Abstracts

Rationale: Stroke is the most commonly identified cause of seizures/epilepsy in the aging population. Post-stroke seizures are associated with high mortality and poor overall outcomes but the underlying pathophysiology is poorly understood. The objective of our current study is to determine whether the rodent model of hypoxia-ischemia (HI) is suitable for studying early-onset post-stroke seizure in aging mice.Methods: The HI model was conducted as per our recent study in adult mice (EI-Hayek et al, Cerebral Cortex 2011, in press). Briefly, C57 black mice of 18-20 months were operated for implanting intracranial EEG electrodes. About 1-2 weeks post implantation, these animals received a permanent occlusion of the right common carotid artery and then a systemic hypoxic episode (8% oxygen for 30 min). Bilateral EEG activities were recorded continuously during and following the hypoxic episode. Some animals received intra-peritoneal injections of memantine (20mg/Kg), fosphenytoin (30mg/kg) and lorazepam (1.5mg/Kg) either immediately post hypoxia or after 1-2 seizure events. The animals were allowed to survive for up to 5 weeks post HI and then euthanized for histological assessments of brain injury.Results: 1) Extensive injury/infarction in the hemisphere ipsilateral to the carotid artery occlusion was recognizable in about 50% of animals following the HI episode, but not in age-matched sham controls or animals that received carotid artery occlusion alone. 2) Vigorous convulsions (such as fast run, jump and barrel roll) were observed only in animals with later recognized extensive brain injury, but not in the animals without such brain injury. These seizures were transiently suppressed by the injection of memantine, fosphenytoin and lorazepam. All animals with these severe seizures encountered mortality within 24-48 hours post HI. 3) Cortical and hippocampal recordings revealed no evident EEG discharges that correlated with these severe seizures. 4) Severe seizures were absent in mice that received injections of memantine, fosphenytoin and lorazepam within 5 min post HI, and such early drug injections appeared to reduce post-HI mortality. Conclusions: 1) The HI model is feasible for studying early-onset post-ischemic seizures in aging mice. 2) Post-HI seizures are a consequence of extensive brain injury and a major causal factor of mortality in aging mice. 3) These seizures may arise largely from deep sub-cortical structures. Work is in progression to confirm the regional generation of post HI seizures and the effects of early anti-seizure drug treatment. These studies can potentially localize the generator of post-stroke seizures, in addition to significantly impacting the administration of prophylactic anti-seizure medications in stroke patients. This work is supported by Canadian Institute of Health Research. Yayi Huang is supported by the Student Fellowships from Epilepsy Canada and University of Toronto Faculty of Medicine.