Increased motor axonal persistent sodium currents predict rapid functional declines in amyotrophic lateral sclerosis

Abstract

Background: Previous studies have shown that increased motor axonal excitability is associated with shorter survival in amyotrophic lateral sclerosis patients. Aim: To study the axonal excitability properties related with motor functional decline. Methods: A total of 60 amyotrophic lateral sclerosis patients were prospectively evaluated at baseline, 3 months and 6 months. Motor function was evaluated with the revised amyotrophic lateral sclerosis functional rating scale. Multiple axonal excitability indices, such as strength-duration time constant (a measure of persistent sodium currents), supernormality and threshold electrotonus, were measured in median nerve motor axons at the wrist. Univariate and multivariate mixed model analyses were used to examine whether clinical and neurophysiological factors were associated with a decline of revised amyotrophic lateral sclerosis functional rating scale scores. Results: In univariate analyses, revised amyotrophic lateral sclerosis functional rating scale changes were significantly worse in patients with longer strength-duration time constant (P = 0.034) and lower vital capacity (P = 0.012). Age, sex, onset site and other excitability indices did not relate with speed of motor decline. Multivariate analysis also showed the longer strength-duration time constant (P = 0.021) and decreased vital capacity (P = 0.020) groups were significantly associated with rapid revised amyotrophic lateral sclerosis functional rating scale declines. Conclusions: Greater axonal persistent sodium currents in motor axons are presumably associated with more rapid functional declines in amyotrophic lateral sclerosis patients. Suppression of persistent sodium currents could be a treatment option for amyotrophic lateral sclerosis.