Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the upper motor neurons in the brain and lower motor neurons in the braiustem and spinal cord. Clinically, ALS causes slowly progressive limb muscle weakness, dysarthria, dysphagia, and respiratory insufficiency. The latter is usually the cause of death within 2-5 years following the onset of the first symptoms. The cause of sporadic ALS is unknown. Proposed etiologies include toxicity from excess excitation of the motor neurons by transmitters such as glutamate, free radical-mediated oxidative cytotoxicity, mitochondrial dysfunction and various combinations of all these mechanisms. Medications which inhibit the release of glutamate pre-synaptic terminals and/or block its entry into the motor neurons have been shown in cell cultures, animal models of ALS, and human trials to slow the progression of the disease and/or to improve survival. Topiramate is an FDA- approved agent used as an adjunctive treatment for partial onset seizures. This medication is believed to block the glutamateric receptor in brain cells and has shown therapeutic benefit on the survival of motor neurons in a cell culture. The purpose of this multi-centered study is to determine whether topiramate will slow disease progression in patients with ALS. It is a double blind placebo-controlled trial with a treatment to placebo ratio of 2:1. Each patient will participate in the study for 12 months, and, pending results, enter into an open-label program. Intentions are to recruit 288 ALS patients from over 18 centers. The primary outcome measure is the change in disease progression rate as measured by the maximum voluntary isometric contraction strength of 8 arm muscle groups using a quantitative motor testing system.. Secondary outcome measures include the rate of decline of forced vital capacity, grip strength, the change in the ALS functional rating scale, the safety and tolerability of topiramate, and survival. Study is still in recruitment phase. This study is being done in collaboration with the GCRC at Massachusetts General Hospital.
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