[Amyotrophic lateral sclerosis--electrophysiologic aspects of its pathophysiology and new therapeutic options]

Abstract

It is essential to perform electromyography and nerve-conduction studies for diagnosis amyotrophic lateral sclerosis (ALS), but these conventional electrophysiologic methods cannot be used for studies on the mechanism underlying ALS. The recently developed nerve-excitability test can provide new insights into the pathophysiology of this disease. Fasciculation is one of the characteristic features of ALS. Ectopic firing of motor units originates usually from the motor nerve terminals and occasionally from the motor neurons, indicating a widespread abnormality in axonal excitability. ALS is a multifactorial disease in which some genetic abnormalities and environmental factors lead to cell death through a complex cascade, which includes oxidative stress, mitochondrial dysfunction, excitotoxicity, and impaired axonal transport. It is important to elucidate the pathophysiology of axonal excitability in ALS because increased axonal excitability enhances oxidative stress and excitotoxicity, ultimately contributing to motor neuron death. To date, 2 axonal ion channel abnormalities have been identified: (1) increased persistent sodium currents and (2) reduced potassium currents; both abnormalities cause an increase in axonal excitability and are responsible for fasciculations. The results for excitability testing in such patients are characterized by the following features: (1) a prolonged strength-duration time constant, which suggests increased persistent sodium currents; (2) greater threshold changes in depolarizing threshold electrotonus; and (3) greater supernormality, which suggests impaired potassium channels. The altered axonal properties in patients with ALS may provide new insights into the pathophysiology of ALS and have implications for the development of ion channel modulators as therapeutic options for patients with ALS.