By Hai Chen, MD, PhD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Patients with super-refractory status epilepticus (SRSE) differed from patients with first-time status epilepticus in clinical presentations and the treatment course. Although seizure control was achieved in most SRSE patients, the in-hospital mortality and the chance of severe disability at discharge were high. A prolonged treatment course is associated with a reduced mortality as well as a higher risk of poor functional outcome at discharge.
SOURCE: Cornwall CD, Krøigård T, Kristensen JSS, et al. Outcomes and treatment approaches for super-refractory status epilepticus: A systematic review and meta-analysis. JAMA Neurol 2023;Jul 31:e232407.
Super-refractory status epilepticus (SRSE) is a status epilepticus (SE) that continues for at least 24 hours despite anesthetic treatment or recurs on an attempted wean of the anesthetic regimen. High-level evidence still is limited because of the low incidence of SRSE and the challenge in conducting systematic, large-scale prospective studies. Using meta-analysis, this study provided a comprehensive overview of SRSE, including the patient characteristics, treatments, outcomes, and prognosis factors.
Three electronic databases and registered clinical trials were searched. The initial search included SRSE studies in adult patients. Case reports and conference abstracts also were included if information required for analysis could be obtained. Studies on post-anoxic SRSE or refractory SE were excluded.
A total of 718 studies were discovered through the initial database search. Ninety-five studies and 30 conference abstracts (n = 1,200 patients) then were identified using Preferred Reporting Items for Systematic Reviews and Meta-Analysis reporting guidelines. The study team further identified 26 articles describing cohorts with 10 or more patients (dataset 1, n = 1,031) and 104 studies with acceptable data quality, which was used for meta-analysis (dataset 2, n = 266).
There were no significance substantial differences in key variables between patients in large cohort studies (dataset 1) and those included in the meta-analysis (dataset 2). The quality of studies also was evaluated by the risk of bias using the CARE checklist and Modified Newcastle-Ottawa Quality Assessment Scale. Eighty-five studies (68%) had a low to moderate risk of bias.
Patient characteristics and relevant clinical information were extracted in SRSE studies using meta-analysis (database 2). For first-time SE patients, historical retrospective cohort studies were used. Compared to patients with first-time SE, SRSE patients were younger, more likely to have nonconvulsive SE, and had a distinct etiological profile, namely more acute and unknown etiologies. In addition, patients with SRSE had a longer seizure duration and had tried more anti-seizure medications than those patients with first-time SE.
The authors then measured the outcome of SRSE patients, including the seizure cessation rate, the in-hospital mortality, and the functional outcome, which was estimated using the modified Rankin Scale at discharge. The overall SRSE outcome was poor, with an in-hospital mortality of 24.1%, and only about 27% patients had no or minor functional deficit at discharge. Mortality stabilized and rate of seizure cessation increased after long-term treatment (> 28 days). However, an increased likelihood of moderate to severe disability also was observed in patients with a prolonged treatment course.
The seizure cessation rate was lower in SRSE compared to SE patients (81.3% vs. 96.7%). There was no statistical difference in the mortality or disability scores at discharge between these two groups. Younger age and lower number of anti-seizure medications were associated with favorable functional outcome in SRSE patients.
Finally, the authors assessed the treatment patterns and responses to treatments. The average reported number of anti-seizure medications tried was 5.0 in SRSE patients. Treatment with more anti-seizure medications did not predict a reduced mortality or a higher chance of seizure cessation. No outcome differences were observed in SRSE patients treated with ketamine, phenobarbital, vagus nerve stimulator, or ketogenic diet compared to patients without those treatments.
COMMENTARY
Currently, there were limited systematic, prospective, or randomized studies regarding SRSE. The authors conducted a meta-analysis comprising case and cohort studies. There was no significant difference in patient characteristics, treatment, or clinical outcome between patients from large cohorts and patients included in the meta-analysis, which suggested the meta-analysis is valid and meaningful.
In this study, SRSE patients differed from patients with new-onset SE in clinical presentations, seizure etiologies, and treatment course. The difference could be the result of either the natural course of SRSE or selecting bias (for example, providers may prioritize treatments for patients for whom a more favorable prognosis is expected).
Although seizures eventually ended in most patients, the mortality and risk of severe disability were high in SRSE patients. In addition, a prolonged treatment course is associated with high odds of seizure session, lower mortality, and poor functional outcome in SRSE patients. Finally, treatments with barbiturates, ketamine, vagus nerve stimulator, or ketogenic diet did not change the outcome. Although this study is subjected to methodological limitations, these findings suggested further research is needed to improve the treatment outcome in SRSE patients.
