Despite the multitude of treatments at the clinician’s disposal, status epilepticus remains associated with high morbidity and mortality. ^{Reference Kämppi, Kämppi and Strzelczyk1} Cenobamate has been associated with greater effectiveness than other third-generation anti-seizure medications in patients with drug-resistant epilepsy, ^{Reference Cerulli Irelli, Roberti and Borioni2,Reference Sperling, Abou-Khalil and Aboumatar3} including those with ultra-refractory and highly active epilepsy. ^{Reference Peña-Ceballos, Moloney and Munteanu4} The article “Cenobamate for Status Epilepticus: A Systematic Review” by Mo et al. ^{Reference Mo, Howard, Jaworska, Bencsik, Bains and Kromm5} is therefore particularly timely and highlights the need for greater evidence on the use of cenobamate in status epilepticus. Information on five patients (all with super-refractory status epilepticus) was identified from four different studies – two of which were conference abstracts. ^{Reference Mo, Howard, Jaworska, Bencsik, Bains and Kromm5} Due to the concurrent administration of other treatments, including immunotherapy in cases of probable autoimmune encephalitis, and the small number of patients included, it is difficult to ascertain the effectiveness of cenobamate in status epilepticus based on the evidence identified by the co-authors.

This paucity of evidence is likely partially explained by reports of hypersensitivity reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), with rapid titration of cenobamate. ^{Reference Krauss, Klein and Brandt6} Early studies of cenobamate in epilepsy identified three patients who developed hypersensitivity reactions, ranging from mild cutaneous reactions to severe DRESS, when cenobamate was started at doses of 50–100 mg/day, with subsequent weekly dose increases of 50–100 mg. No such hypersensitivity reactions were, however, noted when using a slower titration regimen, which started at a lower dose of 12.5 mg and was followed by dose increases every 2 weeks. ^{Reference Sperling, Abou-Khalil and Aboumatar3} This more cautious titration regimen has since been recommended by the manufacturer. Beyond concerns regarding hypersensitivity reactions, cenobamate’s long half-life, enteral route of administration, and pharmacokinetic interactions may further limit its utility in patients with status epilepticus.

Despite the higher starting doses and despite titration schedules that outpaced the recommended 2-week dose increments, no serious adverse effects were reported by the studies identified in the systematic review by Mo et al. However, the number of cases reported is too small to dispel those safety concerns entirely. Altogether, this systematic review highlights the need for a more standardized, prospective reporting of cenobamate use in status epilepticus, with a particular emphasis on safety with rapid titration and identification of predictors of hypersensitivity. Such evidence would allow more balanced discussions of the use of cenobamate in status epilepticus, which would include a weighing of the risks of hypersensitivity reaction against the benefits of, possibly, earlier termination of refractory status epilepticus.