You Say Potato, I Say Potatoe: Seizure Prophylaxis After Pediatric Traumatic Brain Injury*

Seizures occurring early after pediatric severe traumatic brain injury (TBI) can exacerbate secondary brain injury through increases in neuronal metabolic demand, which can result in cerebral hypoxia, hyperemia leading to increased intracranial pressure (ICP), and the release of damaging inflammatory and excitotoxic neurotransmitters (1,2). Early post-traumatic seizures (EPTSs), defined as those occurring in the first week after TBI, occur in up to 70% of children (3). Timely recognition and treatment of seizures is paramount, but prevention may avoid their deleterious consequences. The initial 2003 guidelines for the acute medical management of severe TBI in infants, children, and adolescents had a chapter on the role of anti-seizure prophylaxis following severe pediatric TBI (4). While it acknowledged the lack of available data, it recommended against prophylactic anti-seizure medication to prevent late post-traumatic seizures and said it may be considered in children at high risk after TBI. It noted that in adults, phenytoin and carbamazepine can decrease risk of EPTS (4). The 2012 guidelines included a level III recommendation that anti-seizure medication, phenytoin specifically, be considered for the prevention of EPTS (5). Levetiracetam was Food and Drug Administration approved in 2006 and was quickly adopted in pediatric seizure treatment algorithms since it had a more favorable side effect and safety profile and less drug interactions than phenytoin (6,7). The most recent third edition of the guidelines, published in 2019, revaluated the evidence for prophylactic phenytoin and levetiracetam to prevent EPTS. Several new class 3 studies (i.e., lowest class of evidence) contributed to a level III recommendation that prophylactic treatment was suggested to reduce the occurrence of EPTS (6). The 2012 specific recommendation for phenytoin was removed, and it was noted that there was insufficient evidence to recommend levetiracetam over phenytoin based on either efficacy or toxicity. In this issue of Pediatric Critical Care Medicine, Ahmed et al (8) contributed valuable data to this ongoing discussion by conducting a secondary analysis of the Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT) comparing phenytoin vs. levetiracetam in preventing post-traumatic seizures. The ADAPT trial was a large prospective multicenter cohort study that examined children with severe TBI, defined as Glasgow Coma Scale score of 8 or less who required invasive ICP monitoring as part of clinical care to investigate the impact of management strategies like therapies to treat intracranial hypertension on patient outcomes (9). This dataset is an ideal choice to investigate the efficacy of seizure prophylaxis because it focuses on children with severe TBI who are at the highest risk for post-traumatic seizures. The authors took the necessary and important step of excluding patients who had underlying epilepsy or a history of seizures, and those who had seizures after their TBI, but before hospital admission or receiving an anti-seizure medication. With these criteria, they were able to truly evaluate the efficacy of prophylactic anti-seizure medications. Status epilepticus was used as the outcome metric, which was defined as a clinical or electrographic seizure lasting at least 5 minutes (10). Five hundred sixteen patients were included. It is remarkable that among patients who received either levetiracetam or phenytoin prophylaxis, only 3.8% had post-traumatic seizures, and that number would be even lower if considering only EPTS. Previous studies have shown a post-traumatic seizure rate after severe TBI ranging from 19% to 25% (1,11). This suggests that anti-seizure prophylaxis may be effective in this high-risk population. Overall, 72% of patients who were treated with prophylactic seizure medication received levetiracetam, which is indirect evidence for the growing proportion of institutional TBI pathways and protocols that incorporate levetiracetam rather than phenytoin due to its accessibility and favorable side effect profile. The investigators used propensity score matching to account for potential confounders including patient demographics and cause, type, and severity of initial brain injury. After matching, they analyzed 133 patients in each treatment group. Five patients in the levetiracetam group (3.8%) and one patient in the phenytoin group (0.8%) had status epilepticus, a difference that was not significant. Interestingly, two of the patients in the levetiracetam group had seizures more than 7 days after their TBI (at 12 and 29 d post-injury). Thus, if only considering EPTS, the risk difference would have been even less. Since medications were only documented for the first 7 days of the ICU admission, it is possible that the prophylactic anti-seizure medication may have been discontinued at the time these seizures occurred. Prophylactic anti-seizure medications have not demonstrated reduced rates of late post-traumatic seizures or epilepsy (12). The inclusion of both clinical and electrographic seizures in the outcome metric was a strength of the study given many pediatric centers (including some who participated in ADAPT) do not readily have access to continuous electroencephalogram monitoring or it is not part of routine post-TBI clinical care. However, it is possible that some patients may have had electrographic only seizures that were under-recognized if they did not have electroencephalogram monitoring. Additionally, some patients may have had seizures that were either less than 5 minutes and self-limiting, or identified and treated within 5 minutes, thus, not meeting the study outcome definition. Either of these situations could have been considered a failure of prophylaxis, although it is unlikely that these brief events contributed to secondary brain injury or clinical outcomes. There is no true consensus about the dose and duration of seizure prophylaxis after severe TBI, leading to wide variability in practice (13,14). In the current study by Ahmed et al (8), the investigators did not have access to the dosing regimen or total duration of therapy since this information was not collected in ADAPT. While this confounds the main result as each medication could be dosed differently, it is reassuring that despite the dose chosen at each site, the overall rate of status epilepticus in patients who received prophylaxis was low. It is important to consider that the pharmacokinetics of phenytoin are variable based on patient factors such as albumin, which may be low in critical illness, leading to higher serum levels and potentially increasing efficacy or toxicity. Further research is needed to standardize dosing regimens both for prophylaxis and treatment. The study by Ahmed et al (8) failed to find a difference in mortality or hospital length of stay based on treatment group, but patients who received prophylactic phenytoin had improved functional outcomes at 6 months based on Glasgow Outcome Scale-Extended score compared with those who received levetiracetam. This finding is intriguing, although the study was not powered to evaluate this outcome. There were more patients lost to follow-up in the levetiracetam group, which could impact these results. The levetiracetam group also had a greater proportion of patients with diabetes insipidus, herniation syndromes, ventriculitis, and longer PICU length of stay suggesting that this group might have inherently had more severe brain injury than the phenytoin group. The study by Ahmed et al (8) undertook the important and clinically relevant task of comparing the efficacy of two of the most common prophylactic anti-seizure medications for preventing status epilepticus in children with severe TBI who are managed with invasive ICP monitors. Given the inherent limitations with use of retrospective data and secondary analyses, the results suggest that using prophylactic anti-seizure medications results in a lower rate of status epilepticus and that whether you treat with levetiracetam or phenytoin is the dealer's choice. It is equally important to ensure your institution has a post-TBI pathway that standardizes care so important aspects of post-TBI care like anti-seizure prophylaxis are not overlooked. Studies are needed to determine whether certain patient demographics or metrics of illness severity can further refine which patients are most likely to benefit from seizure prophylaxis.