Supplementary Material for: Efficacy of Levetiracetam as add-on therapy in the treatment of seizures in neonates

Introduction
There is no consensus regarding the efficacy of add-on therapy with levetiracetam (LEV) in the treatment of seizures in neonates. The aim of this study was to evaluate the efficacy of add–on therapy with LEV, for achieving >80% seizure reduction after phenobarbital (PB) treatment.

Methods
Retrospective cohort study of near term neonates admitted to the neonatal intensive care unit with EEG confirmed seizures despite treatment with PB as first-line therapy and using LEV as 2nd, 3rd or 4th line treatment. Antiseizure medication (ASM) was administered according to national guidelines. All neonates were monitored with 2-channel amplitude-integrated electroencephalography (aEEG). The total seizure burden in minutes, 2 hours before and 4 hours after administration of LEV was calculated using raw EEG. Primary outcome was the efficacy of LEV in achieving >80% seizure reduction. The efficacy of additional midazolam (MDZ) and lidocaine (LDC) was also calculated.

Results
A total of 47 full-term neonates were included. The mean total loading dose of LEV was 40 mg/kg (36-44 mg/kg). Seizure etiology consisted of hypoxic-ischemic encephalopathy (n=11), hemorrhagic or ischemic stroke (n=16), central nervous system infection (n= 8), genetic (n=8), metabolic disorders (n=3), and unknown (n=1). Following LEV administration, >80% seizure reduction was observed in 17% (8/47) of neonates, whereas it was 23% (6/26) after MDZ and 92% (23/25) after LDC administration.

Discussion
Although the cumulative loading dose of LEV was low and the group of infants studied was heterogeneous, the efficacy of LEV as add-on therapy for the treatment of seizures in neonates was limited. The highest seizure reduction rate was seen after LDC administration.