Abstracts

Rationale: Previous studies in chronic epileptic rats have demonstrated the presence of diurnal and even circadian rhythmicity in seizure occurrence ¹. An interaction between epilepsy and circadian rhythmicity could provide options for improved treatment, e.g. chronotherapy. The aim of this study was to examine how a frequently used anti-epileptic drug (valproate) affects endogenously mediated seizure rhythms in chronic epileptic rats as a first step in exploring possibilities of chronotherapy. Methods: Seizures were recorded by continuous EEG and video monitoring during a one to two week baseline period (electrically evoked status epilepticus model, n=19 rats) followed by a seven day treatment period with continuous valproate (administered via osmotic minipumps, n=7) and two post-treatment weeks to measure recovery. Results: During the baseline period, a strong diurnal rhythmicity in seizure activity could be detected. All rats presented more seizures during the light than during the dark period. Seizure duration was similar in light and dark. Seizure frequency was dramatically reduced during the first 3 days of treatment with valproate. However, after this initial seizure control, seizures started to reappear inspite of ongoing therapy and proper anti-epileptic drug plasma levels. Interestingly, during this latter phase of the treatment the 24-h rhythmicity in seizure occurrence in the valproate group had completely disappeared. Also, treatment affected seizure duration, however, this did not vary over the 24-hour day period. Conclusions: These results show that normal diurnal rhythmicity in seizure occurrence disappears during continuous drug treatment with valproate This strongly suggests that this anti-epileptic drug treatment has influence on endogenously mediated circadian rhythmicity in seizures. Further studies could elucidate the influence of other AEDs on seizure rhythmicity and further explore the promising possibilities of chronotherapy in epilepsy. Acknowledgments We thank M.C. de Rijke and W.E. Dieters (SEIN, Heemstede, The Netherlands) for analysis of valproate in blood. This work was supported by the ‘Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie’ (to WH) and the Epilepsy Institute in The Netherlands (SEIN)-Lopes da Silva fellowship (to EvV). References ¹ Quigg M, Clayburn H, Straume M, Menaker M, Bertram EH III (2000) Effects of circadian regulation and rest-activity state on spontaneous seizures in a rat model of limbic epilepsy. Epilepsia 41:502-9.