Abstracts

RATIONALE: An important goal of treatment of status epilepticus (SE), in addition to preventing mortality and stopping SE, is to improve long-term outcome. We studied acute effects of topiramate on SE and its ability to prevent epileptogenesis in relation to the time of administration.
METHODS: Status epilepticus (SE) was induced in P28 rat pups by administration of lithium chloride (3meq/kg,i.p.) followed 20 hours later by pilocarpine injection (60 mg/kg,s.c.). We observed latency of SE and duration of behavioral seizures. We injected topiramate (TPM, 10 mg/kg,i.p.) at three different intervals after pilocarpine administration (20, 40 and 70 min) together with atropine sulfate (10 mg/kg,i.p.). Controls received no treatment (C) or pilocarpine and atropine (no TPM). 3 months later we implanted skull electrodes under ketamine -xylazine anesthesia. After one week of recovery, animals were monitored by telemetry-videotape for one week and we measured the number of recurrent spontaneous seizures per week, seizure frequency, mean seizure duration and spike frequency.
RESULTS: Atropine alone given at 10 min post pilocarpine stopped SE, but at 20, 40 or 70 min. it failed to stop SE, demonstrating that self-sustaining SE had been set in motion. Mortality was much higher than in adults: 90% in no TPM animals, 70% in the group treated with TPM at 70 min., 50% in the 40 min. TPM group, and 40% in the TPM 20 min. group. Seizure frequency was 1.7[plusminus]0.6 seizures per day in animals subjected to SE with no treatment; 2[plusminus]1.1 seizures per day in rats treated at 70 min with TPM; none had spontaneous recurrent seizures in 40 min group and one out of five had 1 seizure per week in 20 min TPM group. Spike frequency was 47.5 [plusminus]10.9 spikes per hour in animals subjected to SE without treatment; 34.4[plusminus]9.9 spikes per hour in rats treated at 70 min with TPM; 4[plusminus]0.5 spikes per hour after TPM treatment at 40 min; and 2.4[plusminus]0.8 spikes per hour after TPM treatment at 20 min; which did not differ significantly from untreated controls (2.5[plusminus]0.5 spikes per hour).
CONCLUSIONS: When treating experimental SE, timing of administration of TPM (10 mg/kg) is a crucial factor in the prevention of epileptogenesis.
[Supported by: VA Research Service, by research grant at NS13515 fom NINDS and by a grant from Johnson & Johnson, Pharmaceutical Research and Development.]