Abstracts

Rationale: Epilepsy is a debilitating seizure disorder that can profoundly impact quality of life. It is estimated that ~30% of patients with epilepsy do not have adequate seizure control with their current anti-seizure drug (ASD) regimen. Furthermore, despite the fact that 20 new ASDs have been made available to patients in the last 20 years, the percentage of therapy-resistant patients has remained relatively constant. Thus, there exists a considerable need to develop new methods and models for efficacy testing that includes the use of etiologically relevant epilepsy models. Although there are a number of animal models of therapy-resistant epilepsy, none use a chronic dosing paradigm during the early screening of investigational ASDs. Two key observations from the current literature suggest that removal and restoration of carbamazepine (CBZ) treatment in an animal with epilepsy may be an effective way to induce pharmacoresistance. First, withdrawal of ASD medication is a leading cause of seizures and status epilepticus (SE) observed in the emergency care setting. If seizures beget seizures, this withdrawal may lead to an increase in the severity of epilepsy. Second, recent kindling studies have shown that animals can become resistant to lamotrigine after a single treatment (Srivastava et al., Epilepsia, In Press, 2013). Therefore, we propose a new model of pharmacoresistant epilepsy, which results when rats with epilepsy are subjected to fully non-adherent and fully adherent standardized CBZ treatment.Methods: We describe the results obtained using a novel experimental protocol and an automated, computer-controlled, ASD-dosing system wherein CBZ-in-food (75 mg/kg p.o. q.i.d.) was delivered to newly diagnosed epileptic rats. Sprague Dawley rats were implanted with EEG electrodes and treated with low-dose kainate to induce SE; which leads to the development of epilepsy. After their first observed spontaneous convulsive (Racine Stage 3+) seizure, rats were randomly enrolled into one of two experimental groups (n=8 rats per group) for six weeks; Group 1) a paradigm of 2 weeks on CBZ, 2 weeks off CBZ, and 2 weeks on CBZ, the intermittent non-adherence group; or, Group 2) 6 weeks of continuous CBZ, the perfect adherence group.Results: Preliminary findings from the intermittent non-adherence group showed that the incidence of seizures remained constant between the first and second period of CBZ treatment. Interestingly, only a minority of animals showed full seizure control during any phase of the experiment, including animals in the perfect adherence group.Conclusions: We determined that neither removal of CBZ nor multiple seizures during the non-medicated period was sufficient to alter the level of pharmacosensitivity to CBZ. A future direction of the project is thus to identify those animals that exhibit poor CBZ-sensitivity and use them in a cross-over design to evaluate their sensitivity to both established and investigational ASDs. This could provide a new method for testing ASDs in a novel chronic model of CBZ-resistant epilepsy.