Status epilepticus (SE) is a common and life-threatening condition, which requires urgent medical attention. The incidence of SE ranges from 10 to 20 per 100 000 [
Mortality of SE varies greatly (1.9%–40.0%) in published series [
It has been recently shown that delays in the treatment of SE are unacceptably long [
Treatment of SE is guided by two international guidelines [
SE is a very dynamic process with diagnostic challenges, several treatment stages, and potential misinterpretations over the whole management process. Systematic analysis of the factors related to different parts of the treatment chain is needed to draw definite conclusions on the impact of the delays on prognosis. Our newly published study focussed on factors related to delays in the pre-hospital management of SE [
This study was designed to identify the delays and factors related to markers for cessation of GCSE and particularly to identify factors predicting the return of consciousness after GCSE. We also aim at validation of the stepwise definition for the cessation of SE, published earlier [
This is a retrospective cohort study performed in Helsinki University Central Hospital (HUCH), a tertiary hospital serving a population of 1.4 million. HUCH provides neurological emergency service 24 h a day for the hospital district. The local Emergency Medical Service (EMS) has been instructed to transport patients with GCSE primarily to HUCH Emergency Department (ED). This study conforms to the Finnish legislation concerning medical research and the permission was granted by the HUCH Department of Neurology.
This study material includes consecutive adult patients (over 16 years of age) diagnosed with generalized convulsive status epilepticus (GCSE) and treated in the HUCH ED over a two-year period from January 2002 till December 2003.
The patients were identified in the HUCH electronic patient database by the ICD-10 code G41 (SE), yielding a total of 87 patients. Established SE was defined as continuous seizures lasting over 30 minutes, several recurrent seizures without returning consciousness, or occurrence of more than four seizures within any one hour irrespective of return of consciousness in between. Patients not meeting these criteria were excluded, despite having the SE diagnosis in their records, resulting in a total of 82 patients. The seizure description was collected from original medical records for all these patients. Patients having a convulsive seizure at any point of the SE period were considered as having convulsive SE (CSE). Patients with impaired consciousness, either primarily or secondarily, were considered as having generalized SE (GSE). Altogether 70 patients met the criteria for GCSE and were included in this study.
A trained medical doctor collected the data from the original medical records on a standard form designed for this study. The records consisted of notes made by nurses and doctors of EMS, health care centers, regional hospitals, and HUCH ED, ICU, or neurological ward. Ambiguous data were evaluated in collaboration with the research team and if the consensus concerning the original coding rules changed, the data in question were recollected. The electronic database was created using MS Access for data recording. The information of patient identification was removed before further analyses. The Weighted Accuracy Score
Demographic data, medical history of the cases, etiologic and predisposing factors of GCSE and patients’ condition at HUCH discharge are presented in Online Table 1 in Supplementary Material available online at
We defined and calculated 13 parameters for delay in the management of GCSE. All delays were counted from the onset of GCSE. The time parameters and the median delays are presented in Table
Delay parameters and the delays in the management of GCSE.
Variable |
|
% | Time | Time | MIN | MAX | DA |
|
---|---|---|---|---|---|---|---|---|
All Cases | 70 | 100 | Median | Mean | % | |||
Delays in the treatment | ||||||||
Onset-to-initial-treatment | 67 | 95.7 | 30 min | 57 min | 0 min | 8 h 5 min | 97.0 | 1.8 |
Onset-to-alarm | 60 | 85.7 | 36 min | 2 h 27 min | 0 min | 57 h 44 min | 93.3 | 1.5 |
Onset-to-first-convulsion-end | 70 | 100 | 51 min | 2 h 13 min | 1 min | 63 h 40 min | 97.1 | 1.8 |
Onset-to-diagnosis | 70 | 100 | 1 h 48 min | 4 h | 6 min | 60 h 6 min | 97.1 | 1.5 |
Onset-to-second-stage-medication | 67 | 95.7 | 2 h 40 min | 4 h 49 min | 30 min | 61 h 54 min | 98.5 | 1.6 |
Onset-to-anesthesia | 62 | 88.6 | 2 h 38 min | 5 h 43 min | 0 min | 66 h 20 min | 98.4 | 1.5 |
Onset-to-first-ED | 61 | 87.1 | 2 h 2 min | 3 h 31 min | 0 min | 58 h 29 min | 98.4 | 1.5 |
Onset-to-tertiary-hospital (HUCH) | 70 | 100 | 2 h 25 min | 1 h 25 min | 37 min | 277 h 40 min | 98.6 | 1.5 |
Onset-to-EEG | 57 | 81.4 | 21 h 52 min | 33 h | 2 h 30 min | 142 h | 94.7 | 1.5 |
Onset-to-EEG-monitoring | 42 | 60.0 | 11 h 10 min | 15 h 45 min | 2 h 30 min | 82 h 14 min | 97.6 | 1.5 |
Delays in the markers for cessation of GCSE | ||||||||
Onset-to-burst-suppression | 30 | 42.9 | 14 h 42 min | 25 h 20 min | 5 h 5 min | 137 h 50 min | 100.0 | 1.5 |
Onset-to-clinical-seizure-freedom | 70 | 100 | 5 h 15 min | 31 h 5 min | 26 min | 533 h 15 min | 98.6 | 1.6 |
Onset-to-consciousness | 61 | 87.1 | 42 h 45 min | 66 h 5 min | 2 h 40 min | 444 h 40 min | 96.7 | 1.4 |
We defined 7 grouping variables (prognostic factors and GCSE episode parameters) for subgroup analysis. The variables are presented in Table
Grouping variables (prognostic factors and GCSE episode parameters) for the subgroup analysis.
Variable |
|
% |
---|---|---|
All | 70 | 100 |
Age under 65 | ||
Yes | 51 | 72.9 |
No | 19 | 27.1 |
Epilepsy | ||
Yes | 46 | 65.7 |
No | 23 | 32.9 |
Unknown | 1 | 1.4 |
STESS | ||
2 | 35 | 50.0 |
3 | 16 | 22.9 |
4 | 10 | 14.3 |
5 | 9 | 12.9 |
Prestatus period | ||
Yes | 14 | 20.0 |
No | 56 | 80.0 |
SE onset | ||
Continuous | 45 | 64.3 |
Intermittent | 25 | 35.7 |
Effect of the first medication | ||
Yes | 17 | 24.3 |
No | 39 | 55.7 |
Spontaneous cessation | 11 | 15.7 |
Refractoriness | ||
Non-RSE | 8 | 11.4 |
RSE | 30 | 42.9 |
SRSE | 32 | 45.7 |
Cases with events missing, for example, no burst-suppression (BS) and events happening during prestatus period, or with unknown data were excluded from the final analysis. The missing data information is presented in Online Table 2.
The onset of GCSE was defined as the beginning of the first seizure, fulfilling the criteria for established GCSE. Initial treatment was defined as the first given antiepileptic drug (AED), which was not necessarily the first-stage medication. Alarm delay refers to the primary alarm, in this case the delay in calling the ambulance.
Onset-to-first-convulsion-end refers to the time between the onset of GCSE and the end of the first clinical convulsion. The second-stage medication included i.v. fosphenytoin or valproate, and the third-stage medication included anesthesia with intravenous (i.v.) propofol, thiopental, or midazolam. Induction was considered as the exact time point of anesthesia. First ED was defined as the first emergency department the patient was transported to. Tertiary hospital always refers to HUCH ED.
We defined the markers for cessation of GCSE with three separate parameters for the treatment response [
Age of 65 years was selected as the classification basis for age as a grouping variable. Only patients with previously diagnosed epilepsy were considered as having epilepsy. Status Epilepticus Severity Score (STESS) [
The results are expressed as mean/median and range/interquartile range (IQR) or as number of patients and percentage. The normality of variables was tested with the Kolmogorov-Smirnov test. For the nonnormal data, the Spearman’s correlation coefficient and, for normally distributed data, the Pearson’s correlation coefficient were calculated to find correlation between continuous variables. Bootstrap resampling (1000 samples) was used to calculate the bias corrected percentile confidence intervals for correlation coefficients. Statistical significance of the differences in variables between independent samples was tested with the nonparametric Wilcoxon-Mann–Whitney test. Differences in categorical variables were examined using the Fisher’s exact test. The Kaplan-Meier analysis with the log-rank test was used to analyze time to event data. Linear regression analysis with bootstrap resampling (5000 samples) was used to model delays in treatment response. Statistical analyses were executed using the SPSS software (version 22.0, SPSS, IBM Corp. USA). Statistical significance was defined as
The total-time-correlations, that is, correlations between the onset-to-event and onset-to-treatment-response delays, that is, markers for the cessation of SE, are shown in Table
(a) Total-time-correlations: correlations between the onset-to-event and onset-to-treatment-response delays, that is, markers for cessation of SE. (b) Chronological correlations: correlations between the onset-to-event delays and event-to-treatment-response delays, that is, markers for cessation of SE.
Variable | Onset-to-burst-suppression | Onset-to-clinical-seizure-freedom | Onset-to-consciousness | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Coefficient | 95% CI (min) | 95% CI (max) |
|
|
Coefficient | 95% CI (min) | 95% CI (max) |
|
|
Coefficient | 95% CI (min) | 95% CI (max) |
|
|
Onset-to-initial-treatment | 28 | 0.127 | −0.299 | 0.519 | 0.520 | 65 | 0.054 | −0.181 | 0.289 | 0.668 | 56 | 0.017 | −0.213 | 0.254 | 0.902 |
Onset-to-first-convulsion-end | 29 | 0.303 | −0.093 | 0.640 | 0.110 | 68 | 0.122 | −0.122 | 0.363 | 0.321 | 58 | 0.107 | −0.166 | 0.367 | 0.425 |
Onset-to-alarm | 22 | 0.467 | 0.036 | 0.791 |
|
55 | 0.300 | −0.004 | 0.558 |
|
47 | 0.010 | −0.256 | 0.288 | 0.946 |
Onset-to-diagnosis | 29 | 0.415 | 0.040 | 0.691 |
|
68 | 0.371 | 0.120 | 0.587 |
|
59 | 0.136 | −0.111 | 0.390 | 0.304 |
Onset-to-second-stage-medication | 30 | 0.337 | −0.080 | 0.660 | 0.069 | 66 | 0.334 | 0.087 | 0.535 |
|
56 | 0.402 | 0.165 | 0.610 |
|
Onset-to-anesthesia | 30 | 0.510 | 0.132 | 0.765 |
|
61 | 0.382 | 0.098 | 0.619 |
|
51 | 0.088 | −0.175 | 0.353 | 0.540 |
Onset-to-first-ED | 23 | 0.500 | 0.091 | 0.781 |
|
60 | 0.260 | 0.019 | 0.503 |
|
52 | 0.212 | −0.740 | 0.476 | 0.131 |
Onset-to-tertiary-hospital (HUCH) | 30 | 0.538 | 0.177 | 0.780 |
|
69 | 0.334 | 0.081 | 0.559 |
|
59 | 0.207 | −0.550 | 0.448 | 0.116 |
Onset-to-EEG | 26 | 0.099 | −0.324 | 0.496 | 0.632 | 54 | 0.470 | 0.197 | 0.688 |
|
46 | 0.327 | 0.037 | 0.568 |
|
Onset-to-EEG-monitoring | 30 | 0.775 | 0.503 | 0.929 |
|
41 | 0.413 | 0.096 | 0.677 |
|
31 | 0.239 | −0.135 | 0.542 | 0.194 |
Onset-to-burst-suppression | 30 | 0.558 | 0.165 | 0.857 |
|
21 | 0.527 | 0.071 | 0.815 |
|
|||||
Onset-to-clinical-seizure-freedom | 59 | 0.739 | 0.576 | 0.850 |
|
Variable | Event-to-burst-suppression | Event-to-clinical-seizure freedom | Event-to-consciousness | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Onset-to-event |
|
Coefficient | 95% CI (min) | 95% CI (max) |
|
|
Coefficient | 95% CI (min) | 95% CI (max) |
|
|
Coefficient | 95% CI (min) | 95% CI (max) |
|
Onset-to-initial-treatment | 28 | 0.005 | −0.421 | 0.412 | 0.981 | 65 | −0.095 | −0.344 | 0.156 | 0.453 | 56 | −0.012 | −0.237 | 0.205 | 0.928 |
Onset-to-first-convulsion-end | 29 | 0.109 | −0.282 | 0.474 | 0.573 | 68 | −0.112 | −0.360 | 0.136 | 0.362 | 58 | 0.085 | −0.173 | 0.322 | 0.528 |
Onset-to-alarm | 22 | 0.303 | −0.176 | 0.666 | 0.171 | 55 | 0.020 | −0.253 | 0.295 | 0.883 | 47 | −0.087 | −0.364 | 0.223 | 0.563 |
Onset-to-diagnosis | 29 | 0.169 | −0.198 | 0.497 | 0.382 | 68 | −0.069 | −0.321 | 0.226 | 0.574 | 59 | 0.037 | −0.267 | 0.322 | 0.783 |
Onset-to-second-stage-medication | 30 | 0.057 | −0.345 | 0.421 | 0.765 | 66 | −0.046 | −0.323 | 0.265 | 0.713 | 56 | 0.295 | 0.039 | 0.534 |
|
Onset-to-anesthesia | 30 | −0.152 | −0.488 | 0.175 | 0.424 | 61 | −0.057 | −0.333 | 0.211 | 0.662 | 51 | 0.025 | −0.251 | 0.330 | 0.859 |
Onset-to-first-ED | 23 | 0.343 | −0.062 | 0.732 | 0.109 | 60 | −0.022 | −0.296 | 0.271 | 0.870 | 52 | 0.101 | −0.195 | 0.385 | 0.477 |
Onset-to-tertiary-hospital (HUCH) | 30 | 0.113 | −0.247 | 0.498 | 0.552 | 69 | −0.037 | −0.285 | 0.195 | 0.761 | 59 | 0.068 | −0.220 | 0.338 | 0.610 |
Onset-to-EEG | 26 | −0.753 | −0.914 | −0.473 |
|
54 | −0.198 | −0.475 | 0.081 | 0.152 | 46 | −0.162 | −0.420 | 0.116 | 0.283 |
Onset-to-EEG-monitoring | 30 | −0.183 | −0.579 | 0.278 | 0.332 | 41 | −0.051 | −0.386 | 0.279 | 0.752 | 31 | 0.101 | −0.311 | 0.459 | 0.588 |
Onset-to-burst-suppression | 30 | 0.031 | −0.359 | 0.443 | 0.872 | 21 | 0.584 | 0.058 | 0.863 |
|
|||||
Onset-to-clinical-seizure-freedom | 59 | 0.275 | −0.036 | 0.563 |
|
Spearman’s rho.
Regardless of the method of calculation, the delays in giving the second-stage medication (
Clinical seizure freedom delay among patients regaining consciousness (
Kaplan-Meier curve showing the difference of the onset-to-clinical-seizure-freedom time between patients returning consciousness and remaining unconscious.
The difference in BS delay between patients regaining consciousness (
Out of the 70 GCSE cases, 30 cases (42.9%) obtained BS and 40 cases (57.1%) did not. 42 cases (60.0%) of all cases had EEG-monitoring and 30 cases (71.4%) of them obtained BS. In the BS-group eight cases (26.7%) remained unconscious, whereas in the non-BS-group one case (2.5%) remained unconscious, the difference being statistically significant (
Regression analysis was performed to reveal the correlation of clinical variables with the delays in treatment response. The time parameters having significant effect on the delays of clinical seizure freedom or return of consciousness are shown in Table
The regression analysis of the effect of the chronological delay components on markers for cessation on GCSE.
Variable | TIME | 95% CI | 95% CI |
|
---|---|---|---|---|
(h) | min | max | ||
Onset-to-clinical-seizure-freedom | ||||
|
||||
Intercept | 9.0 | −1.4 | 23.6 | 0.082 |
Onset-to-initial-treatment | 7.8 | −1.6 | 13.2 | 0.008 |
Initial-treatment-to-diagnosis | 2.3 | 0.2 | 4.2 |
|
|
||||
Intercept | 8.2 | −5.6 | 31.3 | 0.273 |
Onset-to-initial-treatment | 6.6 | −2.8 | 11.6 | 0.035 |
Initial-treatment-to-second-stage-medication | 3.0 | 0.4 | 4.8 |
|
|
||||
Onset-to-consciousness | ||||
|
||||
Intercept | 38.1 | 14.8 | 73.4 | 0.008 |
Onset-to-initial-treatment | 0.4 | −15.2 | 8.1 | 0.935 |
Initial-treatment-to-second-stage-medication | 9.7 | 3.9 | 15.8 |
|
Univariate analysis of the factors related to markers for cessation of GCSE is shown in Online Table 3. SRSE cases have significantly longer delays in achieving clinical seizure freedom and returning consciousness than non-SRSE cases (
Univariate analysis of the factors related to return of consciousness is presented in Online Table 4. No significant relations were found, although the non-SRSE cases tended to regain consciousness more likely than the SRSE cases (
In pooled STESS groups 0–2, 42.7% of the cases, and in pooled STESS groups 3–6, 48.6% of the cases presented SRSE. When STESS groups were pooled 0–3 and 4–6, the proportion of cases presenting SRSE was 47.1% and 42.1%, respectively.
This is to our knowledge the first study analysing systematically the delays and factors related to cessation of GCSE. We found that the earlier the clinical seizure freedom is achieved, the earlier and more likely the consciousness returns. Delay of clinical seizure freedom is significantly affected by several delays in the preceding treatment chain. Short delays in giving the second-stage medication and obtaining BS also correlate with early return of consciousness. Surprisingly, several previously reported prognostic factors, such as age, epilepsy, or STESS and the response to initial treatment are related neither to the probability nor the delay of returning consciousness. The present results suggest that the cessation of the GCSE might be more likely related to the delays in the treatment than to the known prognostic factors of SE outcome.
The risk for reporting bias is present in every retrospective study. We controlled the risk by evaluating the adequacy of the data with Data Accuracy (
Although the patient material was collected in 2002-2003 in one tertiary hospital and is relatively small, it is comparable to more recent materials since the treatment recommendations have not markedly changed during the past decade. The increased assortment of intravenously administered second-stage medications in the past years does not affect the interpretation of our results. In this study fosphenytoin was almost exclusively administered as the second-stage medication, providing a relatively homogeneous material. At the time of collection of the material the EEG-monitoring availability was insufficient. Still, the criteria for monitoring and the interpretation of the results have not changed. Direct comparison of the present results to previously published studies should be carried out with caution, since return of consciousness is not widely used in the literature as the marker for cessation of SE. Furthermore, definition of the duration of SE varies considerably among previously published studies. The most commonly used endpoint has been outcome, that is, mortality and/or condition at discharge.
The exact endpoint of SE is conceptually problematic and varies even in the few previous studies that have clearly defined the endpoint. Cessation of GCSE is defined by Rantsch et al. as the end of the convulsion [
Recent evidence indicates that the median delay in giving the second-stage medication and the third-stage medication is nearly the same [
The evidence for the utility of BS as a goal in the treatment of GCSE is scarce and no prospective studies are available. The effect of BS on the prognosis of GCSE patients is controversial [
In our material the risk of remaining unconscious was significantly higher among patients achieving BS than among patients not treated to BS. The BS-group contained a significantly higher proportion of SRSE cases than the non-BS group. The BS-group also needed more often several anesthetizing agents and repeated anesthesia periods during the total anesthesia time of nearly 40 h longer than that of the non-BS-group. We also showed that the SRSE cases remained unconscious more likely than the non-SRSE cases. We propose that it is not the BS itself that increases the risk of remaining unconscious. Rather, the GCSE of the patients requiring anesthesia to BS seems to be more aggressive than that of the non-BS-group.
No previous studies have focused on the association of BS to the ending of the GCSE or to return of consciousness. We found a significant correlation between early obtainment of BS and early return of consciousness. In our study, the delays in achieving BS did not reach the time frames recommended in the guidelines, reflecting the clinical reality. At least the anesthesia-to-BS delay could be dramatically shortened with an accurate management protocol, as shown in two prospective studies [
We found a significant correlation between early clinical seizure freedom and early return of consciousness. These results are in accordance with the previous literature showing the impact of seizure freedom on prognosis. Claassen et al. found that the delayed seizure control has a negative effect on the efficacy of treatment and that it increases mortality [
To our surprise onset-to-initial-treatment time, onset-to-diagnosis time, and onset-to-anesthesia time did not correlate to markers for cessation of GCSE. There are no other studies on the effect of diagnosis- and anesthesia-related delays on duration of GCSE in adult patients. There is evidence from a pediatric study suggesting that prehospital diazepam shortens the duration of SE [
Regression analysis showed that prolonged time between initial treatment and second-stage treatment predicts a delayed clinical seizure freedom and return of consciousness. Also the time between initial treatment and diagnosis may affect the delay to clinical seizure freedom. Thus, it is feasible that a failure or slow-up in any single delay component may ravage the benefits acquired by optimal action of the earlier phases of the treatment chain.
Prognostic factors of SE have been studied in detail, and in most reports the main focus has been on outcome, defined as mortality or clinical status at discharge. To our knowledge, there are no studies on the relation of prognostic factors to cessation of GCSE.
There is a consensus in literature that old age, defined in most studies as the age over 65 years, correlates with worse outcome [
The SE episodes in epilepsy-related cases are commonly thought to be easier to treat, and their outcome is in most studies found to be better than that of patients presenting acute symptomatic seizures [
STESS is an internally and externally validated tool for systematic evaluation of the outcome of SE patients and may be used to recognize the patients who need aggressive treatment [
As can be expected by definition, SRSE cases showed longer delays of clinical seizure freedom and return of consciousness than RSE and non-RSE cases. Interestingly, the delay of obtaining BS did not predict development of SRSE.
In our material, the response to first line treatment neither correlated with any of the markers for cessation of GCSE nor predicted return of consciousness. This may be due to the fact that our material included relatively large number of RSE cases, possibly because SE cases successfully treated with first-stage medication were not referred to the tertiary hospital. A recent study reported that the efficacy of the first-stage treatment does not affect the duration of SE [
Pre-SE period, that is, occurrence of recurring convulsive seizures preceding the actual SE, is a newly introduced concept [
We conclude that early administration of second-stage medication, early cessation of clinical seizures, and early obtainment of BS predict early return of consciousness, which is an unambiguous marker for the cessation of SE. The present retrospective study suggests that delays in treatment chain may be more significant determinants of SE cessation than the previously established outcome predictors. The correlations presented here serve as validation for the use of stepwise definition of the end of SE and speak for consideration of BS as the target of the third-stage treatment. The delays should also be considered in planning protocols, particularly in matching of patient groups, in prospective SE studies.
The authors confirm that they have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Leena Kämppi and Jaakko Ritvanen made an equal contribution to the paper.
This study has been financially supported by Epilepsy Research Foundation in Finland and Maire Taponen Foundation (financial support granted to Leena Kämppi).