Abstracts

Rationale: An important enabler for trials of anti-epileptogenic therapies following traumatic brain injury (TBI) is the identification of predictive biomarkers for individuals at high risk of post-traumatic epilepsy (PTE). Electroencephalographic (EEG) abnormalities such as early post-traumatic seizures, spikes, periodical epileptiform discharges (PED) and high-frequency oscillations (HFO) have been proposed as potential biomarkers of epileptogenesis after TBI. The study reports the Monash data, one of the EpiBioS4Rx sites, on the effects of potential anti-epileptogenic drugs (levetiracetam and sodium selenate) on seizures, spikes, PEDs and HFOs in the acute and subacute post TBI periods in the Lateral Fluid Percussion Injury (LFPI) rat model.

Methods: Male Sprague-Dawley rats (11 weeks old) were used. LFPI rats underwent a left parietal 5mm craniotomy and subjected to ~3.2atm pressure pulse. Rats were divided into three different treatment groups, LFPI control group (saline 0.9% bolus and infusion, n=34), LFPI treated with levetiracetam (LEV; 200mg/kg bolus, infusion 200mg/kg/day, n=15), an approved anti-seizure drug commonly used clinically to suppress seizures after TBI; and LFPI treated with sodium selenate (bolus 0.34mg/kg, infusion 1mg/kg/day, n=15) a drug that reduces hyperphosphorylated tau in brain. Animals received a bolus dose immediately after LFPI. One-hour post-LFPI rats were implanted with osmotic pumps that deliver the different treatments continuously for 7 days, and were implanted with epidural and intracerebral electrodes. EEG was acquired continuously for 14 days. EEG analysis was performed by two independent experts blinded to treatments.

Seizures, slowing, spikes and PEDs were analyzed using the automated software Assyst. HFO analysis was performed using Ripple Lab, separating the events in ripples (80-200Hz) and fast ripples bands (200-500Hz).

Neuroscores were performed before injury, 2-, 7- and 14- days post-LFPI to evaluate neuromotor deficits.

Results: Early seizures (within 7d of LFPI) were present in 67% of vehicle, 54% LEV and 63% of selenate treated animals. None of the treatments had any significant effect at reducing the number of seizures, slowing, spikes or PEDs within 2 weeks post-LFPI. HFOs were observed in ~90% of rats, predominately around the lesion, and were predominantly in the fast ripple band. ANOVA Post hoc tests revealed that LEV treatment reduced fast ripples (p=0.04), but not ripples (p=0.91). Similarly, selenate treatment reduced fast ripples (p=0.02) but not ripples (p=0.73), when compared to vehicle treated controls.

Conclusions: LEV and sodium selenate significantly reduced the numbers of fast ripples in the first two weeks post-LFPI. Confirmation by the multicenter EpiBioS4Rx study is ongoing. If confirmed, and considering previous research that HFOs may be predictive of epileptogenesis in the LFPI rats, the ability for levetiracetam and sodium selenate to suppress fast ripples may suggest a potential anti-epileptogenic effect in this model.

Funding: Please list any funding that was received in support of this abstract.: NINDS U54 NS100064.