Abstracts

Rationale: Recent experimental evidence supports the view that prolonged febrile convulsions are epileptogenic (Dube et al 2006). In our model of febrile SE, hyperthermia greatly increased the epileptogenicity of SE, leading to behavioral seizures not seen in the normothermic group, and increasing the severity and incidence of spontaneous electrographic seizures. The goal of this study was to establish whether correcting hyperthermia after 5 min of seizures prevents the long-term consequences of febrile SE. Methods: SE was induced in rats at postnatal day 10 (P10) by administering lithium(3mEq/kg, i.p.), and 24 hours later pilocarpine (60 mg/kg, s.c.). The animals were then placed in a temperature-controlled chamber. Experimental animals were allowed to seize for 5 minutes after their rectal temperature reached 39 degree Celsius. At that time, randomly selected animals were sponged with 70% isopropanol to maintain a rectal temperature of approximately 35±1 degree Celsius (cooling group). In the hyperthermic group, rectal temperature was maintained at 39±1 degree Celsius during SE. After 30 min. of SE, both groups received diazepam (1 mg/kg, i.p.). The severity of SE was assessed by measuring latency to seizure interruption, duration of SE, and total seizure time. Separate groups of animals were used for brain temperature recording, for video-telemetry of the first 24 hrs of SE and for the detection of spontaneous recurrent seizures (SRS) by continuous telemetry/videotape monitoring for one month, 4 weeks or 4 months after SE. Results: Isopropanol sponging rapidly reduced brain and body temperature to the normothermic range and maintained it there. Diazepam effectively terminated SE in both groups (post-treatment seizure duration was 15.2±2.5 min in the hyperthermic group and 17.3±1.2 min in the cooling group). Total seizure time (60.5±15.8 min after onset of SE in hyperthermic animals and 65.2±11.5 min after SE onset in the cooling group) was similar between groups. The cooling group showed partial protection against neuronal injury in medial amygdala evaluated 24hours after SE. We found 81±21 fluorojade-positive neurons in the hyperthermic group and only 21±3 injured neurons in the cooling group. When we monitored the cooling group 4 weeks after SE, the number of electrographic SRS was reduced to 7±2 seizures per week in the cooling group compared to 30±8 seizures per week in hyperthermic animals. Only hyperthermic animals showed convulsive seizures (50%). Four months after SE, 100% of hyperthermic and 50% of cooling animals developed electrographic seizures. Seizure duration was significantly shorter (3.3±1.7 vs 14.8±2.5 seconds), and spike frequency was significantly reduced (413±97 vs. 1710±544.8 spikes/day) in the cooling group. Conclusions: These results suggest that reducing temperature to the normothermic range after 5 min. of seizures is sufficient to reduce brain damage and modify epileptogenesis associated with this model of SE in immature rats. Supported by VHA Research Service and by grants NS 059704 and NS13515 from NINDS.