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.
