Outcomes and Treatment Approaches for Super-Refractory Status Epilepticus: A Systematic Review and Meta-Analysis

Abstract

Importance: Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues or recurs 24 hours or more after the onset of anesthetic therapy or recurs on the reduction/withdrawal of anesthesia. Current clinical knowledge of the disease and optimal treatment approach is sparse.

Objective: To systematically assess clinical characteristics, causes, outcomes, prognostic factors, and treatment approaches for patients with SRSE.

Design, setting, and participants: In this systematic review and meta-analysis, all studies reporting adult patients (18 years or older) diagnosed with nonanoxic SRSE were considered for inclusion, irrespective of study design. The databases used were MEDLINE, Cochrane Library, EMBASE, and ClinicalTrials.org (database inception through May 5, 2022).

Data extraction and synthesis: The study complied with the PRISMA guidelines for reporting, data extraction, and data synthesis. Different tools were used to assess risk of bias. All available data were extracted and missing data were neither imputed nor completed by contacting the study authors.

Main outcome and measures: Successful treatment of SRSE, in-hospital mortality, and disability at discharge (estimated modified Rankin Scale).

Results: The study team identified a total of 95 articles and 30 conference abstracts reporting 1200 patients with nonanoxic SRSE (266 individual patients were available for meta-analysis). They had a mean SRSE duration of 36.3 days, mean age of 40.8 years, and equal sex distribution. Patients with SRSE had a distinct pattern of etiologies where acute cerebral events and unknown etiologies accounted for 41.6% and 22.3% of all etiologies, respectively. Reports of SRSE caused by, eg, alcohol, drugs, or tumors were rare. At discharge, only 26.8% had none to slight disability (none, 16 [8.4%]; nonsignificant and slight disability, 35 [18.4%]). In-hospital mortality was 24.1%. Mortality stabilized after long-term treatment (more than 28 days) but with increased rates of seizure cessation and moderate to severe disability. Established prognostic factors, such as age and etiology, were not associated with in-hospital mortality. Reported treatment with ketamine, phenobarbital, other barbiturates, vagus nerve stimulator, and ketogenic diet were not associated with outcome.

Conclusion and relevance: Patients with SRSE are distinct due to their pattern of care (eg, long-term treatment to younger patients without negative prognostic factors and unknown/nonmalignant etiologies) and their natural course of SE. Very long-term treatment was associated with lower mortality and high odds of cessation of SRSE but increased risk of moderate to severe disability.

Figure 1.. PRISMA Flowchart

RSE indicates refractory status epilepticus; SRSE, super-refractory status epilepticus.

Figure 2.. Characteristics and Outcome of Super-Refractory Status Epilepticus

A, Year of publication for studies included (all studies including abstracts); B, reported patient age; C, sex distribution in cohort studies with 10 or more patients with available data; D, reported etiologies in patients from cohort studies (n = 488) as compared with patients included in the meta-analysis (n = 233; χ² test); E, successful treatment rate of super-refractory status epilepticus at discharge; and F, in-hospital mortality in cohort studies with 10 or more patients with available data. Data from the current meta-analysis are given in the last row for comparison.

Figure 3.. Individual Patient Meta-Analysis

A, Cumulative frequency (cumulative number of patients) of the estimated disability at discharge assessed using the modified Rankin Scale (mRS) according to the duration of super-refractory status epilepticus (SRSE) (only includes patients with available data); B and C, cumulative frequency (cumulative number of patients) of survival at discharge and cessation of SRSE according to the duration of SRSE (only includes patients with available data); D, association of the status epilepticus severity score (STESS) and survival status at discharge (not significant χ² test; 136 patients with available data); E, most frequently reported antiseizure medications (171 patients with available data); and F, estimated degree of disability at discharge assessed using the mRS in patients with reported treatment with ketamine (190 patients with available data). Phenobarb indicates phenobarbital; ocx, Oxcarbazepine.