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

Matthew B Harms, Nazem Atassi, Merit E Cudkowicz, Jeremy M Shefner, Michael H Rivner, Zachary Simmons, Leo H Wang, Maxwell Ma, Sasha Zivkovic, David Lacomis, Thomas H Brannagan, Michael D Weiss, I-Hweii Amy Chen, Shafeeq S Ladha, Seward B Rutkove, Namita A Goyal, Stephen A Goutman, Matthew C Kiernan, Brian J Wainger, Steve Vucic, Courtney E McIlduff, Eric A Macklin

Journal: Muscle & nerve 2021;63(3):371-383

PMID: 33340120

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Abstract

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.

Address: Department of Neurology, University of Washington, Seattle, Washington, USA.; Department of Medicine, Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.; Department of Neurology, Royal Prince Alfred Hospital; and the Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.; Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.; Department of Neurology, University of California, Irvine, California, USA.; Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA.; Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.; Department of Neurology, Columbia University, New York, New York, USA.; Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Department of Neurology, Penn State University, Hershey, Pennsylvania, USA.; Department of Neurology, Augusta University, Augusta, Georgia, USA.

DOI: 10.1002/mus.27146

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MeSH Terms: Adult, Aged, Amyotrophic Lateral Sclerosis, Axons, Cortical Excitability, Double-Blind Method, Electrodiagnosis, Electromyography, Evoked Potentials, Motor, Female, Humans, Male, Median Nerve, Mexiletine, Middle Aged, Neural Conduction, Preliminary Data, Transcranial Magnetic Stimulation, Voltage-Gated Sodium Channel Blockers