Michael D Weiss1, Eric A Macklin2, Courtney E McIlduff3, Steve Vucic4, Brian J Wainger5, Matthew C Kiernan4, Stephen A Goutman6, Namita A Goyal7, Seward B Rutkove3, Shafeeq S Ladha8, I-Hweii Amy Chen9, Matthew B Harms10, Thomas H Brannagan10, David Lacomis11, Sasha Zivkovic11, Maxwell Ma1, Leo H Wang1, Zachary Simmons12, Michael H Rivner13, Jeremy M Shefner8, Merit E Cudkowicz5, Nazem Atassi5. 1. Department of Neurology, University of Washington, Seattle, Washington, USA. 2. Department of Medicine, Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. 3. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 4. Department of Neurology, Royal Prince Alfred Hospital; and the Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia. 5. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA. 6. Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA. 7. Department of Neurology, University of California, Irvine, California, USA. 8. Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA. 9. Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA. 10. Department of Neurology, Columbia University, New York, New York, USA. 11. Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 12. Department of Neurology, Penn State University, Hershey, Pennsylvania, USA. 13. Department of Neurology, Augusta University, Augusta, Georgia, USA.
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.
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.
Authors: Brian J Wainger; Evangelos Kiskinis; Cassidy Mellin; Ole Wiskow; Steve S W Han; Jackson Sandoe; Numa P Perez; Luis A Williams; Seungkyu Lee; Gabriella Boulting; James D Berry; Robert H Brown; Merit E Cudkowicz; Bruce P Bean; Kevin Eggan; Clifford J Woolf Journal: Cell Rep Date: 2014-04-03 Impact factor: 9.423