Abstracts

Rationale: One in every three patients with epilepsy are refractory to their current treatment, i.e., they do not have full control of their seizures on their current antiseizure drug (ASD) regimen. Thus, new drugs with novel mechanisms of action are required to treat this refractory population. Candidate ASDs must not only demonstrate antiseizure efficacy, but also show dose-dependent efficacy. A novel screening model has been implemented as part of the Epilepsy Therapy Screening Program, which relies on subchronic administration in chronically epileptic rats to block spontaneous seizures. While this model has been previously characterized using multiple ASDs at single doses, a dose response study has not yet been performed. Methods: A cohort of animals were given chronic epilepsy using a repeated low-dose kainic acid paradigm to induce status epilepticus (SE). Following implantation with a Millar wireless telemetry device, animals were placed in a 24/7 video-EEG recording suite and evaluated; rats with the highest seizure rates (n=12) were selected to enter the study. A baseline seizure rate was recorded during the first week. Following, we utilized a crossover design wherein half of the animals (n=6) received topiramate via intraperitoneal injections for five days, and the other half (n=6) received vehicle injections for five days. Injections were performed two times daily. Following a two day washout period, animals received the opposing treatment arm for the following five days, i.e. animals on topiramate crossed over to vehicle, and animals on vehicle crossed over to topiramate. Following an additional washout period of two days, the crossover paradigm was repeated, starting with a baseline evaluation period. Video-EEG data was evaluated using a seizure detection algorithm and behavioral seizure scoring using a modified Racine scale. Results: Topiramate was administered at doses of 10mg/kg, 19mg/kg, 37.5mg/kg, 75mgkg, 150mg/kg and 300mg/kg. Outcome measures included seizure burden (normalized to mean baseline seizure burden) as well as the fraction of animals to gain seizure freedom during drug treatment vs. vehicle treatment. The significant efficacious doses were 75mg/kg, 150mg/kg, and 300 mg/kg, and an ED50 of 31.1mg/kg (95% CI, 1.0-69.8) was calculated using the percent of animals that experienced seizure freedom at each dose. No sedation or other toxicity was observed at any dose. Conclusions: The goal of this project is to demonstrate the dose dependent relationship between the treatment with an ASD and the incidence and severity of spontaneous seizures. Illustrating this relationship is an important step in finding novel therapies for the treatment of refractory epilepsy in the NINDS Epilepsy Therapy Screening Program contract site. Funding: NINDS: HHSN271201600048C