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Keywords:

  • Refractory status epilepticus;
  • Mortality;
  • Hypoxic encephalopathy;
  • Brain tumor;
  • Neurocritical care

Summary

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. Authors’ Contribution
  10. References

Purpose

Refractory status epilepticus (RSE) is a life-threatening neurologic emergency with high mortality and morbidity. The aim of this study was to identify and quantify associations between clinical characteristics of adult RSE patients and outcome.

Methods

Comprehensive medical chart review was performed of all consecutive adult RSE patients treated on the intensive care units of an academic tertiary care center between 2005 and 2011. Demographics, RSE etiologies and duration, comorbidities, as well as outcomes were assessed. Associations between clinical characteristics and death were quantified.

Key Findings

Of 260 patients with status epilepticus, 111 developed RSE. Hypoxic encephalopathy (23%), brain tumors (14%), known and uncontrolled epilepsy (10%), and ischemic stroke (8%) were the main etiologies. During hospitalization 38% of patients died. Hypoxic encephalopathy (HE) and brain tumors were independently associated with death (relative risk [RR] 2.41, 95% confidence interval [CI] 1.40–4.12; p = 0.001 and RR 2.81, 95%CI 1.59–4.96; p < 0.0001). The estimated hazard ratio of death was 3.1 (95% CI1.6–6.0; p = 0.001) for patients with HE and 1.1 (95% CI 0.5–2.3; p = 0.745) for patients with brain tumors. RSE duration and nonconvulsive status epilepticus in coma were independently associated with death (for every hour RR 1.001; 95%CI 1.00–1.002; p = 0.011 and RR 3.62; 95%CI 1.34–9.77; p = 0.005).

Significance

Brain tumors and HE had high relative risks for death and were independently associated with mortality in our cohort of critically ill RSE patients. Other clinical characteristics, as well as the use of intravenous anesthetic drugs and mechanical ventilation, may not be strongly related to outcome and should therefore be used cautiously for informed decision making regarding treatment.

Refractory status epilepticus (RSE) is one of the most life-threatening neurologic emergencies and is characterized by high morbidity and mortality. This severe condition heralds a worse prognosis than treatment-responsive status epilepticus (SE) (Holtkamp et al., 2005; Rossetti et al., 2005), and serious outcome is considered to be mainly related to its etiology. Most studies propose the definition of RSE as a persistent SE after failure of a first-line (intravenous benzodiazepines) and one second-line antiepileptic drug (AED) (mostly phenytoin, valproate, levetiracetam, or phenobarbital), whereas others suggest a SE duration of >60 min (Hanley and Kross, 1998; Mayer et al., 2002). Despite the clinical and socioeconomic impact of RSE, current knowledge relies almost exclusively on retrospective assessments, its management on small case series, and expert opinions (Mayer et al., 2002; Holtkamp et al., 2005; Leppert et al., 2005; Rossetti et al., 2005; Holtkamp, 2011; Rossetti & Lowenstein, 2011). These reports suggest a frequency of RSE of up to 43% of all SE episodes, with nearly all subjects needing critical care and pharmacologic coma induction. Beyond these series one recent prospective study assessed frequency and clinical predictors of RSE emergence, and reported a 40% mortality in a tertiary clinical setting. However, the small sample size of 29 RSE episodes hinders inferences regarding the individual impact of different comorbidities (Novy et al., 2010). In order to respond to the discrepancy of important clinical and socioeconomic impact on the one hand and lack of larger and quantifying studies on the other hand, the Innsbruck Colloquium on SE held in April 2009, underscored the urgent need for more investigations in this field.

The aim of this study was to identify and quantify the association between clinical characteristics and outcome among a large cohort of RSE patients in the setting of a university-affiliated tertiary care center.

Materials and Methods

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. Authors’ Contribution
  10. References

Setting and study design

This retrospective observational cohort study was performed at the intensive care units (ICUs) of the University Hospital Basel (Switzerland), a tertiary care center with >4,000 ICU admissions per year. Data were derived from a cohort study on treatment of RSE from the same time period. The study was approved by the local ethics committee in accordance to the 1964 Declaration of Helsinki. The requirement for informed consent was waived.

Patients and data collection

All consecutive adult patients treated for RSE in the medical, surgical, and cardiac ICUs of the University Hospital Basel between January 2005 and December 2011 were included. In our institution all patients with SE and RSE are treated on the ICUs. Demographics, clinical characteristics, and electrographic features, such as worst seizure type and level of consciousness at SE onset, etiology and duration of RSE, and complications (i.e., infections during SE or severe hypotension) were extracted from our hospital database for all patients by two neurologists who were certified electroencephalography (EEG) readers (R.S. and S.R.). In addition, AEDs and the use of intravenous anesthetic drugs as well as critical interventions, such as mechanical ventilation and cardiopulmonary resuscitation (CPR) preceding RSE were compiled. Hypoxic encephalopathy (HE) comprised two subgroups according to different etiologies: (1) patients with CPR in cardiac arrest and (2) patients with HE of other origins other than cardiac arrest (e.g., suffocation, periinterventional hypoxia). This differentiation allowed additional analysis regarding the outcomes between patients with different causes of hypoxic encephalopathy.

Definition of status epilepticus subtypes

Status epilepticus was defined as seizure activity that lasted at least 5 min or as a series of epileptic seizures that had to be present without complete clinical recovery in between (Young et al., 1996; Lowenstein et al., 1999). Refractory SE was defined as clinical and electroencephalographic evidence of persistent, continuous, or repetitive seizures without interictal mental recovery after initiation of a first-line AED (benzodiazepines) and following second-line treatment with at least one intravenous AED as proposed by Lowenstein et al. (1999). This widely accepted definition allows a comparison with previous works on RSE. According to the results of prior studies on the gradation of SE severity, the worst seizure types at presentation were defined as follows: simple partial, complex partial, and absence seizures; generalized convulsive seizures; and nonconvulsive status epilepticus (NCSE) in coma (Rossetti et al., 2006, 2008).

Duration of SE was defined as the period from the time of diagnosis to the time of cessation of clinical manifestations and first EEG without evidence of seizure activity or death. Before the introduction of continuous video-EEG monitoring in 2008, patients had two or more EEGs for at least 30 min per day. Therefore, the exact SE duration could not be calculated and was estimated with an approximation.

Outcomes

The primary outcome was death during hospital stay. Secondary outcomes were RSE cessation and discharge destinations.

Statistical analyses

Categorical variables were summarized as counts and proportions, and continuous variables were summarized as means and standard deviations. Patients were categorized as survivors and nonsurvivors. A Shapiro-Wilk test was used to distinguish between normal and abnormal distributions. Continuous variables were analyzed with the Student's t-test if normally distributed, or the Mann-Whitney U-test if nonnormally distributed. For comparisons of proportions, chi-square and Fisher's exact test were applied where appropriate. Relative risks of death were estimated by Poisson regression with robust error variance (Zou, 2004) and were adjusted for potential confounders such as age, worst seizure type at SE onset, RSE duration, and etiologies that differed significantly between survivors and nonsurvivors before and after exclusion of HE. Relative risks were used to avoid an overestimation of associations in contrast to odds ratios in this context (Davies et al., 1998).

Survival analyses were described by Kaplan-Meier statistics, and differences between groups were assessed with the log-rank test for equality of survivor functions. p-Values ≤0.05 were considered significant. Statistical analysis was performed with STATA version 12.0 (Stata Corp., College Station, TX, U.S.A.).

All statistical analyses regarding outcome were performed before and after exclusion of patients with HE in order to have a more homogeneous group and because HE as the cause of RSE is know to have mostly poor outcome.

Results

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. Authors’ Contribution
  10. References

Between January 2005 and December 2011, 111 (43%) of 260 adult patients with SE developed RSE, with a mean duration of 101 h (±160). Mean age was 62.2 years (±16.4; median 64.0; range 17–90). The majority of patients were stuporous or comatose at SE onset (84; 76%). The preponderant seizure type at SE onset was NCSE in coma (72; 65%), followed by simple partial, complex partial or absence (29; 26%), and generalized convulsive (10; 9%). The main presumed etiologies of RSE were HE (25; 23%), brain tumors (15; 14%), known and uncontrolled epilepsy (11; 10%), and ischemic stroke (9; 8%). Baseline characteristics are presented in Table 1. Patients were treated with at least three and up to six AEDs. Ninety-one (82%) patients were mechanically ventilated and 17 (15%) received cardiopulmonary resuscitation. Comparisons of demographics, clinical characteristics including number of AEDs and of intravenous anesthetic drugs, RSE duration as well as critical interventions, and complications between survivors and nonsurvivors are presented in Table 2. All analyses were performed before and after exclusion of HE. Among presumed RSE etiologies, brain tumors and HE were significantly more frequent in nonsurvivors (Table 2). Stuporous and comatose state at SE onset was significantly associated with death (p = 0.006), a result that lost significance after exclusion of patients with HE (p = 0.072). In addition, worst seizure types at SE onset were related with mortality (overall p = 0.001). Other clinical characteristics, as age, the use of intravenous anesthetic drugs, mechanical ventilation, and development of infections during RSE were not significantly related to mortality in our cohort.

Table 1. Baseline characteristics
  1. RSE, refractory status epilepticus; SE, status epilepticus; NCSE, nonconvulsive status epilepticus.

Demographics
AgeMeanSD
Years62.2±16.4
 n%
Gender  
Male6054
Female5146
Clinical characteristics  
Presumed etiologies of RSE  
Hypoxic encephalopathy2523
Brain tumor1514
Uncontrolled epilepsy1110
Ischemic stroke98
Meningitis/encephalitis87
Traumatic brain injury76
Intracerebral hemorrhage65
Metabolic problem44
Alcohol withdrawal33
Neurodegenerative33
Others1110
Not known109
Level of consciousness at SE onset  
Awake or somnolent2724
Stuporous or comatose8476
Worst seizure type at SE onset  
Simple partial/complex partial/absence2926
Generalized convulsive109
NCSE in coma7265
Table 2. Demographics and clinical characteristics of surviving and nonsurviving patients after refractory status epilepticus
  1. RSE, refractory status epilepticus; AEDs, antiepileptic drugs; NCSE, nonconvulsive status epilepticus; CPR, cardiopulmonary resuscitation; SE, status epilepticus.

  2. Bold p-values are considered statistically significant.

  3. Continuous variables were analyzed with the Student's t-test if normally distributed or the Mann-Whitney U-test if nonnormally distributed (*). For comparisons of proportions chi-square and Fisher's exact test were applied where appropriate.

 Total cohortAfter exclusion of patients with hypoxic encephalopathy
Survivors (n = 69)Nonsurvivors (n = 42) Survivors (n = 61)Nonsurvivors (n = 25) 
AgeMeanSDMeanSDp-ValueMeanSDMeanSDp-Value
Years60.5±16.665.0±15.80.16261.2±16.765.3±15.00.272
 n%n% n%n% 
Gender
Male3449.32661.90.195294816640.235
Female3550.71638.13252936
Presumed etiology of RSE
Hypoxic encephalopathy8121741 <0.0001
Brain tumor571024 0.021 581040 0.001
Uncontrolled epilepsy812370.5298133121.000
Ischemic stroke710250.470711281.000
Meningitis/encephalitis710120.255711140.428
Traumatic brain injury46371.000473120.409
Intracerebral hemorrhage57120.40658140.667
Other or unknown etiologies2536614 2540624 
Level of consciousness at SE onset
Awake or somnolent2333410 0.006 23384160.072
Stuporous or comatose4667389038622184
Worst seizure type at SE onset
Simple partial/complex partial/absence263837 0.001 2643312 0.010
Generalized convulsive466144714
NCSE in coma3957337931512184
 MeanSDMeanSD MeanSDMeanSD 
Duration of RSE (hours)88.9±158.1120.3±164.10.002*89.4±160159.2±201 0.001 *
Number of AEDs4.4±1.44.4±1.31.000*4.9±1.14.4±1.60.100*
 n%n% n%n% 
Anesthetic drugs
Barbiturates8126140.7718134160.739
Propofol172515360.28016269360.435
Critical interventions (before or during RSE)
Mechanical ventilation547837880.191477721840.569
CPR341433 <0.0001 0000
Complications
Infections during SE284118430.813243913520.282
Severe hypotension (requiring vasopressors)344100.42323141.000

Duration of RSE was significantly longer in nonsurvivors. Cessation of RSE was achieved in 91 (82%) patients. In an overall comparison worst seizure types at SE onset were significantly associated with seizure control (p = 0.015). When compared to patients with simple partial, complex partial, or absence seizures at SE onset, the relative risk for patients with generalized convulsive seizures was significantly high with 7.25 (95% CI 1.65–31.87), and for patients with NCSE in coma 2.42, however, without reaching significance (95% CI 0.57–10.20). Significant associations between seizure control and worst seizure type at SE onset were no longer seen after exclusion of patients with HE.

Data on short-term outcome was available for all patients in our cohort: 42 (38%) died, 11 (10%) were transferred to a nursing home, 7 (6%) were referred to another hospital, 40 (36%) were referred to rehabilitation, and 10 (9%) were discharged home immediately after hospital stay. Relative risks were estimated for death during hospital stay in association with clinical characteristics (Table 3). Univariable analysis revealed both brain tumors and HE to be related with a high risk of death, a result that remained significant after adjustment for possible confounders, suggesting their independent associations with death (relative risk [RR] 2.8; 95% CI 1.59–4.96 and RR 2.41; 95%CI 1.40–4.12, respectively). Although all five surviving RSE patients with brain tumors had frontal tumor localization, nonsurvivors had additional or other brain regions involved (Table 4). Causes of death in the patients with brain tumors were ongoing and uncontrolled seizures in five patients (in combination with respiratory tract infection in one patient, increasing brain edema with brainstem compression in one patient and a large intracerebral hemorrhage in another patient). In the five patients with seizure control, death was caused during palliative care. Two patients died from respiratory tract infections, one from increasing brain edema with brainstem compression, one from a large intracerebral hemorrhage, and one patient died after renal and heart failure. In patients surviving RSE due to hypoxic brain damage the proportion of patients with HE due to causes other than cardiac arrest (i.e., suffocation, periinterventional hypoxia, or unknown origin) was higher (5/8; 63% in survivors versus 3/17; 18%, Table 4). RSE duration was significantly associated with a high relative risk of death; however, the relative risk for every additional hour of RSE was minimal (for every hour, RR 1.0001; 95% CI 1.00–1.002). When compared to patients with simple partial, complex partial, or absence seizures at SE onset, patients with generalized convulsive seizures or NCSE in coma had significant higher relative risks of death (RR 4.72; 95% CI 1.59–13.97 and RR 3.62; 95% CI 1.34–9.77, respectively). After exclusion of patients with HE, the relative risk of death increased for the presence of brain tumors and longer RSE duration (RR 2.88; 95% CI 1.66–4.97 and RR 1.001; 95% CI 1.00–1.002, respectively). The relations between RSE duration and the three most common etiologies in our cohort (i.e., HE, brain tumors as well as known and uncontrolled epilepsy) are presented in Fig. 1. The difference in RSE duration between survivors and nonsurvivors tended to be more distinct in patients with uncontrolled epilepsy, an etiology that was not shown to have significant high relative risks of death in contrast to brain tumors and HE.

Table 3. Univariable and multivariable analysis for death in patients with refractory status epilepticus
 CrudeAdjusteda
RR95% CIp-ValueRR95% CIp-Value
Total cohort (n = 111)      
Death      
Age1.0110.99–1.030.1871.0130.99–1.030.109
Worst seizure type at SE onset      
Simple partial/complex partial/absence Ref.   Ref.  
Generalized convulsive5.8001.76–19.07 0.004 4.7151.59–13.97 0.005
NCSE in coma4.4311.47–13.38 0.008 3.6181.34–9.77 0.011
Brain tumors2.0001.26–3.16 0.003 2.8111.59–4.96 <0.0001
Hypoxic encephalopathy2.3391.53–3.59 <0.0001 2.4051.40–4.12 0.001
RSE duration (per hour)1.0010.99–1.000.2551.0001.00–1.002 0.005
 CrudeAdjustedb
RR95% CIp-ValueRR95% CIp-Value
  1. SE, status epilepticus; RSE, refractory status epilepticus; NCSE, nonconvulsive status epilepticus.

  2. Bold p-values are considered statistically significant.

  3. a

    Adjusted for age, RSE duration, brain tumors, worst seizure type, and hypoxic encephalopathy.

  4. b

    Adjusted for age, RSE duration, brain tumors, worst seizure type, and exclusion of hypoxic encephalopathy.

After exclusion of patients with hypoxic encephalopathy (n = 86)      
Death      
Age1.0120.99–1.030.2851.0090.99–1.030.393
Worst seizure type at SE onset      
Simple partial/complex partial/absence Ref.   Ref.  
Generalized convulsive1.9330.25–15.270.5322.2060.28–17.500.454
NCSE in coma3.9041.26–12.06 0.018 3.8811.41–10.67 0.009
Brain tumors3.1561.77–5.62 <0.0001 2.8751.66–4.97 <0.0001
RSE duration (per hour)1.0011.00–1.002 0.047 1.0011.00–1.002 <0.0001
Table 4. Detailed characteristics of brain tumors and hypoxic encephalopathy
TypenCardiopulmonary resuscitationProminent edemaSeizure control
Hypoxic encephalopathy (HE)    
Survivors    
HIE after cardiac arrest 3 312
HE due to suffocation, periinterventional hypoxia, or unknown origin 5 015
Nonsurvivors    
HIE after cardiac arrest141465
HE due to suffocation, periinterventional hypoxia, or unknown origin 3 003
TypeTumor localizationMaximal diameterProminent edemaSeizure control
  1. RSE, refractory status epilepticus; HE, hypoxic encephalopathy; HIE, hypoxic-ischemic encephalopathy (after cardiac arrest); WHO, World Health Organization; ODG, oligodendroglioma; GBM, glioblastoma multiforme; NSCLC, non-small-cell lung cancer.

Brain tumors    
Survivors    
MeningiomaRight frontal1 cmNoYes
MeningiomaLeft frontal4.5 cmNoYes
Meningioma (recurrent WHO II)Left frontoparietal4 cmYesYes
Anaplastic ODGBifrontal3 cmNoYes
GBMBifrontalLarge (no recent scan)Not knownYes
Nonsurvivors    
1 metastasis of adeno-NSCLCLeft frontoparietal7 cmNoYes
MeningiomaRight parafalxialLarge (no recent scan)Not knownYes
1 metastasis of urothel carcinomaRight parietooccipitalNo recent scanYesYes
1 metastasis of adenocarcinoma of the esophagusLeft occipital2.5 cmYesYes
Metastasis of adenocarcinoma of the unknown originRight parietal3 cmYesYes
2 metastasis of renal cell carcinomaRight frontal; frontotemporalNo recent scansYesNo
Multiple metastases of NSCLCBiparietal; bifrontal; corpus callosum3 cmNoNo
MeningiomaRight parietal2 cmNoNo
Oligoastrocytoma (recurrent WHO III)Bifrontal; left parietal10 cmNoNo
Neoplasm of unknown originLeft parietooccipitalNo recent scansNot knownNo
image

Figure 1. Duration of refractory status epilepticus in survivors and nonsurvivors with the three most frequent etiologies. RSE, refractory status epilepticus.

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Because treatment intensity may have been reduced in patients with these etiologies due to end-of-life decisions, medical chart review for patient management was performed and revealed that all patients received unrestricted treatment during their ICU stay. However, there might have been treatment restrictions that could not be identified by the retrospective chart review. Comparisons of the mean number of AEDs, intravenous anesthetic drugs, and critical interventions between survivors and nonsurvivors are presented in Table 2. Detailed information of the two RSE etiologies with high relative risks of death (i.e., brain tumors and HE) is displayed in Table 4.

Survival analyses by Kaplan-Meier statistics are shown in Fig. 2. Survival curves differed significantly between patients with and without HE, whereas there was no significant difference for patients with brain tumors. The estimated hazard ratio of death for patients with HE as compared to those without was 3.1 (95% CI 1.6–6.0; p = 0.001) at any time during RSE, whereas the hazard ratio of death for patients with brain tumors compared to patients without was 1.1 (95% CI 0.5–2.3; p = 0.745).

image

Figure 2. Kaplan-Meier survival estimates for patients with and without hypoxic-ischemic encephalopathy and brain tumors. HE, hypoxic encephalopathy; RSE, refractory status epilepticus.

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Discussion

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. Authors’ Contribution
  10. References

This observational cohort study explored and quantified the associations of distinct clinical characteristics with short-term outcome of adult RSE patients treated in the ICUs of a university affiliated tertiary care center. To our knowledge this is the largest cohort study of patients with RSE reported to date. In contrast to prior studies, analyses were performed before and after exclusion of patients with HE, as there is ongoing debate about whether HE as the etiology of RSE has to be considered as a separate entity due to its high mortality and distinct pathophysiology with mostly severe and expanded brain damage (Geocadin et al., 2012). In addition, relative risks were used to avoid an overestimation of associations in contrast to odds ratios (Davies et al., 1998).

Our major findings were high relative risks of death for brain tumors and HE and their independent association with mortality. The estimated hazard ratio of death for patients with HE was three times higher than for patients without HE, whereas it was not different between patients with and without brain tumors. The nonsignificant HR in this context reflects the fact that the risk of death in patients with brain tumors was not significantly different from patients without brain tumors at every single time point during RSE—in contrast to patients with HE where the significant HR indicates an instantaneous risk of death during the entire RSE period.

In addition, RSE duration and NCSE in coma were independently associated with death. However, for every additional hour of RSE the relative risk of death was only minimal (RR 1.0001). Consistent with a recent study on 63 RSE episodes (Hocker et al., 2012), but in contrast to prior investigations (Towne et al., 1994; Logroscino et al., 1997), age was not significantly associated with death but tended to be higher in nonsurvivors in our cohort.

The rate of RSE (43% of SE patients) as well as patient age, presumed etiologies of RSE, and clinical characteristics were comparable to other retrospective (Mayer et al., 2002; Holtkamp et al., 2005; Drislane et al., 2008) and prospective observational cohort studies on RSE in the ICU (Novy et al., 2010). Hypoxic encephalopathy was the preponderant etiology, a finding that is difficult to compare as HE was mostly excluded from prior studies. In contrast, infections were the predominant complications in a retrospective study on detection and treatment of RSE with a smaller subgroup of 29 patients with RSE (Drislane et al., 2008), although the main etiology of SE in that cohort was anoxia, most likely HE. In two other studies, encephalitis and metabolic problems were the predominant etiologies (Rossetti et al., 2004; Holtkamp et al., 2005), possibly explained by the smaller and younger cohorts. A referral bias explaining the low number of encephalitis/meningitis in our cohort is unlikely, as the policy of our institution as a tertiary care center is to treat all patients with acute neurologic illnesses. Mean RSE duration (101 h) was comparable with a recent retrospective study of 35 RSE patients (Synowiec et al., 2012), but much longer than in an earlier study mainly on RSE duration and outcome (Drislane et al., 2009). The latter might be explained by the larger proportion of patients with known epilepsy (28%) in that study, who tended to have shorter RSE duration. The predominance of NCSE in our cohort (65%) is well supported by prior studies (Mayer et al., 2002; Novy et al., 2010; Kellinghaus et al., 2011). This high proportion of NCSE was also seen in our entire SE cohort (regardless of the development of RSE) as reported previously (Rudin et al., 2011).

Mortality

Overall mortality in our cohort (38%) was similar to some prior reports, which describe a mortality ranging from 39% to 65% (Cooper et al., 2009; Drislane et al., 2009; Novy et al., 2010), but higher than in other studies (8–26%) (Mayer et al., 2002; Rossetti et al., 20044; Holtkamp et al., 2005; Rossetti et al., 2005), possibly resulting from the high proportion of patients with HE. The high mortality in our cohort may also reflect the retrospective and ICU-based nature of this study. Relative risks of death in patients with brain tumors and HE were 2–3 times higher than for patients with other etiologies in the multivariable analyses, indicating that they are independently associated with mortality. Although the adverse effect of HE after cardiac arrest on outcome in patients with RSE is well described, relative risks were unexpectedly high and have not been reported in such a large sample size. HE after cardiac arrest is known for having a substantial and deleterious influence on mortality (Young et al., 1990; Wijdicks et al., 1994; Hui et al., 2005; Thomke et al., 2005; Rossetti et al., 2007; Kawai et al., 2011; Rittenberger et al., 2012). Remarkably, a high proportion (8/25) of patients with HE survived—an unexpected result that might be at least partially explained by the fact that one third had hypoxic brain damage caused by etiologies other than cardiac arrest. However, further statistical analysis regarding significance of this finding was not performed due to the small sample size. It remains unclear to what extent RSE, substantial hypoxic brain damage, and discontinuation of life-supporting procedures after intensive care, have contributed to this poor outcome in the sense of a vicious circle, that is, self-fulfilling prophecy (Geocadin et al., 2012). In contrast, reports on brain tumors in RSE patients and associations with outcome are limited. In our cohort, 67% of patients with brain tumors died. This finding contrasts with the data of a study on the detection and treatment of RSE in the ICU, which revealed an improvement of the level of consciousness in all patients with brain tumors on anticonvulsants (Drislane et al., 2008). However, the number and proportion (n = 4; 4%) of patients with brain tumors was small, limiting comparability and generalizability. In a recent study by Swisher et al. (2012) on treatment of RSE in 23 patients with metastatic brain tumors, seizure control was achieved in 70% and mortality was 0%. A clear definition of RSE was not provided, thus limiting comparability. Our results show a different trend, although our small sample size limits generalizability as well. Furthermore, size and localization have substantial influence on epileptogenic activity, outcome (van Breemen et al., 2007; You et al., 2012) and therapeutic decisions. Although all five surviving patients with brain tumors in our cohort had frontal tumor localization, nonsurvivors had additional or other brain regions involved; however, there was no significant difference in tumor size between survivors and nonsurvivors. Compared to our cohort, patients of a recent retrospective study on the acute management of RSE were younger (mean age 57 vs. 62 years in our study) and needed less mechanical ventilation (17% vs. 82%), possibly explained by the fact that the AED regimen was selected intentionally to minimize the need for intubation (Swisher et al., 2012). The remaining, independent association of NCSE in coma with an approximately fourfold risk of death is underscored by studies that previously identified this relation (Rossetti et al., 2006, 2008).

Both generalized convulsive seizures at SE onset, as well as NCSE in come, were associated with an increased risk of death in our cohort. However, after exclusion of patients with HE, the association of generalized convulsive seizures with mortality lost significance, as all patients with refractory SE with generalized convulsions at onset had HE as the underlying seizure etiology.

Duration of RSE was significantly longer in nonsurvivors, an association that has already been described (Towne et al., 1994; Towne, 2007; Drislane et al., 2009). Analysis regarding the relations between RSE duration and the three most common etiologies in our cohort (i.e., HE, brain tumors, as well as known and uncontrolled epilepsy) revealed that differences in seizure duration between survivors and nonsurvivors tended to be more distinct in patients with uncontrolled epilepsy, an etiology that was not shown to have significant high relative risks of death in contrast to brain tumors and HE. Our results suggest that the impact of seizure duration on outcome tends to be less pronounced in the presence of an underlying, severe etiology of RSE. However, this inverse correlation did not reach significance, and sound analyses for the effect of RSE duration in other etiologies could not be performed due to small sample sizes. Similar results have been reported from a retrospective study on the duration of RSE and outcome where seizure duration of <10 h was associated with more favorable outcome, a result that lost significance once etiology, presentation in coma, and SE types were accounted for (Drislane et al., 2009). In addition, case reports and case series report survival with meaningful functional and cognitive recovery, even after prolonged RSE (Cooper et al., 2009; Drislane et al., 2009; Standley et al., 2012). Therefore, seizure duration alone should not be considered a reason to discontinue treatment.

Other clinical characteristics, such as age, the use of intravenous anesthetic drugs, mechanical ventilation, and development of infections during RSE were not significantly related to mortality in our cohort. A recent study on outcome in patients with SE contrasts our findings by describing significant associations of age, mechanical ventilation, and treatment with third-line antiepileptic drugs (including intravenous anesthetic drugs) with poor outcome (Kowalski et al., 2012). This discrepancy may result from the differences in the study populations regarding treatment refractoriness (i.e., RSE in our cohort vs. SE patients) and seizure type (9% CSE in our cohort vs. 92% CSE) as well as possible confounding by indication, as patients with more severe SE may be more likely to receive intravenous anesthetic drugs.

Survival

The presence of brain tumors and HE were both associated with high mortality; however, there was a distinct difference in survival dependent on duration of RSE. The Kaplan-Meier survival curves of patients with HE showed a significantly faster decrease than those of patients without HE, whereas the survival curves of patients with and without brain tumors showed several intersections. Correspondingly, the estimated hazard ratio of death for patients with HE as compared to those without was 3.1 at any time during RSE, whereas the hazard ratio of death for patients with brain tumors, when compared to patients without was 1.1. This difference might be explained by the fact that HE mostly affects large cortical regions while damage is more focal in patients with brain tumors. In addition, treatment intensity of patients with HE might be reconsidered early in the course of critical care, as clinical neurologic examination, EEG patterns, levels of neuron specific enolase, and brain imaging yield valuable prognostication and may often indicate poor outcome (Wu et al., 2009, 2011; Greer et al., 2012; Rossetti et al., 2012). However, medical chart review did not reveal significant differences in intensive care or antiepileptic treatment during ICU stay between survivors and nonsurvivors in our cohort.

Because this is a retrospective single center observation, further prospective and multicenter studies are needed to better elucidate underlying mechanisms and to design algorithms for prediction of mortality and recovery of RSE patients during early critical care treatment.

Advantages and limitations

The strengths of this study are the large cohort, the use of relative risks to avoid an overestimation of associations in contrast to odds ratios (McNutt et al., 2003) and adjustments for age, RSE duration, brain tumors, and hypoxic encephalopathy as well as the additional analyzes after subsequent exclusion of patients with HE.

Nevertheless, the small sample size of several subgroups reflected by broad confidence intervals of the point estimates, the retrospective design, and the data collection from a single center may restrict generalizability. However, patient demographics and clinical characteristics are largely similar to prior studies on RSE. The analyzed cohort is ICUbased, and not hospital based—a potential selection bias possibly increasing the prevalence of RSE among the SE patients and limiting comparison with some published series. However, all SE and RSE patients in our institution are treated on the ICU. Therefore, the possible selection bias is limited to patients who were not transferred to the ICUs because their SE or RSE was unrecognized. Given that in our center continuous video-EEG monitoring was implemented on the ICUs in 2008 (Sutter et al., 2011), RSE duration of patients that were treated before 2008 had to be approximated, leading to an inaccuracy of about 12 h. Despite this limitation, the mean RSE duration in our cohort appeared to be similar compared to earlier studies. In addition, patients who did not develop SE during but prior to their ICU admission might have had an underestimated SE duration, as the diagnosis was always made after EEG confirmation of the clinical suspected seizure activity. However, this inaccuracy has no influence on our primary categorical outcome (death). Additional characteristics and their impact on outcome, such as for example the differentiation between cortical and subcortical myoclonus in HE patients could not be analyzed due to the retrospective nature of the study.

Conclusions

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. Authors’ Contribution
  10. References

To conclude, brain tumors and HE were distinctly and independently associated with death in our cohort of critically ill patients with RSE. Other clinical characteristics as well as the use of intravenous anesthetic drugs and mechanical ventilation may not be related to outcome and should therefore be used cautiously for informed decision making regarding treatment, once RSE is diagnosed. Prospective studies are warranted to strengthen our findings and elucidate underlying mechanisms.

Acknowledgments

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. Authors’ Contribution
  10. References

We thank Dr. Sarah Tschudin-Sutter for her statistical work. There were no sources of support for this study. The corresponding author has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. R.S. is supported by the Research Funds of the University of Basel, the Scientific Society Basel, and the Gottfried Julia Bangerter-Rhyner Foundation. S.R. received unconditional research grants from UCB. He received honoraria from serving on the scientific advisory boards of Eisai and UCB; travel grants from GlaxoSmithKline, Janssen-Cilag, and UCB; speaker fees from UCB; and from serving as a consultant for Eisai, GlaxoSmithKline, Janssen-Cilag, Pfizer, Novartis, and UCB. He does not hold any stocks of any pharmaceutical industries or manufacturers of medical devices. The research of P.F. is supported by the Swiss National Science Foundation, the Swiss Parkinson's Disease Society, the Gossweiler Foundation, the Mach-Gaensslen Foundation, the Botnar Foundation, the Scientific Society Basel, the Novartis Foundation, Novartis, and Roche. He received honoraria from serving on the advisory boards of UCB and Abbott.

Disclosures

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. Authors’ Contribution
  10. References

None of the authors have received any reimbursements, fees, funding, or salary from an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future. None of the authors hold any stocks or shares in an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future. None of the authors have any other financial competing interests. There are no nonfinancial competing interests (political, personal, religious, academic, intellectual, commercial, or any other) to declare in relation to this manuscript. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Authors’ Contribution

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. Authors’ Contribution
  10. References

R.S. conceived and planned the work, acquired, analyzed and interpreted the data, and wrote a first draft of the manuscript. S.R has conceived and planned the study, and participated in its design and coordination and drafted the manuscript. S.M. and P.F. interpreted the data, gave substantial input to and improved the inaugural draft. All authors approved the final submitted version.

References

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. Authors’ Contribution
  10. References