The purpose of this study was to determine how early seizure blockade with ethosuximide (ESX) would influence ion channel expression and long-term spike-wave discharge (SWD) activity in epileptic WAG/Rij rats. The goal was to elucidate the question Do seizures beget seizures? in a genetically prone model and if so, to attempt to interrupt this cycle by early intervention. In our first experiment, we used immunocytochemistry to determine the effect of ESX on cortical expression of ion channels in treated and untreated WAG/Rij rats and age-matched Wistar controls. This experiment revealed that treatment with ESX blocked the upregulation of Nav1.1 and Nav1.6 as well as the downregulation of HCN1 that is associated with epileptic activity in rats (p < .05). In a second experiment, WAG/Rij rats were divided into 3 groups: untreated (H2O), temporary early treatment (ESX 4 month), and continuous early treatment (ESX continuous), and SWD activity was measured by electroencephalogram (EEG) at various timepoints. This second experiment revealed that animals in the ESX 4 month group spent less percent time in SWD (0.242 ± .068 SEM) than animals in the H2O group (0.769 ± .060 SEM, p < .001), although they spent slightly more percent time in SWD than animals in the ESX continuous group (0.020 ± .065 SEM, p = .003). This effect was predominantly due to seizure number, and average seizure duration did not vary among the three groups. Additionally, power spectrum analysis revealed a significant correlation when the difference between power spectra for H2O and ESX 4 month rats was compared to the power spectrum of a seizure (Pearson correlation equals 0.955, 2-tailed significance < .000000001), suggesting quantitatively that seizures were reduced by temporary early treatment. This suggests that early prevention of SWD may reduce the burden of seizures later in life, and that possibilities for prevention of genetic absence epilepsy should be further investigated.

Epilepsy accounts for 0.5% of the global burden of disease, and primary prevention of epilepsy represents one of the three 2007 NINDS Epilepsy Research Benchmarks. Efforts to understand and intervene in the process of epileptogenesis have yielded fruitful preventative strategies in animal models. This article reviews the current understanding of epileptogenesis, introduces the concept of a "critical period" for epileptogenesis, and examines strategies for epilepsy prevention in animal models of both acquired and genetic epilepsies. As proof of principle, we investigated whether early preventative treatment during epileptogenesis in the WAG/Rij rat model of primary generalized epilepsy would persistently suppress the epilepsy phenotype in adulthood. Oral ethosuximide was given from age p21 to 5 months, covering the established period for epileptogenesis in this model. We then assessed the epilepsy phenotype by performing electroencephpalogram (EEG) recordings at serial time points after treatment cessation and by immunocytochemically measuring the cortical expression of ion channels Nav1.1, Nav1.6, and HCN1, which are dysregulated in epileptic WAG/Rij rats. Treatment both persistently suppressed seizures, even up to 3 months after treatment cessation, and blocked ion channel dysregulation. These findings indicated that treatment during epileptogenesis prevented the development of the epileptic phenotype. Subsequently, we investigated the C3H/HeJ mouse model of genetic epilepsy as a candidate for future studies in preventative treatment during epileptogenesis. Serial EEG recordings were performed from p5 to 3 months of age. We found that C3H/HeJ mice underwent three distinct, stereotyped phases of seizure development, which suggests that this model would be an appropriate candidate for future research on prevention of epileptogenesis.