Prevention of epilepsy after head trauma: do we need new drugs or a new approach?

Annually in the U.S. about 500,000 head injuries are severe enough to require hospitalization. Past studies of severe head trauma estimate the risk of late seizures, which are synonymous with epilepsy, to be from 26 to 53%. Furthermore, head trauma accounts for 5% of all epilepsy cases and 20% of symptomatic epilepsy. Although potentially preventable, no effective prophylaxis for posttraumatic epilepsy currently exists. Prior attempts to prevent posttraumatic epileptogenesis used various anticonvulsants, usually given many hours after injury. Generally these studies showed these agents suppressed seizures in the first week after trauma, but had no effect on the incidence of late posttraumatic seizures. Brain trauma engages a rapid excitotoxic process triggered by glutamate release, similar to that seen with ischemia. For ischemic cell damage early and rapid delivery of agents has been a key to rescuing or protecting neurons. Yet, no study has addressed whether the rapidity of drug delivery is critical in the prophylaxis of late seizures. Perhaps excitotoxicity proximate to the brain injury also leads to the neurological deficits seen after severe trauma, initiating and promoting epileptogenesis, and that disrupting this process may prevent epilepsy. While experimental models of epileptogenesis have shown that GABAergic drugs, including valproate (VPA), may be antiepileptogenic, the timing of treatment with putative prophylactic drugs has not been studied. Recent laboratory work explored this issue using an in vitro model of posttraumatic epileptogenesis. The data suggest that a limited time domain exists for VPA to intervene in the epileptogenic process, requiring the earliest possible intervention. We contend that protection from posttraumatic epileptogenesis can be conferred only if agents are given soon after trauma. A pilot study is proposed to begin to translate these findings to explore the feasibility of early VPA delivery to severe head trauma patients admitted to Kings County Hospital Center in Brooklyn, NY, a Level 1 trauma center.