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

Abstract

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).

Keywords: Epilepsy; Levetiracetam; Neonatal seizures; Phenytoin.

Fig. 1

Flow chart of the study. ∗8 neonates had ongoing electrographic seizures after levetiracetam, but the clinicians decided not to administer further ASM as seizure burden was low.

Fig. 2

Seizure freedom after second line levetiracetam versus third line phenytoin. Kaplan–Meier plots showing the proportion of neonates with seizure freedom (endpoint, Y-axis) against time (minutes) from the start of initial levetiracetam 20 mg/kg infusion (X-axis) for second line levetiracetam (blue, 3A) and for neonates who also received third-line phenytoin (red, 3B). Note: The Kaplan–Meier estimates of seizure freedom are different to a simple percentage of babies with seizure freedom, as the follow-up time for babies without seizure freedom varied from 25 min to over 3 h. Neonates were censored when they reached endpoint or when the EEG monitoring stopped.

Fig. 3

Seizure burden evolution over time. “|” = Levetiracetam, “•” = Phenytoin, “X” = age of onset of seizure (clinical or EEG), Upper panel (3A) shows the seizure burden evolution in neonates with HIE (n = 66) and lower panel (3B) shows non-HIE etiologies (n = 75). X axis- Time elapsed from the birth of baby in hours, Y axis–Each row denotes the evolution of seizure burden in a baby. Seizure burden is represented in minutes per hour and colour coded from white (0 min/h, minimum) to red (60 min/h, maximum). Blue areas represent areas where EEG monitoring was not done. The vertical black line (levetiracetam) and black dot (phenytoin) are points at which each ASM was administered, if two doses were given more than an hour apart, discrete lines are shown.