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For Your Patients-Infantile Epilepsy

Levetiracetam May Be Superior to Phenobarbital in Non-syndromic Epilepsy in Infants

Bender, Eve

doi: 10.1097/01.NT.0000534165.26360.b4
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Infants treated with levetiracetam were free from failure from monotherapy at six months significantly more often than infants treated with phenobarbital — 40.2 percent versus 15.8 percent — according to an observational study.

Levetiracetam may be more effective than phenobarbital in the treatment of non-syndromic epilepsy in infants, according to an observational study of infants being treated in 17 pediatric epilepsy centers in the United States. The findings were published in the April issue of JAMA Pediatrics.

Infants treated with levetiracetam were free from failure from monotherapy at six months significantly more often than infants treated with phenobarbital — 40.2 percent versus 15.8 percent — reported Anne T. Berg, PhD, research professor of pediatrics in neurology at the Ann & Robert H. Lurie Children's Hospital of Chicago, and co-authors. This finding persisted even after researchers adjusted for covariates, observable selection bias, and the correlation of outcomes within each center.

An infant was considered to be free from monotherapy failure at six months if no second antiepileptic drug was prescribed and the infant was free of seizures within three months of treatment initiation. The study authors noted that more than half of infants with new-onset epilepsy have non-syndromic epilepsy, electroencephalographic and clinical features that do not confirm to known electroclinical syndromes.

According to the study authors, if 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16, by the estimates in this study. They stressed, however, that randomized clinical trials are necessary to confirm these findings.

“Our team's sentiment is that a direct head-to-head comparison of the two drugs in a randomized trial could provide the definitive evidence needed to establish practice formally and provide a definitive basis for establishing guidelines, but practice has to a large extent reached its own consensus,” Dr. Berg told Neurology Today.

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As part of the Early Life Epilepsy Study, Dr. Berg and her colleagues reviewed medical records at 17 US pediatric centers participating in the Pediatric Epilepsy Research Consortium; they enrolled infants with epilepsy between March 2012 and April 2015. Infants in the sample experienced their first seizure between one month and one year of age and started treatment with either phenobarbital or levetiracetam following diagnosis. The median age of infants in the sample was 4.7 months.

The researchers found that in their sample of 155 infants, 117 had been treated with levetiracetam and 38 with phenobarbital. The median target dose was 25 mg/kg daily for those being treated with levetiracetam and 5 mg/kg daily for phenobarbital.

Forty-seven infants (40.2 percent) treated with levetiracetam were free from monotherapy failure compared with six infants (15.8 percent); p=0.1) treated with phenobarbital. The results held even after controlling for a variety of factors, such as selection bias and within-center correlation and missing data.

The children treated with levetiracetam in the study were on average two months older at the time of seizure onset than children treated with phenobarbital, according to the findings, and tended to have less developmental delay at the time of epilepsy diagnosis. Although these differences “could be clinically important,” the authors noted, they were not statistically significant.

Phenobarbital and levetiracetam are the two most commonly used drugs to combat seizures in infants. Phenobarbital has been in use for more than 100 years, but has been associated with poorer cognitive outcomes than placebo in otherwise healthy children, the study authors noted.

The US Food and Drug Administration (FDA) approved levetiracetam in 1999 as an add-on treatment for partial (focal), myoclonic, and tonic-clonic seizures.

“The findings are particularly relevant given the mismatch between current practice and regulatory approval for levetiracetam in infantile seizures,” the study authors wrote. “Both in our multicenter US cohort and in international practice, levetiracetam is routinely used as the first-line monotherapy in infants with epilepsy, yet the US FDA has not approved levetiracetam as monotherapy for any age group and has approved it only as adjunctive treatment of partial seizures in infants aged one month or older.”

There were a number of limitations to the study. The authors noted that there may have been unobserved confounders that could not be controlled for in their analyses. For instance, clinicians may have selected phenobarbital for children perceived as having more serious cases of epilepsy (or levetiracetam for more benign epilepsy) based on information not recorded in the Early Life Epilepsy Study. Information on outcomes iwas missing for more infants treated with levetiracetam than those treated with phenobarbital, which may have biased the analyses, according to the authors. For example, it could be possible that children with poor seizure control are more likely to follow up (or, alternatively, be more likely to seek care elsewhere). And although the analyses found strong evidence of a benefit of levetiracetam compared with phenobarbital, that estimate of the effect size remains uncertain given the wide 95 percent confidence intervals in the final result.

The authors added that they would have liked to see follow-up data beyond six months, which the study design did not permit, and concluded that a randomized, controlled trial is needed to confirm the present findings.



The study was funded by the Pediatric Epilepsy Research Foundation.

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Sarah Kelley, MD, assistant professor of neurology and director of the pediatric epilepsy monitoring unit at Johns Hopkins Hospital, called the findings “exciting,” adding that they demonstrate promise that levetiracetam may provide better seizure control in infants and perhaps also improved cognitive outcomes.

“As clinicians, we are aware of negative cognitive outcomes that have been identified in children who have taken phenobarbital, as well as the evidence of neuronal apoptosis in animals given the medication. This leads to the question of whether phenobarbital, often referred to as the gold standard medication for infants, is truly the best choice,” Dr. Kelley said.

She noted that to date levetiracetam has not demonstrated an increased risk for negative cognitive outcomes. “Although there has already been a shift in the clinical community to using levetiracetam more frequently in this population, this article importantly demonstrates that infants who received levetiracetam as their first-line treatment for non-syndromic epilepsy actually had improved seizure outcomes at six months.”

Dr. Kelley added that randomized studies are necessary to determine if this finding holds up when not susceptible to physician bias regarding medication choice.

“While many variables were controlled for in this study, there are likely reasons for choosing one medication over another that were not captured, and a randomized controlled study is necessary to adequately compare the groups. Assessing long term seizure and developmental outcome would also be beneficial for future study,” she said.

Laurie Seltzer, DO, assistant professor of neurology and pediatrics at the University of Rochester in New York, agreed with the need for randomized controlled trials in order to further elucidate the findings.



“Accounting for the differences between these populations, levetiracetam was superior to phenobarbital in leading to freedom from seizures. This is a significant finding since phenobarbital is associated with concerning side effects including sedation and cognitive slowing. It also confirms the clinical practice of many child neurologists using levetiracetam as a first-line [therapy] in infants with non-syndromic epilepsy,” Dr. Seltzer said. “This study demonstrates the need for a prospective, double-blind clinical trial in a well-circumscribed group to confirm these findings.”

Dr. Seltzer pointed out that there is limited research-based evidence regarding the treatment of epilepsy in infants. “There are multiple reasons for this, including the diversity in etiologies of epilepsy, and research in infants poses particular challenges in clinical trials.”

“The Pediatric Epilepsy Research Consortium is a group of academic medical centers that collaborates in order to study these challenging patient populations,” Dr. Seltzer noted. “Enrollment for a trial in any one center may be challenging, but many groups working together [can] increase the numbers in a study.”

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Dr. Berg and the independent commentators reported no conflicts.

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•. Grinspan ZM, Shellhaas RA, Coryell J, et al Comparative effectiveness of levetiracetam vs phenobarbital for infantile epilepsy JAMA Pediatr 2018; 172(4: 352–360.
    © 2018 American Academy of Neurology