A 72-year-old man develops generalized tonic-clonic activity at home. He receives lorazepam 4 mg intravenously during the 7-minute transport to the ED. He continues to have witnessed convulsions on your examination. Point-of-care glucose is normal. After supporting his airway, breathing and circulation, what medication should be administered second line for status epilepticus (SE)? 

Benzodiazepenes are the first-line treatment for status epilepticus. However, approximately one third of patients fail to respond to this initial therapy. The only FDA-approved therapy for refractory SE is fosphenytoin; however, there has been limited investigation of alternative agents. The Established Status Epilepticus Treatment Trial (ESETT) was published in the New England Journal of Medicineon November 28, 2019. ESETT was an NIH and FDA-funded multicenter, blinded, randomized trial comparing levetiracetam, fosphenytoin and valproate for treatment of patients with SE in the ED. The authors obtained exception from informed consent for emergency research. Subjects included adults and children 2 years of age or older treated with cumulative benzodiazepenes (defined as at least 10 mg of diazepam or midazolam, or 4 mg of lorazepam) for seizure lasting greater than 5 minutes, who continued to have witnessed convulsions or recurrent convulsions at least 5 minutes after the last benzodiazepine dose. Patients were randomized to receive levetiracetam 60 mg per kg, fosphenytoin 20 mgPE per kg or valproate 40 mg per kg. The primary outcome was absence of “clinically apparent” seizures and improvement in consciousness as determined by the ED physician at 60 minutes following trial drug administration. Data on adverse events were collected for 24 hours and a composite of severe hypotension or cardiac arrhythmias served as the primary safety outcome. 

Approximately 2 years after initial enrollment, the trial was stopped for futility in a planned interim analysis. A total of 384 patients were enrolled. Absence of seizures and improvement in level of consciousness was observed in 47% of patients in the levetiracetam group, 45% in the fosphenytoin group and 46% in the valproate group. As a secondary outcome, median time to cessation of seizure was assessed for patients with treatment success. While there was a trend toward shorter duration to seizure cessation in the valproate group (7.0 minutes valproate versus 10.5 minutes levetiracetam and 11.7 minutes fosphenytoin), these times could only be analyzed in the 10% of patients with audio recordings available. Safety analysis showed that the frequency of severe hypotension and arrythmias was similar among treatment groups. 

Based on this high-quality, randomized controlled trial, our patient with benzodiazepine-refractory status epilepticus can be treated with levetiracetam, fosphenytoin or valproate with equal effectiveness as a second-line agent. This allows the emergency medicine physician or intensivist to choose second-line therapy for SE based on individual patient factors. It is important to keep in mind that termination of seizures in this trial was determined clinically, rather than by EEG criteria, due to the limited availability of this resource within 1 hour of presentation to the ED. Therefore, it was not possible to distinguish a post-ictal state from nonconvulsive status epilepticus in those patients with cessation of tonic-clonic activity without improvement in responsiveness. It is vital to keep nonconvulsive SE on the differential diagnosis of comatose patients presenting with seizure to the emergency department and to obtain EEG to exclude this life-threatening diagnosis when indicated. 

References:

Kapur J, Elm J, Chamberlain J, et al. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. New Eng J Med. 2019;381(22):2103-2113.

Smith PE. Management of Established Status Epilepticus. New Eng J Med. 2019;381(22):2171-2172.