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Levetiracetam and Phenobarbital are Equal (and weak) in Efficacy for Neonatal Seizures

By Daniel J. Bonthius, MD, PhD | Winter 2023

Levetiracetam versus phenobarbital for neonatal seizures: A retrospective cohort study. L. Battig, C. Dunner, D Cserpan et al. Pediatric Neurology 2023;138:62-70.

What the researchers did:

As all pediatric neurologists know, neonatal seizures are common and problematic. They have many etiologies, can be difficult to detect, and their presence can increase the risk for neurologic sequalae. Perhaps most troublesome of all is the fact that neonatal seizures can be difficult to control. This lack of effective control of neonatal seizures fuels controversy regarding their optimal management. Phenobarbital is the most commonly used first line anti-epileptic drug (AED) for neonatal seizures. But it is efficacious in only half of cases and often produces electroclinical uncoupling (persistence of electrographic seizures despite elimination of clinical seizures) in neonates. Furthermore, rat models have suggested that phenobarbital impairs brain development, and the drug can cause substantial side effects in humans. For all of these reasons, some clinicians seek an alternative to phenobarbital for neonatal seizures, and levetiracetam is often the alternative to which they turn. Relative to phenobarbital, levetiracetam has better pharmacokinetics, fewer drug interactions, and less severe side effects. However, levetiracetam may not be as effective at controlling neonatal seizures as phenobarbital. To examine the relative merits of phenobarbital and levetiracetam for the treatment of neonatal seizures, a group of researchers at University Children’s Hospital in Zurich, Switzerland conducted a retrospective cohort study comparing the efficacy and adverse effects of phenobarbital and levetiracetam in neonatal seizures.

What the researchers found:

The researchers reviewed 108 neonates with EEG-confirmed seizures in which the babies were treated with first-line levetiracetam or phenobarbital. Groups were analyzed based on gestational age (preterm or full term) and seizure etiology (hypoxic-ischemic, vascular, structural, genetic, infectious, metabolic, and unknown). The researchers found that levetiracetam and phenobarbital were equally efficacious as first-line agents. However, both agents had limited efficacy, as fewer than 40% of neonates reached seizure freedom following first-line therapy with either drug. Treatment responses for the two drugs remained equivalent, even when considering gestational age and seizure etiology. Both agents had lowered efficacy in babies with frequent seizures. Adverse events, including hypotension, respiratory suppression, and sedation, were significantly more common in babies treated with phenobarbital than in those treated with levetiracetam. While 24% of the neonates treated with phenobarbital had an adverse event, only 1% of the neonates treated with levetiracetam did so.

What the research means:

In this study, phenobarbital and levetiracetam had equal, but limited, efficacy in treating neonatal seizures. This essential equivalence was observed irrespective of gestational age at birth and seizure etiology. The finding that levetiracetam has fewer adverse events than phenobarbital suggests that it may be a safe and effective alternative to phenobarbital as a first-line agent for neonatal seizures. Perhaps an even more important message of this study, however, is that neither agent is particularly efficacious and that there is an urgent need to develop new therapeutic agents for the treatment of newborns with seizures.