Genetic linkage and mutational analyses have identified the molecular basis for several of the myotonic muscle disorders and periodic paralysis syndromes, resulting in the classification of these disorders based on a specific ion channel or protein kinase defect. Classification of these disorders now can be accomplished based on clinical, electrophysiologic, and molecular findings (Table 36–1). Once myotonia is identified on clinical or needle EMG examination, the electrophysiologic evaluation is directed toward answering several key questions to arrive at the correct diagnosis. To answer these questions, a variety of tests can be performed in the EMG laboratory to distinguish among the dystrophic and nondystrophic myotonic muscle disorders, the periodic paralysis syndromes, and other disorders of muscle with accompanying EMG myotonia. In addition to routine nerve conduction studies and needle EMG, muscle cooling, exercise testing, and repetitive nerve stimulation often are very helpful in differentiating among these disorders (Box 36–2).

Table 36–1 Clinical Features of Myotonic and Periodic Paralysis Disorders

Box 36–2

Protocol for Evaluation of Myotonic and Periodic Paralysis Disorders

1. Routine motor and sensory nerve conduction studies should be done first. Generally one or two motor and sensory conduction studies and corresponding F responses in an upper and lower extremity should be performed. Distal CMAPs may be low in the dystrophic myopathies. Proceed to needle EMG.

2. Needle EMG study is carried out after standard conduction studies are completed. The study should include proximal and distal muscles of one upper and lower extremity, as well as facial and paraspinal muscles. Careful note should be made of abnormal spontaneous activity, including myotonic discharges, complex repetitive discharges, fibrillation potentials and positive waves, and MUAP potential configuration and recruitment pattern.

3. Muscle cooling is carried out if there is a clinical suspicion of paramyotonia congenita.

A. Wrap the limb in a plastic bag, submerge in ice water for about 10 to 20 minutes to bring skin temperature to 20°C. Remove the patient’s hand from water. The hand should always be removed from the ice water if weakness develops.

B. Needle EMG of a distal forearm or hand muscle is performed, noting the presence of abnormal spontaneous activity (e.g., fibrillation potentials, myotonic bursts) and MUAPs with voluntary contraction.

C. Allow muscle to rewarm to precooling temperature and continue to record EMG activity (may take >1 hour).

4. Short exercise test is performed if steps 1, 2, and 3 do not yield a definitive diagnosis.

A. Immobilize hand. Record supramaximal CMAP at abductor digiti minimi stimulating ulnar nerve at the wrist.

B. Record the CMAP once per minute for 5 minutes with muscle at rest to ensure no decrease in the baseline CMAP.

C. Have the patient perform maximum voluntary contraction for 5 to 10 seconds.

D. Record the CMAP immediately. If a decrement in amplitude is seen, continue to record the CMAP every 10 seconds until it recovers to baseline (typically 1–2 minutes).

E. In cases where a decrement is seen after exercise, repeat the same procedure several times to see if a decrement in the CMAP continues to occur or habituates.

5. Prolonged exercise test is performed if steps 1, 2, 3, and 4 do not yield a definitive diagnosis.

A. Immobilize hand. Record supramaximal CMAP at abductor digiti minimi, stimulating ulnar nerve at the wrist.

B. Record the CMAP once per minute for 5 minutes with muscle at rest to ensure a stable baseline.

C. Have the patient perform maximal voluntary muscle contraction for 2 to 5 minutes, resting every 15 seconds for 3 to 4 seconds.

D. After the 5 minutes of exercise are complete, have the patient relax completely.

E. Record the CMAP immediately, then every 1 to 2 minutes for 40 to 60 minutes afterward or until there is no further decline observed in the CMAP (this can go on for >1 hour). Decrement is calculated as follows: (Highest CMAP amplitude after exercise − Smallest CMAP amplitude after exercise)/(Highest CMAP amplitude after exercise × 100). Any decrement >40% definitely is abnormal.

F. Note that immediately after exercise, the CMAP may be larger, before the slow decline in amplitude takes place. This finding is more common when the pre-exercise rest produces a drop in CMAP, as seen in the periodic paralyses.

6. Repetitive nerve stimulation at 10 Hz.

CMAP, compound muscle action potential; EMG, electromyography; MUAP, motor unit action potential.

Muscle Cooling

In some of the myotonic disorders, muscle cooling can be used to enhance myotonic discharges or bring out other characteristic abnormalities (see sections on Myotonia Congenita and Paramyotonia Congenita). Muscle cooling is best accomplished by wrapping the limb in a plastic bag and submerging it in ice water for 10 to 20 minutes. After the skin temperature is brought down to 20°C, needle EMG of the extremity is performed, with the electromyographer looking for abnormalities. Note that the limb should always be removed from the ice water if weakness develops.

Exercise Testing

Exercise testing can play an important role in the periodic paralysis and myotonic syndromes. Both short and prolonged exercise tests can be performed. In both, a routine distal compound muscle action potential (CMAP) is evoked with supramaximal stimulation (e.g., stimulating the ulnar nerve at the wrist, recording the abductor digiti minimi [ADM]). The nerve then is stimulated at 1-minute intervals for several minutes to ensure a stable baseline, before exercise is begun.

Short Exercise Test

For the short exercise test, the patient is asked to rest for about 5 minutes while a CMAP is recorded every minute, to ensure that the baseline is stable and does not decrease at rest. The patient is then asked to perform maximal voluntary contraction for 5 to 10 seconds. Immediately afterward, a CMAP is recorded. If a decrement in amplitude is seen, then a CMAP is recorded every 10 seconds until the CMAP recovers to baseline (typically 1–2 minutes) (Figure 36–2). If a decrement occurs after brief exercise and then recovers, the same procedure is repeated several times to see if the decrement continues to occur or habituates, which can help differentiate among some of the myotonic syndromes (discussed later).

FIGURE 36–2 Short exercise test in the myotonic syndromes.

After a brief maximal voluntary contraction, the compound muscle action potential (CMAP) immediately decrements in the myotonic syndromes. If subsequent CMAPs are evoked every 10 seconds, the decrement recovers to baseline in 1 to 2 minutes in myotonic dystrophy and myotonia congenita (top). Numbers on the left refer to the time in seconds measured after the exercise. In paramyotonia congenita, the recovery may be quite delayed, in the range of 10 to 60 minutes.

(From Streib, E.W., 1987. AAEE minimonograph, no. 27: differential diagnosis of myotonic syndromes. Muscle Nerve 10, 606, with permission.)

Prolonged Exercise Test

For the prolonged exercise test, the recording procedure is the same. The patient is asked to rest for about 5 minutes while a CMAP is recorded every minute, to ensure the baseline is stable and does not decrease at rest. After ensuring a stable baseline, the patient is asked to voluntarily contract his or her muscle maximally for 5 minutes, resting every 15 seconds for a few seconds. After the 5 minutes of exercise are complete, the patient relaxes completely. A CMAP is recorded immediately and then every 1 to 2 minutes for the next 40 to 60 minutes. In the periodic paralysis syndromes, both inherited and acquired, the CMAP amplitude may be unchanged or slightly larger immediately after prolonged exercise and then decline substantially over the next 20 to 60 minutes (Figure 36–3).

FIGURE 36–3 Typical pattern of response on prolonged exercise test in periodic paralysis.

After 3 to 5 minutes of prolonged exercise, the compound muscle action potential (CMAP) amplitude recorded every 1 to 2 minutes shows little change in normal controls (top). In the periodic paralysis syndromes, there is frequently an increment immediately after exercise, followed by a slow decrement over the next 30 to 40 minutes (bottom). Decrements of more than 40% definitely are abnormal.

(Reprinted from McManis, P.G., Lambert, E.H., Daube, J.R., 1986. The exercise test in periodic paralysis. Muscle Nerve 9, 704, with permission.)

Repetitive Nerve Stimulation

Many of the same findings on exercise testing can also be found with repetitive nerve stimulation (RNS). Decrements are not uncommon with RNS in the myotonic syndromes. Although decrements may be seen with slow repetitive stimulation (3 Hz), they are more common with faster frequencies, typically 10 Hz. Abnormalities are not seen in all patients; when present, they are not specific to any individual syndrome.

When all the available electrophysiologic techniques are used, the correct diagnosis usually can be determined by answering several key questions (Table 36–2):

Table 36–2 Electrophysiologic Testing in Myotonic and Periodic Paralysis Disorders

Dystrophic Myotonic Muscle Disorders

Myotonic Dystrophy

The myotonic dystrophies are among the most common of the myotonic muscle disorders. They are an autosomal dominant inherited, multisystem disorder characterized by progressive facial and limb muscle weakness, myotonia, and involvement of several organ systems outside of skeletal muscle. Myotonic dystrophy type 1 (DM1) is the most common; it is due to a defect in the protein kinase myotonin [dystrophia myotonica-protein kinase (DMPK)] gene on chromosome 19q. The gene defect itself is an unstable expansion of a CTG trinucleotide repeat in the untranslated region of the myotonin gene. Age of onset and severity of symptoms are variable and proportional to the size of the abnormal CTG trinucleotide repeats, which expands over subsequent generations. This phenomenon of “anticipation” results in an earlier onset and more severe course in subsequent generations. Myotonic dystrophy type 2 (DM2), also known as proximal myotonic myopathy (PROMM syndrome) and proximal myotonic dystrophy (PDM), is due to a defect in the zinc-finger protein-9 (ZNF9) gene on chromosome 3q. The gene defect itself is an unstable expansion of a CCTG repeat in intron 1 of the zinc-finger protein-9 gene.

Myotonic Dystrophy Type 1

Clinical

Patients with DM1 generally present in their late teens with mild distal weakness and delayed muscle relaxation, such as difficulty releasing their hand grip. This disorder is distinguished from other muscle disorders by the distal rather than proximal predominance of weakness, as well as the myotonia. The myotonia is less marked than in the myotonia congenitas. In classic myotonic dystrophy, patients experience stiffness that improves with repeated contractions. Thus, patients often report that repeated opening and closing of the hand results in a faster relaxation time with each grip. As the weakness progresses over years, the myotonic symptoms generally recede.

There is a distinctive clinical appearance characterized by bifacial weakness, temporal wasting, and frontal balding, resulting in a narrow, elongated face and horizontal smile, with ptosis, and distal muscle wasting and weakness (Figure 36–4). Patients with a smaller CTG repeat may not have the typical facial appearance. Weakness of neck flexion is also an early sign, and patients may notice difficulty lifting their head off the pillow or a tendency for the head to fall backwards during acceleration. DM1 is distinguished from many of the other myotonic disorders by the progressive distal weakness as well as involvement of several organ systems outside of skeletal muscle resulting in cataracts, cardiac conduction and pulmonary defects, endocrine dysfunction, testicular atrophy, hypersomnia, gynecologic problems, and, in some patients, mild to moderate cognitive impairment. As in the other myotonic and periodic paralysis syndromes, patients with myotonic dystrophy should be warned against potential anesthetic complications of succinylcholine and anticholinesterase agents.

FIGURE 36–4 Typical facies in myotonic dystrophy.

Note frontal balding, ptosis, temporal wasting, elongated face, horizontal smile.

(Reprinted from Brooke, M.H., 1986. A clinician’s view of neuromuscular disease. Williams & Wilkins, Baltimore, with permission.)

The clinical examination in a patient suspected of having myotonic dystrophy is directed at recognition of the typical facies, i.e., demonstration of bifacial, neck flexor, and distal wasting and weakness, and demonstration of grip and percussion myotonia. Percussion myotonia can generally be elicited most easily over the thenar muscles and long finger extensors. Eyelid myotonia is not seen. Deep tendon reflexes often are reduced or absent in the lower extremities as the disease progresses. Slit lamp examination reveals posterior capsular cataracts, which early on have a characteristic multicolored pattern. Approximately 10% of cases are congenital, characterized by severe weakness and hypotonia at birth and mental retardation. Children with the congenital form are floppy at birth, have a typical tented upper lip with poor sucking and swallowing, and often have contractures. Surprisingly, clinical myotonia is not present the first year of life. The congenital form nearly always is maternally inherited. In many cases, the mother may be so minimally affected that her diagnosis is not made until the infant is born with severe hypotonia and a myopathic facies.

Creatine kinase (CK) levels may be mildly to moderately elevated. Muscle biopsy typically reveals a mild increase in connective tissue, increased variation in fiber size, atrophy of type I muscle fibers, increase in central nuclei, ring fibers, and occasional small angulated fibers.

The clinical severity of DM1 is directly related to the number of CTG repeats. In normals, the number varies between 5 and 37, whereas in patients with DM1 the number of CTG repeats may range into the thousands. In patients with a very small increase in the number of repeats (50–100), less than a half of these patients are symptomatic, and most of these patients have cataracts only. More typically symptoms and signs of DM1 are present in patients with over 100 repeats.

Electrophysiologic Evaluation

The electrophysiologic evaluation of DM1 (Table 36–2) consists of routine nerve conduction studies, electromyography, muscle cooling, and exercise testing.

1. Routine motor and sensory nerve conduction studies are normal as a rule. Generally, one motor and sensory nerve conduction study and F responses in an upper and lower extremity will suffice. A mild neuropathy has been described, perhaps secondary to the accompanying endocrine changes. Low CMAP amplitudes may be noted secondary to the distal myopathy in patients with severe disease.

2. Concentric needle EMG of at least one upper and one lower extremity should be performed, in addition to sampling facial and paraspinal muscles. Most but not all patients with DM1 will demonstrate myotonic discharges on EMG. In very mild cases (e.g., in patients with a small increase in the number of repeats), myotonic discharges may be difficult to find. Otherwise, myotonic discharges are generally most prominent in the distal hand, forearm extensor, foot dorsiflexor (tibialis anterior), and facial muscles but usually are not found in proximal muscles. The distribution of myotonic discharges follows the same pattern as the weakness. Myotonic discharges in DM1 are the classic waxing and waning muscle fiber action potentials (Figure 36–5A). MUAP analysis may be difficult because of the myotonic discharges provoked by needle insertion or muscle contraction. However, careful examination reveals myopathic (low amplitude, short duration, polyphasic) MUAPs with early recruitment, which are generally noted in the forearm extensor and tibialis anterior muscles, consistent with the distal predominant weakness on clinical examination.

3. Muscle cooling to 20°C has no appreciable effect on the EMG examination.

4. The short exercise test produces a drop in the CMAP amplitude immediately after exercise. If the CMAP then is recorded every 10 seconds up to 2 minutes, it recovers to baseline. If short exercise is repeated, the decremental response habituates after one or two cycles, with no further decrement in the CMAP occurring immediately after exercise.

5. Repetitive nerve stimulation at 10 Hz produces a decrement, similar to the short exercise test.

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