This study attempts to assess clinical characteristics, causes, outcomes, prognostic factors, and treatment approaches for patients with super-refractory status epilepticus.
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.
Key Points
Question
How do patients with super-refractory status epilepticus (SRSE) differ from patients with nonrefractory status epilepticus (SE)?
Findings
In this systematic review and meta-analysis, patients with super-refractory status epilepticus had more often acute or unknown etiologies. Patients treated for more than 28 days had a higher chance of SE cessation, but also a high risk of moderate to severe disability at discharge; this systematic review and meta-analysis did not provide data supporting the use of ketamine, phenobarbital, or ketogenic diet.
Meaning
Patients with SRSE are distinct due to their pattern of care and their natural course of SE; the chances of surviving SRSE with only minor disability are low despite high rates of successful treatment that increased with long-term treatment.
Introduction
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, including those cases where SE recurs on the reduction or withdrawal of anesthesia (usually propofol, midazolam, or pentobarbital/thiopental).1 Despite substantial improvements in the understanding, diagnosis, and treatment of nonrefractory SE, SRSE is still considered an evidence-free area.2
In a prospective Swiss study,3 the proportion of patients with SE that developed SRSE was 4.1% and the in-hospital mortality of this group was 43.7%. A retrospective Finnish study4 reported that 21% of all patients with refractory SE developed SRSE with an estimated incidence of 0.7 per 100 000 inhabitants and an in-hospital mortality of 10%. Differences in definitions, treatment approaches, and study methods may explain the differences between these studies and the lower incidence as compared with a recent German study5 suggesting an incidence rate of SRSE of 3 per 100 000 inhabitants based on health insurance data.
In 2011, Shorvon and Ferlisi1 published a landmark article conceptualizing SRSE and providing an overview of treatment options. Although most statements and conclusions are still widely accepted, supportive high-class evidence is still lacking for virtually all aspects of SRSE. The low incidence of SRSE challenges the collection of large prospective population-based data sets.3,6 Register-based studies are challenged by the lack of correct diagnostic coding and are often based on indirect parameters, such as time on ventilator.5
In the last decade, a rapidly increasing body of literature on SRSE was published, including small case series that often included identifiable patients. The aim of this systematic review and meta-analysis was to assess the current evidence to provide a comprehensive overview of the clinical characteristics of patients with SRSE, including clinical characteristics, etiologies, outcomes, prognostic factors, and treatment approaches.
Methods
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines.7 The protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42021254363; accepted June 1, 2021).
Eligibility Criteria for Studies
All studies including adult patients (18 years or older) diagnosed with SRSE were considered for inclusion. SRSE was defined as “status epilepticus that continues or recurs 24 hours or more after the onset of anesthetic therapy, including those cases where status epilepticus recurs on reduction or withdrawal of anesthesia.”8 Case reports and conference abstracts were included if it was possible to obtain all the information required for analysis. If the same cohort was included in multiple reports, we included the most recent report. We excluded animal studies, review articles, and studies with patients diagnosed with refractory SE (but not SRSE). Studies that only reported on patients with postanoxic SRSE were excluded. Two studies reporting on mixed cohorts containing identifiable patients with and without postanoxic SRSE were included.9,10 Studies reporting mixed cohorts of refractory SE and SRSE that initially met the eligibility criteria but did not provide unambiguous descriptions of individual patients or subgroups with SRSE were also excluded.
Search Strategy and Selection of Studies
Three electronic databases were searched; MEDLINE literature database through PubMed, Cochrane Library, and EMBASE (latest search date May 5, 2022), using the following search strategy: “super-refractory status epilepticus” or “super refractory status epilepticus” without filters and limits. There were no restrictions regarding the language of publication or the publication date. ClinicalTrials.gov was searched for registered trials. To identify additional eligible studies, reference lists of included studies were manually searched. All studies were exported to the Covidence software for screening of eligibility. Two authors (C.D.C. and T.K.) independently carried out the search and selection of literature. Any disagreements were resolved through discussion with a third assessor (C.P.B.).
Data Extraction and Outcomes
The extracted data included year of publication, patient age and sex, etiology, previous SE episodes, duration of SE, number and type of reported antiseizure medication (ASM), and semiology of SE (worst seizure type reported: generalized tonic-clonic seizures, focal seizures with/without impaired consciousness, nonconvulsive SE with coma11,12), type of anesthetics, and pharmacological and nonpharmacological treatment approaches. Semiology was also used to estimate the level of consciousness at admission for the status epilepticus severity score as described in Rossetti et al12; patients with nonconvulsive SE in coma received 1 point.
If specific ASMs were mentioned, patients were classified as being exposed to the ASM being mentioned and as unexposed for all other ASMs not mentioned in the respective report. If no specific ASM or just the numbers of ASM were reported, all ASM data were classified as missing data. The number of individual ASMs given was calculated by combining the individual ASMs reported and adding any unspecified ASM. Reported treatment was classified as a treatment attempt irrespective of specific doses or duration of application. Study authors were not contacted if information was missing.
Etiology was classified by C.D.C. into the following groups: established and previously known epilepsy diagnosis (including nonadherence to ASM in patients with known epilepsy and known difficult-to-treat epilepsy), acute cerebral event (including acute stroke, intracerebral hemorrhages, infectious disease, and autoimmune encephalitis), new SE due to remote symptomatic causes and without an established epilepsy diagnosis,13 other causes (including metabolic causes,14 alcohol- or drug-related SE, and tumor-associated SE), and unknown causes. Unclassifiable data were reported as missing. Disability at discharge was estimated using the modified Rankin Scale (mRS) based on the published information, if not reported explicitly.
Risk of Bias Assessment
Risk of bias assessment was carried out by T.K. and reviewed by C.P.B. The CARE checklist15 was used for case reports. Studies that reported at least 14 items were considered to have a low risk of bias, while studies with 7 or less reported items were considered to have a high risk of bias. Cohort and case-control studies were assessed with the Modified Newcastle-Ottawa Quality Assessment Scale.16 Studies with 7 or more stars were considered to have a low risk of bias, while studies with 4 or less stars were considered to have a high risk of bias. We used Risk of Bias-217 for randomized clinical trials and ROBINS-I18 for nonrandomized intervention studies, both provided by Cochrane. Conference abstracts were consistently classified as high risk of bias without further quality assessment.
Data Analysis
Patients’ raw data were divided into 2 different but partly overlapping data sets for analysis: data set 1—patient characteristics for cohorts with 10 or more patients and data set 2—data extracted on individual patients from all types of studies with acceptable data quality combined into 1 pooled data set (meta-analysis). For the meta-analysis, all available data from identifiable individual patients were collected in 1 data file, which was used for all further analyses. Missing data were not imputed and participants with a high degree of missing data were included in the analysis. For the sake of clarity, missing data are not reported explicitly but all numbers necessary to calculate it are provided in the Tables for all data points.
Statistics
Data were stored using REDCap provided by the Region of Southern Denmark.19 Data were analyzed using Stata (StataCorp) and SPSS version 28 (IBM). The χ2 test was used for categorical data and the Kruskal-Wallis test was used for continuous variables. The statistical tests used are given in the Tables.
Results
Literature Search and Description of the Included Studies
A flowchart showing the inclusion of studies is provided in Figure 1. A total of 718 studies were identified. Following removal of duplicates, 457 studies were assessed on title and abstract. Of these, 309 were included for full-text evaluation, leading to the final inclusion of 95 studies (60 case reports, 2 interventional studies, and 33 case-control/cohort studies; for references see eTable 1 and 2 in Supplement 1 and a list of excluded studies is given in eTable 3 in Supplement 1), and 30 conference abstracts (n = 1200 reported patients). The study team identified 26 studies describing cohorts with 10 or more patients (data set 1, n = 1031 patients; Figure 1)5,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43 and 104 studies describing individual patient data in sufficient detail (data set 2, n = 266 patients; Figure 1). The data sets partly overlapped and 97 patients were included in both. The studies were published between 2012 and 2022 (Figure 2A).
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.
Risk of Bias in the Included Studies
Key demographic data differed between the study types included (eTable 2 in Supplement 1). According to the CARE Checklist and the Modified Newcastle-Ottawa Scale for individual study types (eTable 1 in Supplement 1), 35 studies had a low risk of bias (28%), 50 had a medium risk of bias (40%), and 38 had a high risk of bias (30.4%). One randomized study was assessed as low risk and the other as high risk, based on the Risk of Bias-2 assessment tools. A comparison between the patients reported in larger cohort 10 or more patients (including population-based epidemiological studies; data set 1) and those included in the meta-analysis (data set 2) indicated no substantial differences in key variables, however (Figures 2B-F).
Patient Characteristics
In larger cohort studies (data set 1; 10 or more patients), the mean reported age of patients with SRSE was 53.4 (SD, 5.9) years but this varied substantially between studies (Figure 2B); sex distribution was equal and similar across most studies (Figure 2C). Characteristics and reported etiologies of patients with SRSE included in the meta-analysis (data set 2) are given in Table 1. The cohort of patients with SRSE included in the meta-analysis (data set 2) differed only slightly from patients reported in larger cohort studies (data set 1; Figure 2B-2F). In contrast, patients with SRSE included in the meta-analysis (data set 2) differed substantially from our historical, retrospective unselected cohort of patients with first-time overall SE (Table 1) and similar historical population-based cohorts that were used for comparison44,45,46 (eTable 4 in Supplement 1). Patients with SRSE included in the meta-analysis (data set 2) were younger, more likely had nonconvulsive SE in a coma, and had a distinct etiological profile comprising more acute and unknown etiologies but fewer cases of remote symptomatic etiologies and other etiologies (including tumors, metabolic causes, and alcohol; Table 1) than unselected patients with first time overall SE. As expected by the definition of SRSE, patients with SRSE had a longer seizure duration and had tried more ASMs than did patients with unselected first-time SE.
Table 1. Demographics and Clinical Characteristics of Patients With Super-Refractory Status Epilepticus (SRSE) Reported in Studies Providing Individual Patient Data as Compared With a Previously Published Nonselected Cohorta.
| Patients | Meta-analysis (n = 266) | Roberg et al19 (n = 261) | P valueb |
|---|---|---|---|
| Sex, No. (%) | |||
| Male | 105 (49.5) | 129 (49.4) | .99 |
| Female | 107 (50.5) | 132 (50.6) | |
| Mean age, y (25% IQR) | 40.9 (23.0-56.5) | 67.2 (58.0-78.0) | <.001c |
| Previous status epilepticus episode, No. (%) | 7 (4.8) | NA | NA |
| Mean duration, d (25% IQR) | 36.3 (10.5-50.5) | 5.7 (0.9-6.5) | <.001c |
| No. of ASMs reported (25% IQR) | 5.0 (3.0-6.0) | 2.7 (2.0-4.0) | <.001c |
| Convulsive SE, No. (%) | 94 (53.1) | 95 (36.7) | <.001 |
| Nonconvulsive SE in coma, No. (%) | 61 (34.5) | 82 (31.4) | |
| Focal SE with impaired consciousness, No. (%) | 22 (12.4) | 84 (32.2) | |
| Etiology, No. (%) | |||
| Acute cerebral event | 96 (41.2) | 71 (27.2) | <.001 |
| Remote symptomatic | 16 (6.9) | 75 (28.7) | |
| Known epilepsy | 35 (15.0) | 14 (3.4) | |
| Other causes | 34 (14.6) | 79 (30.3) | |
| Unknown | 52 (22.3) | 22 (8.4) | |
| Successful treatment of SRSE, No. (%) | |||
| Yes | 205 (81.3) | 208 (96.7) | <.001 |
| No | 47 (18.7) | 7 (3.3) | |
| In-hospital mortality, No. (%) | |||
| Alive at discharge | 189 (75.9) | 215 (82.4) | .07 |
| Dead | 60 (24.1) | 46 (17.6) | |
| Estimated modified Rankin Scale score at discharge, No. (%) | |||
| 0-2 | 51 (26.8) | 63 (24.0) | .59 |
| 3-6 | 139 (73.2) | 152 (58.2) |
Abbreviations: ASM, antiseizure medication; NA, not applicable; SE, status epilepticus.
Categorical variables are reported as numbers with percentage of total group population in round brackets.
χ2 Test/Fisher exact test was used unless otherwise stated.
Kruskal-Wallis test.
Patient Outcomes
Outcome measures (proportion of successful SRSE treatment and in-hospital survival) were similar for the cohort group (data set 1) and the meta-analysis group (data set 2; Figure 2E and F). The reported in-hospital mortality for patients included in the meta-analysis (data set 2) was 24.1% and in 81.3% of all patients treatment successfully ceased the SRSE (Table 1). Of all patients analyzed in the meta-analysis (data set 2), 26.8% were discharged from the hospital with no or minor to moderate disability. The remainder were either dead or severely disabled at discharge (Table 1; Figure 3A). Reported mortality of patients depended on the duration of SRSE and stabilized if SRSE lasted for more than 28 days (Figure 3B); the rate of successful seizure termination continued to rise with increasing duration (Figure 3C). However, the proportion of patients with substantial disability defined as an mRS of 3 to 5 also increased substantially (Figure 3A) with longer duration of SRSE.
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.
Prognostic Factors
Analysis of risk factors for different outcomes measures in data set 2 showed null associations for most factors, including etiology. Favorable functional outcome was associated with younger age and lower number of ASMs tried but not with duration of SE (Table 2). The status epilepticus severity score was not consistently associated with in-hospital mortality (nonsignificant for a cutoff of 3; P = .02 for a cutoff of 4; Figure 3D), and there were insufficient data for the analysis of other prognostic scores.
Table 2. Clinical Characteristics of Patients With Super-Refractory Status Epilepticus (SRSE) According to Their Outcome (n = 266).
| Characteristic | Successful treatment, mean (IQR) | P valuea | In-hospital mortality, mean (IQR) | P valuea | Functional outcome, mean (IQR) | P valuea | |||
|---|---|---|---|---|---|---|---|---|---|
| Yes | No | Alive | Dead | mRS 0-2 | mRS 3-6 | ||||
| Age, y | 40.9 (23.0-54.0) | 41.2 (24.0-60.0) | .50 | 39.8 (23.0-5.0) | 45.3 (27.0-66.0) | .27 | 36.0 (23.0-45.0) | 45.0 (27.5-61.5) | .01 |
| Duration of SE, d | 40.6 (14.0-60.0) | 22.9 (4.0-22.0) | .002 | 42.0 (14.0-60.0) | 23.4 (5.0-22.0) | <.001 | 41.8 (15.0-60.0) | 39.7 (9.0-60.0) | .13 |
| No. of ASMs tried | 5.1 (3.0-6.0) | 4.5 (3.0-6.0) | .96 | 5.2 (4.0-7.0) | 4.4 (3.0-6.0) | .16 | 4.7 (3.0-6.0) | 5.4 (4.0-7.0) | .03 |
| No. (%) | P value b | No. (%) | P value b | No. (%) | P valueb | ||||
| Sex | |||||||||
| Female | 81 (47.9) | 19 (65.5) | .08 | 78 (49.4) | 22 (57.9) | .35 | 18 (40.9) | 56 (53.8) | .15 |
| Male | 88 (52.1) | 10 (34.5) | 80 (50.6) | 16 (42.1) | 26 (59.1) | 48 (46.2) | |||
| Previous SE | 7 (6.1) | 0 (0) | .28 | 6 (5.8) | 0 (0) | .19 | 1 (3.2) | 4 (6.0) | .57 |
| Convulsive SRSE | 75 (53.2) | 13 (54.2) | .99 | 69 (53.1) | 18 (54.5) | .70 | 22 (55.0) | 46 (55.4) | .31 |
| NCSE in coma | 47 (33.3) | 8 (33.3) | 42 (32.3) | 12 (36.4) | 16 (40.0) | 26 (31.3) | |||
| NCSE with focal impaired seizures | 19 (13.5) | 3 (12.5) | 19 (14.6) | 3 (9.1) | 2 (5.0) | 11 (13.3) | |||
| Acute cerebral damage | 79 (44.1) | 16 (40.0) | .08 | 75 (44.9) | 20 (40.0) | .70 | 21 (47.7) | 49 (41.5) | .31 |
| Unknown | 33 (18.4) | 7 (17.5) | 30 (18.0) | 10 (20.0) | 8 (18.2) | 28 (23.7) | |||
| Other | 24 (13.4) | 10 (25.0) | 20 (12.0) | 12 (24.0) | 10 (22.7) | 15 (12.7) | |||
| Known epilepsy | 32 (17.9) | 2 (5.0) | 31 (18.6) | 3 (6.0) | 3 (6.8) | 13 (11.0) | |||
| Remote symptomatic | 11 (6.1) | 5 (12.5) | 11 (6.6) | 5 (10.0) | 2 (4.5) | 13 (11.0) | |||
| Any barbiturate | 102 (70.8) | 23 (63.9) | .42 | 96 (72.2) | 28 (62.2) | .21 | 26 (72.2) | 70 (72.2) | 1.00 |
| No barbiturate | 42 (29.2) | 13 (36.1) | 37 (27.8) | 17 (37.8) | 10 (27.8) | 27 (27.8) | |||
| Phenobarbital treatment | 50 (38.2) | 15 (51.7) | .18 | 47 (39.8) | 17 (42.5) | .77 | 8 (27.6) | 40 (47.6) | .06 |
| No phenobarbital treatment | 81 (61.8) | 14 (48.3) | 71 (60.2) | 23 (57.5) | 21 (72.4) | 44 (52.4) | |||
| Ketamine treatment | 65 (31.7) | 19 (40.4) | .25 | 60 (31.7) | 21 (35.0) | .64 | 21 (41.2) | 44 (31.7) | .22 |
| No ketamine treatment | 140 (68.3) | 28 (59.6) | 129 (68.3) | 39 (65.0) | 30 (58.8) | 95 (68.3) | |||
| VNS treatment | 5 (3.2) | 0 (0) | .27 | 4 (2.8) | 1 (2.0) | .77 | 0 (0) | 4 (3.4) | .26 |
| No VNS treatment | 153 (96.8) | 38 (100) | 141 (97.2) | 49 (98.0) | 36 (100) | 114 (96.6) | |||
| Ketogenic diet | 51 (24.9) | 8 (17.0) | .25 | 49 (25.9) | 10 (16.7) | .14 | 11 (21.6) | 40 (28.8) | .32 |
| No ketogenic diet | 154 (75.1) | 39 (83.0) | 140 (74.1) | 50 (83.3) | 40 (78.4) | 99 (71.2) | |||
Abbreviations: ASM, antiseizure medication; mRS, modified Rankin scale; NCSE, nonconvulsive status epilepticus; SE, status epilepticus; VNS, vagus nerve stimulator.
Kruskal-Wallis test.
χ2 Test/Fisher exact test.
Patterns of Treatment and Associated Response
In data set 2, the average reported number of ASMs tried was 5.0 and 50% of the patients tried between 3 and 6 ASMs. Levetiracetam, valproic acid, phenytoin, and lacosamide were the most commonly reported ASMs (Figure 3E). The number of ASMs reported was associated with higher disability at discharge but not with reduced in-hospital mortality or higher rates of treatment success (Table 2). All patients received anesthetics at intensive care. The 3 most commonly used anesthetics were propofol followed by midazolam and thiopental (data not shown).
Exploratory analysis of different commonly used treatment approaches and outcome parameters remained nonsignificant for ketamine (Figure 3F; Table 2), phenobarbital, any kind of barbiturate treatment, vagus nerve stimulator, and ketogenic diet (Table 2). The eFigure in Supplement 1 provides an overview of the data reported as compared with the primary outcome measure of the reporting publication.
Discussion
We show that the outcome of SRSE is poor with a reported in-hospital mortality of 24.1%. Only around one-quarter of patients had an mRS of 2 or less and less than 10% were completely independent at discharge.
In-hospital mortality and duration of treatment were similar to those of a large cohort of patients with SRSE identified retrospectively based on German insurance data5 and basic demographics were in line with larger cohorts (Figure 2C-F). Given that larger cohorts are less likely influenced by the selection of favorable outcomes and assuming that the insurance data are unbiased, these analyses indicate that the cohort included in the meta-analysis is not substantially affected by reporting bias making its analysis meaningful. However, it is important to be aware of some possible biases, especially in data set 2 that was used for meta-analysis. SRSE is likely a spectrum that may differ between hospitals. There is a risk that the case studies included in data set 2 reported more extreme patients from this spectrum. Conversely, there may be a bias toward reporting good outcomes only. Determining the exact degree of bias is, however, impossible.
Due to the rarity of SRSE, it is difficult to carry out systematic, prospective, or randomized studies, which explains the low level of evidence of the publications used and the moderate to high assessed risk of bias. However, a meta-analysis comprising case and cohort studies remains an important instrument to increase the understanding of rare conditions, where a higher level of evidence is unavailable and where clinical studies are not a practicable option.47 Thus, our results are only estimates that summarize the limited but best currently available evidence.
Patients with reported SRSE differed significantly from unselected patients with first-time overall SE. The treating physicians may have prioritized patients with an expected more favorable overall prognosis and unknown diagnoses and avoided treatment with poorer prospects, eg, patients with brain tumors or more fragile, older patients. This may explain why established prognostic factors for in-hospital mortality, such as age and etiology, did not apply for SRSE. The plateau in mortality after 28 days of treatment might be due to a combination of survival of the most robust patients and the reluctance of the treating physicians to terminate treatment once they had decided to continue treatment for more than 1 month (effort justification bias). The continuously increasing rate of seizure cessation after 28 days of treatment probably results from a combination of genuine treatment successes, reporting bias, and, conceivably, substantial brain damage destroying the epileptic focus after many weeks of continuous seizures. Irrespective of the cause, very long-term treatment for more than 28 days was associated with a high proportion of patients with moderate to severe disability at discharge, although good outcomes were consistently reported, irrespective of the duration of SE. The available data do not allow us to investigate whether patients’ high disability was due to intensive care–related complications (eg, critical illness neuropathies), the underlying etiology, high ASM load, or SE-induced brain damage.
The etiologies triggering SRSE in the patients included in this study differ substantially from established SE triggers. In population-based cohort studies, remote symptomatic SE makes up about one-third to half of the entire cohort46,48 and few patients have unknown causes (2.4% in our retrospective cohort;44 1.8% in the Salzburg cohort46). Around 40% to 50% have known epilepsy before admission.46,49 In patients with SRSE, remote symptomatic seizures (eg, poststroke epilepsy) and a history of previous seizures are less common, in line with both factors being established as favorable and rarely associated with progression to SRSE.12,50 Conversely, the proportion of acute cerebral events, like intracerebral hemorrhages, was higher in the patients with SRSE included in this meta-analysis and in nonselected patient populations.50 Thus, SRSE comprises a defined subgroup of patients with distinct characteristics caused by a combination of a selection bias of the treating physicians and the natural course and aggressiveness of the different etiologies.
Data on the treatment of SRSE are sparse. Given that this study analyzed reports from specialized centers worldwide, the ASMs given in Figure 3E likely illustrate the international standard of care. While the most frequently used ASMs correspond to the recommended treatment of SE,51 most centers consider lacosamide, phenobarbital, and topiramate as third-line ASM treatments for SRSE.
Phenobarbital was recently suggested as an effective therapeutic approach.52 In this meta-analysis, it was used late during the course of SE and in younger patients (data not shown) and resulted in a nonsignificant trend toward worse outcomes at discharge. Similar nonsignificant tendencies were seen for treatment with ketamine, ketogenic diet, and vagus nerve stimulator. Importantly and despite possible reporting bias, we found no differences in outcome for these 4 treatments. Given the heterogeneity of the patients included, this does not exclude an effect in subgroups but certainly indicates the need for prospective trials or large, multinational registers.
Limitations
Methodological limitations included the review authors not being blinded during the selection of literature and that we did not try to contact authors in the event of missing data. Furthermore, the exclusion of important contributions due to the reporting of mixed cohorts of refractory SE and SRSE (eg, in a recent randomized trial studying hypothermia53) limited the number of patients and cohorts amenable for analysis.
Conclusion
In conclusion, in this observational meta-analysis, patients with SRSE are a distinct subpopulation of patients with SE likely due to patient selection and the natural course of SE. Established prognostic factors for first-time overall SE do not reliably predict in-hospital mortality in patients with SRSE. While treatment remains successful (at least in stopping seizures) in most patients, the risk of death or severe disability at discharge is high. Very long-term treatment longer than 28 days is associated with low mortality and high odds of cessation of SRSE but also increased risk of moderate to severe disability. We found no data indicating altered outcomes after treatment with barbiturates, ketamine, vagus nerve stimulator, or ketogenic diet.
eTable 1. Evaluation of bias of included studies
eTable 2. Key demographics of patients with super-refractory status epilepticus (SRSE) according to study type
eTable 3. Overview of excluded studies
eTable 4. Comparison of patients included in the meta-analysis (dataset 2) and published cohorts
eFigure. Overview of data sources (dataset 2)
eReferences
Data sharing statement
References
- 1.Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain. 2011;134(Pt 10):2802-2818. doi: 10.1093/brain/awr215 [DOI] [PubMed] [Google Scholar]
- 2.Trinka E, Leitinger M. Management of status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Continuum (Minneap Minn). 2022;28(2):559-602. doi: 10.1212/CON.0000000000001103 [DOI] [PubMed] [Google Scholar]
- 3.Delaj L, Novy J, Ryvlin P, Marchi NA, Rossetti AO. Refractory and super-refractory status epilepticus in adults: a 9-year cohort study. Acta Neurol Scand. 2017;135(1):92-99. doi: 10.1111/ane.12605 [DOI] [PubMed] [Google Scholar]
- 4.Kantanen AM, Reinikainen M, Parviainen I, Kälviäinen R. Long-term outcome of refractory status epilepticus in adults: a retrospective population-based study. Epilepsy Res. 2017;133:13-21. doi: 10.1016/j.eplepsyres.2017.03.009 [DOI] [PubMed] [Google Scholar]
- 5.Strzelczyk A, Ansorge S, Hapfelmeier J, Bonthapally V, Erder MH, Rosenow F. Costs, length of stay, and mortality of super-refractory status epilepticus: a population-based study from Germany. Epilepsia. 2017;58(9):1533-1541. doi: 10.1111/epi.13837 [DOI] [PubMed] [Google Scholar]
- 6.Kantanen AM, Kälviäinen R, Parviainen I, et al. Predictors of hospital and one-year mortality in intensive care patients with refractory status epilepticus: a population-based study. Crit Care. 2017;21(1):71. doi: 10.1186/s13054-017-1661-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372(71):n71. doi: 10.1136/bmj.n71 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Shorvon S, Trinka E. The London-Innsbruck Status Epilepticus Colloquia 2007-2011, and the main advances in the topic of status epilepticus over this period. Epilepsia. 2013;54(s6)(suppl 6):11-13. doi: 10.1111/epi.12265 [DOI] [PubMed] [Google Scholar]
- 9.Dutta K, Satishchandra P, Borkotokey M. Medium-chain triglyceride ketogenic diet as a treatment strategy for adult super-refractory status epilepticus. Indian J Crit Care Med. 2022;26(1):139-140. doi: 10.5005/jp-journals-10071-24073 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Newey CR, Mullaguri N, Hantus S, Punia V, George P. Super-refractory status epilepticus treated with high dose perampanel: case series and review of the literature. Case Rep Crit Care. 2019;2019:3218231. doi: 10.1155/2019/3218231 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):522-530. doi: 10.1111/epi.13670 [DOI] [PubMed] [Google Scholar]
- 12.Rossetti AO, Logroscino G, Milligan TA, Michaelides C, Ruffieux C, Bromfield EB. Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy. J Neurol. 2008;255(10):1561-1566. doi: 10.1007/s00415-008-0989-1 [DOI] [PubMed] [Google Scholar]
- 13.Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Epilepsia. 1993;34(4):592-596. doi: 10.1111/j.1528-1157.1993.tb00433.x [DOI] [PubMed] [Google Scholar]
- 14.Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010;51(4):671-675. doi: 10.1111/j.1528-1167.2009.02285.x [DOI] [PubMed] [Google Scholar]
- 15.Riley DS, Barber MS, Kienle GS, et al. CARE guidelines for case reports: explanation and elaboration document. J Clin Epidemiol. 2017;89:218-235. doi: 10.1016/j.jclinepi.2017.04.026 [DOI] [PubMed] [Google Scholar]
- 16.Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
- 17.Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi: 10.1136/bmj.l4898 [DOI] [PubMed] [Google Scholar]
- 18.Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. doi: 10.1136/bmj.i4919 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Harris PA, Taylor R, Minor BL, et al. ; REDCap Consortium . The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208. doi: 10.1016/j.jbi.2019.103208 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Caranzano L, Novy J, Rossetti AO. Ketamine in adult super-refractory status epilepticus: efficacy analysis on a prospective registry. Acta Neurol Scand. 2022;145(6):737-742. doi: 10.1111/ane.13610 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Strzelczyk A, Knake S, Kälviäinen R, et al. Perampanel for treatment of status epilepticus in Austria, Finland, Germany, and Spain. Acta Neurol Scand. 2019;139(4):369-376. doi: 10.1111/ane.13061 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Tian L, Li Y, Xue X, et al. Super-refractory status epilepticus in West China. Acta Neurol Scand. 2015;132(1):1-6. doi: 10.1111/ane.12336 [DOI] [PubMed] [Google Scholar]
- 23.Uchida Y, Terada K, Madokoro Y, et al. Stiripentol for the treatment of super-refractory status epilepticus with cross-sensitivity. Acta Neurol Scand. 2018;137(4):432-437. doi: 10.1111/ane.12888 [DOI] [PubMed] [Google Scholar]
- 24.Thakur KT, Probasco JC, Hocker SE, et al. Ketogenic diet for adults in super-refractory status epilepticus. Neurology. 2014;82(8):665-670. doi: 10.1212/WNL.0000000000000151 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Anand S, Vibhute AS, Das A, Pandey S, Paliwal VK. Ketogenic diet for super-refractory status epilepticus: a case series and review of literature. Ann Indian Acad Neurol. 2021;24(1):111-115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Rosenthal ES, Claassen J, Wainwright MS, et al. Brexanolone as adjunctive therapy in super-refractory status epilepticus. Ann Neurol. 2017;82(3):342-352. doi: 10.1002/ana.25008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Höfler J, Rohracher A, Kalss G, et al. (S)-Ketamine in refractory and super-refractory status epilepticus: a retrospective study. CNS Drugs. 2016;30(9):869-876. doi: 10.1007/s40263-016-0371-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Pugin D, Foreman B, De Marchis GM, et al. Is pentobarbital safe and efficacious in the treatment of super-refractory status epilepticus: a cohort study. Crit Care. 2014;18(3):R103. doi: 10.1186/cc13883 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Jose J, Keni RR, Hassan H, et al. Predictors of outcome in super refractory status epilepticus. Epilepsy Behav. 2021;118:107929. doi: 10.1016/j.yebeh.2021.107929 [DOI] [PubMed] [Google Scholar]
- 30.Kantanen AM, Reinikainen M, Parviainen I, et al. Incidence and mortality of super-refractory status epilepticus in adults. Epilepsy Behav. 2015;49:131-134. doi: 10.1016/j.yebeh.2015.04.065 [DOI] [PubMed] [Google Scholar]
- 31.Sabharwal V, Poongkunran M, Talahma M, et al. Secondary hypothermia in patients with super-refractory status epilepticus managed with propofol and ketamine. Epilepsy Behav. 2020;105:106960. doi: 10.1016/j.yebeh.2020.106960 [DOI] [PubMed] [Google Scholar]
- 32.Byun JI, Chu K, Sunwoo JS, et al. Mega-dose phenobarbital therapy for super-refractory status epilepticus. Epileptic Disord. 2015;17(4):444-452. doi: 10.1684/epd.2015.0778 [DOI] [PubMed] [Google Scholar]
- 33.Koh S, Kim TJ, Lim TS, et al. Pentobarbital coma therapy for super-refractory status epilepticus and in-hospital mortality: an observational study. Epileptic Disord. 2021;23(6):833-842. doi: 10.1684/epd.2021.1333 [DOI] [PubMed] [Google Scholar]
- 34.Lin CH, Lu YT, Ho CJ, Shih FY, Tsai MH. The different clinical features between autoimmune and infectious status epilepticus. Front Neurol. 2019;10:25. doi: 10.3389/fneur.2019.00025 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Misra UK, Kalita J, Dubey D. A study of super refractory status epilepticus from India. Front Neurol. 2017;8:636. doi: 10.3389/fneur.2017.00636 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Hocker S, Nagarajan E, Rabinstein AA, Hanson D, Britton JW. Progressive brain atrophy in super-refractory status epilepticus. JAMA Neurol. 2016;73(10):1201-1207. doi: 10.1001/jamaneurol.2016.1572 [DOI] [PubMed] [Google Scholar]
- 37.Kaul N, Nation J, Laing J, et al. Modified low ratio ketogenic therapy in the treatment of adults with super-refractory status epilepticus. JPEN J Parenter Enteral Nutr. 2022;46(8):1819-1827. doi: 10.1002/jpen.2373 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Alkhachroum A, Ganesan SL, Koren JP, et al. Quantitative EEG-based seizure estimation in super-refractory status epilepticus. Neurocrit Care. 2021;36(3):897-904. doi: 10.1007/s12028-021-01395-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Gugger JJ, Husari K, Probasco JC, Cervenka MC. New-onset refractory status epilepticus: a retrospective cohort study. Seizure. 2020;74:41-48. doi: 10.1016/j.seizure.2019.12.002 [DOI] [PubMed] [Google Scholar]
- 40.Kerin B, Rajakulendran S, Kullmann DM, Neligan A, Walker MC. A retrospective cohort study of super-refractory status epilepticus in a tertiary neuro-ICU setting. Seizure. 2021;85:90-94. doi: 10.1016/j.seizure.2020.12.020 [DOI] [PubMed] [Google Scholar]
- 41.Madžar D, Knappe RU, Reindl C, et al. Factors associated with occurrence and outcome of super-refractory status epilepticus. Seizure. 2017;52:53-59. doi: 10.1016/j.seizure.2017.09.003 [DOI] [PubMed] [Google Scholar]
- 42.Dubey D, Bhoi SK, Kalita J, Misra UK. Spectrum and predictors of refractory status epilepticus in a developing country. Can J Neurol Sci. 2017;44(5):538-546. doi: 10.1017/cjn.2017.28 [DOI] [PubMed] [Google Scholar]
- 43.Chateauneuf A-L, Moyer J-D, Jacq G, Cavelot S, Bedos J-P, Legriel S. Super-refractory status epilepticus: epidemiology, early predictors, and outcomes. Intensive Care Med. 2017;43(10):1532-1534. doi: 10.1007/s00134-017-4837-6 [DOI] [PubMed] [Google Scholar]
- 44.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):604-613. doi: 10.1001/jamaneurol.2022.0609 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Kortland LM, 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. doi: 10.1111/epi.13584 [DOI] [PubMed] [Google Scholar]
- 46.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. doi: 10.1111/epi.14607 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med. 2018;23(2):60-63. doi: 10.1136/bmjebm-2017-110853 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Rodin E, Krogstad MH, Aukland P, et al. High long-term mortality after incident status epilepticus in adults: results from a population-based study. Epilepsia. 2019;60(1):33-41. doi: 10.1111/epi.14602 [DOI] [PubMed] [Google Scholar]
- 49.Novy J, Logroscino G, Rossetti AO. Refractory status epilepticus: a prospective observational study. Epilepsia. 2010;51(2):251-256. doi: 10.1111/j.1528-1167.2009.02323.x [DOI] [PubMed] [Google Scholar]
- 50.Leitinger M, Höller Y, Kalss G, et al. Epidemiology-based mortality score in status epilepticus (EMSE). Neurocrit Care. 2015;22(2):273-282. doi: 10.1007/s12028-014-0080-y [DOI] [PubMed] [Google Scholar]
- 51.Kapur J, Elm J, Chamberlain JM, et al. ; NETT and PECARN Investigators . Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med. 2019;381(22):2103-2113. doi: 10.1056/NEJMoa1905795 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Brigo F, Del Giovane C, Nardone R, Trinka E, Lattanzi S. Intravenous antiepileptic drugs in adults with benzodiazepine-resistant convulsive status epilepticus: a systematic review and network meta-analysis. Epilepsy Behav. 2019;101(Pt B):106466. doi: 10.1016/j.yebeh.2019.106466 [DOI] [PubMed] [Google Scholar]
- 53.Legriel S, Lemiale V, Schenck M, et al. ; HYBERNATUS Study Group . Hypothermia for neuroprotection in convulsive status epilepticus. N Engl J Med. 2016;375(25):2457-2467. doi: 10.1056/NEJMoa1608193 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Evaluation of bias of included studies
eTable 2. Key demographics of patients with super-refractory status epilepticus (SRSE) according to study type
eTable 3. Overview of excluded studies
eTable 4. Comparison of patients included in the meta-analysis (dataset 2) and published cohorts
eFigure. Overview of data sources (dataset 2)
eReferences
Data sharing statement