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Treatment of status epilepticus in a large community hospital
Epilepsy & Behavior 23 (2012) 235–240
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Treatment of status epilepticus in a large community hospital Christoph Kellinghaus ⁎, Florian Stögbauer Dept. of Neurology, Klinikum Osnabrück, Osnabrück, Germany
a r t i c l e
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Article history: Received 8 October 2011 Revised 6 December 2011 Accepted 12 December 2011 Available online 16 February 2012 Keywords: Intravenous Anticonvulsant Outcome Efficacy Status epilepticus
a b s t r a c t Background: Status epilepticus (SE) is a neurological emergency usually requiring immediate medical treatment. Due to the lack of adequate studies, treatment guidelines and their application vary between countries and institutions. We intended to analyze current treatment of SE in a German community hospital. Methods: We retrospectively identified patients from a large community hospital in northern Germany who had been diagnosed with SE between August 2008 and December 2010. Their charts were reviewed regarding sociodemographic variables, treatment and outcome. Results: We studied the first SE episode in 172 patients with a median age of 69 years (range 18–90 years). The etiology was acute symptomatic in 30 patients, progressive symptomatic in 22 patients and remote symptomatic in 120 patients. Presentation was generalized convulsive in 60 patients, non-convulsive in 72 patients and simple motor/aura in 40 patients. Median latency from onset to treatment start was 0.75 h (range 0.2–336 h). Initial treatment had a success rate (SR) of 40%. Second line treatment had a success rate of 54%. In patients whose seizures were refractory to the first two drugs, success rates were between 31% and 55%, with only a minority of the patients receiving established drugs such as phenytoin or barbiturates. Multivariate analysis revealed non-convulsive semiology as the only factor significantly associated with refractoriness. SE could be terminated in 95% of the patients and in-hospital mortality was 10%. Benzodiazepines and phenytoin had the most severe side effects. Conclusions: Status epilepticus can be terminated successfully and with low in-hospital mortality in the vast majority of the patients treated in a large community hospital. The success rate of each treatment step is between 30% and 55% regardless of the substances used. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Status epilepticus (SE), i.e. a prolonged and sustained epileptic seizure, is a potentially life-threatening neurological emergency. According to population-based studies, its incidence is estimated as 10–20/100,000/year in western industrialized countries [1–3]. In spite of the incidence and emergency character of SE, there are only very few randomized, blinded, and controlled trials regarding SE therapy [4–6]. These studies suggest that lorazepam, diazepam, phenobarbital and phenytoin are more or less equally efficient in initial treatment of SE when phenytoin is combined with benzodiazepines. Valproate may be equally effective as phenytoin, but has not been compared to phenytoin and benzodiazepines in combination [7]. Based on these few studies, current SE treatment guidelines propose intravenous (i.v.) administration of lorazepam or diazepam followed by i.v. administration of phenytoin as first treatment steps [8,9]. Since most of the randomized studies were performed more than 15 years ago when modern non-sedating i.v. anticonvulants like valproate, levetiracetam, fosphenytoin and lacosamide were not available, their role in initial treatment of SE is ⁎ Corresponding author at: Dept. of Neurology, Klinikum Osnabrück, Am Finkenhügel 1, 49076 Osnabrück, Germany. Fax: + 49 541 405 6599. E-mail address: [email protected] (C. Kellinghaus). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2011.12.020
undetermined. Data regarding treatment of refractory status epilepticus almost exclusively consist of uncontrolled prospective or retrospective case series, and thus treatment recommendations vary greatly between authors and countries. As a consequence, surveys among epileptologists and critical care neurologists in the U.S. as well as in Europe have demonstrated that there is no consensus over treatment strategies once benzodiazepines and phenytoin have failed [10,11]. Particularly uncertain is the value of the new agents that as yet have mainly been used in refractory SE. Most authors retrospectively analyzed single cases or small series with a large range of success rates and without comparison to standard treatment or other new drugs [12–15]. It is very likely that treatment approaches differ significantly between hospitals or departments of a region. The best way to reach consensus about the optimal treatment of SE would be a large prospective, randomized and controlled multicenter study that includes benzodiazepines and phenytoin as well as valproate, levetiracetam and lacosamide. However, there are many legal, ethical and financial obstacles that have yet precluded such an approach. Prospective case documentations or registries are second best, but have been limited to a single agent [16], to university hospitals [17,18], were performed before modern non-sedating i.v. anticonvulsants were available [19], or were performed in countries with predominantly infectious etiologies [20]. However, most cases of SE are treated in non-academic,
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community-based hospitals that care for distinctly different patient cohorts and rely on different resources and hospital policies than the tertiary-level academic hospitals where most scientific publications are generated. With this study we document and analyze the current treatment of SE in a large community hospital in Germany. Although formally it is a retrospective study, data quality is high because we could rely on SE-specific patient treatment documentation that has been used in our department since 2007. With this study we try to narrow the gap between the urgently needed but unavailable data from large randomized controlled trials and the currently available small case series that mainly serve as ‘proof of principle’ for one of the new i.v. anticonvulsants. 2. Methods We retrospectively identified all patients treated for SE in our hospital between July 2008 and December 2010. For identification we searched the hospital database using the search terms ‘status epilepticus’, ‘prolonged epileptic seizure’ as well as the ICD-10 codes G41.xx that cover status epilepticus. In addition, the EEG database was searched using the same search terms. If a patient was admitted more than once for treatment of SE during the study period, only the data of the first admission were analyzed further. Patients with postanoxic status epilepticus were excluded. The hospital charts were reviewed for sociodemographic data, etiology, semiology, onset of SE, and discharge. Time, dose and effect of anticonvulsant treatment were taken from a standardized SE documentation form that was introduced in our institution for quality control purposes in 2007. Once the diagnosis of SE has been made, the form is introduced into the individual patient chart and documents time, efficacy and tolerability of each treatment step, starting with preclinical treatment. Original imaging data were reviewed by at least one of the authors, and all EEG data were reviewed by an experienced electroencephalographer (C.K.). All patients underwent neurological examination and cranial imaging (CT or MRI) at admission. EEG was performed for at least 20 min using the electrodes of the international 10/20 system with additional anterior temporal electrodes (FT9/FT10) in all patients to document cessation of SE and get information about seizure onset at latest at the first working day following admission. Ictal EEG could be performed in 91/172 patients. Comorbidity and clinical outcome were assessed with the modified Rankin Scale (mRS) [21,22] that allows an overview of the patient's disabilities using basic information about neurological symptoms and the patient's need for support in everyday life. A mRS score of 0 is assigned when the patient is free of symptoms, a score of 1 when the patient has no significant disabilities despite some symptoms, a score of 2 when there is a slight disability, a score of 3 when the patient requires some help but is able to walk unassisted, a score of 4 when the patient is unable to attend to own bodily needs without assistance, a score of 5 when the patient requires constant nursing care and attention, and a score of 6 when the patient is dead. The mRS score was determined using all available information about the patient's state before onset of SE and at the time of discharge from hospital. In addition, we counted the ICD-10 diagnoses that were assigned to the case by medical documentation specialists for reimbursement purposes. Epilepsy diagnoses (ICD 10G 40.xx and G41.xx) were subtracted from the total count. SE was defined as a) seizures lasting >10 min, or b) recurrent seizures without regaining recovery of awareness. In EEG, SE was defined according to the criteria stated by Young et al. [23]. SE semiology was categorized pragmatically into generalized convulsive, loss of consciousness without major motor symptoms, aphasic/dyscognitive, simple motor and other simple partial (e.g. aura). Loss of consciousness and aphasic/dyscognitive was lumped into the category ‘non-convulsive’ for some analyses. If SE started with a generalized convulsive seizure followed by EEG-confirmed non-convulsive SE, it was
nevertheless considered as ‘generalized convulsive’ because this type of SE, also described as ‘subtle SE’, most likely has similar pathophysiological and treatment implications. Time of cessation of SE was defined by the time when the seizure symptoms ceased, or – if in doubt – by the time of the first EEG showing cessation of the electroencephalographic signs of SE. An anticonvulsant drug was considered as successful when no further anticonvulsant was introduced until cessation of SE. Different substances of the benzodiazepine class such as lorazepam, diazepam, midazolam and clonazepam were lumped into the group ‘benzodiazepine’. Equivalent doses were calculated according to established pharmacologic tables [24,25]: 10 mg diazepam = 1 mg lorazepam = 0.5 mg clonazepam = 7.5 mg midazolam. Two subgroups were formed retrospectively according to the response to the first two substances used for treatment. If SE ceased after the first or second anticonvulsant, SE was considered ‘nonrefractory’. If SE did not cease after the second anticonvulsant, SE was considered ‘refractory’. Different benzodiazepines were considered as one anticonvulsant. Statistical analysis was performed using OPENSTAT (http:// statpages.org, Version June 2010). Ranked variables were described using mean and standard deviation, and median/quartiles when normal distribution could not be assumed. For univariate analysis of categorical data, chi-square test and Fisher's exact test (2 × 2 tables) were used. Interval-scaled or ordinal-scaled data were analyzed with the Mann–Whitney U test (comparison of two groups), or the Kruskal–Wallis test (comparison of three or more groups). In a second step, backward multiple logistic regression was performed (p = 0.05 for inclusion, p = 0.10 for exclusion) to determine the contribution of individual treatment-independent factors to the refractoriness (i.e. no cessation after the second anticonvulsant). 3. Results During the 29 months that were analyzed, 204 episodes of SE were documented in 172 patients. One hundred forty-nine patients had one episode, 17 patients had two episodes, three patients had three episodes, and three patients had four episodes of SE. Only the first episode during this time period was analyzed. Most patients were elderly patients above 65 years of age, and half of them were women (see Table 1). In the majority of patients, the underlying etiology was remote symptomatic. Thirty patients (17%) had an acute, non-progressive CNS lesion (e.g. stroke, trauma), and 22 patients (13%) a progressive CNS lesion (tumor, metastasis). Semiology was generalized convulsive in a third of the patients, while only 3 patients were treated for an aura status. More than half of the patients were treated with anticonvulsant drugs (AED) before SE onset. Most patients suffered from moderate or major impairment according to the mRS score. Only a third had a mRS score of 2 or lower before SE, and less than a quarter of the patients were discharged with less than 5 diagnoses. Treatment started after a median of 45 min (range 10 min to 336 h), with approximately half of the patients having received the first medication between 10 and 30 min after SE onset. The first drug was almost always a benzodiazepine (lorazepam, diazepam, clonazepam or midazolam, or a successive combination) (see Table 2). SE ceased after administration of the first drug in 69 patients (40%) after a median of 0.13 h. In the remaining 103 patients, a second drug was administered after a median latency of 0.4 h. Most patients (78) received levetiracetam, a minority was treated with other intravenous AEDs such as valproate, phenytoin or lacosamide. Six patients were directly treated with anesthetic agents. The second substance was successful in terminating the SE in 56 patients (54%). Seizures in the other 47 patients were considered refractory. In one patient with glioblastoma multiforme, treatment and life support were withdrawn according to the patients previously-stated wishes after failure of the
C. Kellinghaus, F. Stögbauer / Epilepsy & Behavior 23 (2012) 235–240 Table 1 Sociodemographic characteristic. Variable Age (years) Gender Etiology
Semiology
Ictal EEG
AED before SE No. of diagnoses
mRS before SE
Table 2 Course of treatment. All patients (N = 172)
Mean/standard deviation Median/range Female Acute symptomatic Remote symptomatic first man Remote symptomatic old Remote sympt all Progressive symptomatic Generalized convulsive LOC only Simple Motor Aphasic/dyscognitive Other simple partial No ictal EEG performed Generalized Lateralized Regional Yes Median/range 0–4 5–9 10–14 15–19 20 or more Median 0 1+2 3 4 5
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64.56/+/−17.98 69 (18–90) 82 (48%) 30 (17%) 44 (26%) 76 (44%) 120 (70%) 22 (13%) 60 (35%) 45 (26%) 37 (22%) 27 (16%) 3 (1%) 81 (47%) 15 (9%) 46 (27%) 29 (17%) 74 (43%) 9 (0–33) 37 (22%) 53 (30%) 41 (24%) 20 (12%) 21 (12%) 3 30 (17%) 33 (19%) 48 (28%) 33 (19%) 28 (16%)
Latency SE onset- treatment onset (n = 172)
Latency treatment onset-SE end (hours) (n = 163)
0.75 (0.2–336)
10–30 min 31–60 min 61–120 min 121 min to 6 h >6 h to 24 h >24 h Median/range
90 (52%) 18 (10%) 17(10%) 25 (15%) 13 (8%) 9 (15%) 1.5 (0.1–814.25) No. of patients
AED 1
Latency AED1–AED2 (h) AED 2
Latency AED 2–AED 3(h) AED3
Latency AED 3–AED 4 (h) AED 4
Latency AED 4–AED 5 (h) AED 5
AED = anticonvulsant drug; SE = status epilepticus; mRS = modified Rankin Scale; LOC = loss of consciousness. first man = first manifestation of seizures/epilepsy; old = established epilepsy.
second AED. All other patients received a third AED – in most cases lacosamide or phenytoin – after a median latency of 0.5 h. The third AED was successful in 16 (35%) of the patients. The fourth effort of treatment in the 30 remaining non-responders also consisted mainly of phenytoin and lacosamide, with some patients already receiving an enteral AED such as carbamazepine or oxcarbazepine. In the fourth to seventh step of treatment, success rates were between 30 and 50% using a variety of intravenous and enteral AEDs. All further efforts in the few patients remaining in SE were unsuccessful. Anesthesia for treatment of refractory SE was performed with propofol in 9 patients and with thiopenthal in 1 patient. Only 4 of these patients had a nonconvulsive SE, all other patients were admitted for generalized convulsive SE. SE was terminated successfully in 163 patients (95%). In 140 patients (82%), mRS at discharge was the same as before SE onset (see Table 3). Eighteen patients died, the majority of them after cessation of SE. Patients with refractory SE did not differ from those successfully treated with the first or second AED regarding age, gender, or broad etiological categories as used here (see Table 4). The number of diagnoses was significantly higher in the patients with drug-resistant seizures, whereas mRS before SE onset only numerically differed. Significantly more patients with nonconvulsive SE (i.e. loss of consciousness or aphasia or cognitive dysfunction) had drug-resistant seizures, and latency until treatment start tended to be longer in these patients without reaching statistical significance. As expected, patients with drug-resistant seizures had more adverse events and worse global outcome as expressed as higher mRS scores. However, median benzodiazepine and levetiracetam bolus doses did not differ. Multiple logistic regression was performed using refractoriness as dependent variable. Independent variables were age, gender, etiology (remote symptomatic yes/no as dummy variable), semiology (nonconvulsive semiology yes/no as dummy variable), latency from SE onset to treatment, mRS before admission, benzodiazepine dose. Backward
Median/range (hours)
Latency AED 5–AED 6 (h) AED 6 Latency AED 6–AED 7 (h) AED 7 Latency AED 7–AED 8 (h) AED 8 AED 9 AED 10
Benzo other All Median/range LEV other All Median/range PHT LCM other All Median/range PHT LCM VPA other All Median/range PHT VPA CBZ/OXC Other All Median/range All Median/range All Median/range All All All
168 4 172 0.4/0.15–91.3 78 24 102 0.5/0.1–61 15 21 10 46 17/0.25–208 10 9 6 5 30 27.5/2–319 3 3 5 4 16 37/0.5–470 11 121/43–168 3 317.5/216–419 2 1 1
Success rate* 39% 40% 49% 52% 54% 40% 33% 30% 35% 50%
37%
31% 55% 33% 0 0 0
SE = status epilepticus; AED = anticonvulsant drug; benzo = benzodiazepine; LEV = levetiracetam; PHT = phenytoin; LCM = lacosamide; VPA = valproate; CBZ = carbamazepine; OXC = oxcarbazepine.
multiple logistic regression showed nonconvulsive semiology as the only independently contributing variable (Beta 0.167, standard error 0.068, t = 2.212, p = 0.028).
Table 3 Outcome. Variable SE terminated mRS at discharge
mRS difference
Patients Yes 0 1+2 3 4 5 6 −6 −5 −4 −3 −2 −1 0
SE = status epilepticus; mRS = modified Rankin Scale.
163 (95%) 22 (13%) 33 (19%) 43 (25%) 31 (18%) 25 (15%) 18 (10%) 3 (2%) 1 (0.5%) 1 (0.5%) 4 (2%) 8 (5%) 15 (9%) 140 (82%)
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Table 4 Comparison of patients with drug-resistant seizures to patients with drug-responsive seizures. Variable
Non-refractory (n = 125)
Refractory (n = 47)
Test p-value
Median/range Female Remote sympt all Generalized convulsive Simple motor Nonconvulsive No Median/range 0–4 5–9 10–14 15–19 20 or more Mean/SD 0 1+2 3 4 5 Median/range (hours) 10–30 min 31–60 min 61–120 min 121 min–6 h > 6 h–24 h > 24 h Yes Bolus EQ Units mean/SD Sedation
58/19–89 66 88 (70%) 48 (38%) 29 (23%) 46 (37%) 70 (56%) 9/0–24 33 (26%) 47 (38%) 26 (21%) 15 (12%) 4 (3%) 2.61+/−1.68 22 (18%) 27 (22%) 33 (26%) 26 (21%) 17 (14%) 0.5/0.1–120 68 (64%) 12 (10%) 12 (10%) 19 (15%) 9 (7%) 5 (4%) 86 (69%) 3.43/2.14 83 (66%)
62/18–90 23 32 (68%) 12 (26%) 8 (17%) 26 (55%) 28 (60%) 7/1–33 4 (8%) 17 (36%) 15 (31%) 5 (11%) 6 (14%) 2.94/1.78 8 (17%) 6 (13%) 15 (32%) 7 (15%) 11 (23%) 0.5/0.2–336 22 (47%) 6 (13%) 5 (11%) 6 (13%) 4 (9%) 4 (9%) 41 (87%) 3.82/2.47 40 (85%)
MWU 0.19 FET 0.83 FET 0.70
LEV
Respiratory insufficiency Bolus in mg mean/SD
mRS after discharge
Median
10 (8%) (n = 42) 2773/496 3 (mean 2.82+/−1.72) 112 (90%)
4 (10%) (n = 40) 2675/605 4 (3.87/1.94)
Age (years) Gender Etiology Semiology
AED before SE No. of diagnoses
mRS before SE
Latency SE onset->treatment onset
Adverse event Benzo
No mRS difference
28 (60%)
MWU 0.03 FET 0.67 MWU 0.005
MWU 0.14
MWU 0.14
FET 0.014 MWU 0.26 FET for all AE Benzo 0.018 MWU 0.21 MWU 0.0003 MWU 0.001
SE = status epilepticus; mRS = modified Rankin Scale; Benzo = benzodiazepine; LEV = levetiracetam; SD = standard deviation; EQ = equivalence; FET = Fisher's exact test; MWU = Mann–Whitney U test; AE = adverse event.
4. Discussion In a large community hospital in Germany, status epilepticus was diagnosed in predominantly elderly patients with a remote symptomatic etiology and significant comorbidity. In population-based studies in western industrialized countries, the incidence of status epilepticus was age-dependent and much higher in the elderly population [1–3], explaining the high proportion of elderly patients in our cohort. The mean age in our cohort was almost 65 years, with the median age even higher. Three recent hospital-based studies from Switzerland [17,18] and Turkey [26] showed similar mean ages. In contrast, an earlier report from a large public hospital in San Francisco found a mean age of approximately 15 years less [27], most likely owing to a completely different recruitment population. Almost 50% of our patients were diagnosed with epilepsy before the SE episode, and more than two-thirds had a remote etiology. Only 17% were diagnosed with an acute etiology, and only 13% with a progressive etiology. This corresponds to the almost identical findings of the only German population-based study 10 years ago [2]. On the other hand, in the hospital-based registries from Switzerland and Turkey [26,17], an acute etiology was found in approximately 60% of the SE cases. Even more cases with acute etiology were seen in the San Francisco hospital based study [27]. In the latter study, the most frequent SE etiologies were alcohol-related or anticonvulsant withdrawal, each accounting for more than 40% of the cases. In the former studies, acute infections, metabolic disturbances, acute strokes and anticonvulsant withdrawal were most frequent. The recruitment population of a large urban public hospital in San Francisco clearly differs from ours
regarding age-structure, comorbidities and risk factors. The other two study cohorts were recruited in large university hospitals with tertiary referral status. Therefore, a selection bias favoring patients with severe acute CNS diseases can be assumed. Our department is the only neurological department accessible for emergencies for a region of approximately 350,000 inhabitants in a mixed urban and rural area and has no dedicated neurological intensive care unit. Thus, our patients may more closely resemble a general population cohort than most large university hospitals do. These differences should be kept in mind when comparing our treatment data with those of other reports. Success rates of the treatment steps were between 30% and 55% regardless of the substances used, with a tendency of lower success rates in later steps of treatment and complete failure after the seventh drug in those few patients needing these efforts. With the first step of treatment, in almost all cases a benzodiazepine, SE could be terminated in 40% of the cases. This success rate seems low compared to the success rates of the randomized prospective pre-hospital trial [4] and the VA study [6] where lorazepam could terminate SE in approximately 60% of the cases within a brief interval. However, both cohorts differ markedly from our patients in various aspects. The pre-hospital trial enrolled patients with a mean age of 15 years less and a high percentage of patients with a low anticonvulsant level as sole etiology [4]. The patients of the VA study were mostly elderly patients with remote etiology as in our patient group, but had received treatment for the index SE episode before randomization in 50% of the cases, and were treated with a much higher dose of benzodiazepines compared to our patients. In addition, owing to the prospective design, only a
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fraction of the screened patients finally was enrolled into both studies, suggesting a relevant sampling bias. Levetiracetam was used as second treatment step in the majority of the patients with ongoing SE after benzodiazepine treatment. It was able to stop the SE in almost half of the cases. This is well within the range of previous retrospective series focussing on levetiracetam that found success rates between 26% [28] and 89% [14]. In a recent large prospective observational series, levetiracetam was successful as a second step of treatment in 52% [17]. A retrospective study comparing levetiracetam with phenytoin and valproate suggested a lower success rate for levetiracetam, but the mean bolus dose was only 1600 mg and thus much lower than in our study [17]. In a randomized prospective study comparing lorazepam with levetiracetam as first-line treatment in status epilepticus, both drugs showed a success rate of more than 70% [29]. However, the protocol used a very aggressive treatment approach resulting in a significantly higher adverse event rate. In addition, the patient cohort was recruited in India where etiologies are different from European or U.S. cohorts. As of yet, there has been no randomized trial comparing levetiracetam with other anticonvulsants for treatment of SE after failure of benzodiazepines. Although it is supposed to be common knowledge that the success rate of anticonvulsant therapy in SE decreases strongly with the number of previously failed anticonvulsants, our data do not support this view. Success rates were between 31% and 50% after the failure of the second drug. This may be due to the small group sizes in latter stages of treatment that do not allow us to find a consistent trend in our data. Indeed, our data suggest the existence of truly ‘superrefractory’ status epilepticus. Although the retrospective design precludes proper comparison of the efficacy of the substances used, our success rates and refractoriness rates are similar to other studies using different proportions of established and new drugs. General outcome in our cohort was good. The overall in-hospital mortality was less than 10%, compared to 18% both in the Swiss study [18] and the Turkish study [26]. Our in-hospital mortality closely resembles the case fatality rate of 9.3% found in the German population-based study [2]. Five percent of our patients remained in SE at the time of their death or discharge. Seizures in only 27% of our patients were refractory according to our definition (failure of both first-line and second-line therapy). This is in line with the prospective study from Switzerland that found a slightly lower rate of 22% [18] and in contrast to the Turkish registry with a higher rate of 38% [26]. Both studies used comparable criteria for defining refractoriness. When using the definition ‘intubation and admission to ICU’, as other studies did [30,31], our rate of refractory SE episodes would be about 10% compared to 30% and 45% in those studies. This is most likely due to the inclusion of hypoxic/anoxic patients into the SE group as well as to the selection of the patients mainly from the ICU. In our group, refractoriness was associated with non-convulsive semiology, more adverse events and worse outcome despite similarly high doses of first- and second-line drugs. In univariate analysis, the Turkish study also found an association between non-convulsive SE and refractoriness that failed to remain significant in multivariate analysis [26]. Loss of consciousness as well as nonconvulsive SE in coma are relevant scoring points in the Status Epilepticus Severity Score (STESS) [32], which is strongly associated with mortality as well as refractoriness in SE [18,32,33,6]. The majority of our patients classified as having non-convulsive SE had significantly impaired consciousness. Most likely, loss of consciousness in association with SE signals either a more severe underlying brain disorder or more significant extracerebral comorbidity, or both. No significant impact of time from SE onset to treatment onset was found. This is in agreement with the literature [26,34,32,35,36], although some authors found development of refractoriness over time in SE [37,6].
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Our study has several limitations. First, the retrospective design may result in selection bias and poor data quality. However, case ascertainment was made thoroughly and by using all available data. Therefore, only a small number of patients with SE will have been missed. In addition, standardized documentation of treatment and effect that has been established in our hospital was extremely helpful in extracting all important treatment data retrospectively. Thus, our series is close to a prospective design. A second limitation when comparing treatment steps is the lack of randomization, resulting in selection bias that is inherent in all non-randomized studies. Finally, our cohort represents the patients and the resources and policies of one single center. Although our cohort is quite similar to a German population-based cohort in several aspects, our results and experiences cannot be transferred on a one-to-one basis to other institutions, let alone other countries. However, our data represent a coherent and detailed exploratory dataset that could be used to design and develop prospective or even randomized studies that are urgently needed. Conflict of interest statement Dr. Kellinghaus received honoraria and travel support from UCB, Eisai, Pfizer, Desitin, Novartis and Sanofi-Aventis. He has served on advisory boards for UCB (2010 to present). Dr. Stögbauer received honoraria and travel support from Bayer, Biogen TAD, Novartis, Biogen, Merck Serono, Pfizer, TEVA and Sanofi-Aventis. References [1] Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Incidence of status epilepticus in Rochester, Minnesota, 1965-1984. Neurology 1998;50:735–41. [2] Knake S, Rosenow F, Vescovi M, et al. Incidence of status epilepticus in adults in Germany: a prospective, population-based study. Epilepsia 2001;42:714–8. [3] Vignatelli L, Tonon C, D'Alessandro R. Incidence and short-term prognosis of status epilepticus in adults in Bologna, Italy. Epilepsia 2003;44:964–8. [4] Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631–7. [5] Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay RE, Patrick B. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452–4. [6] Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792–8. [7] Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology 2006;67:340–2. [8] Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 2009;17:348–55. [9] Minicucci F, Muscas G, Perucca E, Capovilla G, Vigevano F, Tinuper P. Treatment of status epilepticus in adults: guidelines of the Italian League against Epilepsy. Epilepsia 2006;47(Suppl 5):9–15. [10] Claassen J, Hirsch LJ, Mayer SA. Treatment of status epilepticus: a survey of neurologists. J Neurol Sci 2003;211:37–41. [11] Holtkamp M, Masuhr F, Harms L, Einhaupl KM, Meierkord H, Buchheim K. The management of refractory generalised convulsive and complex partial status epilepticus in three European countries: a survey among epileptologists and critical care neurologists. J Neurol Neurosurg Psychiatry 2003;74:1095–9. [12] Berning S, Boesebeck F, Van Baalen A, Kellinghaus C. Intravenous levetiracetam as treatment for status epilepticus. J Neurol 2009;256:1634–42. [13] Kellinghaus C, Berning S, Immisch I, et al. Intravenous lacosamide for treatment of status epilepticus. Acta Neurol Scand 2011;123:137–41. [14] Knake S, Gruener J, Hattemer K, et al. Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus. J Neurol Neurosurg Psychiatry 2008;79:588–9. [15] Möddel G, Bunten S, Dobis C, et al. Intravenous levetiracetam: a new treatment alternative for refractory status epilepticus. J Neurol Neurosurg Psychiatry 2009;80: 689–92. [16] Stephani U, Esser W, Evers S, et al. Intravenous levetiracetam in clinical practice — 90 patients reported to an independent registry. Epilepsia 2009;50 48-P212. [17] Alvarez V, Januel JM, Burnand B, Rossetti AO. Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia 2011;52: 1292–6. [18] Novy J, Logroscino G, Rossetti AO. Refractory status epilepticus: a prospective observational study. Epilepsia 2010;51:251–6. [19] Martin PJ, Millac PA. Status epilepticus: management and outcome of 107 episodes. Seizure 1994;3:107–13. [20] Kalita J, Nair PP, Misra UK. A clinical, radiological and outcome study of status epilepticus from India. J Neurol 2010;257:224–9.
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[21] Rankin L. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 1957;2:200–15. [22] van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604–7. [23] Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an investigation of variables associated with mortality. Neurology 1996;47:83–9. [24] Ashton CH. Benzodiazepines — How they work and how to withdraw (The Ashton manual). URL http://www.benzo.org.uk/manual/ accessed 20-April-2011. [25] Sostmann HJ, Sostmann H, Crevoisier C, Bircher J. Dose equivalence of midazolam and triazolam. A psychometric study based on flicker sensitivity, reaction time and digit symbol substitution test. Eur J Clin Pharmacol 1989;36:181–7. [26] Agan K, Afsar N, Midi I, Us O, Aktan S, Aykut-Bingol C. Predictors of refractoriness in a Turkish status epilepticus data bank. Epilepsy Behav 2009;14:651–4. [27] Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43:483–8. [28] Rossetti AO, Bromfield EB. Levetiracetam in the treatment of status epilepticus in adults: a study of 13 episodes. Eur Neurol 2005;54:34–8. [29] Misra UK, Kalita J, Maurya PK. Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study. J Neurol 2011 Sep 6. doi:10.1007/s00415-0116227-2 [Electronic publication ahead of print].
[30] Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 2005;76:534–9. [31] Rossetti AO, Logroscino G, Bromfield EB. Refractory status epilepticus: effect of treatment aggressiveness on prognosis. Arch Neurol 2005;62:1698–702. [32] Rossetti AO, Logroscino G, Bromfield EB. A clinical score for prognosis of status epilepticus in adults. Neurology 2006;66:1736–8. [33] 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;255:1561–6. [34] Logroscino G, Hesdorffer DC, Cascino G, Annegers JF, Hauser WA. Short-term mortality after a first episode of status epilepticus. Epilepsia 1997;38: 1344–9. [35] Rossetti AO, Hurwitz S, Logroscino G, Bromfield EB. Prognosis of status epilepticus: role of aetiology, age, and consciousness impairment at presentation. J Neurol Neurosurg Psychiatry 2006;77:611–5. [36] Towne AR, Pellock JM, Ko D, DeLorenzo RJ. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27–34. [37] DeLorenzo RJ, Waterhouse EJ, Towne AR, et al. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia 1998;39: 833–40.
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Treatment of status epilepticus in a large community hospital Christoph Kellinghaus ⁎, Florian Stögbauer Dept. of Neurology, Klinikum Osnabrück, Osnabrück, Germany
a r t i c l e
i n f o
Article history: Received 8 October 2011 Revised 6 December 2011 Accepted 12 December 2011 Available online 16 February 2012 Keywords: Intravenous Anticonvulsant Outcome Efficacy Status epilepticus
a b s t r a c t Background: Status epilepticus (SE) is a neurological emergency usually requiring immediate medical treatment. Due to the lack of adequate studies, treatment guidelines and their application vary between countries and institutions. We intended to analyze current treatment of SE in a German community hospital. Methods: We retrospectively identified patients from a large community hospital in northern Germany who had been diagnosed with SE between August 2008 and December 2010. Their charts were reviewed regarding sociodemographic variables, treatment and outcome. Results: We studied the first SE episode in 172 patients with a median age of 69 years (range 18–90 years). The etiology was acute symptomatic in 30 patients, progressive symptomatic in 22 patients and remote symptomatic in 120 patients. Presentation was generalized convulsive in 60 patients, non-convulsive in 72 patients and simple motor/aura in 40 patients. Median latency from onset to treatment start was 0.75 h (range 0.2–336 h). Initial treatment had a success rate (SR) of 40%. Second line treatment had a success rate of 54%. In patients whose seizures were refractory to the first two drugs, success rates were between 31% and 55%, with only a minority of the patients receiving established drugs such as phenytoin or barbiturates. Multivariate analysis revealed non-convulsive semiology as the only factor significantly associated with refractoriness. SE could be terminated in 95% of the patients and in-hospital mortality was 10%. Benzodiazepines and phenytoin had the most severe side effects. Conclusions: Status epilepticus can be terminated successfully and with low in-hospital mortality in the vast majority of the patients treated in a large community hospital. The success rate of each treatment step is between 30% and 55% regardless of the substances used. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Status epilepticus (SE), i.e. a prolonged and sustained epileptic seizure, is a potentially life-threatening neurological emergency. According to population-based studies, its incidence is estimated as 10–20/100,000/year in western industrialized countries [1–3]. In spite of the incidence and emergency character of SE, there are only very few randomized, blinded, and controlled trials regarding SE therapy [4–6]. These studies suggest that lorazepam, diazepam, phenobarbital and phenytoin are more or less equally efficient in initial treatment of SE when phenytoin is combined with benzodiazepines. Valproate may be equally effective as phenytoin, but has not been compared to phenytoin and benzodiazepines in combination [7]. Based on these few studies, current SE treatment guidelines propose intravenous (i.v.) administration of lorazepam or diazepam followed by i.v. administration of phenytoin as first treatment steps [8,9]. Since most of the randomized studies were performed more than 15 years ago when modern non-sedating i.v. anticonvulants like valproate, levetiracetam, fosphenytoin and lacosamide were not available, their role in initial treatment of SE is ⁎ Corresponding author at: Dept. of Neurology, Klinikum Osnabrück, Am Finkenhügel 1, 49076 Osnabrück, Germany. Fax: + 49 541 405 6599. E-mail address: [email protected] (C. Kellinghaus). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2011.12.020
undetermined. Data regarding treatment of refractory status epilepticus almost exclusively consist of uncontrolled prospective or retrospective case series, and thus treatment recommendations vary greatly between authors and countries. As a consequence, surveys among epileptologists and critical care neurologists in the U.S. as well as in Europe have demonstrated that there is no consensus over treatment strategies once benzodiazepines and phenytoin have failed [10,11]. Particularly uncertain is the value of the new agents that as yet have mainly been used in refractory SE. Most authors retrospectively analyzed single cases or small series with a large range of success rates and without comparison to standard treatment or other new drugs [12–15]. It is very likely that treatment approaches differ significantly between hospitals or departments of a region. The best way to reach consensus about the optimal treatment of SE would be a large prospective, randomized and controlled multicenter study that includes benzodiazepines and phenytoin as well as valproate, levetiracetam and lacosamide. However, there are many legal, ethical and financial obstacles that have yet precluded such an approach. Prospective case documentations or registries are second best, but have been limited to a single agent [16], to university hospitals [17,18], were performed before modern non-sedating i.v. anticonvulsants were available [19], or were performed in countries with predominantly infectious etiologies [20]. However, most cases of SE are treated in non-academic,
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community-based hospitals that care for distinctly different patient cohorts and rely on different resources and hospital policies than the tertiary-level academic hospitals where most scientific publications are generated. With this study we document and analyze the current treatment of SE in a large community hospital in Germany. Although formally it is a retrospective study, data quality is high because we could rely on SE-specific patient treatment documentation that has been used in our department since 2007. With this study we try to narrow the gap between the urgently needed but unavailable data from large randomized controlled trials and the currently available small case series that mainly serve as ‘proof of principle’ for one of the new i.v. anticonvulsants. 2. Methods We retrospectively identified all patients treated for SE in our hospital between July 2008 and December 2010. For identification we searched the hospital database using the search terms ‘status epilepticus’, ‘prolonged epileptic seizure’ as well as the ICD-10 codes G41.xx that cover status epilepticus. In addition, the EEG database was searched using the same search terms. If a patient was admitted more than once for treatment of SE during the study period, only the data of the first admission were analyzed further. Patients with postanoxic status epilepticus were excluded. The hospital charts were reviewed for sociodemographic data, etiology, semiology, onset of SE, and discharge. Time, dose and effect of anticonvulsant treatment were taken from a standardized SE documentation form that was introduced in our institution for quality control purposes in 2007. Once the diagnosis of SE has been made, the form is introduced into the individual patient chart and documents time, efficacy and tolerability of each treatment step, starting with preclinical treatment. Original imaging data were reviewed by at least one of the authors, and all EEG data were reviewed by an experienced electroencephalographer (C.K.). All patients underwent neurological examination and cranial imaging (CT or MRI) at admission. EEG was performed for at least 20 min using the electrodes of the international 10/20 system with additional anterior temporal electrodes (FT9/FT10) in all patients to document cessation of SE and get information about seizure onset at latest at the first working day following admission. Ictal EEG could be performed in 91/172 patients. Comorbidity and clinical outcome were assessed with the modified Rankin Scale (mRS) [21,22] that allows an overview of the patient's disabilities using basic information about neurological symptoms and the patient's need for support in everyday life. A mRS score of 0 is assigned when the patient is free of symptoms, a score of 1 when the patient has no significant disabilities despite some symptoms, a score of 2 when there is a slight disability, a score of 3 when the patient requires some help but is able to walk unassisted, a score of 4 when the patient is unable to attend to own bodily needs without assistance, a score of 5 when the patient requires constant nursing care and attention, and a score of 6 when the patient is dead. The mRS score was determined using all available information about the patient's state before onset of SE and at the time of discharge from hospital. In addition, we counted the ICD-10 diagnoses that were assigned to the case by medical documentation specialists for reimbursement purposes. Epilepsy diagnoses (ICD 10G 40.xx and G41.xx) were subtracted from the total count. SE was defined as a) seizures lasting >10 min, or b) recurrent seizures without regaining recovery of awareness. In EEG, SE was defined according to the criteria stated by Young et al. [23]. SE semiology was categorized pragmatically into generalized convulsive, loss of consciousness without major motor symptoms, aphasic/dyscognitive, simple motor and other simple partial (e.g. aura). Loss of consciousness and aphasic/dyscognitive was lumped into the category ‘non-convulsive’ for some analyses. If SE started with a generalized convulsive seizure followed by EEG-confirmed non-convulsive SE, it was
nevertheless considered as ‘generalized convulsive’ because this type of SE, also described as ‘subtle SE’, most likely has similar pathophysiological and treatment implications. Time of cessation of SE was defined by the time when the seizure symptoms ceased, or – if in doubt – by the time of the first EEG showing cessation of the electroencephalographic signs of SE. An anticonvulsant drug was considered as successful when no further anticonvulsant was introduced until cessation of SE. Different substances of the benzodiazepine class such as lorazepam, diazepam, midazolam and clonazepam were lumped into the group ‘benzodiazepine’. Equivalent doses were calculated according to established pharmacologic tables [24,25]: 10 mg diazepam = 1 mg lorazepam = 0.5 mg clonazepam = 7.5 mg midazolam. Two subgroups were formed retrospectively according to the response to the first two substances used for treatment. If SE ceased after the first or second anticonvulsant, SE was considered ‘nonrefractory’. If SE did not cease after the second anticonvulsant, SE was considered ‘refractory’. Different benzodiazepines were considered as one anticonvulsant. Statistical analysis was performed using OPENSTAT (http:// statpages.org, Version June 2010). Ranked variables were described using mean and standard deviation, and median/quartiles when normal distribution could not be assumed. For univariate analysis of categorical data, chi-square test and Fisher's exact test (2 × 2 tables) were used. Interval-scaled or ordinal-scaled data were analyzed with the Mann–Whitney U test (comparison of two groups), or the Kruskal–Wallis test (comparison of three or more groups). In a second step, backward multiple logistic regression was performed (p = 0.05 for inclusion, p = 0.10 for exclusion) to determine the contribution of individual treatment-independent factors to the refractoriness (i.e. no cessation after the second anticonvulsant). 3. Results During the 29 months that were analyzed, 204 episodes of SE were documented in 172 patients. One hundred forty-nine patients had one episode, 17 patients had two episodes, three patients had three episodes, and three patients had four episodes of SE. Only the first episode during this time period was analyzed. Most patients were elderly patients above 65 years of age, and half of them were women (see Table 1). In the majority of patients, the underlying etiology was remote symptomatic. Thirty patients (17%) had an acute, non-progressive CNS lesion (e.g. stroke, trauma), and 22 patients (13%) a progressive CNS lesion (tumor, metastasis). Semiology was generalized convulsive in a third of the patients, while only 3 patients were treated for an aura status. More than half of the patients were treated with anticonvulsant drugs (AED) before SE onset. Most patients suffered from moderate or major impairment according to the mRS score. Only a third had a mRS score of 2 or lower before SE, and less than a quarter of the patients were discharged with less than 5 diagnoses. Treatment started after a median of 45 min (range 10 min to 336 h), with approximately half of the patients having received the first medication between 10 and 30 min after SE onset. The first drug was almost always a benzodiazepine (lorazepam, diazepam, clonazepam or midazolam, or a successive combination) (see Table 2). SE ceased after administration of the first drug in 69 patients (40%) after a median of 0.13 h. In the remaining 103 patients, a second drug was administered after a median latency of 0.4 h. Most patients (78) received levetiracetam, a minority was treated with other intravenous AEDs such as valproate, phenytoin or lacosamide. Six patients were directly treated with anesthetic agents. The second substance was successful in terminating the SE in 56 patients (54%). Seizures in the other 47 patients were considered refractory. In one patient with glioblastoma multiforme, treatment and life support were withdrawn according to the patients previously-stated wishes after failure of the
C. Kellinghaus, F. Stögbauer / Epilepsy & Behavior 23 (2012) 235–240 Table 1 Sociodemographic characteristic. Variable Age (years) Gender Etiology
Semiology
Ictal EEG
AED before SE No. of diagnoses
mRS before SE
Table 2 Course of treatment. All patients (N = 172)
Mean/standard deviation Median/range Female Acute symptomatic Remote symptomatic first man Remote symptomatic old Remote sympt all Progressive symptomatic Generalized convulsive LOC only Simple Motor Aphasic/dyscognitive Other simple partial No ictal EEG performed Generalized Lateralized Regional Yes Median/range 0–4 5–9 10–14 15–19 20 or more Median 0 1+2 3 4 5
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64.56/+/−17.98 69 (18–90) 82 (48%) 30 (17%) 44 (26%) 76 (44%) 120 (70%) 22 (13%) 60 (35%) 45 (26%) 37 (22%) 27 (16%) 3 (1%) 81 (47%) 15 (9%) 46 (27%) 29 (17%) 74 (43%) 9 (0–33) 37 (22%) 53 (30%) 41 (24%) 20 (12%) 21 (12%) 3 30 (17%) 33 (19%) 48 (28%) 33 (19%) 28 (16%)
Latency SE onset- treatment onset (n = 172)
Latency treatment onset-SE end (hours) (n = 163)
0.75 (0.2–336)
10–30 min 31–60 min 61–120 min 121 min to 6 h >6 h to 24 h >24 h Median/range
90 (52%) 18 (10%) 17(10%) 25 (15%) 13 (8%) 9 (15%) 1.5 (0.1–814.25) No. of patients
AED 1
Latency AED1–AED2 (h) AED 2
Latency AED 2–AED 3(h) AED3
Latency AED 3–AED 4 (h) AED 4
Latency AED 4–AED 5 (h) AED 5
AED = anticonvulsant drug; SE = status epilepticus; mRS = modified Rankin Scale; LOC = loss of consciousness. first man = first manifestation of seizures/epilepsy; old = established epilepsy.
second AED. All other patients received a third AED – in most cases lacosamide or phenytoin – after a median latency of 0.5 h. The third AED was successful in 16 (35%) of the patients. The fourth effort of treatment in the 30 remaining non-responders also consisted mainly of phenytoin and lacosamide, with some patients already receiving an enteral AED such as carbamazepine or oxcarbazepine. In the fourth to seventh step of treatment, success rates were between 30 and 50% using a variety of intravenous and enteral AEDs. All further efforts in the few patients remaining in SE were unsuccessful. Anesthesia for treatment of refractory SE was performed with propofol in 9 patients and with thiopenthal in 1 patient. Only 4 of these patients had a nonconvulsive SE, all other patients were admitted for generalized convulsive SE. SE was terminated successfully in 163 patients (95%). In 140 patients (82%), mRS at discharge was the same as before SE onset (see Table 3). Eighteen patients died, the majority of them after cessation of SE. Patients with refractory SE did not differ from those successfully treated with the first or second AED regarding age, gender, or broad etiological categories as used here (see Table 4). The number of diagnoses was significantly higher in the patients with drug-resistant seizures, whereas mRS before SE onset only numerically differed. Significantly more patients with nonconvulsive SE (i.e. loss of consciousness or aphasia or cognitive dysfunction) had drug-resistant seizures, and latency until treatment start tended to be longer in these patients without reaching statistical significance. As expected, patients with drug-resistant seizures had more adverse events and worse global outcome as expressed as higher mRS scores. However, median benzodiazepine and levetiracetam bolus doses did not differ. Multiple logistic regression was performed using refractoriness as dependent variable. Independent variables were age, gender, etiology (remote symptomatic yes/no as dummy variable), semiology (nonconvulsive semiology yes/no as dummy variable), latency from SE onset to treatment, mRS before admission, benzodiazepine dose. Backward
Median/range (hours)
Latency AED 5–AED 6 (h) AED 6 Latency AED 6–AED 7 (h) AED 7 Latency AED 7–AED 8 (h) AED 8 AED 9 AED 10
Benzo other All Median/range LEV other All Median/range PHT LCM other All Median/range PHT LCM VPA other All Median/range PHT VPA CBZ/OXC Other All Median/range All Median/range All Median/range All All All
168 4 172 0.4/0.15–91.3 78 24 102 0.5/0.1–61 15 21 10 46 17/0.25–208 10 9 6 5 30 27.5/2–319 3 3 5 4 16 37/0.5–470 11 121/43–168 3 317.5/216–419 2 1 1
Success rate* 39% 40% 49% 52% 54% 40% 33% 30% 35% 50%
37%
31% 55% 33% 0 0 0
SE = status epilepticus; AED = anticonvulsant drug; benzo = benzodiazepine; LEV = levetiracetam; PHT = phenytoin; LCM = lacosamide; VPA = valproate; CBZ = carbamazepine; OXC = oxcarbazepine.
multiple logistic regression showed nonconvulsive semiology as the only independently contributing variable (Beta 0.167, standard error 0.068, t = 2.212, p = 0.028).
Table 3 Outcome. Variable SE terminated mRS at discharge
mRS difference
Patients Yes 0 1+2 3 4 5 6 −6 −5 −4 −3 −2 −1 0
SE = status epilepticus; mRS = modified Rankin Scale.
163 (95%) 22 (13%) 33 (19%) 43 (25%) 31 (18%) 25 (15%) 18 (10%) 3 (2%) 1 (0.5%) 1 (0.5%) 4 (2%) 8 (5%) 15 (9%) 140 (82%)
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Table 4 Comparison of patients with drug-resistant seizures to patients with drug-responsive seizures. Variable
Non-refractory (n = 125)
Refractory (n = 47)
Test p-value
Median/range Female Remote sympt all Generalized convulsive Simple motor Nonconvulsive No Median/range 0–4 5–9 10–14 15–19 20 or more Mean/SD 0 1+2 3 4 5 Median/range (hours) 10–30 min 31–60 min 61–120 min 121 min–6 h > 6 h–24 h > 24 h Yes Bolus EQ Units mean/SD Sedation
58/19–89 66 88 (70%) 48 (38%) 29 (23%) 46 (37%) 70 (56%) 9/0–24 33 (26%) 47 (38%) 26 (21%) 15 (12%) 4 (3%) 2.61+/−1.68 22 (18%) 27 (22%) 33 (26%) 26 (21%) 17 (14%) 0.5/0.1–120 68 (64%) 12 (10%) 12 (10%) 19 (15%) 9 (7%) 5 (4%) 86 (69%) 3.43/2.14 83 (66%)
62/18–90 23 32 (68%) 12 (26%) 8 (17%) 26 (55%) 28 (60%) 7/1–33 4 (8%) 17 (36%) 15 (31%) 5 (11%) 6 (14%) 2.94/1.78 8 (17%) 6 (13%) 15 (32%) 7 (15%) 11 (23%) 0.5/0.2–336 22 (47%) 6 (13%) 5 (11%) 6 (13%) 4 (9%) 4 (9%) 41 (87%) 3.82/2.47 40 (85%)
MWU 0.19 FET 0.83 FET 0.70
LEV
Respiratory insufficiency Bolus in mg mean/SD
mRS after discharge
Median
10 (8%) (n = 42) 2773/496 3 (mean 2.82+/−1.72) 112 (90%)
4 (10%) (n = 40) 2675/605 4 (3.87/1.94)
Age (years) Gender Etiology Semiology
AED before SE No. of diagnoses
mRS before SE
Latency SE onset->treatment onset
Adverse event Benzo
No mRS difference
28 (60%)
MWU 0.03 FET 0.67 MWU 0.005
MWU 0.14
MWU 0.14
FET 0.014 MWU 0.26 FET for all AE Benzo 0.018 MWU 0.21 MWU 0.0003 MWU 0.001
SE = status epilepticus; mRS = modified Rankin Scale; Benzo = benzodiazepine; LEV = levetiracetam; SD = standard deviation; EQ = equivalence; FET = Fisher's exact test; MWU = Mann–Whitney U test; AE = adverse event.
4. Discussion In a large community hospital in Germany, status epilepticus was diagnosed in predominantly elderly patients with a remote symptomatic etiology and significant comorbidity. In population-based studies in western industrialized countries, the incidence of status epilepticus was age-dependent and much higher in the elderly population [1–3], explaining the high proportion of elderly patients in our cohort. The mean age in our cohort was almost 65 years, with the median age even higher. Three recent hospital-based studies from Switzerland [17,18] and Turkey [26] showed similar mean ages. In contrast, an earlier report from a large public hospital in San Francisco found a mean age of approximately 15 years less [27], most likely owing to a completely different recruitment population. Almost 50% of our patients were diagnosed with epilepsy before the SE episode, and more than two-thirds had a remote etiology. Only 17% were diagnosed with an acute etiology, and only 13% with a progressive etiology. This corresponds to the almost identical findings of the only German population-based study 10 years ago [2]. On the other hand, in the hospital-based registries from Switzerland and Turkey [26,17], an acute etiology was found in approximately 60% of the SE cases. Even more cases with acute etiology were seen in the San Francisco hospital based study [27]. In the latter study, the most frequent SE etiologies were alcohol-related or anticonvulsant withdrawal, each accounting for more than 40% of the cases. In the former studies, acute infections, metabolic disturbances, acute strokes and anticonvulsant withdrawal were most frequent. The recruitment population of a large urban public hospital in San Francisco clearly differs from ours
regarding age-structure, comorbidities and risk factors. The other two study cohorts were recruited in large university hospitals with tertiary referral status. Therefore, a selection bias favoring patients with severe acute CNS diseases can be assumed. Our department is the only neurological department accessible for emergencies for a region of approximately 350,000 inhabitants in a mixed urban and rural area and has no dedicated neurological intensive care unit. Thus, our patients may more closely resemble a general population cohort than most large university hospitals do. These differences should be kept in mind when comparing our treatment data with those of other reports. Success rates of the treatment steps were between 30% and 55% regardless of the substances used, with a tendency of lower success rates in later steps of treatment and complete failure after the seventh drug in those few patients needing these efforts. With the first step of treatment, in almost all cases a benzodiazepine, SE could be terminated in 40% of the cases. This success rate seems low compared to the success rates of the randomized prospective pre-hospital trial [4] and the VA study [6] where lorazepam could terminate SE in approximately 60% of the cases within a brief interval. However, both cohorts differ markedly from our patients in various aspects. The pre-hospital trial enrolled patients with a mean age of 15 years less and a high percentage of patients with a low anticonvulsant level as sole etiology [4]. The patients of the VA study were mostly elderly patients with remote etiology as in our patient group, but had received treatment for the index SE episode before randomization in 50% of the cases, and were treated with a much higher dose of benzodiazepines compared to our patients. In addition, owing to the prospective design, only a
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fraction of the screened patients finally was enrolled into both studies, suggesting a relevant sampling bias. Levetiracetam was used as second treatment step in the majority of the patients with ongoing SE after benzodiazepine treatment. It was able to stop the SE in almost half of the cases. This is well within the range of previous retrospective series focussing on levetiracetam that found success rates between 26% [28] and 89% [14]. In a recent large prospective observational series, levetiracetam was successful as a second step of treatment in 52% [17]. A retrospective study comparing levetiracetam with phenytoin and valproate suggested a lower success rate for levetiracetam, but the mean bolus dose was only 1600 mg and thus much lower than in our study [17]. In a randomized prospective study comparing lorazepam with levetiracetam as first-line treatment in status epilepticus, both drugs showed a success rate of more than 70% [29]. However, the protocol used a very aggressive treatment approach resulting in a significantly higher adverse event rate. In addition, the patient cohort was recruited in India where etiologies are different from European or U.S. cohorts. As of yet, there has been no randomized trial comparing levetiracetam with other anticonvulsants for treatment of SE after failure of benzodiazepines. Although it is supposed to be common knowledge that the success rate of anticonvulsant therapy in SE decreases strongly with the number of previously failed anticonvulsants, our data do not support this view. Success rates were between 31% and 50% after the failure of the second drug. This may be due to the small group sizes in latter stages of treatment that do not allow us to find a consistent trend in our data. Indeed, our data suggest the existence of truly ‘superrefractory’ status epilepticus. Although the retrospective design precludes proper comparison of the efficacy of the substances used, our success rates and refractoriness rates are similar to other studies using different proportions of established and new drugs. General outcome in our cohort was good. The overall in-hospital mortality was less than 10%, compared to 18% both in the Swiss study [18] and the Turkish study [26]. Our in-hospital mortality closely resembles the case fatality rate of 9.3% found in the German population-based study [2]. Five percent of our patients remained in SE at the time of their death or discharge. Seizures in only 27% of our patients were refractory according to our definition (failure of both first-line and second-line therapy). This is in line with the prospective study from Switzerland that found a slightly lower rate of 22% [18] and in contrast to the Turkish registry with a higher rate of 38% [26]. Both studies used comparable criteria for defining refractoriness. When using the definition ‘intubation and admission to ICU’, as other studies did [30,31], our rate of refractory SE episodes would be about 10% compared to 30% and 45% in those studies. This is most likely due to the inclusion of hypoxic/anoxic patients into the SE group as well as to the selection of the patients mainly from the ICU. In our group, refractoriness was associated with non-convulsive semiology, more adverse events and worse outcome despite similarly high doses of first- and second-line drugs. In univariate analysis, the Turkish study also found an association between non-convulsive SE and refractoriness that failed to remain significant in multivariate analysis [26]. Loss of consciousness as well as nonconvulsive SE in coma are relevant scoring points in the Status Epilepticus Severity Score (STESS) [32], which is strongly associated with mortality as well as refractoriness in SE [18,32,33,6]. The majority of our patients classified as having non-convulsive SE had significantly impaired consciousness. Most likely, loss of consciousness in association with SE signals either a more severe underlying brain disorder or more significant extracerebral comorbidity, or both. No significant impact of time from SE onset to treatment onset was found. This is in agreement with the literature [26,34,32,35,36], although some authors found development of refractoriness over time in SE [37,6].
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Our study has several limitations. First, the retrospective design may result in selection bias and poor data quality. However, case ascertainment was made thoroughly and by using all available data. Therefore, only a small number of patients with SE will have been missed. In addition, standardized documentation of treatment and effect that has been established in our hospital was extremely helpful in extracting all important treatment data retrospectively. Thus, our series is close to a prospective design. A second limitation when comparing treatment steps is the lack of randomization, resulting in selection bias that is inherent in all non-randomized studies. Finally, our cohort represents the patients and the resources and policies of one single center. Although our cohort is quite similar to a German population-based cohort in several aspects, our results and experiences cannot be transferred on a one-to-one basis to other institutions, let alone other countries. However, our data represent a coherent and detailed exploratory dataset that could be used to design and develop prospective or even randomized studies that are urgently needed. Conflict of interest statement Dr. Kellinghaus received honoraria and travel support from UCB, Eisai, Pfizer, Desitin, Novartis and Sanofi-Aventis. He has served on advisory boards for UCB (2010 to present). Dr. Stögbauer received honoraria and travel support from Bayer, Biogen TAD, Novartis, Biogen, Merck Serono, Pfizer, TEVA and Sanofi-Aventis. References [1] Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Incidence of status epilepticus in Rochester, Minnesota, 1965-1984. Neurology 1998;50:735–41. [2] Knake S, Rosenow F, Vescovi M, et al. Incidence of status epilepticus in adults in Germany: a prospective, population-based study. Epilepsia 2001;42:714–8. [3] Vignatelli L, Tonon C, D'Alessandro R. Incidence and short-term prognosis of status epilepticus in adults in Bologna, Italy. Epilepsia 2003;44:964–8. [4] Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631–7. [5] Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay RE, Patrick B. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452–4. [6] Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792–8. [7] Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology 2006;67:340–2. [8] Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 2009;17:348–55. [9] Minicucci F, Muscas G, Perucca E, Capovilla G, Vigevano F, Tinuper P. Treatment of status epilepticus in adults: guidelines of the Italian League against Epilepsy. Epilepsia 2006;47(Suppl 5):9–15. [10] Claassen J, Hirsch LJ, Mayer SA. Treatment of status epilepticus: a survey of neurologists. J Neurol Sci 2003;211:37–41. [11] Holtkamp M, Masuhr F, Harms L, Einhaupl KM, Meierkord H, Buchheim K. The management of refractory generalised convulsive and complex partial status epilepticus in three European countries: a survey among epileptologists and critical care neurologists. J Neurol Neurosurg Psychiatry 2003;74:1095–9. [12] Berning S, Boesebeck F, Van Baalen A, Kellinghaus C. Intravenous levetiracetam as treatment for status epilepticus. J Neurol 2009;256:1634–42. [13] Kellinghaus C, Berning S, Immisch I, et al. Intravenous lacosamide for treatment of status epilepticus. Acta Neurol Scand 2011;123:137–41. [14] Knake S, Gruener J, Hattemer K, et al. Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus. J Neurol Neurosurg Psychiatry 2008;79:588–9. [15] Möddel G, Bunten S, Dobis C, et al. Intravenous levetiracetam: a new treatment alternative for refractory status epilepticus. J Neurol Neurosurg Psychiatry 2009;80: 689–92. [16] Stephani U, Esser W, Evers S, et al. Intravenous levetiracetam in clinical practice — 90 patients reported to an independent registry. Epilepsia 2009;50 48-P212. [17] Alvarez V, Januel JM, Burnand B, Rossetti AO. Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia 2011;52: 1292–6. [18] Novy J, Logroscino G, Rossetti AO. Refractory status epilepticus: a prospective observational study. Epilepsia 2010;51:251–6. [19] Martin PJ, Millac PA. Status epilepticus: management and outcome of 107 episodes. Seizure 1994;3:107–13. [20] Kalita J, Nair PP, Misra UK. A clinical, radiological and outcome study of status epilepticus from India. J Neurol 2010;257:224–9.
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