Comparative efficacy of levetiracetam to phenobarbital in the treatment of neonatal seizures
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1 COMMENTARY
Neonatal seizures pose a diagnostic and therapeutic challenge in neonatal care.1 Prolonged seizures are associated with developmental and cognitive impairment and higher neonatal mortality.2 Rapid recognition and effective treatment are essential in reducing these harmful impacts on the developing brain.3
Neonatal seizures often lack definitive clinical features and are under- or overdiagnosed.4 Although continuous electroencephalogram (cEEG) remains the diagnostic gold standard, poor availability and resource-intensive nature limit its routine use in many neonatal units.2, 3 Furthermore, the controversy regarding the endpoints of neonatal seizure management (clinical or electroencephalographic) is not resolved.
Phenobarbital is the most common anticonvulsant used in neonatal care.4 However, phenobarbital is associated with neuronal toxicity in animal models and poor neurocognitive and motor development in neonates.2 Emerging evidence suggests that levetiracetam may be a promising alternative.2 Levetiracetam has been identified to have neuroprotective effects on the developing brain and seems to have a better safety profile compared with other anticonvulsant drugs.2, 4 However, most prior levetiracetam studies in neonates examine the medication as a second-line treatment.5
A systematic review by Sharma et al (includes pre-print NEOLEV2 trial) suggested levetiracetam achieved better safety and side effect profile compared with phenobarbital, but evidence for its clinical use is unclear.2 A recent study examined levetiracetam use in clinical seizures. The open-labelled RCT by Gowda et al6 found increased efficacy of levetiracetam compared with phenobarbital in clinical seizures, but did not account for a possible electrographic-uncoupling effect (electrographic seizure activity without clinical manifestations) of levetiracetam.
NEOLEV2 is the first RCT directly comparing the efficacy and safety of levetiracetam to phenobarbital in EEG detected seizures. The authors conclude that phenobarbital is a better anticonvulsant of choice in electrographic seizures after analysing both clinical and electrographic cessations of seizures. The adverse effects reported in the levetiracetam arm were fewer compared with phenobarbital although not statistically significant. Neonates experienced increased rates of respiratory depression, hypotension and sedation in the phenobarbital arm. A potential source of selection bias may exist due to only neonates with cEEG confirmed seizures being recruited as participants. This probably resulted in exclusion of neonates with short-lasting clinical seizures that may have terminated prior to cEEG application. A previous study estimated 12 minutes for application of the electrodes to obtain an EEG record.7
The NEOLEV2 RCT was a rigorously conducted study and provides important evidence regarding the use of levetiracetam and phenobarbital in neonatal seizures. However, its generalisability into all clinical contexts is inconclusive considering the lack of availability of cEEG and trained personnel for interpreting them in many neonatal units.8 The study is also limited by the lack of long-term neurodevelopmental follow-up.
The current evidence regarding levetiracetam's use as a first-line therapy and optimal dosing in neonatal seizures is inconclusive.2 Rigorous studies investigating EEG-uncoupling effects of anticonvulsants and randomised controlled trials investigating long-term neurodevelopmental effects of treating clinical versus EEG seizures are important to determine optimal treatment strategies for neonatal seizures.
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CONFLICT OF INTEREST
None declared.