Sequential levetiracetam and phenytoin in electroencephalographic neonatal seizures unresponsive to phenobarbital: a multicenter prospective observational study in India.

Background: Although levetiracetam and phenytoin are widely used antiseizure medications (ASM) in neonates, their efficacy on seizure freedom is unclear. We evaluated electroencephalographic (EEG) seizure freedom following sequential levetiracetam and phenytoin in neonatal seizures unresponsive to phenobarbital. Methods: We recruited neonates born ≥35 weeks and aged <72 h who had continued electrographic seizures despite phenobarbital, from three Indian hospitals, between 20 June 2020 and 31 July 2022. The neonates were treated with intravenous levetiracetam (20 mg/kg x 2 doses, second line) followed by phenytoin (20 mg/kg x 2 doses, third line) if seizures persisted. The primary outcome was complete seizure freedom, defined as an absence of seizures on EEG for at least 60 min within 40 min from the start of infusion. Findings: Of the 206 neonates with continued seizures despite phenobarbital, 152 received levetiracetam with EEG. Of these one EEG was missing, 47 (31.1%) were in status epilepticus, and primary outcome data were available in 145. Seizure freedom occurred in 20 (13.8%; 95% CI 8.6%-20.5%) after levetiracetam; 16 (80.0%) responded to the first dose and 4 (20.0%) to the second dose. Of the 125 neonates with persisting seizures after levetiracetam, 114 received phenytoin under EEG monitoring. Of these, the primary outcome data were available in 104. Seizure freedom occurred in 59 (56.7%; 95% CI 46.7%-66.4%) neonates; 54 (91.5%) responded to the first dose and 5 (8.5%) to the second dose. Interpretation: With the conventional doses, levetiracetam was associated with immediate EEG seizure cessation in only 14% of phenobarbital unresponsive neonatal seizures. Additional treatment with phenytoin along with levetiracetam attained seizure freedom in further 57%. Safety and efficacy of higher doses of levetiracetam should be evaluated in well-designed randomised controlled trials. Funding: National Institute for Health and Care Research (NIHR) Research and Innovation for Global Health Transformation (NIHR200144).