Traumatic brain injury (TBI) is an anatomical and functional insult to the brain due to direct mechanical trauma from external forces. TBI-induced cerebral injury is a combination of physical, cellular, and vascular insults [1]. Although TBI is preventable, it is associated with high mortality and disability for thousands of people each year and has remained an increasingly significant public health concern throughout the world [2]. In 2014, approximately 2.87 million emergency department visits, hospitalizations, and deaths were caused by TBI in the United States, and over 837,000 (30%) of these cases were among children [3]. TBI is responsible for 30% of all injury-related deaths in the United States [4]. Post-traumatic seizure (PTS) is a common sequela of TBI, with reported incidence rates between 4% and 25%. PTS is usually classified as immediate, occurring within 24 hours after injury, early, occurring within 24 hours to 7 days after injury, and late, occurring after seven days of injury [5], [6]. Early PTS appears to increase the risk of late PTS, which is associated with post-traumatic epilepsy (PTE), another debilitating complication that occurs at least one week after head injury [7]. Early PTS also increases rates of morbidity and mortality in patients post-TBI. Post-traumatic seizures and subclinical status epilepticus worsen TBI outcomes and are associated with hippocampal atrophy [8]. Based on the American Academy of Neurology (AAN) and Brain Trauma Foundation (BTF) recommendations, using anti-seizure drugs (ASDs) during the first seven days after an injury has become the standard of care for PTS prophylaxis in severe TBI patients [9], [10]. Currently, BTF advises the use of phenytoin for early PTS prophylaxis in patients with severe TBI. Some studies in the past have reported that levetiracetam has equivalent efficacy as phenytoin for early PTS prophylaxis [11], [12], [13]. Other anti-seizure medications such as valproate, carbamazepine, and phenobarbital are not commonly used for PTS prophylaxis. Although some cost-effectiveness studies showed levetiracetam is more expensive than phenytoin, there is a growing trend now to use levetiracetam rather than phenytoin due to ease of dosing, fewer interactions with other drugs, and lack of need for frequent blood level monitoring [9], [14], [15], [16], [17]. Several studies have proven the effectiveness of AEDs for early PTS prophylaxis; however, there is not enough evidence to demonstrate the preventive effects of these drugs for late PTS prophylaxis [11], [18]. Furthermore, AEDs can cause several side effects, the most impactful being its effect on clarity, concentration, speed of thinking, and memory [19].

Since there are controversies among physicians about the choice of AEDs in PTS and considering the negative impact of seizures on neurological and functional outcomes in TBI patients, and due to the fact that new related articles have been published on this topic in the last few years, we have considered it necessary to do a meta-analysis regarding the efficacy and safety of Levetiracetam in comparison to Phenytoin as first-line treatments for seizure prophylaxis in TBI patients to update our knowledge in this field.