The Effectiveness of Antiepileptic Medications as Prophylaxis of Early Seizure in Patients with Traumatic Brain Injury Compared with Placebo or No Treatment: A Systematic Review and Meta-Analysis

Background The use of antiepileptic drugs (AEDs) to prevent early posttraumatic seizure (PTS) for patients with severe traumatic brain injury (TBI) is currently recommended, although published studies present contradictory results concerning the protective effect of AEDs. Objective The purpose of this study was to quantify the association between the use of prophylactic AEDs, particularly of the 4 main drugs of interest (phenytoin, levetiracetam, valproate, or carbamazepine) versus placebo or no treatment, and risk of early seizures after TBI. Methods A comprehensive search was performed on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov . The selection criteria were English written randomized controlled trials (RCTs) and observational studies, comparing AEDs with placebo or no treatment, for prevention of early PTS. Random-effects models were used to calculate pooled relative risk (RR). Subgroup analysis and meta-regression were used to assess heterogeneity sources. Results This research included 3 RCTs (750 patients) and 6 observational studies (3362 patients), analyzing the efficacy of phenytoin, levetiracetam, and valproate. The pooled RR estimate across RCTs trended toward a protective effect (RR, 0.58; 95% confidence interval, 0.20–1.72; I 2  = 59.5%); a significant protective association was shown when pooling the results across all 6 observational studies (RR, 0.42; 95% confidence interval, 0.29–0.62; I 2  = 0%). When stratifying the observational studies by drug, no significant difference was observed ( P interaction = 0.73). Begg and Egger tests indicated no publication bias among observational studies. Conclusions Only modest evidence suggested effectiveness of AEDs as prophylaxis of early PTS. Phenytoin was the most studied drug; more prospective studies are needed to assess the efficacy of other AEDs.