Status epilepticus (SE) remains life thereatening condition with limited therepautic options. Benzodiazepine-refractory, or established, SE is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy (Chamberlain et al., 2020). The results of double-blind, response-adaptive, randomised controlled clinical trial (ESETT) comparing levetiracetam, phosphenytoin and valproate in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines were recently published (Kapur et al., 2019; Chamberlain et al., 2020). The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The weight-based infusion rate provided levetiracetam at a dose of 60 mg per kilogram (maximum, 4500 mg), fosphenytoin at a dose of 20 phenytoin equivalents [mgPE] per kilogram (maximum, 1500 mgPE), or valproate at a dose of 40 mg per kilogram (maximum, 3000 mg). The interim analysis was performed after successful enrolment of 400 patients, and meeting a predefined futility criterion for stopping the trial. The anticonvulsant study drugs each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events.
The other report (Chamberlain et al., 2020) demonstrated further data after study continuation and enrolment of children to enrich the planned secondary age analysis. In total 462 unique patients were included: 225 children (aged <18 years), 186 adults (18–65 years), and 51 older adults (>65 years). Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18–65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. It was found that children, adults, and older adults with established SE responded similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients.
It was concluded, any of the three drugs could be considered as a potential first-choice, second-line drug for benzodiazepine-refractory SE.
Key points:
Status epilepticus, treatment, levetiracetam, fosphenytoin, valproate
References:
1: Chamberlain JM, Kapur J, Shinnar S, Elm J, Holsti M, Babcock L, Rogers A, Barsan W, Cloyd J, Lowenstein D, Bleck TP, Conwit R, Meinzer C, Cock H, Fountain NB, Underwood E, Connor JT, Silbergleit R; Neurological Emergencies Treatment Trials; Pediatric Emergency Care Applied Research Network investigators. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. Lancet. 2020;395(10231):1217-1224.
2: Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, Shinnar S, Conwit R, Meinzer C, Cock H, Fountain N, Connor JT, Silbergleit R; NETT and PECARN Investigators. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019;381(22):2103-2113.