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 ).

Nerve Conduction Studies

In any patient suspected of having MG, routine motor and sensory nerve conduction studies cannot be omitted. At least one motor and sensory conduction study should be performed in an upper and lower extremity, but the number of nerves studied often depends on the clinical context. Particular attention must be paid to compound muscle action potential (CMAP) amplitudes. Normal CMAP amplitudes are an important and expected finding in MG, in direct contrast to LEMS, where baseline CMAPs usually are diffusely low. In only a small number of patients with MG (3–15%), the baseline CMAPs at rest are below the normal range.

Routine nerve conduction studies also must be performed to ensure the integrity of any nerve that subsequently will be used for RNS. A decrement on RNS can be seen in various denervating conditions (e.g., neuropathies, motor neuron disorders, inflammatory myopathies) and myotonic disorders, in addition to primary disorders of the NMJ. For instance, a decrement on RNS of the ulnar nerve may be seen in a severe ulnar neuropathy with denervation; such a finding in this context does not imply a primary NMJ disorder.

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).

Repetitive nerve stimulation (3 Hz) in myasthenia gravis.

Stimulating the ulnar nerve at the wrist, recording the first dorsal interosseous. Maximal decrement noted to right of traces. A: Baseline. B: Immediately after 10 seconds of exercise (post-exercise facilitation). C, D: Two and 3 minutes after 60 seconds of exercise (post-exercise exhaustion). E: Immediately after 10 seconds of exercise again (post-exercise facilitation and repair of the decrement).

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.

Single-fiber electromyography (SF-EMG).

After depolarization of a neuron and its axon, all muscle fibers of the motor unit fire at approximately the same time. Variation among the firing times of individual muscle fibers occurs primarily due to different lengths of the terminal axons and neuromuscular junction transmission times. An SF-EMG needle placed between two individual muscle fibers can record the variation in firing times of two adjacent muscle fibers of the same motor unit.

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).

Single-fiber electromyography needle.

The active electrode (G1) is located in a port along the posterior shaft of the needle, with a smaller leading surface area than a conventional concentric needle electrode. The reference electrode (G2) is the needle shaft.

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).

Single-fiber electromyography recordings.

A: Normal. B: Increased jitter. C: Blocking. In each set, five rastered traces (top) and superimposed traces (bottom) are shown. Both increased jitter and blocking are seen in neuromuscular junction disorders.

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.

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 ).

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.)

Rapid repetitive nerve stimulation (50 Hz) in Lambert–Eaton myasthenic syndrome.

Note marked increment (>250%) in compound muscle action potential amplitude.

Slow (3 Hz) repetitive nerve stimulation in LEMS, before and after brief exercise.

In both situations, there is a prominent decrement. However, after brief exercise, the baseline compound muscle action potential (CMAP) is significantly larger compared with the CMAP before exercise. In this case, the CMAP increment after brief exercise was 2000%.

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.

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