Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial

• Published in: Muscle & nerve 2021-03, Vol.63 (3), p.371-383
• Main Authors: Weiss, Michael D., Macklin, Eric A., McIlduff, Courtney E., Vucic, Steve, Wainger, Brian J., Kiernan, Matthew C., Goutman, Stephen A., Goyal, Namita A., Rutkove, Seward B., Ladha, Shafeeq S., Chen, I‐Hweii Amy, Harms, Matthew B., Brannagan, Thomas H., Lacomis, David, Zivkovic, Sasha, Ma, Maxwell, Wang, Leo H., Simmons, Zachary, Rivner, Michael H., Shefner, Jeremy M., Cudkowicz, Merit E., Atassi, Nazem
• Format: Article
• Language: English
• Subjects: Accommodation; Adult; Aged; Amplitudes; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - physiopathology; axonal excitability; Axons; Clinical trials; Cortical Excitability; Double-Blind Method; Electrodiagnosis; Electromyography; Evoked Potentials, Motor - physiology; Excitability; Female; Humans; Magnetic fields; Male; Median Nerve - physiopathology; Mexiletine - therapeutic use; Middle Aged; Motor evoked potentials; Neural Conduction - physiology; Neuromodulation; outcome research; Placebos; Preliminary Data; randomized controlled clinical trial; Transcranial Magnetic Stimulation; Voltage-Gated Sodium Channel Blockers - therapeutic use
• ISSN: 0148-639X; 1097-4598
• DOI: 10.1002/mus.27146

Background To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double‐blind randomized controlled trial. Methods Twenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT). Results RMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half‐time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine. Conclusions The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half‐time supports the reduction of cortical and axonal hyperexcitability with mexiletine.