Emg

The first described clinical neurophysiological abnormality in MG was by Harvey and Masland in 1941, when they reported variability in motor unit potential (MUP) amplitudes. The defect in MG is widespread but not universal; individual motor end plates are affected to varying degrees, even within the same motor unit. Some NMJs may be nonfunctional, some may have marginal safety factors, and others may be healthy. Because of this variable involvement, during muscle contraction, NMT may fail at a variable number of NMJs with each MUP firing, resulting in variation in amplitude and area of the MUP. This is not specific to MG, because it can be observed in any disorder of NMT, including presynaptic and postsynaptic diseases. It is a common finding in ongoing reinnervation after nerve injury, but can also be observed in acute denervation, old polio and postpolio syndrome, amyotrophic lateral sclerosis, and myopathic injury and recovery.

2.2. Repetitive Stimulation

Repetitive stimulation of nerve (RNS) while recording from muscle has been a valuable tool in the assessment of NMT since 1941, and remains the technique in widest use. It is easy to learn, easy to perform, not invasive, and requires no special equipment or training. On the negative side, it is often painful and poorly tolerated, is prone to artifact if not performed properly, and has a limited sensitivity, especially in localized diseases affecting NMT, such as ocular MG. The usual technique is to give a train of supramaximal electrical stimulations to a motor or mixed nerve while recording from an appropriate muscle. The train is usually four to nine stimuli long. For most indications, a rate of 2 to 3 Hz is most appropriate. This should be performed at rest, with the amplitude of the first compound motor action potential (CMAP) compared with the fourth or fifth. Significant decrement is usually defined as exceeding 10% (Fig. 3). After this, the patient should maximally contract the muscle for 1 min, if possible, which is followed by trains of stimuli immediately and at 30-s intervals out to at least 3 min. Decrement may repair immediately after exercise but should reach a maximum amount between 2 and 3 min after exercise, a phenomenon known as postactivation exhaustion. The improvement in decrement is called facilitation and is caused by increased calcium concentration in the terminal axon leading to enhanced release of acetylcholine. Small increments in CMAP amplitude can also be observed in healthy people.

10 m Sec

Fig. 3. Repetitive stimulation in a patient with myasthenia gravis demonstrating typical U-shaped decrement: maximal by the third or fourth stimulation in the train of nine, with return toward normal by the ninth stimulation. Decrement, calculated by comparing the fourth evoked response amplitude to that of the first, exceeds 65%.

There are several caveats worth noting regarding RNS:

1. Two- to 5-Hz stimulation is preferred if looking for decrement. One-hertz stimulation is usually too slow to produce decrement, and rates faster than 5 Hz may produce facilitation of the response, masking any decrement.

2. Maximal voluntary contraction for 10 to 60 s (depending on the strength of the patient) followed by a supramaximal nerve stimulus is the preferred method for looking for increment. In patients who cannot cooperate, or are too weak to voluntarily contract the muscle, rapid stimulation up to 50 Hz can be performed but this is exquisitely painful and should not be performed for more than 10 s unless the patient is deeply comatose.

3. Proximal muscles are more likely to show decrement in MG than are distal muscles, but proximal muscles are more prone to technical artifact and are more painful.

4. Decrement disappears as muscle temperature drops, therefore, a cool limb can result in failure to elicit decrement even if there is a defect in NMT. This is a greater problem with distal muscles, which should be warmed to at least 32°C. On the other hand, warming a limb above standard temperature may enhance a mild decrement.

5. In healthy individuals, CMAPs can increase up to approx 40% in amplitude simply because of the phenomenon of pseudofacilitation. Hence, increments of greater than 40% should be considered abnormal, although most patients with LEMS have considerably greater increments, in the range of 100 to 400% (see below).

6. Stimulation site and intensity must remain constant throughout the test because decreases in intensity may mimic decrement.

7. A healthy NMJ should have no decrement, but, because of the technical limitations of RNS, a decrement of up to 10% is within normal limits.

There have been several studies of the sensitivity of RNS in MG and LEMS, including comparisons to other techniques. In summary, RNS in MG is more likely to be abnormal in generalized disease than in ocular MG, is marginally more sensitive than measurement of acetylcholine receptor antibodies, is less sensitive than single-fiber EMG (SFEMG) at all levels of disease, and the diagnostic yield increases as more muscles are studied. The yield for a distal muscle RNS in generalized disease is 40% and approaches 70% for a proximal muscle.

NMT is an energy-dependent activity and ischemia will affect it adversely. This is the basis for an uncommonly used procedure, called double-step repetitive stimulation. This method

Repetitive Stimulation Myasthenie

Fig. 3. Repetitive stimulation in a patient with myasthenia gravis demonstrating typical U-shaped decrement: maximal by the third or fourth stimulation in the train of nine, with return toward normal by the ninth stimulation. Decrement, calculated by comparing the fourth evoked response amplitude to that of the first, exceeds 65%.

PRE-EXERCISE

POST-EXERCISE

50 HZ STIMULATION

POST-EXERCISE

50 HZ STIMULATION

Lamert Eaton Inkrement

1 MV

Fig. 4. Repetitive stimulation in a patient with Lambert-Eaton myasthenia syndrome. Pre-exercise shows a very small CMAP with decrement at low rates of stimulation. When repeated after exercise, the CMAP amplitude has increased by several hundred fold but decrement persists. The bottom trace is at 50 Hz stimulation and shows initial decrement followed by dramatic increment in CMAP amplitude. From Maselli R, 1998.

1 MV

Fig. 4. Repetitive stimulation in a patient with Lambert-Eaton myasthenia syndrome. Pre-exercise shows a very small CMAP with decrement at low rates of stimulation. When repeated after exercise, the CMAP amplitude has increased by several hundred fold but decrement persists. The bottom trace is at 50 Hz stimulation and shows initial decrement followed by dramatic increment in CMAP amplitude. From Maselli R, 1998.

requires near-nerve needle stimulation of the ulnar nerve at the wrist at 3 Hz for 4 min while recording from the abductor digiti quinti muscle, measuring decrement, then repeating the 4 min of 3-Hz stimulation with a sphygmomanometer inflated above systolic blood pressure, measuring decrement after the cuff is deflated. This technique has been shown to increase sensitivity in MG comparable to proximal muscle RNS, but still lags considerably behind

Eaton and Lambert first described RNS in LEMS in 1956. At a low rate of stimulation, these patients will have decrement indistinguishable from MG. At high rates of stimulation, or after maximal voluntary activation of the muscle, there will be an increment in the response reaching and exceeding 100% in most patients (Fig. 4). This facilitation of the CMAP is not unique to LEMS, and up to 90% CMAP facilitation has been reported in MG. However, increase in the CMAP by 100% should be considered diagnostic of a presynaptic defect. A recent large study of LEMS found 98% of patients had decrement with 3-Hz stimulation, 88% of patients had CMAP potentiation greater than 100% in at least one muscle, but only 39% had potentiation greater than 100% in all three muscles studied.

2.3. Single-Fiber EMG

SFEMG is the selective recording of a limited number of single muscle fiber action potentials from one motor unit in vivo. This requires a needle electrode with different specifications from a concentric or monopolar needle electrode, and SFEMG needle electrodes have a dramatically smaller recording area than either. A SFEMG recording surface is 25 ^m in diameter, with an effective recording area of 300 ^m3, as compared with a concentric needle

SFEMG.

electrode, which records from approx 1 cm3. A smaller electrode emphasizes the amplitude difference between close and distant fiber potentials. A smaller recording surface will also restrict the number of recordable muscle fiber potentials. In addition, muscle fiber potentials adjacent to the recording electrode will have high amplitudes and short duration, and relatively more high-frequency components compared with more distant potentials. By using a high-pass filter of 500 Hz, much of the amplitude of distant muscle fiber potentials will be attenuated while preserving that of the nearby potentials. This allows single muscle fiber potentials to be selectively studied while the rest of the MUP is effectively dampened to nil.

By counting the number of single muscle fiber potentials observed with each MUP firing, the number of muscle fibers from that MUP within the small recording territory of the SFEMG needle electrode can be determined. For the most part, this should be one or two. Sampling 20 different sites in a muscle allows calculation an average number of single muscle fiber potentials per recording site. This is called the fiber density. In conditions with loss of random distribution of MUP muscle fibers, such as reinnervation, fiber density will increase. Specific disorders that can increase fiber density include anterior horn cell diseases, such as spinal muscular atrophy, polio, postpolio muscular atrophy, and amyotrophic lateral sclerosis; and any peripheral or cranial neuropathy with axonal loss, specifically, those caused by diabetes, alcohol, uremia, toxins, amyloidosis, Guillain-Barré syndrome, chronic demyelinating inflammatory polyneuropathy, and multiorgan failure. The only study to compare etiologies found that alcoholic polyneuropathy produced higher fiber densities than did uremic or diabetic neuropathy, despite (or because of) better nerve conduction velocities. A variety of muscle disorders will also have increased fiber densities, especially as the disease progresses and chronic disability ensues, including muscular dystrophies, inflammatory myopathies, mitochondrial myopathies, and congenital myopathies.

In those instances in which two or more fiber potentials from a single MUP are recorded, an interpotential interval (IPI) can be calculated. By recording multiple consecutive firings of the muscle fiber potentials, the difference between consecutive IPIs can be calculated. The variation amongst these consecutive IPIs is called jitter. Jitter is most accurately determined by calculating a mean consecutive difference using the formula:

Mean consecutive difference = [(IPI1 - IPI2) + ... + (IPIn-1 - IPIn)]/(n-1)

Jitter is thought to derive from variation in the time in takes the NMJ EPP to reach threshold for action potential generation at the postsynaptic membrane. In disorders with disturbed NMT, there will be an increased variation in the time taken to attain an EPP capable of reaching threshold. This will lead to increased jitter (Fig. 5). Therefore, abnormal jitter is an indicator of abnormal NMT.

In those instances in which an EPP fails to reach threshold for action potential generation, one of the muscle fiber potentials in the pair will be absent. This is called impulse blockade (Fig. 5). It is another indicator of abnormal NMT, usually indicating a more severe disturbance than increased jitter alone. Impulse blocking, often referred to simply as blocking, is usually intermittent, with the affected fiber potential appearing and disappearing in an unpredictable pattern. Blocking is uncommonly observed with jitter less than 100 ^s.

Increase jitter, and even blocking, are not specific to MG or LEMS, and can be observed in any disorder of NMT. It is an early finding in any neuropathy with axonal loss, including

Abnormal Emg Findings

NORMAL JITTER ABNORMAL JITTER ABNORMAL JITTER

AND BLOCKING

Fig. 5. Single-fiber EMG examination for jitter in normal and abnormal motor end plates. (A) Superimposed and (B) serial traces indicating (from left to right) normal jitter, increased jitter without impulse blocking, and increased jitter as well as blocking.

NORMAL JITTER ABNORMAL JITTER ABNORMAL JITTER

AND BLOCKING

Fig. 5. Single-fiber EMG examination for jitter in normal and abnormal motor end plates. (A) Superimposed and (B) serial traces indicating (from left to right) normal jitter, increased jitter without impulse blocking, and increased jitter as well as blocking.

acute transection. Wallerian degeneration after nerve fiber transection transpires over 11 to 14 d, and sensory nerve action potentials become unobtainable below the transection by 11 d. However, CMAPs are lost within 7 d of nerve transection, because NMT fails before the nerve fiber becomes inexcitable. Increased jitter will be observed in anterior horn cell disorders, acute and chronic peripheral neuropathies, and myopathies. It is a reflection of acute denervation and subsequent failure of NMT, as the nerve terminus degenerates, and reinnervation, as the nerve terminus regenerates and the NMJ matures. In muscle disease, jitter indicates degeneration of motor end plates caused by myofiber degeneration as well as myofiber regeneration with immature motor end plates. However, it is in the primary disorders of NMT that SFEMG jitter studies are most useful.

SFEMG has been used in the diagnosis of MG since at least 1971. Since then, there have been numerous studies of the sensitivity of SFEMG in diagnosing MG, and comparisons to other diagnostic techniques. The largest series of SFEMG studies in MG reported the results of 788 patients. Results of SFEMG of the extensor digitorum communis muscle was abnormal in 85% of all patients with MG at the time of initial examination. If the extensor digito-rum communis muscle was healthy, and a second muscle was studied, 85% of those patients had abnormal jitter studies. Thus, if two muscles were studied when the first was normal, results of SFEMG for jitter analysis were abnormal in 98% of all patients with MG. This far exceeds the sensitivity of all other diagnostic tests for MG, as further illustrated by several comparative studies, which, in one study, found SFEMG to be the most sensitive, at 92% (testing a single muscle); with RNS at 77% (testing multiple muscles) and acetylcholine receptor antibody testing at 73%. SFEMG was sensitive regardless of whether disease was generalized or ocular; the yield was higher than 90%, even in ocular disease, if more than one muscle was studied.

The enhanced sensitivity of SFEMG makes physiological sense: RNS results will not be abnormal until at least 10% of muscle fiber end plates undergo impulse blockade and, therefore, fail to generate or propagate a muscle fiber action potential. Muscle fibers with slowed and unstable NMT, but not so affected that they are blocked, will count as normal. SFEMG not only can determine the fibers with impulse blockade, but, by assessing jitter, will allow those fibers with disturbed but still functional NMT to be measured.

SFEMG studies of jitter and impulse block also correlate well with the clinical severity of the disease. Mean jitter, percentage of fiber pairs with increased jitter, and percentage of fiber pairs with blocking all increase with worsening disease. Mean jitter worsens by at least 10% in two-thirds of patients when their disease worsens, and mean jitter improves by at least 10% in 80% of patients who clinically improve. Despite the sensitivity of SFEMG to changes in NMT, SFEMG does not predict progression of ocular MG to generalized disease.

Results of SFEMG jitter studies are also abnormal in LEMS, often more so than would be expected from the clinical picture. Large case series with SFEMG studies are not available, but virtually all patients reported have had markedly abnormal jitter and large percentages of blocking fibers. Because of the presynaptic nature of LEMS, a relationship between jitter and firing rate would be predicted, but, in fact, this is variable. It is safe to say that a dramatic improvement in jitter and blocking with increasing firing rate is suggestive of a presynaptic defect in NMT.

Botulism arises from defective presynaptic release of acetylcholine caused by the toxin of Clostridium botulinum. Results of SFEMG are abnormal in 95% of patients with botulism, and in 100% of botulism patients with clinical weakness. Results of SFEMG studies improve as patients improve. Initially, fiber density is normal but, because botulism causes an irreversible block of acetylcholine release, patients improve by reinnervation and fiber density increases.

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