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Sequential levetiracetam and phenytoin in electroencephalographic neonatal seizures unresponsive to phenobarbital: a
Vaisakh Krishnan1, Vidya Ujjanappa1, Hemadri Vegda1
1Centre for Perinatal Neuroscience, Imperial College, London, United Kingdom.
Insights
Levetiracetam achieved seizure freedom in 14% of neonates with seizures unresponsive to phenobarbital. Adding phenytoin increased seizure freedom to 57%, highlighting its efficacy in neonatal epilepsy management.
Area of Science:
- Neonatal neurology
- Clinical pharmacology
- Epileptology
Background:
- Levetiracetam and phenytoin are common antiseizure medications (ASM) for neonatal seizures.
- Their comparative efficacy in achieving seizure freedom remains unclear.
- This study evaluates sequential use in phenobarbital-refractory neonatal seizures.
Purpose of the Study:
- To assess electroencephalographic (EEG) seizure freedom following sequential levetiracetam and phenytoin administration.
- To determine the efficacy of levetiracetam as a second-line ASM.
- To evaluate the effectiveness of phenytoin as a third-line ASM in neonates.
Main Methods:
- A prospective study involving neonates (≥35 weeks gestation, <72 hours old) with persistent seizures despite phenobarbital.
- Sequential intravenous administration of levetiracetam (20 mg/kg x 2 doses) followed by phenytoin (20 mg/kg x 2 doses) if seizures continued.
- Primary outcome: complete seizure freedom (no EEG seizures for ≥60 minutes within 40 minutes of infusion start).
Main Results:
- Levetiracetam achieved EEG seizure freedom in 13.8% of 145 neonates.
- Phenytoin, added for persistent seizures, achieved seizure freedom in 56.7% of 104 neonates.
- Response to the first dose was high for both levetiracetam (80%) and phenytoin (91.5%).
Conclusions:
- Conventional doses of levetiracetam provide limited seizure freedom (14%) in phenobarbital-refractory neonatal seizures.
- Sequential addition of phenytoin significantly improves seizure control, achieving freedom in an additional 57%.
- Further research into higher levetiracetam doses is warranted.
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).
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