1. Dose-dependent ezogabine was shown to decrease motor neuron excitability, a marker of disease progression, in patients with amyotrophic lateral sclerosis.
Evidence Level Rating: 1 (Excellent)
Associated with the progressive loss of cortical and spinal motor neurons, amyotrophic lateral sclerosis (ALS) portends a poor prognosis. Studies have shown that greater motor neuron excitability is prognostic of disease progression. This phase 2, randomized study investigated whether ezogabine, an antieplietptic medication that activates KCNQ potassium channels, decreases cortical and motor neuron excitability in patients with ALS. 23 patients were randomized to receive 600 mg/day of ezogabine (mean [SD] age = 58.8 [9.5] years, 17.4% female), 19 to receive 900 mg/day of ezogabine (mean [SD] age = 58.9 [9.1] years, 31.6% female), and 23 to receive a placebo (mean [SD] age = 57.4 [8.0] years, 43.5% female). The primary outcome was change in short-interval intracortical inhibition (SICI), a decrease of which is seen in early ALS and is associated with cortical hyperexcitability. SICI-1, a log transformation differing from SICI only in sign, was used in analysis so that greater inhibition resulted in increased amplitude. A dose-dependent increase in SICI as measured by SICI-1, the primary outcome, was observed across the treatment groups compared with the placebo group (mean ratio 600 mg/day ezogabine group: 1.15, 95% CI 0.87 to 1.52, p = 0.31; 900 mg/day ezogabine group: 1.53, 95% CI 1.12 to 2.09, p = 0.009). Furthermore, ezogabine exhibited dose-dependent changes in specific parameters related to axonal excitability, including a decrease in strength-duration time constant (SDTC) and an increase in rheobase, both markers of membrane excitability, threshold electrotonus, and recovery cycles. In all, this study demonstrated that ezogabine decreased motor neuron excitability among patients with ALS. Further studies, though, are needed to assess whether it has sustained effects on excitability and can slow disease progression.
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