Abstracts

Status epilepticus (SE) is a dynamic state, with progressive changes in its underlying pathophysiology the longer it persists. A consequence of such changes is an increased refractoriness to treatment with antiepileptic drugs. The underlying mechanisms for this phenomenon are not well understood, but probably involve progressive impairment of GABA-mediated inhibition. Treiman et al ([italic]Epilepsy Res[/italic] 49-60, 1990) described a progressive sequence of EEG changes during experimental and clinical SE, and have suggested these EEG changes (Stages I-V) are a marker of the severity of SE. We tested the hypothesis that the later the EEG stage, the greater the impairment of GABA-mediated inhibition would be. SE was induced in P20-P28 male Sprague-Dawley rats with kainic acid (KA), 15 mg/kg IP. Continuous EEG recording from epidural screw electrodes was done from before injection to sacrifice at SE EEG Stage III (continuous ictal activity) or V Plus (continuous periodic epileptiform discharges overnight: approximately 20 hrs). Rats that were given KA but did not develop SE, were used as controls. Brains were rapidly removed at the time of sacrifice. Standard field recording methods in the CA1 region were then utilized to assess GABAergic function in 400 [mu]m transverse hippocampal slices prepared in cold artificial cerebrospinal fluid. A single stimulus to the Schaffer collateral pathway induced a single field potential spike in slices obtained from control and Stage III rats, but multiple field potential spikes in slices obtained from Stage V rats. Tetanic stimulation (100 Hz, 20 trains) induced a robust [gamma]-oscillation in the slices from control animals, but the [gamma]-oscillation was diminished in the slices from Stage III rats and absent in slices from Stage V rats. Perfusion of diazepam (1 [mu]M) to the slice completely restored [gamma]-oscillations in Stage III rats. Paired pulse stimulation with a 50 ms pulse interval induced a reduction of the second response (paired pulse inhibition) in slices from control rats, but not in slices from Stage III or Stage V rats. However, paired pulse stimulation with a 150 ms pulse interval induced a potentiation of the second response (paired pulse facilitation) in slices from control rats, which was enhanced in slices from Stage III and Stage V rats. These data demonstrate progressive impairment of GABAergic function during prolonged KA-induced SE in juvenile rats, which may help explain the progressive refractoriness to treatment. The mechanism of this progressive impairment is not yet understood. None-the-less, this observation has important implications for the management of prolonged SE in human patients. Further elucidation of the underlying mechanisms may lead to more effective treatment interventions in clinical SE. (Supported by Barrow Neurological Institute.)