Project Summary/Abstract The aim of this proposal is to improve the treatment of neonatal seizures. Neonatal seizures affect 1 in 300 infants. Survivors have high rates (40-60%) of permanent disabilities such as cerebral palsy, global developmental delay and epilepsy. There is mounting evidence that seizures contribute to brain injury and neurodevelopmental disability; better treatment may improve long-term neurodevelopmental outcomes. Despite the randomized NEOLEV2 clinical trial showing greater seizure control with phenobarbital (PHB), PHB produced increased acute side effects in comparison to standard dose Levetiracetam (LEV). These side effects included respiratory suppression, hypotension, and sedation. Furthermore, there has been concern regarding long-term neurocognitive side effects of PHB. This proposed project will refine the standard clinical paradigm for neonatal seizure treatment by demonstrating a stratified approach; using an anti-seizure treatment with a significantly improved effect profile, LEV, targeted at reducing mild to moderate seizure burden, reserving PHB with its associated side effects for neonates with high seizure burden. Research Objectives are to (1) optimize the use of a newer, safer, non-toxic anticonvulsant medication for neonates with seizures and (2) develop technologies that will allow for accurate immediate automated diagnosis of seizures. A dose escalation and safety study will be performed to determine the maximum tolerated dose of LEV. Infants who continue to have seizures following standard dose LEV will receive either higher dose LEV or the control drug PHB, randomized in a 3:1 allocation ratio. Dose escalation will proceed in 3 phases to the maximal loading dose of 150mg/kg. A minimum of 10 subjects will be studied at each dosing level and safety data will determine if dose limiting toxicity has been demonstrated before further dose escalation. The primary endpoint will be the maximum tolerated dose. A secondary endpoint will be the additional efficacy of higher doses of LEV compared with standard dose LEV. The pharmacokinetics of high dose LEV in neonates will be studied. Facilitating early detection and rapid treatment of neonatal seizures is of equal importance to developing better drugs in improving outcomes. The usefulness of current seizure detection algorithms is limited by their low accuracy. Within the proposed study the accuracy of the new and improved Persyst neonatal seizure detection algorithm will be evaluated.