Breaking Down Super-Refractory Status Epilepticus: Insights from a Systematic Review and Meta-Analysis
Published on: April 22, 2024
Original Article: Camilla Dyremose Cornwall, et al. "Outcomes and Treatment Approaches for Super-Refractory Status Epilepticus: A Systematic Review and Meta-Analysis." JAMA Neurology (2023).
Background
Super-refractory status epilepticus (SRSE), defined as refractory status epilepticus persisting for over 24 hours after initiation of anesthetics, is a diverse condition with multiple underlying causes. Despite sufficient data on the treatment and management of impending and established status epilepticus, there is a scarcity of high-quality evidence guiding healthcare providers, particularly in the context of SRSE.
Methods
This systematic review focuses on summarizing the clinical characteristics, causes, outcomes, prognostic factors, and treatment strategies for patients with SRSE. The review encompassed studies involving adults (18 years or older) diagnosed with non-anoxic SRSE. Case reports and conference abstracts were incorporated into the analysis when all pertinent data were available.
Acknowledging the reliance on suboptimal evidence, such as case reports and conference abstracts, an internal quality assessment was conducted. Raw data from cohorts with 10 or more patients (data set 1) underwent a comparative analysis with refined data from all types of studies selected for inclusion in the meta-analysis (data set 2). This internal validity check aimed to ensure the reliability of the findings.
Results
The literature search identified 125 studies, comprising a total of 1200 patients for inclusion in the analysis. From this pool, the authors compiled data from 266 patients in 104 individual sources for formal meta-analysis (data set 2). The mean age was 40.9 years, with 53% experiencing convulsive status epilepticus, 34% nonconvulsive status epilepticus, and 12% focal status epilepticus with impaired consciousness. These patients had a mean SRSE duration of 36 days, requiring an average of 5 antiepileptic drugs. Acute cerebral events accounted for 41% of SRSE etiologies in data set 2, with smaller percentages attributed to established epilepsy, metabolic causes, alcohol/drug-related causes, tumor-related causes, or cases with no determined etiology.
In-hospital mortality was 24%, but long-term treatment (for more than 28 days) was associated with lower mortality rates and higher rates of seizure cessation. Although only 26% of patients achieved a modified Rankin score of 0-2 at discharge, no long-term outcome data were provided.
Commentary
While the systematic review is commendable for its thorough examination of SRSE literature, heavy reliance on data from case reports and lower-quality sources raises concerns about the findings' reliability (89 out of 125 sources exhibiting medium or high risk of bias). To address this, the systematic review makes comparisons with data set 2, as well as internally selected cohorts of SRSE patients (data set 1) and previous trials serving as external controls.1-3
However, there were significant between-group age disparities, with patients in data set 2 tending to be younger (mean age 40.9 years) than patients in data set 1 (53.4 years) and external control trials (65-70 years). Differences in SRSE duration were also present, with data set 2 reporting a mean duration of over 5 weeks, while the comparison cohort had a mean duration of less than 1 week. These differences have implications for understanding SRSE etiologies and the meta-analysis's applicability across diverse populations (e.g., acute stroke vs. autoimmune encephalitis), and may be attributable to data set 2’s inclusion of more diverse sources, including case reports and abstracts (eTable 2).4
Despite heterogeneous SRSE subgroups in data set 2, observed mortality and functional disability rates align with previous studies.3 Still, it is uncertain whether this similarity originated from an irreversible cerebral injury threshold reached uniformly across all SRSE patients or signifies compensation for a younger (and ostensibly healthier) cohort with a disproportionately greater burden of epileptogenic cerebral injury than their older (and potentially less healthy) counterparts. Finally, although exploratory analyses did not find an association between less conventional interventions (e.g., barbiturates, ketamine, or a ketogenic diet) and subsequent outcomes, the heterogeneity of patients and included studies does not definitively exclude an effect in some patients with SRSE.
References
1. Leitinger M, Trinka E, Giovannini G, et al. Epidemiology of status epilepticus in adults: A population‐based study on incidence, causes, and outcomes. Epilepsia. 2019;60(1):53-62.
2. Kortland L, Alfter A, Bähr O, et al. Costs and cost‐driving factors for acute treatment of adults with status epilepticus: A multicenter cohort study from Germany. Epilepsia. 2016;57(12):2056-2066.
3. Roberg LE, Monsson O, Kristensen SB, et al. Prediction of Long-term Survival After Status Epilepticus Using the ACD Score. JAMA Neurol. 2022;79(6):604.
4. Supplemental Online Content to: Cornwall CD, Krøigård T, Kristensen JSS, Callesen HE, Beier CP. Outcomes and treatment approaches for super-refractory status epilepticus: a systematic review and meta-analysis. JAMA Neurol. Published online July 31, 2023. doi:10.1001/jamaneurol.2023.2407