Other Peripheral Hyperexcitability Syndromes

Pathogenesis

Most cases of PNH are acquired, often due to autoimmune causes (e.g., voltage-gated potassium channel [VGKC] antibodies). Paraneoplastic autoimmunity may be present, with thymoma and lung cancer occurring most commonly. Exposure to specific toxins such as that of the rattlesnake, radiation-induced neuropathy, or hereditary motor neuropathy are less frequent mechanisms. Antibodies to VGKCs occur in up to 50% of patients with Isaac syndrome and less frequently in the other PNH forms. These antibodies target various proteins associated with different subtypes of voltage-gated potassium channels. The two best-characterized antigens are leucine-rich glioma-inactivated protein 1 (Lgi1) in the CNS and contactin-associated protein 2 (Caspr2) in peripheral nerves; the latter is associated with Isaac syndrome.

Isaac Syndrome/Acquired Neuromyotonia

Isaac syndrome is characterized by the continuous firing of peripheral motor axons, leading to continuous activity of motor units. Patients complain of muscle cramps worsened by voluntary contraction. Excessive sweating, muscle hypertrophy, and weight loss may also occur. On exam, widespread fasciculations and myokymia are seen. Fasciculations are irregular, spontaneous contractions of a group of muscle fibers belonging to the same motor unit, producing movement of the overlying skin. Myokymia, in contrast, is an undulating wavelike movement visible under the skin. An interesting phenomenon of pseudomyotonia (delayed relaxation after contraction) can be observed. Strength and deep tendon reflexes are usually normal. Diagnosis is suggested when EMG demonstrates continuous firing of normal motor unit potentials (MUAPs), most notably in the form of neuromyotonic discharges. These persist during sleep and are abolished by neuromuscular blockade, suggesting that the generator may be in the motor axon. Autoimmune pathogenesis of Isaac syndrome is suggested by its association with other autoimmune conditions, most notably myasthenia gravis and thyroiditis, and by detection of antibodies against VGKCs in a large proportion of patients. Association with malignancy is well recognized, thymoma and lung in particular.

Various drugs have been used for symptomatic relief, including carbamazepine, phenytoin, gabapentin, and mexiletine, but they do not address the underlying autoimmune process. Various combinations of plasma exchange, corticosteroids, and immunosuppressants such as azathioprine can be effective.