Post-traumatic seizure prophylaxis part 2 (Part 1 here)

Although there are several studies evaluating the use of LEV in seizure prophylaxis, these trials often include patients with a variety of neurologic pathologies, so its important to recognize that the results of a trial evaluating patient with primary ICH or SAH may not be applicable to TBI. So considering we’re just looking at studies involving TBI patients, we’re not left with a whole lot of data.

Two of the most recent studies I’ve highlighted here have attempted to address whether LEV is able to translate its proposed theoretical benefits into favorable outcomes in TBI patients specifically.

One observational study by Jones prospectively collected data on severe TBI patients receiving LEV 500mg q12 for 7days and compared the occurrence of early PTS detected by EEG to a historical control of patients who received phenytoin. Patients underwent EEG examination only if there was a suspicion of a seizure on the basis of mental status changes or persistent coma or if clinical seizure activity has occurred. In the current study, only patients who received an EEG examination were included in the analysis.

The second study, this time sTBI patients were randomized to either LEV 20mg/kg followed by 1000mg q12 for 7 days or phenytoin (using fosPHT LD) followed by weight based phenytoin maintenance dose again for 7 days. This study similarly utilized continuous EEG monitoring, but did so in all patients for the firs 72 hours after the primary injury.  Study participants were followed for signs of adverse events, which included the occurrence of seizures among others.

While the observational study demonstrated an association with more abnormal EEGs in patients who received LEV compared to PHT, the randomized study suggested no difference in adverse events, which including seizure activity between the two treatment strategies.

Interestingly in the randomized trial conducted by Szaflarski, phenytoin was associated with worsening neurologic function and more frequent adverse drug events compared to LEV.  Surviving patients were followed for 6 months and those who received LEV demonstrated favorable Glasgow Outcomes Scale- Extended (GOSE), Disability Rating Scale suggesting potential long term benefit, however several other confounding variables like less severe TBI in these surviving patients require further study into this finding.

But nevertheless, this research paints the picture seen throughout the literature evaluating LEV for TBI. Small studies, conflicting results, and generally more questions then answers at the end.

Without clear data regarding the optimal dose and timing of LEV or PHT for that matter, solid recommendations cannot be made.

Consequently, phenytoin remains our first line agent to reduce the incidence of early PTS.  If indicated, we should consider using fosphenytoin for loading doses in the emergency department, since fosphenytoin has always had favorable characteristics that afford faster administration rates and fewer complications from administration and is now virtually the same cost as phenytoin.

But like I mentioned before, there are many unanswered questions surrounding the best management of TBI patients.  With so many various pathologic mechanisms at play, treatments directed at one mechanism or another might not be beneficial, where global treatment, like therapeutic hypothermia may be advantageous.

Reference for Post-traumatic seizure prophylaxis part 2:
1Jones KE et al. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus2008;25(4):1-5

2Szaflarski JP et al. Prospective, randomized, single blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care 2010;12:165-172