Abstracts

Rationale: One in every three patients with epilepsy are refractory to their current treatment, i.e., they do not achieve full control of their seizures on their current antiseizure drug (ASD) regimen. Thus, new drugs are needed for this refractory population. We have developed a screening model which relies on intraperitoneal (i.p.) administration of ASDs, thus providing important information about a compound’s efficacy. However, this approach is limited by the necessity for repeated injections and is not optimized for compounds with short half-lives. In contrast, an automated feeding system that delivers drug in food pellets allows for optimized treatment coverage and can be administered for longer durations in a less stressful manner.  In addition, this automated approach provides additional information on the efficacy and tolerability of drugs by extending the treatment period. 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, during which animals were given control food pellets at a rate of 40g/kg/day, split into 4 meals. After the baseline week, all animals were placed on a drug-in-food diet for 14 days. Following a washout period of three to five days, the treatment paradigm was repeated with a different ASD, starting with a baseline evaluation period. Video-EEG data was evaluated using an automated seizure detection algorithm and behavioral seizure scoring using a modified Racine scale. Results: Doses were chosen based on efficacy in the i.p. administration screening test. Only carbamazepine, administered at a dose of 600 mg/kg/day, was effective in significantly reducing seizures, and resulted in a reduction of 54.6±23.5% (p<0.05). In contrast, phenytoin (20 mg/kg/day), topiramate (75 mg/kg/day), and levetiracetam (300 mg/kg/day) had no significant effect of seizure burden.   Conclusions: The ultimate goal of this project is to demonstrate the ability to further differentiate potential new therapies for the treatment of epilepsy by administering compounds orally over a two week period to rats with spontaneous recurrent seizures. This longer treatment period serves to reduce the randomness that is inherent in seizure occurrence in KA-induced epilepsy. This model is included in the screening paradigm in the NINDS Epilepsy Therapy Screening Program. Funding: NINDS: HHSN271201100029C