– In a study published in The New England Journal of Medicine
and led by James Chamberlain, M.D.
, director of Data Analytics and Informatics in the Division of Emergency Medicine
at Children’s National Hospital, found that levetiracetam, fosphenytoin and valproate led to the cessation of status epilepticus and overall improvement in the level of consciousness for patients.
For the study, the researchers conducted a randomized, blinded and adaptive trial that compared the efficacy and safety of three intravenous anticonvulsive agents – levetiracetam, fosphenytoin and valproate – in children and adults with convulsive status epilepticus
that were unresponsive to treatment with benzodiazepines. In the study, a total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118 patients) or valproate (121 patients).
“There are approximately 150,000 episodes of status epilepticus, also known as continuous convulsions annually in the United States. In this study of 384 patients from 57 hospital emergency departments, the three most commonly used agents, fosphenytoin, levetiracetam and valproate, each stopped status epilepticus in approximately half of patients,” Chamberlain says.
The primary outcome was the absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of the drug infusion, without additional anticonvulsant medication.
Evidence supports the use of benzodiazepines as the initial treatment for status epilepticus; however, seizures do not respond to benzodiazepines in up to a third of patients. Out of the three medications used to treat benzodiazepine-refractory epilepticus, only fosphenytoin is labeled by the Food and Drug Administration (FDA) for this indication in adults, and none have been approved for children.
The first line therapy is to use benzodiazepines such as midazolam or lorazepam. The optimal second line therapy for those who fail benzodiazepines is unknown. “We noticed that there were no differences in effectiveness or safety among the three medications. Therefore, doctors may choose medication based on other factors such as availability, cost and ease of administration,” Chamberlain added.
Furthermore, early termination of convulsive status epilepticus decreases the risk of cardiac and respiratory complications and is associated with a reduced risk of admission to an intensive care unit and decreased mortality among children.
Based on clinical guidelines, it emphasized the need for rapid control of benzodiazepine-refractory status epilepticus, but doesn’t provide guidance regarding the choice of medication on the basis of either efficacy or safety.
“We believe that future studies looking at genomics and biomarkers will be needed to determine prospectively whether one medication is more likely than another to be effective in an individual patient,” Chamberlain said.
At the conclusion of the study, researchers were able to determine the superiority or inferiority of the three commonly used anticonvulsant medications with regard to treatment success among patients with status epilepticus in the emergency department.
Other researchers who contributed to this study include Jaideep Kapur, M.B., B.S., Ph.D., Jordan Elm, Ph.D., William Barsan, M.D., James Cloyd, Pharm.D., Daniel Lowenstein, M.D., Shlomo Shinar, M.D., Ph.D., Robin Condit, M.D., Caitlyn Mainer, Ph.D., Hannah Cock, M.D., Nathan Fountain, M.D., Jason T. Connor, Ph.D., and Robert Silbergleit, M.D., et al., for the NETT and PECARN Investigators*
The trial was developed through a program funded by the National Institutes of Health and
The FDA and was conducted by the Neurological Emergencies Treatment Trials (NETT) Network and the Pediatric Emergency Care Applied Research Network (PECARN)