Abstracts

Rationale: Traumatic brain injury (TBI) is a leading cause of symptomatic epilepsy in adults. TBI is a highly complex disorder that includes varying degrees of contusion, brain injury, hemorrhage and hypoxia, as well as long-term neurological deficits and epileptic seizures. Post-traumatic epilepsy (PTE) is characterized by spontaneous recurrent seizures that occur within a few months or years after TBI. The more severe the brain trauma is, the more likely a person is to suffer from PTE. In this study, we sought to optimize a mouse model of TBI and advance the paradigm into a PTE model via chronic characterization of epileptogenic and behavioral patterns. Methods: We utilized a controlled cortical impact (CCI) model, which simulates many aspects of concussions, brain contusions, and hemorrhages seen in human TBI. We investigated the impact of severe cortico-hippocampal injury on the functional outcomes and development of PTE in mice. Seizures were identified by continuous 24/7 video-EEG monitoring for a period of 4 months. The outcome indices include extent of neurodegeneration, neuroinflammation, and post-traumatic 'epileptic' seizures as well as behavioral/ cognitive dysfunction. Results: CCI injury produced a large lesion extending into the hippocampus layer, as evident from histological Nissl analysis of brain sections. Mice were found to exhibit profound deficits up to 60 days post-TBI. They were also tested for anxiety and cognitive behavior; the mice were found to exhibit severe memory impairment following CCI injury. We evaluated the neuroprotective potential of a neurosteroid in this TBI model. EEG analysis shows that the first spontaneous seizure was evident on day 21, indicating progressive epileptogenesis after TBI. The frequency of spontaneous seizures was variable with a range of 1 to 4 seizures per day. The electrographic seizure duration was between 10 to 40 seconds. Conclusions: These studies show the feasibility of CCI model of TBI-induced chronic epilepsy in mice. The incidence and latency for epileptic seizures are greater than a post-stroke model. This model will be advanced further in a larger cohort to fully characterize the epileptogenesis with or without therapeutic interventions to reduce or prevent PTE. Funding: N/A