Clinical Pearls & Morning Reports

Posted by Carla Rothaus

Published November 27, 2019


How do levetiracetam, fosphenytoin, and valproate compare for the treatment of benzodiazepine-refractory status epilepticus? 

Kapur et al. performed a randomized clinical 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 was unresponsive to treatment with benzodiazepines. Read the Original Article here.

Clinical Pearls

Q: What percentage of patients do not respond to benzodiazepines as the initial treatment for status epilepticus?

A: 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. The treatment for this type of benzodiazepine-refractory status epilepticus has not been well studied.

Q: What complications are reduced with early termination of status epilepticus?

A: 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. Convulsive and nonconvulsive status epilepticus are also associated with neuroimaging evidence of brain injury in humans and with neuronal loss in experimental models. Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety.

Morning Report Questions

Q: How do levetiracetam, fosphenytoin, and valproate compare for the treatment of benzodiazepine-refractory status epilepticus?

A: In the trial by Kapur et al., the authors found no significant difference in the percentage of patients with seizure cessation among the levetiracetam group, fosphenytoin group, and valproate group. The results of a planned interim analysis performed at the time that 400 patients had been enrolled met a predefined futility criterion for stopping the trial. Status epilepticus stopped in approximately 50% of patients in each treatment group. Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant.

Q: How do the results of the trial by Kapur et al. compare with other analyses of these three drugs?

A: The results of the trial by Kapur et al. contrast with those of previous, mostly observational studies that used varying definitions of cessation of status epilepticus. In a retrospective review involving 279 adult patients with benzodiazepine-refractory status epilepticus who were not randomly assigned to a drug treatment, the percentage of patients in whom seizures were stopped was 51.7% with levetiracetam, and the percentages with valproate and phenytoin (74.6% and 59.6%, respectively) were higher than those in the current trial. A meta-analysis of 22 studies showed higher effectiveness with levetiracetam (68.5%) and valproate (75.7%) than was seen in the current trial, but similar effectiveness with phenytoin (50.2%).

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