Abstracts

Rationale: Five to 50% of people who suffer traumatic brain injury (TBI) eventually develop post-traumatic epilepsy (PTE). TBI is a leading cause of death and disability in children. Factors that influence the development of PTE, in addition to the severity of the brain insult, are poorly understood. This is a report of an ongoing study to test the hypothesis that prior insult (febrile seizures) increases the likelihood of mortality associated with TBI and the probability of subsequently developing PTE. Methods: Offspring of timed-pregnant Sprague-Dawley rats (Charles River Laboratories) were used in these experiments. Litters were reduced to 8 pups (4 males, 4 females) on post-natal day (PND) 1. On PND 10 febrile seizures were induced in half of each litter using a hyperthermia chamber. One week later (PND 17) TBI was created by controlled cortical impact (CCI) using a pneumatically controlled impactor with a 6 mm tip traveling at 4 m/s to compresses the exposed cortex 2.0 mm. Sham animals were subjected to all procedures except impact. The bone flap was replaced. Four weeks later cortical screw electrodes were implanted into the skull for EEG recording at three and six months post TBI. Death within 72 hours of TBI-induction was included in the determination of mortality. Epileptiform activity and seizure frequency were determined by visual inspection of the EEG. Some animals were sacrificed at 2 weeks and 6 weeks for histology Results: There were four experimental groups: Group 1 - Febrile seizures (FS) plus CCI; Group 2 - FS plus craniotomy only; Group 3 - no-FS plus CCI; Group 4 - no-FS plus craniotomy only. There were clear differences in mortality associated with surgery. Mortality rates were Group 1: 29.4% (10/34), Group 2: 19.2% (5/26), Group 3: 13.3% (4/30), Group 4: 6.1% (2/33). Overall, mortality was greater for FS animals: 25% (15/60) compared to no-FS animals: 9.5% (6/63). Post-traumatic epilepsy after CCI or craniotomy was surprisingly infrequent: Group 1: 28.6% (2/7), Group 2: 20% (1/5), Group 3: 14.2% (1/7), Group 4: 0% (0/5). None-the-less, the incidence of PTE was greater in FS rats: 25% (3/12) than for no-FS animals: 8.3% (1/12). A number of animals exhibited epileptiform discharges without definite seizures. Histology studies for extent of injury (hematoxylin and eosin) and mossy fiber sprouting (Timm stain), and studies of RNA expression from selected areas of the brain, harvested by using laser capture microscopy are underway and will be presented. Conclusions: Febrile seizures one week before traumatic brain injury in immature rats markedly increases mortality associated with TBI and increases the likelihood of PTE developing after TBI. These observations support the hypothesis that prior insult (febrile seizures) increase the likelihood of mortality associated with TBI and the probability of subsequently developing PTE.