Head-to-Head Comparison Finds Three Anti-Seizure Drugs Equally Effective for Severe Form of Epilepsy

NIH-funded research shows no difference in efficacy or adverse effects of commonly used treatments.

March 31, 2020

(COLUMBUS, Ohio) – There are three treatment options commonly used by doctors in the emergency room to treat patients with refractory status epilepticus, severe seizures that continue even after benzodiazepine medications, which are effective in controlling seizures in more than two-thirds of patients.

Findings published in the New England Journal of Medicine reveal that the three drugs, levetiracetam, fosphenytoin and valproate, are equally safe and effective in treating patients with this condition. The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, and Nationwide Children’s Hospital was one of the study sites.

“Doctors can be confident that the particular treatment they choose for their patients with status epilepticus is safe and effective and may help them avoid the need to intubate the patient as well as stays in the intensive care unit,” said Robin Conwit, M.D., NINDS program director and an author of the study. “This was a truly collaborative, multidisciplinary study that involved pediatricians, emergency medicine doctors, neurologists, pharmacologists and biostatisticians all contributing their expertise.”

In the Established Status Epilepticus Treatment Trial (ESETT), led by Robert Silbergleit, MD, professor at the University of Michigan, Ann Arbor; Jordan Elm, PhD, professor at Medical University of South Carolina; James Chamberlain, MD, professor at George Washington University; and Jaideep Kapur, MB, BS, PhD, professor at the University of Virginia, more than 380 children and adults were randomized to receive levetiracetam, fosphenytoin or valproate when they came to the emergency room experiencing a seizure. The researchers were trying to determine which of the anticonvulsant drugs was most effective in stopping seizures and improving a patient’s level of responsiveness within 60 minutes of administering treatment.

Daniel Cohen, MD, a site principal investigator for ESETT, and associate director and research director of Emergency Medicine at Nationwide Children’s said, “This study is ground breaking in both how the research was done and how the results clearly inform our current practice in caring for children and adults with prolonged seizures. These lessons will propel forward future studies and improvement science for our patients.”

The results showed that the three drugs stopped seizures and improved responsiveness in approximately half of the study participants. Specifically, these benefits were seen in 47 percent of subjects in the levetiracetam group, in 45 percent of participants in the fosphenytoin group and in 46 percent of subjects in the valproate group. These differences were not statistically significant, and there were no differences in serious side effects among the drugs.

The study was stopped early when a planned interim analysis found that the drugs were equally safe and effective.

ESETT researchers utilized a clinical trial design known as response adaptive randomization to improve the study’s efficiency and maximize the chances of identifying the best treatment. The study used an algorithm to determine which drugs patients would receive based on accumulating trial data.

Status epilepticus is characterized by individual seizures or multiple seizures close together lasting more than five minutes, with a loss of consciousness. If not treated, it can lead to severe brain damage or death. Benzodiazepines are the first line of treatment for status epilepticus and are effective in two-thirds of patients. Refractory status epilepticus occurs in those patients in whom benzodiazepines do not stop their seizures.

Additional research is needed to prevent refractory status epilepticus and to find treatment options for the patients whose seizures do not respond to the three drugs investigated in this study.

About Nationwide Children's Hospital

Named to the Top 10 Honor Roll on U.S. News & World Report’s 2019-20 list of “Best Children’s Hospitals,” Nationwide Children’s Hospital is one of America’s largest not-for-profit freestanding pediatric health care systems providing wellness, preventive, diagnostic, treatment and rehabilitative care for infants, children and adolescents, as well as adult patients with congenital disease. Nationwide Children’s has a staff of more than 13,000 providing state-of-the-art pediatric care during more than 1.5 million patient visits annually. As home to the Department of Pediatrics of The Ohio State University College of Medicine, Nationwide Children’s physicians train the next generation of pediatricians and pediatric specialists. The Abigail Wexner Research Institute at Nationwide Children’s Hospital is one of the Top 10 National Institutes of Health-funded freestanding pediatric research facilities. More information is available at NationwideChildrens.org.