Progressive axonal dysfunction and clinical impairment in amyotrophic lateral sclerosis

ObjectiveTo elucidate longitudinal changes in axonal function in amyotrophic lateral sclerosis (ALS) patients, and to relate such changes with motor unit loss and functional impairment.Methods37 ALS patients (age, 53.7 ± 1.7 years; 22 males) were studied using axonal excitability techniques at baseline and 12 weeks follow-up.ResultsLongitudinal measurements across excitability parameters suggested increasing K+ channel dysfunction, with further increases in depolarising threshold electrotonus (90-100 ms, baseline, 46.8 ± 1.0%; follow-up, 48.7 ± 0.8%; P = 0.02) and superexcitability (baseline, −24.0 ± 1.2%; 12 weeks, −26.0 ± 1.2%; P = 0.04). Patients with preserved compound muscle action potential (CMAP) amplitude at follow-up developed more severe changes in axonal excitability than those in whom CMAP decreased from baseline, suggesting that the most pronounced disease effects were on motor axons immediately prior to axonal loss in ALS patients. Fine motor decline was associated with more severe changes in axonal excitability, suggesting that functional impairment was related to axonal dysfunction.ConclusionsLongitudinal changes in axonal excitability in ALS patients suggest increasing K+ channel dysfunction in motor axons.SignificanceAxonal excitability studies enable investigation of longitudinal changes in axonal ion channel dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS.

► Initial 12-week changes in axonal excitability in ALS patients suggest increasing K+ channel dysfunction in motor axons. ► Activity-dependent hyperpolarization contributes to longitudinal abnormalities in ALS patients. ► Changes in axonal excitability correlate with clinical assessments that demonstrate functional decline. ► Axonal excitability studies may be sensitive to identify progressive dysfunction of surviving axons in ALS patients.