Amyotrophic lateral sclerosis (ALS) is a progressive, uniformly lethal neurodegenerative disorder. Recent genetic and biochemical studies implicate glutamate excitotoxicity, free radical toxicity, and mitochondrial dysfunction as possible causes of familial ALS and sporadic ALS. This study will test the hypothesis that glutamate excitotoxicity plays a role in the pathogenesis of ALS. If this hypothesis is correct, pharmacological agents that block glutamate receptors may be therapeutic in ALS. The proposed study will determine whether therapeutic intervention with the topiramate, a glutamate receptor blocking agent, will slow the progressive deterioration of motor function in subjects with ALS. Topiramate is a FDA approved agent for epilepsy. Topiramate has modulatory effects on glutamate neurotransmission by blocking kainate/alpha-amino-3-hydroxy-5- methyl-4-isoxazole-propionic acid (AMPA) excitatory receptors. Topiramate protected motor neurons in an in vitro model of chronic glutamate toxicity in a dose dependent fashion. The applicant will conduct a double-blind, randomized, placebo- controlled, study of the safety and efficacy of Topiramate therapy in slowing of disease progression in 288 patients with ALS. All patients will be recruited from the Massachusetts General Hospital and 15 other clinical sites. The primary outcome measure is change in upper extremity motor function after twelve months of experimental therapy as tested with quantitative neuromuscular examination. Secondary outcome measures include grip strength, forced vital capacity, the ALS functional rating scale, and the safety and tolerability of topiramate in this population.
| Cudkowicz, M E; Shefner, J M; Schoenfeld, D A et al. (2003) A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Neurology 61:456-64 |
