Abstracts

Rationale: There is no effective prophylactic treatment for posttraumatic epilepsy (PTE). In addition, PTE results in complex partial seizures, which are more frequently resistant to antiepileptic drugs. Therefore better treatments are needed to prevent and control PTE. However, there is growing concern that epilepsy models used to screen for these treatments may be too dissimilar from PTE to allow the identification of better AEDs and develop the first antiepileptogenic treatments. Thus, we investigated whether brain cooling, a novel non-pharmacological treatment modality, could prevent or control PTE induced by rostral parasaggital fluid percussion injury (rpFPI), a rodent model that closely reproduces the mechanical features of human contusive closed head injury and produces focal neocortical seizures that can be studied by ECoG (D’Ambrosio et al., Brain 2004, 127(Pt2): 304-14; Brain 2005, 128(Pt1):174-88). This study was blind and randomized. Methods: Severe rpFPI (3.5 atm) was induced in 4-week old Sprague-Dawley male rats. Rats (n=36) were injured and then randomized to four experimental groups (n=9 per group), that included one control and three experimental groups subjected to different temperatures to test dose-response. Cooling headsets, with 5 ECoG electrodes and one cooling piece, were implanted 6 days after injury. Chronic video-ECoG was acquired 2-5 weeks postinjury. Cooling was delivered continuously 24h/day for 4 weeks after headset implant. All data acquired were analyzed blind to the treatment. Results: The probability of developing PTE by 1 month postinjury was inversely related to the degree of cooling. It was 100% in the control group, but only 50% with the greatest temperature reduction. Seizure frequency in epileptic animals was also inversely proportional to the intensity of cooling, and was decreased to 0.04±0.01 seizures/hour in the group cooled the most, compared to 3.16±1.4 seizures/hour in controls. Seizures did not return during a 6-8 hour period of re-warming to body temperature (37oC) at 5 weeks post-injury. During cooling all animals presented normal activity and grooming behavior, and were indistinguishable from control rpFPI animals. Conclusions: This blind and randomized preclinical study demonstrates that focal cooling is effective in inhibiting epilepsy induced by head injury in the rat. Further work is necessary to determine 1) the critical period after injury necessary to achieve epileptogenesis, and 2) whether the observed loss in chronic recurrent spontaneous seizures may be permanent. Supported by NIH NS053928 (RD), NS042936 (SMR), and CURE 5154001.05 (MS).