Abstracts

Rationale: Temporal lobe epilepsy (TLE) remains one of the most difficult to treat forms of epilepsy. One third of the patients is or becomes refractory to anti-epileptic drugs, emphasizing the need for new therapeutic strategies. Hippocampal Deep Brain Stimulation (DBS) is a promising experimental approach, shown to be effective in both animal models of epilepsy as in patients suffering from TLE. However, optimal stimulation paradigms are still to be resolved. In this study we demonstrate the efficacy of a new stimulation paradigm: Poisson distributed stimulation (PDS) in the kainic acid model, a validated model for human TLE. Methods: Status epilepticus (SE) was induced by intraperitoneal injection of kainic acid (2-5 injections of 5mg/kg). More than fifty days following SE, rats (n=24) with spontaneous seizures were implanted with depth stimulation- and recording electrodes in the hippocampus. After 15 days of continuous baseline EEG monitoring, rats were randomly assigned to one of two treatment groups. One group (n=13) received continuous PDS (mean frequency of 130 Hz but with Poisson distributed, asynchronous, interpulse intervals) and 11 received regular, synchronous, High Frequency Stimulation (HFS at 130 Hz) during the following 10 days. Seizure frequency and seizure duration were continuously monitored before, during and after 10 days of continuous DBS. Stimulation intensity was 100 A below the threshold for induction of epileptiform EEG activity. Results: Seven out of 13 rats (54%) treated with PDS and 5 out of 11 rats (45%) treated with HFS experienced a significant reduction in seizure frequency. In them seizure frequency was reduced to 33% of baseline (p<0.01) during PDS and to 50% of baseline (p<0.01) during HFS. None of the stimulation modalities affected mean seizure duration. After termination of the stimulation, the effect induced by PDS faded away in days restoring seizure frequency to its pre-stimulus levels. The other 12 non-responder rats did not demonstrate any reduction in seizure frequency. The maximum stimulus intensity at which rats could be stimulated without experiencing EEG and/or behavioral side effects was significantly lower for PDS than for HFS (p<0.02).