| Description |
One in 26 people in America will develop epilepsy at some point in their life. Approximately one-third of patients with epilepsy do not have full control of their seizures on their current antiseizure drug (ASD) regimen. In the past 20 years, 16 new ASDs have been made available to the patient with epilepsy. However, the percentage of pharmacoresistant patients has remained relatively constant. Thus, it is necessary to explore alternative avenues to explain the lack of seizure control in these patients. It is unknown how the practice of nonadherence contributes to the percentage of refractory patients. An animal model of nonadherence would permit the study of nonadherence and its consequences on seizure control. To model nonadherence, a computer-automated system was created to dose animals with antiseizure drugs (ASDs) using a drug-in-food protocol. Two studies were conducted and serve as a first-pass characterization. In the first study, newly-diagnosed epileptic rats were administered carbamazepine (CBZ) at varying levels of adherence. Two groups, one adherent (100%), and one nonadherent (50%), were compared to placebo control (0%). The 50% group displayed similar seizure frequency and severity to the placebo controls, while the 100% adherent group were observed to have fewer seizures overall. This suggesting that taking medication 50% of the time had no measurable effect on seizure control. In the second study, a group of newly diagnosed epileptic rats was subjected to a two-week on (100%), two-week off (0%) and two-week on CBZ (100%) paradigm. Despite numerous seizures after discontinuation of CBZ treatment, animals regained the same level of seizure control when CBZ treatment was reinstituted. Finally, nonadherence can lead to status epilepticus (SE), a severe seizure lasting several minutes. In an effort to aid drug discovery, a new and simple method which results in an unbiased method to assess the duration and severity of the electrographic component of SE was created. This method has been used to quantify the response of electrographic SE to novel investigational compounds. Together, this dissertation aims to aid in the treatment of epilepsy by providing etiologically relevant models of nonadherence and analysis of electrographic SE. |
