiagnosed with myopathy.

In contrast to the clinical syndrome seen in MG with anti-ACHR antibodies, the clinical characteristics of anti-MuSK MG include female predominance, prominent bulbar, neck, shoulder and respiratory involvement, and a severe presentation that occurs at a younger age than MG with anti-ACHR antibodies. Three clinical patterns are present in anti-MuSK MG: (1) severe oculobulbar weakness along with tongue and facial atrophy, (2) marked neck, shoulder, and respiratory weakness with little or no ocular weakness, and (3) a pattern similar to anti-ACHR antibody MG. In addition, patients with anti-MuSK MG are often unresponsive or intolerant to cholinesterase inhibitors, and some have actually worsened.

The distinguishing clinical feature of MG, whether seropositive (ACHR or MuSK) or seronegative, is pathologic fatigability (i.e., muscle weakness that develops with continued use). Patients improve after rest or upon rising in the morning and worsen as the day proceeds. Although generalized fatigue is common in many neurologic and non-neurologic disorders, NMJ fatigue is limited to muscular fatigue alone, which progresses to frank muscle weakness with use. Patients with MG do not generally experience a sense of mental fatigue, tiredness, or sleepiness.

The clinical examination in a patient suspected of having MG is directed at examining muscular strength and demonstrating pathologic fatigability. To demonstrate subtle weakness, it is helpful to observe the patient performing functional tasks, such as rising from a chair or from the floor or walking, rather than relying on manual muscle strength testing alone. Pathologic fatigability may be demonstrated by having the patient look up for several minutes (to determine if ptosis or extraocular weakness is present), count aloud to 100 (to determine if nasal or slurred speech is present), or by repetitively testing the neck or the proximal limb muscles (for example, with both shoulders abducted, the examiner repetitively pushes down on both arms several times, looking for fatigable weakness). In patients with ptosis, the ice bag test can be very helpful. Ice is applied over the forehead for several minutes to cool the underlying muscles. In MG, ptosis may improve markedly with cooling. The remainder of the neurologic examination should be normal. Deep tendon reflexes are generally preserved or, if reduced, are reduced in proportion to the degree of muscle weakness.

Most patients with MG have generalized disease. However, as many as 15% of patients have the restricted ocular form of the disease. In these patients, myasthenic symptoms remain restricted to the extraocular and eyelid muscles. When a patient first presents with fluctuating extraocular weakness, it is impossible to predict from either clinical or laboratory testing which patients subsequently will generalize and which will remain with relatively benign restricted ocular symptoms. If a patient’s symptoms remain restricted to the ocular muscles for one to two years, however, there is a high probability that the myasthenia will never generalize and will remain restricted to the extraocular and eyelid muscles.

Autoimmune MG may be seen in two other groups of patients aside from those with idiopathic autoimmune myasthenia. First, transient neonatal MG may occur in babies born to mothers with MG. This occurs when maternal autoantibodies pass through the placenta, resulting in the same clinical syndrome in newborn infants. The illness usually is mild and self-limited and disappears after the first few months of life as the maternal antibodies are degraded. MG also may be seen in patients treated with penicillamine. The clinical syndrome is similar to idiopathic MG, including the presence of anti-acetylcholine receptor antibodies, except that most patients slowly improve once the penicillamine has been discontinued.

Electrophysiologic Evaluation

Like other disorders affecting the NMJ, the electrophysiologic evaluation of MG involves routine nerve conduction studies, repetitive nerve stimulation (RNS), exercise testing, routine EMG, and, in some cases, single-fiber EMG (SF-EMG) (Box 34–2).

Box 34–2

Electrophysiologic Evaluation of Myasthenia Gravis

1. Routine motor and sensory nerve conduction studies. Perform routine motor and sensory nerve conduction studies, preferably a motor and sensory nerve in one upper and one lower extremity. CMAP amplitudes should be normal. If CMAP amplitudes are low or borderline, repeat distal stimulation immediately after 10 seconds of exercise to exclude a presynaptic NMJ transmission disorder (e.g., Lambert–Eaton myasthenic syndrome).

2. Repetitive nerve stimulation (RNS) and exercise testing. Perform slow RNS (3 Hz) on at least one proximal and one distal motor nerve. Always try to study weak muscles. If any significant decrement (>10%) is present, repeat to ensure decrement is reproducible. If there is no significant decrement at baseline, exercise the muscle for 1 minute, and repeat RNS at 1, 2, 3, and 4 minutes looking for a decrement, secondary to post-exercise exhaustion. If at any time a significant decrement is present (at baseline or following post-exercise exhaustion), exercise the muscle for 10 seconds and immediately repeat RNS, looking for post-exercise facilitation (repair of the decrement).

3. Needle electromyography (EMG). Perform routine needle EMG of distal and proximal muscles, especially weak muscles. Patients with moderate to severe myasthenia gravis may display unstable or short, small, polyphasic motor unit action potentials. Recruitment is normal or early. Needle EMG must exclude severe denervating disorders or myotonic disorders, which may display an abnormal decrement on RNS.

4. Single-fiber EMG (SF-EMG). If the above are normal or equivocal in a patient strongly suspected of having myasthenia gravis, perform SF-EMG in the extensor digitorum communis and, if necessary, one other muscle, looking for jitter and blocking. It is always best to study a weak muscle. Normal SF-EMG in a clinically weak muscle excludes an NMJ disorder.

CMAP, compound muscle action potential; NMJ, neuromuscular junction.

Repetitive Nerve Stimulation

After the routine nerve conduction studies are completed, RNS studies are performed (see Chapter 6). These studies are abnormal in more than 50 to 70% of patients with generalized MG but often are normal in patients with the restricted ocular form of MG. A decremental response on RNS is the electrical correlate of clinical muscle fatigue and weakness. In normal subjects, slow RNS (3 Hz) results in little or no decrement of the CMAP, whereas in MG, a CMAP decrement of 10% or more is characteristically seen (Figure 34–1A). Both distal and proximal nerves should be tested. Although distal nerves are technically easier to study, the diagnostic yield increases with stimulation of proximal nerves (e.g., spinal accessory or facial nerves). This is not unexpected, because the proximal muscles usually are much more involved clinically than the distal ones. Facial RNS is especially important to perform in suspected anti-MuSK MG, where the yield of finding an abnormal decrement is much higher when examining a facial muscle than a limb muscle (probably reflecting the severe facial and bulbar involvement in some patients with anti-MuSK MG).

Exercise Testing

Exercise testing should be routinely used with all RNS studies (see Chapter 6). If there is no significant decrement on RNS studies at baseline (<10% decrement), the patient should perform 1 minute of exercise, followed by RNS at 1-minute intervals for the next 3 to 4 minutes, looking for a CMAP decrement secondary to post-exercise exhaustion. If at any time, either at baseline or following exercise, a significant decrement develops, the patient should perform a brief 10-second maximum isometric contraction, immediately followed by slow RNS, looking for an increment in the CMAP and “repair” of the decrement secondary to post-exercise facilitation (Figure 34–1).

Electromyography

Every patient evaluated for a possible NMJ disorder should have routine needle EMG performed, paying particular attention to weak muscles. EMG examination is done for two reasons. First, and most important, severe denervating disorders (e.g., motor neuron disease, polyneuropathy, inflammatory myopathy) and myotonic disorders need to be excluded because they also can show a decremental CMAP response on RNS. Second, the needle examination may demonstrate motor unit action potential (MUAP) abnormalities suggestive of an NMJ disorder: unstable MUAPs; small, short-duration MUAPs similar to myopathic motor unit action potentials; or both.

Unstable MUAPs (see Chapter 15) occur when individual muscle fibers are either blocked or come to action potential at varying intervals, which leads to MUAPs that change in configuration from impulse to impulse. If some muscle fibers of a motor unit are blocked and never come to action potential, the motor unit effectively loses muscle fibers, becoming short, small, and polyphasic, similar to MUAPs seen in myopathy. Otherwise, the needle EMG findings in NMJ disorders usually are normal. In general, fibrillation potentials and other abnormal spontaneous activity are not seen in NMJ disorders, with the important exception of botulism (see section on Botulism).

Single-fiber Electromyography

When a motor axon is depolarized, the action potential normally travels distally and excites all the muscle fibers within that motor unit at more or less the same time (Figure 34–2). This variation in the time interval between the firing of adjacent single muscle fibers from the same motor unit is termed jitter and primarily reflects variation in NMJ transmission time. If the NMJ is compromised, the time it takes for the endplate potential to reach threshold is prolonged, which results in greater-than-normal variation between firing of adjacent muscle fibers. If the prolongation is severe enough, the muscle fiber may never reach action potential, resulting in blocking of the muscle fiber.

SF-EMG is used to measure the relative firing of adjacent single muscle fibers from the same motor unit and can detect both prolonged jitter as well as blocking of muscle fibers. It is important to note that, whereas the clinical correlate of blocking is muscle weakness, there is no clinical correlate to increased jitter. Thus, the main advantage of SF-EMG over RNS is that the single-fiber study may be abnormal, showing increased jitter, even in patients without overt clinical weakness. In contrast, for RNS studies to be abnormal, the NMJ disorder must be sufficiently severe that blocking (the electrophysiologic correlate of weakness) also occurs, leading to a decremental response.

SF-EMG is best reserved for those electromyographers who are well trained in its use and who perform SF-EMG on a routine basis. It is a technically demanding procedure for both the patient and the electromyographer. In contrast to routine EMG, usually only one or two muscles are studied. Often, the extensor digitorum communis muscle in the forearm is selected for study. For most patients, this muscle can be steadily activated for a prolonged period and is relatively free of age-related changes. In addition, studying a clinically involved muscle is always useful. A normal single-fiber examination of a clinically weak muscle effectively rules out the diagnosis of MG.

The goal of SF-EMG is to study two adjacent single muscle fibers, known as a pair, from the same motor unit. This is accomplished by changing the filters on the EMG machine and using a specialized SF-EMG needle. The low-frequency filter (high-pass) is increased to 500 Hz (normally 10 Hz in routine EMG). By using a high-pass filter of 500 Hz, the amplitudes of distant muscle fiber potentials are attenuated while those of the nearby fibers are preserved. The SF-EMG needle is a specially constructed needle with the active electrode (G1) located in a port along the posterior shaft of the needle and with a smaller leading surface area than the conventional concentric needle electrode (Figure 34–3). The reference electrode (G2) is the needle shaft. The result of these two modifications is that single-fiber muscle action potentials are recorded only if they are within 200 to 300 µm of the needle. The needle is placed in the muscle, and the patient is asked to activate the muscle in an even and constant fashion. The needle is moved until a single muscle fiber potential is located. With this single muscle fiber potential triggered on a delay line, the needle is slightly and carefully moved or rotated to look for a second potential that is time locked to the first potential (signifying that it is from the same motor unit).

More recently, the regular disposable concentric EMG needle has been used for SF-EMG studies. The standard SF-EMG needle is expensive, and needs to be surgically sanitized between patients. Thus, the cost of the standard SF-EMG needle, along with the theoretical risk of transmitting infection (including prion diseases) despite sanitizing the needle, have prompted this change. In general, the values for jitter are comparable between the traditional SF and the concentric EMG needles. Single-fiber potentials should be accepted for analysis only if the potential is at least 200 µV in amplitude with a rise time of less than 300 µs. If a time-locked second potential is located, an interpotential interval between the two potentials (i.e., the pair) can be measured. By recording multiple consecutive firings of the muscle fiber action potential pairs, the difference between consecutive interpotential intervals can be calculated. This variation between consecutive interpotential intervals is the jitter. By recording 50 to 100 subsequent potentials, the mean consecutive difference (MCD), a measure of jitter, can be calculated between the triggered potential and the time-locked second single muscle fiber potential. Most modern EMG machines have programs that automatically perform the MCD calculation. This procedure is then repeated until 20 separate single-fiber pairs are collected, to calculate a mean MCD. This value is compared with the normal mean MCD for the muscle studied and the patient’s age (Table 34–3). There is also an upper limit of normal jitter for an individual pair, based on the muscle studied and the patient’s age. To call the latter abnormal, more than 10% of the pairs must exceed the limit (e.g., for 20 pairs, at least two must be abnormal). To make a diagnosis of an NMJ disorder, either the mean jitter must be abnormal or the upper limit of normal jitter must be abnormal in more than 10% of individual pairs. However, in most NMJ disorders, both will be abnormal. Increased jitter is consistent with an NMJ disorder (Figure 34–4). In addition to increased jitter, blocking may be seen on SF-EMG. Two time-locked, single-fiber muscle potentials from the same motor unit normally fire together. If the triggered potential fires steadily while the second potential fires only intermittently, blocking is occurring. Blocking, which is another marker of NMJ disease, usually occurs only when the jitter is markedly prolonged (e.g., MCD > 80–100 µs).

SF-EMG is the most sensitive test to demonstrate impaired NMJ transmission (abnormal in 95–99% of patients with generalized MG). However, it must be emphasized that although SF-EMG is very sensitive, it is not specific. SF-EMG can be abnormal in both neuropathic and myopathic diseases. Although it might be tempting to perform SF-EMG on any patient with fatigue, this test is best reserved for patients in whom the diagnosis of MG or another NMJ disorder is strongly suspected and in whom all other diagnostic test results, including RNS, have been negative or equivocal. In some patients with the restricted ocular form of MG, all study results, including SF-EMG, may be normal.

Lambert–eaton Myasthenic Syndrome

LEMS is a disorder of NMJ transmission characterized by reduced release of ACH from the presynaptic terminal. There is now clear evidence that this disorder, like MG, is an immune-mediated disorder. The pathogenesis of LEMS is fairly well understood and in most cases involves the production of IgG antibodies directed at the presynaptic P/Q-type voltage-gated calcium channel (VGCC). These antibodies interfere with the calcium-dependent release of ACH quanta from the presynaptic membrane and subsequently cause a reduced endplate potential on the postsynaptic membrane, resulting in NMJ transmission failure. This has been shown by passively transferring IgG from LEMS patients to animals, where it produces the same physiologic and morphologic changes seen in humans.

Clinical

LEMS is quite rare. Clinically, these patients present with proximal muscle weakness (especially the lower extremities) and fatigability. In addition, deep tendon reflexes are characteristically reduced or absent, which is unusual in MG or myopathy. Autonomic complaints (especially dry mouth) and transient sensory paresthesias may be present. Bulbar symptoms (ptosis, dysarthria, dysphagia) usually, but not always, are mild, which helps to distinguish this illness from botulism and MG. The distinctive clinical finding is that of muscle facilitation. After a brief period (10 seconds) of intense exercise of a muscle, the power and the deep tendon reflex to that muscle are transiently increased. Rare patients have been diagnosed with the disorder after they have been prescribed calcium channel blockers or have failed to wean from the respirator after anesthesia.

It affects adults, generally those older than 20 years and usually older than 40 years, of whom 70% are male and 30% are female. Patients older than 40 years, usually males and smokers, are at greatest risk. Small cell lung cancer (SCLC) is eventually found in 60% of patients with LEMS. SCLCs express VGCCs, which then initiate and maintain the autoimmune process. Rarely, other tumors are associated with LEMS. The remaining patients, usually younger women, have a primary autoimmune disease without any evidence of carcinoma. Some of these patients also have antibodies to VGCCs. Commercial testing for antibodies to VGCCs is available, although the sensitivity of the test varies depending on the specific antibodies tested and whether the patient has an underlying carcinoma or primary autoimmune disease.

Electrophysiologic Evaluation

In the appropriate clinical setting, the electrophysiology of LEMS is diagnostic (Box 34–3). Single stimuli produce a reduced release of ACH quanta and a reduced endplate potential. At rest, many of the endplate potentials do not reach threshold, resulting in small-amplitude CMAPs on routine motor nerve conduction studies (Figure 34–5). Slow RNS (3 Hz) results in a decremental response similar to MG. However, rapid RNS (30–50 Hz) or brief (10 seconds) intense isometric exercise produces a marked increase in the CMAP amplitude (post-exercise facilitation) due to calcium accumulation in the presynaptic nerve terminal with subsequent enhancement of the release of ACH quanta (Figure 34–6). The CMAP commonly increments in amplitude by more than 100% (calculated by 100  ×  [(Highest amplitude − Initial amplitude)/Initial amplitude]. Brief, intense isometric exercise is preferable to rapid RNS, which can be quite painful. Brief exercise means 10 seconds of exercise. It has been definitely proven that the maximal increment occurs after 10 seconds. If longer exercise is used (e.g., 30 seconds), the increment may not reach the threshold criteria of a 100% increase in some patients. In the EMG laboratory, this marked post-exercise facilitation of the CMAP is the electrical correlate of the clinical facilitation of muscle strength and reflexes seen after brief exercise. Somewhat confusing in LEMS is the issue of slow RNS (3 Hz) before and after brief exercise. In both situations, there will be a decremental response. However, after brief exercise, the baseline CMAP is significantly larger (i.e., an incremental response) compared with the pre-exercise CMAP (Figure 34–7).

Box 34–3

Electrophysiologic Evaluation of Lambert–Eaton Myasthenic Syndrome

1. Routine motor and sensory nerve conduction studies. Perform routine motor and sensory nerve conduction studies in at least two nerves, preferably a motor and sensory nerve in one upper and one lower extremity. CMAP amplitudes usually are diffusely low or borderline, with normal latencies and conduction velocities.

2. Repetitive nerve stimulation (RNS) and exercise testing. To look for facilitation, either perform high-frequency (30–50 Hz) RNS or record a CMAP with distal stimulation before and after 10 seconds of maximal voluntary exercise. Exercise testing is better tolerated by patients and is always preferable to fast RNS unless the patient cannot cooperate (e.g., sedated patient, young child). Any increment greater than 40% is abnormal (calculated by [100  ×  (Highest amplitude − Initial amplitude)/Initial amplitude]). Most patients with LEMS have increments greater than 100%. Increments between 40 and 100% are equivocal for presynaptic disorders.

Perform slow RNS (3 Hz) on at least one proximal and one distal motor nerve as in MG (see Box 34–2). Decrements on slow RNS are common in LEMS but cannot differentiate this disorder from MG.

3. Needle electromyography (EMG). Perform routine needle EMG of distal and proximal muscles, especially weak muscles. Needle examination is usually normal. Similar to MG, motor unit action potentials may be unstable or short, small, and polyphasic with normal or early recruitment.

4. Single-fiber EMG (usually not required in LEMS). If performed, findings will be consistent with a neuromuscular junction disorder (increased jitter and blocking), but single-fiber EMG cannot routinely differentiate LEMS from other disorders of the neuromuscular junction.

CMAP, compound muscle action potential; LEMS, Lambert–Eaton myasthenic syndrome; MG, myasthenia gravis.

image

FIGURE 34–5 Compound muscle action potential amplitude in disorders of the neuromuscular junction.

Note the normal amplitude in myasthenia gravis (right) compared with Lambert–Eaton myasthenic syndrome (middle).

(Reprinted from EH Lambert, et al. Myasthenic syndrome occasionally associated with bronchial neoplasm: neurophysiologic studies. In Viets HR, ed. Myasthenia gravis: the Second International Symposium. Springfield, IL: Thomas, 1961:363. With permission.)

Needle EMG results in LEMS are similar to those in MG. Insertional activity is normal, and abnormal spontaneous activity is generally not seen. MUAPs usually are normal. Occasionally they are unstable; rarely they are short, small and polyphasic, similar to myopathic MUAPs. SF-EMG shows increased jitter or blocking, similar to MG, and cannot routinely differentiate between these two disorders.

The diagnosis of LEMS is based on the clinical findings and a diagnostic study demonstrating marked post-exercise facilitation. Prior history of SCLC in a patient with proximal weakness should suggest the diagnosis. The diagnosis of LEMS must be suspected in any patient whose nerve conduction studies show low or borderline low CMAP amplitudes at rest with normal sensory responses. It is not unusual for these findings to be misinterpreted as neuropathy (low amplitudes, normal conduction velocities), even though the sensory potentials are normal. If a patient with LEMS also has a superimposed neuropathy, either from an unrelated cause or as a paraneoplastic process from underlying carcinoma, the diagnosis of LEMS is missed frequently. In any patient with low or borderline low CMAP amplitudes at rest, the distal motor stimulation should be repeated after 10 seconds of maximal exercise looking for post-exercise facilitation of the CMAP (Figure 34–8). Complicating the issue further is the fact that slow RNS in LEMS causes a decremental CMAP response similar to the decrement seen in MG. Many patients with LEMS initially are misdiagnosed with MG when their nerve conduction and RNS studies do not include exercise testing.

Last, patients with an overlap syndrome of both LEMS and MG have been described. Although these cases are exceptionally rare, they have been documented by the presence of ACH receptor antibodies (MG) and a diagnostic EMG with marked CMAP facilitation after exercise (LEMS). These cases tend to occur in patients with primary autoimmune disorders and have not been reported in patients with SCLC or other tumors. As mentioned earlier, many cases of LEMS are initially misdiagnosed as MG. Proximal weakness (with or without mild bulbar or ocular weakness, or both) and a decrement on slow repetitive stimulation may occur in both disorders.

Botulism

Botulism is caused by the potent exotoxin of Clostridium botulinum, which blocks presynaptic release of ACH at both somatic and autonomic synapses. The result is NMJ and parasympathetic blockade.

Clinical

Classically, botulism has been associated with ingestion of improperly prepared food which allows the exotoxin to grow, especially canned vegetables or fish. Botulism also can occur as the result of a wound infection. In the last two decades, the most frequent setting for wound botulism has been in intravenous drug users. The most common clinical presentation of botulism, however, is infantile botulism. In infantile botulism, spores are introduced into the gastrointestinal tract that then germinate and create the toxin that is absorbed. Spores are ubiquitous in the soil and are often found in fresh produce and especially honey. Although there are eight strains of botulism, three are most commonly associated with clinical disease: types A, B, E, and F. In adult botulism, after ingestion of the exotoxin or elaboration of the toxin in a deep wound, symptoms usually occur within 2 to 72 hours. Nausea, vomiting, and abdominal pain are common initially. These symptoms are followed by blurred vision, diplopia, and dysarthria. Rapidly progressive descending weakness follows, usually resulting in a flaccid, areflexic quadriparesis, respiratory compromise, and ophthalmoplegia. The pupils are paralyzed in 50% of patients. Other manifestations of parasympathetic dysfunction include ileus, decreased salivation, and impaired accommodation (cause of initial blurred vision). The illness progresses for 1 to 2 weeks, with recovery occurring slowly over several months. The most important disorder to exclude in the differential diagnosis is MG. Clinically, MG is not usually associated with such a rapid progression, nor is there any autonomic dysfunction in MG. Guillain–Barré syndrome is included in the differential diagnosis, but sensory complaints usually are prominent.

Infantile botulism seldom presents with the dramatic findings of foodborne or wound botulism. The presenting symptoms are often decreased muscle tone and movement, a weak cry, and constipation.

Electrophysiologic Evaluation

The pathophysiology of botulism is presynaptic blocking of ACH, similar to LEMS. Likewise, the electrophysiologic evaluation and findings in botulism and LEMS are similar (Box 34–4). Sensory conduction studies are normal. CMAP amplitudes are decreased with normal latencies and conduction velocities. A decremental response may be seen with slow RNS. An incremental response characteristically occurs after brief exercise (10 seconds) or fast RNS (30–50 Hz). This finding usually is present in mild or early cases. However, the amount of increment is often not as dramatic as in LEMS, and many times it is lower than 100%. Note, in addition, that in severe botulism, if the amount of ACH release has dropped severely below threshold, even facilitation with rapid RNS or brief exercise may not result in a threshold response, and no increment occurs in the CMAP amplitude. Thus, the lack of an incremental response to rapid RNS or brief exercise cannot completely exclude the diagnosis of botulism.

Box 34–4

Electrophysiologic Evaluation of Botulism

1. Routine motor and sensory nerve conduction studies. Perform routine motor and sensory nerve conduction studies in at least two nerves, preferably a motor and sensory nerve in one upper and one lower extremity. CMAP amplitudes usually are diffusely low in amplitude or absent. Latencies and conduction velocities are normal.

2. Repetitive nerve stimulation (RNS) and exercise testing. To look for facilitation, either perform high-frequency (30–50 Hz) RNS or record a CMAP with distal stimulation before and after 10 seconds of maximal voluntary exercise. Exercise testing is better tolerated by patients and is always preferable to fast RNS unless the patient cannot cooperate (e.g., sedated patient, young child). Any increment greater than 40% is abnormal (calculated by [100  ×  (Highest amplitude − Initial amplitude)/Initial amplitude]). Most patients with botulism have increments greater than 100%. Increments between 40 and 100% are equivocal for presynaptic disorders. However, in severe botulism, the neuromuscular junction may be so blocked that facilitation following exercise or rapid RNS may not be seen, and there will be no CMAP increment. The absence of an increment does not exclude the diagnosis of botulism.

Perform slow RNS (3 Hz) on at least one proximal and one distal motor nerve as in myasthenia gravis (see Box 34–2). Decrements on slow RNS may be seen in botulism.

3. Needle electromyography (EMG). Perform routine needle EMG of distal and proximal muscles, especially weak muscles. Needle examination usually is markedly abnormal. After 4 to 5 days, denervating potentials (fibrillation potentials, positive sharp waves) are common. Motor unit action potentials usually are unstable or often short, small, and polyphasic, similar to myopathic motor unit action potentials. Recruitment may be normal, early, or reduced. If every muscle fiber of a motor unit is blocked by the toxin, there is an effective loss of motor units and decreased recruitment.

CMAP, compound muscle action potential.

The needle EMG of botulism is quite interesting. Fibrillation potentials and positive sharp waves, signs of denervation, are common (Figure 34–9). Botulinum toxin is such a potent NMJ blocker that the muscle fibers are effectively chemo-denervated. Similar to other NMJ disorders, MUAPs may be normal or small, short and polyphasic, similar to myopathic MUAPs. Depending on the severity, recruitment may be normal, early, or reduced. The latter may occur if every muscle fiber of a motor unit is blocked by the botulinum toxin, effectively reducing the number of motor units. Likewise, SF-EMG shows increased jitter and blocking, signifying the underlying NMJ dysfunction.

Usually, differentiating between botulism and MG is straightforward, both by clinical and electrodiagnostic findings. In contrast, the electrodiagnostic findings in botulism and LEMS may be indistinguishable (depending on the degree of denervation present in botulism), yet their clinical presentations are markedly different.

Congenital Myasthenic Syndromes

The congenital myasthenic syndromes (CMS) are a group of exceptionally rare disorders caused by an inherited defect in NMJ transmission. These disorders are not immune mediated and thus are not associated with autoantibodies in the blood and do not respond to prednisone, other immunosuppressants, or plasma exchange. They are different from transient neonatal MG, which is caused by the transfer of antibodies via the placenta from a mother with MG to her baby. This latter disorder is self-limited and resolves after several months of life as the maternal antibodies are degraded.

Congenital myasthenic syndromes usually present shortly after birth or in early childhood. The range of CMS phenotypes is large, ranging from severe weakness and arthrogryposis at birth to mild weakness later in life. Similar to autoimmune MG, extraocular, bulbar, and proximal muscles often are affected. Many of the clinical manifestations are static or slowly progressive. Most are autosomal recessive in inheritance.

The CMS syndromes are classified into subgroups depending on the part of the NMJ involved: presynaptic, synaptic, and postsynaptic. Deficiency of the enzyme acetylcholinesterase was the first CMS identified. This was followed by the discovery of other defects, including presynaptic defects of ACH packaging and release, and postsynaptic defects of the ACHR itself. Several kinetic anomalies of ACHR have been demonstrated, as well as reduced numbers of receptors in other patients. In general, postsynaptic CMSs are more common than acetylcholinesterase deficiency which in turn is much more common than presynaptic CMSs.

More recently, the number of gene defects in CMS has expanded greatly, including defects in ACHR subunits and in the collagen tail of the acetylcholinesterase enzyme, as well as mutations in the genes that code for choline acetyltransferase, rapsyn, DOK-7, and the muscle sodium channel SCN4A. Of these, much attention has been focused on rapsyn and DOK-7. Rapsyn is a postsynaptic protein important in ACHR assembly and clustering. RAPSN mutations result in a reduced number and density of ACHRs, and a loss of folds on the postsynaptic membrane. DOK-7 is an activator of MuSK that is essential for formation of the neuromuscular junction (note: this is the same MuSK that is now identified with antibodies in a subset of patients with autoimmune myasthenia gravis). In CMS patients with DOK-7 mutations, the postsynaptic membrane is markedly simplified with fewer postsynaptic folds and clefts. Genetic mutations in DOK-7 and especially rapsyn now account for a sizable number of CMSs. To further complicate things, there are reports of patients with mutations of either RAPSN or DOK-7 that present as young adults, and who are mistaken for seronegative MG.

Similar to the clinical presentations, the electrophysiology of these syndromes is heterogeneous. SF-EMG findings usually are abnormal. Some of the disorders display a decremental response on slow RNS, although prolonged exercise (e.g., 5 minutes) may be necessary to bring out the decrement. Those patients with either a deficiency of endplate acetylcholinesterase or an abnormality in the postsynaptic ion channel (“slow channel syndrome”) may display an unusual finding on routine motor nerve conduction studies: a single impulse results in a repetitive CMAP potential.

Full characterization of these syndromes usually requires a morphologic and in vitro electrophysiologic analysis of an NMJ from a biopsied muscle, in addition to genetic analysis. Patients suspected of having a congenital myasthenic syndrome are best referred to one of the few centers where this special expertise in diagnosis is available.

image Example Cases

image Case 34–1

Summary

The history is that of a young woman with muscle fatigue and weakness affecting extraocular, bulbar, and proximal muscles. Some fatigue is common in most neuromuscular syndromes, as well as in many non-neurologic conditions (e.g., hypothyroidism, anemia). However, muscle fatigue that worsens to frank muscle weakness usually is a sign of an NMJ transmission disorder. On neurologic examination there is evidence of weakness of the left levator palpebrae muscle, accounting for the left ptosis. More importantly, the left ptosis worsens after 1 minute of upgaze. Muscle bulk, tone, and reflexes are normal. This latter finding is important because the reflexes are commonly depressed in LEMS.

In addition, there is mild weakness of proximal upper and lower extremity muscles, including the neck extensors. Weakness of the neck extensors has important diagnostic implications, because patients with MG often have more weakness of neck extension than neck flexion. The opposite pattern is generally seen in patients with myopathic disorders. Therefore, before proceeding to the electrodiagnostic studies, the possibility of an NMJ disorder in this young woman should be considered. Other pure motor syndromes, including myopathy, demyelinating motor neuropathies, and motor neuron disease, remain possible but appear less likely based on the clinical findings.

On nerve conduction studies, the median and ulnar motor conduction studies in the right upper extremity are performed first. Both studies are normal, including the CMAP amplitudes. This finding is important, as CMAP amplitudes are generally preserved in patients with MG and decreased in patients with LEMS. The distal motor latencies, conduction velocities, and F responses are normal, making a demyelinating motor polyneuropathy unlikely. Next, the respective sensory conduction studies also are normal, corresponding to the clinical absence of any sensory abnormalities.

RNS is performed next. Remember that in patients with MG, slow RNS of weak muscles shows a decremental response. The ulnar nerve is selected first for study. The ulnar and other distal nerves have the major advantage of being technically easy to study. The stimulator and recording electrodes can be secured in place and the entire forearm and hand immobilized with an arm board to prevent any movement artifact. At baseline, 3 Hz RNS demonstrates a 4% decrement, which is well within the normal range of 0 to 10%. Next, a more proximal nerve, the spinal accessory, is selected. Of the proximal nerves available for routine RNS, the spinal accessory has very few technical difficulties.

The spinal accessory nerve can easily be stimulated using a low current posterior to the sternocleidomastoid muscle and recorded over the upper trapezius muscle. Although the shoulder cannot be completely immobilized, gentle pressure downward on the shoulder can prevent most movement artifact. RNS at 3 Hz shows a 15% decrement in CMAP amplitude. This amount of decrement is abnormal and is consistent with an NMJ transmission disorder. Because a decrement is seen at rest, the next logical step is to exercise the muscle for 10 seconds and immediately repeat the RNS, looking for the expected post-exercise facilitation. After brief exercise, the 15% decrement at baseline improves to 0% decrement, that is, there is a “repair” of the decrement after brief exercise.

Moving next to the needle EMG, both distal and proximal muscles are examined. Sampling proximal muscles is most important in this case, because these are the ones that are clinically weak. The EMG shows no evidence of abnormal spontaneous activity, and the MUAPs have normal morphology and a normal recruitment pattern. The standard needle EMG examination must always be performed to exclude severe denervating and myotonic disorders, because they also may show a decremental response on RNS. The only abnormality seen on the EMG study is unstable MUAPs, manifested by some variation in the morphology of MUAPs from impulse to impulse. At this time, we are ready to formulate our electrophysiologic impression.

The history, neurologic examination, and subsequent electrophysiologic studies are consistent with a postsynaptic NMJ disorder, in this case, MG. MG commonly presents in a subacute fashion predominantly affecting extraocular and bulbar muscles. Electrophysiologic studies usually show normal motor and sensory nerve conduction studies at rest. RNS at 3 Hz often shows a decremental response at baseline predominantly affecting proximal nerves, if the nerves studied subserve clinically weak muscles. If a decremental response is seen, the decrement can be improved or repaired after 10 seconds of exercise (post-exercise facilitation). If no decrement is seen at rest, 1 minute of exercise followed by RNS at 1, 2, 3, and 4 minutes often can bring out a decremental response (post-exercise exhaustion) after 2 to 3 minutes. This case raises several important questions.

image Case 34–2

Summary

The history and neurologic examination are somewhat complex. This patient has a history of weakness and fatigue but no difficulty with extraocular or bulbar muscles suggesting MG. Indeed, she describes her major problems as difficulty getting out of chairs and going up and down stairs, both of which are suggestive of proximal muscle weakness. In the absence of associated pain or paresthesias, the diagnosis of myopathy seems most likely. The neurologic examination confirms that this is a pure motor problem, given the completely normal sensory examination. As expected from the history, strength testing demonstrates upper and lower extremity proximal weakness and, correspondingly, a waddling gait. No extraocular or bulbar weakness or fatigue is demonstrated. Also noted are hypoactive to absent deep tendon reflexes throughout. Areflexia typically is a neuropathic sign, associated with either severe loss of axons or demyelination.

Before proceeding to the nerve conduction and EMG studies, the differential diagnosis of pure motor weakness predominantly affecting the proximal muscles, with depressed reflexes, should be considered. The most likely diagnosis is myopathy. Next, an NMJ disorder with isolated proximal muscle weakness and depressed reflexes should be considered. Third, some cases of motor neuron disease predominantly affect the proximal muscles, such as seen in the adult-onset spinal muscular atrophies or the progressive muscular atrophy variant of amyotrophic lateral sclerosis. Finally, some rare cases of demyelinating polyneuropathy may be associated with pure muscle weakness predominantly affecting the proximal muscles.

Moving on to the nerve conduction studies, median, ulnar, tibial, and peroneal motor conduction studies, F responses, as well as median, ulnar, and sural sensory conduction studies are performed. All of the sensory conduction studies are normal, which corresponds to the patient’s lack of sensory symptoms and signs. In contrast, all of the motor conduction studies are abnormal. The CMAP amplitudes are reduced in every nerve studied, with normal conduction velocities, distal motor latencies, and F responses. Although the presence of decreased CMAP amplitudes with normal conduction velocities usually implies axonal loss (i.e., from neuropathy, radiculopathy, motor neuron disease), decreased CMAP amplitudes also can be seen in myopathies that affect distal muscles and in NMJ transmission disorders associated with block.

Reviewing the needle EMG findings next, proximal and distal muscles in the right upper and lower extremity are sampled. No spontaneous activity is seen. All MUAPs are normal, with a normal activation and recruitment pattern. At this point, the differential diagnosis can be narrowed further. The differential diagnosis initially included the possibility of a pure motor demyelinating polyneuropathy. The normal distal motor latencies and conduction velocities, and the absence of conduction block and temporal dispersion, virtually exclude a demyelinating polyneuropathy. The possibility of motor neuron disease or a pure axonal motor neuropathy was also considered. Although the neurologic examination was consistent with these, the combination of the nerve conduction and EMG findings excludes these possibilities. It is not possible to have reduced CMAP amplitudes due to axonal loss and normal EMG findings in the muscles used to record those CMAPs. Even in the unusual situation where there has been an acute axonal loss lesion and there has not been enough time for fibrillation potentials to develop, recruitment of MUAPs should be dramatically reduced.

This leaves the possibility of either an NMJ transmission disorder or a myopathy. Myopathies only rarely result in decreased CMAP amplitudes, because most myopathies clinically affect proximal muscles, with relative sparing of the distal muscles that typically are used for recording during motor nerve conduction studies. However, there are some distal myopathies (e.g., myotonic dystrophy, myotubular myopathy, distal recessive inherited myopathy) that may show decreased CMAP amplitudes on routine nerve conduction studies. In such cases, a reduced CMAP amplitude associated with myopathy should show changes on the EMG examination consistent with myopathy, none of which were seen in this case.

Lastly, the possibility of an NMJ transmission disorder must be considered. From the clinical point of view, the possibility of MG seems unlikely because of the absence of extraocular or bulbar weakness, although rare cases of limb girdle MG do occur. In addition, the CMAP amplitudes are reduced, which would be an unusual finding in patients with MG. The other possible diagnosis is LEMS. Patients with LEMS present with proximal weakness and depressed reflexes. On nerve conduction studies, the CMAP amplitudes are characteristically reduced throughout. Note that although the electrophysiologic findings seen in botulism are similar to those in this case, the clinical history of slowly progressive weakness over months, with no ocular or bulbar symptoms, is not consistent with adult botulism.

The next logical step in this case is to perform fast RNS (30–50 Hz) or brief exercise (10 seconds) to look for facilitation. Brief exercise allows the patient to effectively activate his or her nerve at 30 to 50 Hz voluntarily and is always preferable to electrically stimulating the nerve at 50 Hz, which can be quite painful. This procedure is quite simple and straightforward to perform. A single supramaximal distal CMAP is recorded. The patient then is asked to activate his or her muscle maximally for 10 seconds and then quickly relax. A second single supramaximal shock is immediately given, and the CMAP amplitude is measured and compared with the pre-exercise potential. In the present case, the following study (brief exercise) was performed on the median nerve.

After 10 seconds of maximal exercise, the median CMAP amplitude increment is 300% [(10 − 2.5)/2.5 × 100]. This is a dramatic increase that suggests a presynaptic NMJ transmission disorder. At this point, we are ready to formulate our electrophysiologic impression.

After the exercise testing, the study is complete. Taken together, the history, neurologic examination, nerve conduction studies, EMG, and exercise testing suggest one clear diagnosis: that of LEMS. LEMS is a rare autoimmune disorder caused by decreased release of ACH. Patients commonly present with proximal muscle weakness and hyporeflexia or areflexia. The diagnosis often is suggested on routine motor nerve conduction studies, which show diffusely reduced or borderline-reduced CMAP amplitudes with normal distal motor latencies and conduction velocities. In contrast, the sensory potentials are well preserved. This pattern often is mistaken for axonal loss and probable polyneuropathy by many electromyographers. The key to not mistaking this pattern for a polyneuropathy with axonal loss is first recognizing that the sensory potentials are normal. Few axonal polyneuropathies have normal sensory potentials with reduced motor responses. Next, the needle EMG–nerve conduction correlation must be considered. If the nerve conduction studies show decreased CMAP amplitudes due to axonal loss, there should be clear findings of denervation and reinnervation on the needle EMG. If the needle EMG does not show denervation or reinnervation or reduced recruitment of MUAPs, the diagnosis of motor neuron disease or axonal loss of any etiology is not tenable. This case raises several important questions.

image Case 34–3

Summary

The history is that of a woman presenting with the acute onset of rapidly progressive bulbofacial, extraocular, respiratory, and proximal limb muscle weakness, accompanied by poor pupillary responses and areflexia. Sensation is spared. There is no history of toxin exposure, recent travel, tick bite, flu, or vaccinations. The differential diagnosis of a rapidly progressive paralytic disorder includes Guillain–Barré syndrome, as well as MG, botulism, poliomyelitis, tick paralysis, acute intermittent porphyria, and organophosphate poisoning.

Reviewing the nerve conduction studies, the left median, ulnar, tibial, and bilateral facial CMAP amplitudes are either markedly reduced, with preserved distal motor latencies and conduction velocities, or absent. The F responses are absent. In contrast, the left median, ulnar, and sural sensory potentials are normal. Thus far, the nerve conduction studies are not unlike the previous case (diffusely low CMAPs with normal sensory potentials), although the clinical presentation is quite different: that of rapidly evolving weakness involving bulbofacial, extraocular, pupillary, and respiratory muscles.

Just as in the previous case, the combination of normal sensory conduction studies and low amplitude CMAPs with normal distal motor latencies and conduction velocities suggests a differential diagnosis of myopathy, motor neuron disease, polyradiculopathy, or NMJ transmission disorder. To evaluate the possibility of an NMJ transmission disorder, RNS and exercise testing are done next. Three-hertz RNS of the left ulnar nerve recording the abductor digiti minimi reveals a 15% decrement in the CMAP amplitude. In contrast, 30 Hz RNS results in a 250% increment, findings suggestive of a presynaptic NMJ transmission defect. Similar increments are found after 10 seconds of exercise with ulnar, median, and tibial CMAPs recorded.

Moving next to the EMG study, there is increased insertional activity in all muscles studied, with fibrillation potentials in several muscles. The MUAPs are small, short, and polyphasic, with a normal or early recruitment pattern. The findings on the needle EMG examination suggest that denervation also has taken place, with associated “myopathic” findings on the needle study. We now are ready to formulate our electrophysiologic impression.

The findings of acute onset of bulbofacial, extraocular, respiratory, and proximal muscle weakness, in conjunction with the nerve conduction studies, RNS studies, exercise testing, and needle EMG findings, are most consistent with a diagnosis of botulism. Subsequently, the patient revealed that she had tasted some home-preserved peaches but had discarded the canning jar because it smelled rancid. Trivalent botulinum antitoxin was administered within 24 hours, with slight clinical improvement over the next week. Clostridium toxin type B was isolated in the stool extract as well as from the residue from the canning jar, but it was not found in the serum.

This case raises several important questions.

Are the Clinical and Electrophysiologic Findings Consistent with a Diagnosis of Myasthenia Gravis or Lambert–Eaton Myasthenic Syndrome?

MG may present with rapid onset of bulbar, extraocular, respiratory, and limb weakness. However, several clinical and electrophysiologic findings are not consistent with MG. Autonomic dysfunction (i.e., poor pupillary response) is not seen in MG, as is seen in this case. Although the decremental response to slow repetitive stimulation is consistent with a diagnosis of MG, a prominent incremental response after brief exercise or rapid RNS, as well as the low baseline CMAPs, would be extremely unusual in MG. Furthermore, although MUAPs may be small and short with early recruitment, fibrillation potentials would be unusual in MG.

In LEMS, low baseline CMAP amplitudes, accompanied by incremental responses to brief exercise or rapid repetitive stimulation, are seen, as in this case. However, the needle EMG examination in LEMS usually is entirely normal, without fibrillation potentials, although occasionally small, short MUAPs can occur with early recruitment. Otherwise, it is the clinical, not the electrophysiologic, findings that differentiate LEMS from botulism. The two are distinctly different clinically. LEMS usually presents over months with proximal weakness and hyporeflexia, whereas botulism presents acutely and dramatically, with paralysis involving extraocular, bulbar, and respiratory muscles, often with prominent autonomic dysfunction.

What Other Diagnoses should be Considered?

Electrodiagnostic testing helps differentiate botulism from other paralytic disorders, including Guillain–Barré syndrome, tick paralysis, poliomyelitis, porphyria, and organophosphate poisoning. Guillain–Barré syndrome, poliomyelitis, tick paralysis, and acute intermittent porphyria all may reveal low CMAP amplitudes, but there should be no incremental response to brief exercise or fast repetitive stimulation in any of these disorders. Furthermore, Guillain–Barré syndrome usually reveals acquired demyelination on nerve conduction studies (e.g., conduction velocity slowing, prolonged late responses, conduction block), with reduced recruitment of MUAPs on needle EMG. Acute poliomyelitis generally presents as a febrile illness followed within days by focal, asymmetric paralysis. Although CMAP amplitudes may be low and fibrillation potentials noted on EMG, there is reduced recruitment of MUAPs in poliomyelitis. Tick paralysis results in rapidly ascending weakness. Although the CMAP amplitudes are low, with prolonged distal motor latencies and mild conduction velocity slowing, no incremental response is seen with brief exercise. Porphyria is generally accompanied by abdominal pain and psychiatric disturbance. Electrodiagnosis reveals an axonal neuropathy with reduced recruitment of MUAPs. Organophosphate poisoning may present with acute weakness, but miosis and fasciculations differentiate this poisoning from botulism. Nerve conduction studies may show repetitive CMAPs to a single stimulus, with no incremental response to fast repetitive stimulation or brief exercise.

Suggested Readings

Alseth E.H., Maniaol A.H., Elsais A., et al. Investigation for RAPSN and DOK-7 mutations in a cohort of seronegative myasthenia gravis patients. Muscle Nerve. 2011;43(4):574–577.

Engel A.G. Congenital myasthenic syndromes. Neurol Clin. 1994;2:401.

Engel A.G. Lambert–Eaton myasthenic syndrome. Ann Neurol. 1987;22:193.

Engel A.G. Congenital myasthenic syndromes. In: Katirji B., Kaminski H.J., Preston D.C., et al. Neuromuscular disorders in clinical practice. Boston: Butterworth-Heinemann, 2002.

Gilchrist J.M. Single fiber EMG. In: Katirji B., Kaminski H.J., Preston D.C., et al. Neuromuscular disorders in clinical practice. Boston: Butterworth-Heinemann, 2002.

Hantay D., Richard P., Koeniga J., et al. Congenital myasthenic syndromes. Curr Opin Neurol. 2004;17:539–551.

Hatanaka Y., Oh S.J. Ten-second exercise is superior to 30-second exercise for post-exercise facilitation in diagnosing Lambert–Eaton myasthenic syndrome. Muscle Nerve. 2008;37:572–575.

Hubbard J.I. Microphysiology of vertebrate neuromuscular transmission. Physiol Rev. 1973;53(Suppl):674.

Jablecki C. AAEM case report no. 3: myasthenia gravis. AAEM. 1991.

Jablecki C. Lambert–Eaton myasthenic syndrome. Muscle Nerve. 1984;7:250.

Keesey J.C. AAEM minimonograph, no. 33: electrodiagnostic approach to defects of neuromuscular transmission. AAEM. 1989.

Kimura J. Electrodiagnosis in diseases of nerve and muscle. Philadelphia: FA Davis; 1989.

Macdonell R.A., Rich J.M., Cros D., et al. The Lambert–Eaton myasthenic syndrome: a cause of delayed recovery from general anesthesia. Arch Phys Med Rehabil. 1992;73:98.

Milone M., Shen X.M., Selcen D., et al. Myasthenic syndrome due to defects in rapsyn: clinical and molecular findings in 39 patients. Neurology. 2009;73:228–235.

ONeill J.H., Murray N.M.F., Newsom-Davis J. The Lambert–Eaton myasthenic syndrome: a review of 50 cases. Brain. 1988;111:577.

Pasnoor M., Wolfe G.I., Nations S., et al. Clinical findings in MuSK-antibody positive myasthenia gravis: a U.S. experience. Muscle Nerve. 2010;41:370–374.

Shapiro B.E., Soto O., Shafquat S., et al. Adult botulism. Muscle Nerve. 1997;20:100.