Ethosuximide and Phenytoin Dose-Dependently Attenuate Acute Nonconvulsive Seizures after Traumatic Brain Injury in Rats

Abstract

Acute seizures frequently occur following severe traumatic brain injury (TBI) and have been associated with poor patient prognosis. Silent or nonconvulsive seizures (NCS) manifest in the absence of motor convulsion, can only be detected via continuous electroencephalographic (EEG) recordings, and are often unidentified and untreated. Identification of effective anti-epileptic drugs (AED) against post-traumatic NCS remains crucial to improve neurological outcome. Here, we assessed the anti-seizure profile of ethosuximide (ETX, 12.5-187.5 mg/kg) and phenytoin (PHT, 5-30 mg/kg) in a spontaneously occurring NCS model associated with penetrating ballistic-like brain injury (PBBI). Rats were divided between two drug cohorts, PHT or ETX, and randomly assigned to one of four doses or vehicle within each cohort. Following PBBI, NCS were detected by continuous EEG monitoring for 72 h post-injury. Drug efficacy was evaluated on NCS parameters of incidence, frequency, episode duration, total duration, and onset latency. Both PHT and ETX attenuated NCS in a dose-dependent manner. In vehicle-treated animals, 69-73% experienced NCS (averaging 9-10 episodes/rat) with average onset of NCS occurring at 30 h post-injury. Compared with control treatment, the two highest PHT and ETX doses significantly reduced NCS incidence to 13-40%, reduced NCS frequency (1.8-6.2 episodes/rat), and delayed seizure onset: < 20% of treated animals exhibited NCS within the first 48 h. NCS durations were also dosedependently mitigated. For the first time, we demonstrate that ETX and PHT are effective against spontaneously occurring NCS following PBBI, and suggest that these AEDs may be effective at treating post-traumatic NCS.

Traumatic Brain Injury Pathophysiology and Treatments: Early, Intermediate, and Late Phases Post-Injury

“…Topiramate, yet another anticonvulsant, is currently being studied in the PEPTO trial to compare it to PHT in preventing epilepsy after TBI. Recent evidence demonstrates ethosuximide, another anti-convulsant, as capable of decreasing the incidence, frequency, and delaying the onset of non-convulsive seizures in rats suffering a penetrating ballistic-like brain injury [ 179 ]. However, ethosuximide treatment has not been attempted in the clinical arena ( Table 5 ).…”

Modeling of post-traumatic epilepsy and experimental research aimed at its prevention

“…According to Dash et al ( 84 ), the administration of valproate starting at 30 min or 3 h after CCI promoted improvement of blood-brain barrier (BBB) integrity, decrease of hippocampal dendritic damage, improved spatial memory and motor function, and lessened cortical contusion volume. High doses of ethosuximide and phenytoin administered 30 min after penetrating ballistic-like brain injury attenuated spontaneous non-convulsive seizures, but lower doses failed to have the same effect ( 85 ). The clinical relevance of such findings, however, is hampered by the extremely short time interval between injury and drug administration.…”

Epilepsy Related to Traumatic Brain Injury

“…Chronic spontaneous seizures were reported after FP-and CCIinduced TBI, both in rats and mice. Acute epileptiform activity/seizures (up to 3 days after injury) has been reported in a rat model of penetrating ballistic injury [28][29][30][31] and blast injury [32], but whether late spontaneous seizures develop after these injury mechanisms remains to be studied. So far, studies have not found acute/late seizures after repeated mild concussive TBI [33].…”