Abstracts

The availability of animal models of status epilepticus (SE)-induced epileptogenesis, in which a latent period precedes the development of spontaneous recurrent seizures, opens an opportunity to test the effects of delayed anticonvulsant treatment on the chronic consequences of SE. Here we report the efficacy of delayed treatment with levetiracetam (LEV) in reducing the long-term consequences of SE in an animal model of self-sustaining SE induced by stimulation of the perforant path.
SE was induced by perforant path stimulation (PPS) for 30 min. in awake rats with chronically implanted stimulating and recording electrodes implanted into the angular bundle of the perforant path, and the ipsilateral granule cell layer of dorsal hippocampus, respectively. Seizures and spikes were recorded continuously for 24 hours during SE, and for two week one to two months later, and analyzed off-line using Harmonie software. One, 3 and 6 hrs after PPS, animals were injected with LEV i.p. (230 mg/kg). Twenty four hours after PPS, ALZET pumps were implanted s.c. under halotane anesthesia. Pumps delivered 700 mg/kg of LEV per day for 14 days. Two weeks after implantation, the pumps were replaced. Therefore, total duration of LEV delivery was 29 days. LEV was dissolved in distilled water. Control animals were treated similarly, except that injections and pumps delivered 0.9% saline. Twenty nine days after implantation, pumps were removed, and the animals were implanted s.c. with an EEG transmitter unit connected to the screw electrodes. Animals were recorded continuously for 14 days after implantation.
LEV treatment slightly reduced the duration of SE from 934 [plusmn] 43 min. to 606 [plusmn] 14 min. (p[lt]0.05). Chronic recordings showed that the number of recurrent spontaneous seizures per day was reduced from 5.38 [plusmn] 0.39 in untreated animals to 0.8 [plusmn] 0.15 in animals that received LEV during the latent period. The number of seizure-free days averaged 0 for untreated rats, and 8.7 for LEV-treated animals. However, all LEV-treated rats exhibited at least one seizure during the 2 weeks of chronic recording. This is not surprising, since it has been demonstrated that the 90 min. of SE which elapsed before treatment began are sufficient to cause extensive neuronal loss.
These studies suggest that LEV treatment during the latent period may reduce the severity of seizure-induced epileptogenesis.
[Supported by: A research grant from UCB-Pharma, by the Research Service of VHA and by grant NS13515 from NINDS.]