Neuromuscular Junction Disorders

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, wherein 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%–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 ( Fig. 37.1A ). 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 antibody–associated MG, wherein the yield of finding an abnormal decrement is much higher when examining a facial muscle than a limb muscle. This likely reflects the severe facial and bulbar involvement in some patients with anti-MuSK antibody–associated 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 3–4 minutes, looking for a CMAP decrement secondary to postexercise 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 postexercise facilitation ( Fig. 37.1 ).

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 MUAPs; 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 ( Fig. 37.2 ). 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 first changing the filters on the EMG machine. The low-frequency filter (high-pass) is increased to either 500 or 1000 Hz (normally 10 Hz in routine EMG). By using a high-pass filter of 500 or 1000 Hz, the amplitudes of distant muscle fiber potentials are attenuated while those of the nearby fibers are preserved. The dedicated 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 ( Fig. 37.3 ). 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 200–300 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).

SF-EMG is technically demanding. The optimal single-fiber potentials are those in which the amplitude is at least 200 μV in amplitude and the rise time is 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 50–100 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 37.3 ). There is also an upper limit of normal jitter for an individual pair, based on the muscle studied and the patient’s age. For the upper limit of jitter of a muscle to be deemed abnormal, more than 10% of the pairs must exceed the upper limit of normal (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 measures will be abnormal. Increased jitter is consistent with an NMJ disorder ( Fig. 37.4 ). 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).

The classic SF-EMG procedure is based on voluntary activation. The patient is instructed to maintain a low level of constant contraction as the electromyographer slowly moves the SF-EMG needle to a location where one spike is seen and triggered. Other spikes which are time locked to the index potential are then looked for, often by slightly rotating the needle. However, in normal muscle, it is uncommon for two muscle fibers from the same motor unit to be located adjacent to each other (recall the “mosaic pattern” of motor unit innervation of muscle). Thus finding a “pair” on SF-EMG is often difficult and time consuming. An alternative method was devised using stimulated single fiber . Using this method, recording with the SF-EMG needle is identical. However, voluntary activation is not used. The nerve to the muscle being recorded is stimulated, either with a needle or surface electrode, usually at 10 Hz. This greatly simplifies recording single-fiber potentials. However, this method has created several technical challenges. One cannot supramaximally stimulate a nerve as this would cause too much artifact from the contracting muscle, as well as being too painful for the patient. Thus submaximal stimulation is used. However, this often results in some fibers being consistently stimulated whereas others (potentially slightly farther away or deeper) are on the edge of depolarization. If not recognized, recording these potentials can lead to the mistaken appearance of increased jitter and block. In addition, the jitter using stimulated SF-EMG only represents the variation in firing of one NMJ. In conventional voluntary SF-EMG, one is triggering off of one single fiber, with its own jitter, and recording another single fiber of the same motor unit, with its separate jitter. Thus normal jitter values in voluntary SF-EMG are larger than stimulated SF-EMG values as they represent two as opposed to one NMJ. Although stimulated SF-EMG can be performed much more quickly than voluntary SF-EMG, it is a much more advanced skill with many more technical challenges to obtaining valid data.

More recently, the regular disposable concentric EMG needle has become the preferred needle for SF-EMG studies. The dedicated SF-EMG needle is expensive and needs to be surgically sanitized between patients. Thus the cost of the standard SF-EMG needle, the theoretical risk of transmitting infection (including prion diseases), and patient reluctance to have any procedure performed with a “reused” needle (despite surgical sanitization) prompted this change. Despite the recording area from the smallest concentric needle being much larger than that of the dedicated SF-EMG needle, concentric needles have been found to be acceptable for SF-EMG studies. In one large multicenter study of normal subjects, the jitter of three muscles (orbicularis oculi, frontalis, and extensor digitorum communis) was determined both for voluntary and stimulated studies ( Table 37.4 ). In general, the values for jitter are slightly smaller using a concentric EMG needle compared with a traditional SF-EMG needle.

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.