Previous meta-analyses have compared the efficacy and safety of Levetiracetam versus Phenytoin in brain injury, producing varied results. This umbrella review aims to pool evidence from these meta-analyses to draw a definitive conclusion on which drug is safer and more effective for seizure prophylaxis after brain injury.

Annually, around 1.7 million individuals in the U.S. sustain brain injuries, with 10% going on to develop seizures, which contribute to severe disabilities. Traditionally, a range of Anti-epileptic drugs (AEDs) have been employed for seizure prevention.

Systematic reviews and meta-analyses were searched across PubMed, Scopus, and ScienceDirect till September 2024. The primary outcome was response rate of overall seizures. Secondary endpoints were response rates of early and late seizures, length of ICU and hospital stay, mortality, and adverse effects. The AMSTAR 2 and the Cochrane Rob 2.0 tool evaluated the reviews’ quality while the GRADE assessment analyzed the certainty of evidence. Analysis was performed on Review Manager 5.4.1 employing a random effects model.

Six systematic reviews and meta-analyses including 13,841 patients were included. Levetiracetam showed no significant improvement in response rate of overall seizures (RR= 0.72; 95% CI: [0.45,1.15]; p=0.16; I²=64%), early (RR= 0.81; 95% CI: [0.63,1.04]; p=0.10; I²=0%) and late seizures (RR= 0.77; 95% CI: [0.47,1.26]; p=0.30; I²=0%). The length of the hospital stay (MD=0.49; 95% CI: [-2.91,3.90]; p=0.78; I²=60%) and ICU stay (MD= -1.27; 95% CI: [-3.30,0.75]; p=0.22; I²=73%) were also comparable. Levetiracetam was associated with decreased adverse effects (RR= 0.60; 95% CI: [0.45,0.79]; p=0.0003; I²=1%) but the overall mortality rate was higher in it (RR= 1.18; 95% CI: [1.01,1.38]; p=0.04; I²=0%).

Levetiracetam has comparable efficacy to phenytoin with a better safety profile and increased mortality. This suggests the need for more rigorous research to gain a definite conclusion.