Levetiracetam vs Phenobarbitone for the control of neonatal seizures: A double blind randomised controlled Trial

Seizures occur in 1% to 5% of infants during the first month of life (the neonatal period), which is one of the highest-risk periods for seizures during the human life span(1,2) and may adversely impact neurodevelopmental outcome(3). Currently there are no class A evidence-based guidelines for the pharmacologic treatment of neonatal seizures (4) and hence the treatment is highly varied (4). The most commonly used anticonvulsant   in neonatal period is phenobarbitone which acts via GABAnergic mechanisms(4,5).  But phenobarbitone  results in complete termination of electroencephalogrphically confirmed seizures in only around 43% f patients when used as a first line medication (6). Other first line medications such as phenytoin and the benzodiazepines are also incompletely efficacious, prompting clinicians to use a number of  other anticonvulsants with minimal supporting evidence of safety, tolerability, and efficacy in neonates(7,8). Also the GABA receptor on which the phenobarbitone acts is shown to be deficient in the neonatal brain.  Also studies have shown that  phenobarbital causes neuronal apoptosis in animal models, and long term adverse neurodevelopmental effects related to pheno-barbital have been demonstrated(9). Levetiracetam is increasingly being used as an antiepileptic drug in the neonatal period,and is recognized as an antiepileptic drug with neuroprotective properties(10,11). Koppelstäetter et al. reported on the use of levetiracetam in term and preterm neonates with rarely observed adverse effects in their analysis of surveys from neonatologists and pediatric neurologists (12). A study by Kilicdag et al. demonstrated a significant decrease in the number of apoptotic neuronal cells in a levetiracetam treated group of rat pups who underwent a hypoxic-ischemic brain injury (11). Several retrospective trials and a few randomised trials are there demonstrating the usefulness of levetiracetam in neonatal seizures(7,13–19). Levetiracetam has a better neurodevelopmental outcome compared to phenobarbitone (9). Pharmacokinetics of levetiracetam in neonates has been well studies and the dosing, routes of elimination are well described(20–24). Levetiracetam can easily be administered to neonates because of the oral solution and intravenous formulations. Furthermore, it has little serum protein binding, is not hepatically metabolized, creates no drug-to-drug interactions and levetiracetam has few known serious adverse side effects, in contrast to other antiseizure medications, which may cause cardiopulmonary depression, arrhythmia, and coagulopathy. Levetiracetam  could be safe and efficacious in treating neonatal seizures and hence this study comparing the efficacy of levetiracetam with phenobarbitone in acute control of seizures as well as the long term outcome.

Hypothesis - Levetiracetam is more effective in seizure reduction in neonates compared to phenobarbitone