Anticonvulsant effects of gamma surgery in a model of chronic spontaneous limbic epilepsy in rats

Object. The management of intractable epilepsy remains a challenge, despite advances in its surgical and nonsurgical treatment. The identification of low-risk, low-cost therapeutic strategies that lead to improved outcome is therefore an important ongoing goal of basic and clinical research. Single- dose focal ionizing beam radiation delivered at necrosis-inducing and subne crotic levels was investigated for its effects on seizure activity by using an established model of chronic recurrent spontaneous limbic seizures in r ats. Methods. A single 90-minute period of repetitive electrical stimulation (in ducing stimulus) of the hippocampus in rats elicited a single episode of st atus epilepticus, followed by a 2- to 4-week seizure-free period. Spontaneo us recurrent seizures developed subsequently and persisted for the duration of monitoring (2-10 months). Simultaneous computerized electroencephalogra phy and video recording were used to monitor the animals. After the establi shment of spontaneous recurrent seizures, bilateral radiation centered in t he ventral hippocampal formation was administered with the Leksell gamma kn ife, aided by a stereotactic device custom made for small animals. A center dose of 10, 20, or 40 Gy was administered using a 4-mm collimator. Control animals were subjected to the same seizure-inducing stimulus but underwent a sham treatment instead of gamma irradiation. In a second experiment, the authors examined the effects of gamma irradiati on on the proclivity of hippocampal neurons to display epileptiform dischar ges. Naive animals were irradiated with a single 40-Gy dose, as already des cribed. Slices of the hippocampus were prepared from animals killed between 1 and 178 days postirradiation. Sensitivity to penicillin-induced epilepti form spiking was examined in vitro in slices prepared from control and irra diated rat brains. Conclusions. In the first experiment, single doses of 20 or 40 Cy (but not 10 Gy) reduced substantially, and in some cases eliminated, behaviorally an d electrographically recognized seizures. Significant reductions in both th e frequency and duration of spontaneous seizures were observed during a fol low-up period of up to 10 months postradiation. Histological examination of the targeted region did not reveal signs of necrosis. These findings indic ate that single-dose focal ionizing beam irradiation at subnecrotic dosages reduces or eliminates repetitive spontaneous seizures in a rat model of te mporal lobe epilepsy. In the second experiment, synaptically driven neurona l firing was shown to be intact in hippocampal neurons subjected to 40-Gy d oses. However, the susceptibility to penicillin-induced epileptiform activi ty was reduced in the brain slices of animals receiving 40-Gy doses, compar ed with those from control rats that were not irradiated. The results provi de rational support for the utility of subnecrotic gamma irradiation as a t herapeutic strategy for treating epilepsy. These findings also provide evid ence that a functional increase in the seizure threshold of hippocampal neu rons contributes to the anticonvulsant influence of subnecrotic gamma irrad iation.