Insights into epileptogenesis from post-traumatic epilepsy

Abstract

Post-traumatic epilepsy (PTE) accounts for 5% of all epilepsies. The incidence of PTE after traumatic brain injury (TBI) depends on the severity of injury, approaching one in three in groups with the most severe injuries. The repeated seizures that characterize PTE impair neurological recovery and increase the risk of poor outcomes after TBI. Given this high risk of recurrent seizures and the relatively short latency period for their development after injury, PTE serves as a model disease to understand human epileptogenesis and trial novel anti-epileptogenic therapies. Epileptogenesis is the process whereby previously normal brain tissue becomes prone to recurrent abnormal electrical activity, ultimately resulting in seizures. In this Review, we describe the clinical course of PTE and highlight promising research into epileptogenesis and treatment using animal models of PTE. Clinical, imaging, EEG and fluid biomarkers are being developed to aid the identification of patients at high risk of PTE who might benefit from anti-epileptogenic therapies. Studies in preclinical models of PTE have identified tractable pathways and novel therapeutic strategies that can potentially prevent epilepsy, which remain to be validated in humans. In addition to improving outcomes after TBI, advances in PTE research are likely to provide therapeutic insights that are relevant to all epilepsies.

Fig. 1 |. Prevalence of post-traumatic epilepsy after moderate or severe traumatic brain injury.

The graph shows the prevalence of post-traumatic epilepsy (PTE) over time after traumatic brain injury (TBI) for selected representative cohorts. Burke et al., Englander et al., Temkin et al., Ritter et al. and Tubi et al. prospectively recorded seizures using physician visits, patient forms or phone calls. Pease et al. recorded seizures through retrospective chart review of a prospectively maintained database, whereas DeGrauw et al. used insurance claims data. The data indicate that the PTE onset occurs during the first year post-TBI in most cases, although the risk of developing PTE persists for at least 5 years.

Fig. 2 |. Mechanisms of epileptogenesis after traumatic brain injury.

Epileptogenesis is the chronic process whereby normally functioning brain tissue is altered to become prone to recurrent abnormal electrical activity that results in seizures. In the case of traumatic brain injury, the initial insult is followed by a latency period, during which a multitude of biological processes result in the formation of epileptogenic circuitry, ultimately leading to post-traumatic epilepsy (PTE). The epileptogenic process continues after seizure onset to reinforce and develop new abnormal circuits, causing the repetitive, spontaneous seizures that characterize PTE. AMPAR, AMPA receptor; NMDAR, NMDA receptor; NOS, nitric oxide synthase; ROS, reactive oxygen species.