Drug Trials in Status Epilepticus: Current Evidence and Future Concepts

Abstract

Summary: Status epilepticus (SE) is a neurologic emergency with high morbidity and mortality. After many advances in the field, several unanswered questions remain for optimal treatment after the early stage of SE. This narrative review describes some of the important drug trials for SE treatment that have shaped the understanding of the treatment of SE. The authors also propose possible clinical trial designs for the later stages of SE that may allow assessment of currently available and new treatment options. Status epilepticus can be divided into four stages for treatment purposes: early, established, refractory, and superrefractory. Ongoing convulsive seizures for more than 5 minutes or nonconvulsive seizure activity for more than 10 to 30 minutes is considered early SE. Failure to control the seizure with first-line treatment (usually benzodiazepines) is defined as established SE. If SE continues despite treatment with an antiseizure medicine, it is considered refractory SE, which is usually treated with additional antiseizure medicines or intravenous anesthetic agents. Continued seizures for more than 24 hours despite use of intravenous anesthetic agents is termed superrefractory SE. Evidence-based treatment recommendations from high-quality clinical trials are available for only the early stages of SE. Among the challenges for designing a treatment trial for the later stages SE is the heterogeneity of semiology, etiology, age groups, and EEG correlates. In many instances, SE is nonconvulsive in later stages and diagnosis is possible only with EEG. EEG patterns can be challenging to interpret and only recently have consensus criteria for EEG diagnosis of SE emerged. Despite having these EEG criteria, interrater agreement in EEG interpretation can be challenging. Defining successful treatment can also be difficult. Finally, the ethics of randomizing treatment and possibly using a placebo in critically ill patients must also be considered. Despite these challenges, clinical trials can be designed that navigate these issues and provide useful answers for how best to treat SE at various stages.

Advances in the Treatment of Status Epilepticus

“…Propofol should not be infused for more than two to three days preferably, to minimize the risk of propofol infusion syndrome. The latter can be potentially fatal and consist of a constellation of heart and renal failure, acidosis, and rhabdomyolysis [2,3,17,18].…”

“…ASMs not deployed in the early stages can be tried, even through a nasogastric tube, if the chosen drug is not manufactured in an IV formulation [2,7,18,19].…”

“…A more recent metanalysis suggested success with ketamine in 74% of adult cases and rare adverse events. A potential advantage of this drug is the lack of significant hypotension compared to other anesthetics [18,20,21].…”

“…Although successful treatments with electroconvulsive therapy, responsive neurostimulation, deep brain stimulation, and other neuromodulation procedures are reported, the data remains sparse and inconclusive. As such patients are typically receiving numerous ASMs and anesthetics concomitantly, the contribution from the neuromodulator procedure specifically is not always obvious [18,19].…”

What You Don’t Look for, You Won’t Find: Value of EEG After Clinical Resolution of Convulsive Status Epilepticus

“…A recent review discusses the issues that need to be addressed in clinical trials in various stages of SE (early, established, refractory and super refractory). 18 While the emergent deployment of EEG in the diagnosis and treatment of SE remains challenging, technological advances have made “quick look” EEGs possible. Confirmation of true termination of SE will not only allow better differentiation between ASM in clinical trials but also allow more effective treatment of critically ill patients.…”