NS-PEACE Neonatal Seizures -Predicting Epilepsy and Assessing Comparative Effectiveness - ABSTRACT (30 lines) Neonatal seizures occur once per 1000 live births and are associated with subsequent development of epilepsy, cerebral palsy, and intellectual disability. Most (85%) are acute symptomatic seizures (i.e., due to an acute injury). Roughly one-quarter of survivors will subsequently develop epilepsy (i.e., chronic unprovoked seizures) after a months-to-years delay. We propose to address three questions in the management of acute symptomatic neonatal seizures. Our central hypothesis is that optimizing the clinical management of this vulnerable population will reduce the development of epilepsy. First, what is the best second-line anti-seizure medication (ASM) for acute neonatal seizures? Our preliminary data suggest the two most used ASMs, levetiracetam (LEV) and phenytoin/fosphenytoin (PHT), have roughly equivalent effectiveness. We will conduct in-depth chart abstraction (780 neonates at 18 centers) and apply modern statistical techniques to compare their effectiveness for short-term (seizure cessation) and long-term (epilepsy by age 2) outcomes. Demonstration of equivalence would favor the use of LEV, given its tolerability and safety profile. Second, if neonates with seizures (age 0-28 days) continue ASM therapy in infancy (age 1-12 months), does ASM selection alter the risk to develop infantile spasms syndrome (ISS)? Our preliminary analyses found an association of oxcarbazepine (OXC) use with ISS, in alignment with recent work demonstrating that voltage- gated sodium channel blockade can induce epileptic spasms in mice (using tetrodotoxin) and may increase the risk for ISS in human infants (case reports and single-center data). This finding needs confirmation before recommending avoidance of OXC in infants, particularly given the effectiveness of OXC and other voltage- gated sodium channel blockers for some monogenetic epilepsies that begin in the first year of life. We will confirm this finding in 587 infants. Third, after discharge from the neonatal intensive care unit, which infants will develop epilepsy? We propose to validate our published epilepsy prediction rule in 1800 neonates for subsequent use as enrollment criteria for epilepsy prevention trials. We will conduct this work using the Pediatric Epilepsy Learning Health System (PELHS), a consortium of US academic pediatric epilepsy programs that work collaboratively to improve outcomes for children with epilepsy through cycles of electronic health record (EHR) collection and analysis. This rigorous set of studies will generate much-needed evidence to support treatment decisions in a vulnerable population, in alignment with the 2020 Epilepsy Research Benchmarks, including II-3 (biomarkers), II-5 (interventions to prevent epileptogenesis), and III-4 (predict, prevent seizures). The proposal is aligned with a long-standing goal of clinical neuroscience research: to predict and prevent epilepsy in high-risk individuals. The results will directly inform clinical care for neonates with acute symptomatic seizures as well as lay the foundation for epilepsy prevention trials.
