Clinical manifestations In this disease, attacks of periodic paralysis are associated with myotonia, which may be paradoxical in type—that is, developing during exercise and worsening as the exercise continues. In addition, a widespread myotonia, often coupled with weakness, is induced by exposure to cold. In some patients, the myotonia can be elicited even in a warm environment. The weakness may be diffuse, as in hyperkalemic periodic paralysis, or limited to the part of the body that is cooled. As commented in the earlier sections, cold exaggerates many types of myotonia to some extent, but this property is most characteristic of paramyotonia and it is in this condition that cold-induced weakness persists for up to several hours once started, even after the body is rewarmed. Percussion myotonia can be evoked in the tongue and thenar eminence. According to Haass and colleagues, myotonia that is constantly present in a warm environment diminishes with repeated contraction, whereas myotonia induced by cold increases with repeated contraction (paradoxical myotonia).
Like hyperkalemic periodic paralysis, paramyotonia congenita is transmitted in an autosomal dominant manner and both diseases have been linked to the same gene (SCN4A), which encodes the alpha subunit of the muscle membrane sodium channel; the two mutations are allelic.
Laboratory findings In both hyperkalemic periodic paralysis and paramyotonia congenita, the serum K is usually above the normal range during bouts of weakness, but paralysis has been observed at levels of 5 mEq/L and lower. Each patient appears to have a critical level of serum K, which, if exceeded, will be associated with weakness. (This has led some authors to term the periodic paralysis as potassium dependent.) The administration of KCl, raising serum K to above 7 mEq/L, a level that has no effect on normal individuals, invariably induces an attack. As mentioned earlier, the ECG must be monitored during such provocative testing. The EMG shows myotonic discharge in all muscles, even at normal temperatures. The CK may be elevated.
In vitro studies of muscle from patients with cold-induced stiffness and weakness have shown that as temperature is reduced, the muscle membrane is progressively depolarized to the point where the fibers are inexcitable (Lehmann-Horn et al, 1987). A sodium channel blocker (tetrodotoxin) prevents the cold-induced depolarization. In patients with paramyotonia, but not in those with hyperkalemic periodic paralysis, Subramony and colleagues observed a diminution of the compound muscle action potential in response to the cooling of muscle, largely settling the argument as to whether the two syndromes (hyperkalemic paralysis and paramyotonia) are the same or different.
Some patients with paramyotonia, like those with certain other forms of periodic paralysis, may in later life slowly develop a myopathy that causes persistent weakness. In some cases this is sufficiently severe that it mimics the pattern of late-onset limb-girdle muscular dystrophy. However, in the case of paramyotonia there are relatively few histologic changes, primarily vacuoles in some of the muscle fibers and minimal evidence of myofiber degeneration.
Treatment Most patients with hyperkalemic periodic paralysis and its variants benefit from prophylactic use of the carbonic anhydrase inhibitor acetazolamide, 125 to 250 mg bid or tid (paradoxically, as it has a tendency to produce potassium retention). Acetazolamide reduces the frequency of attacks and may provide some relief from myotonia. There are no controlled studies of acetazolamide in these disorders, but trials of the related carbonic anhydrase inhibitor, dichlorphenamide demonstrated a reduced frequency of paralytic spells in both hyperand hypokalemic forms of periodic paralysis (Tawil et al and Sansone et al). However, in some patients the attacks of hyperkalemic paralysis and of paramyotonia congenita are too infrequent, too brief, or too mild to require continuous treatment.