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J Neurol (1998) 245 : 640–646

© Springer-Verlag 1998 O R I G I N A L C O M M U N I C AT I O N

Ayse Sagduyu Generalized tonic-clonic status epilepticus:


Sultan Tarlaci
Hadiye Sirin causes, treatment, complications
and predictors of case fatality

Received: 9 December 1997


Abstract We retrospectively re- remainder were considered to have
Received in revised form: 23 February 1998 viewed the clinical course of 66 pa- refractory status epilepticus and re-
Accepted: 30 March 1998 tients treated for generalized tonic- quired pentobarbital anaesthesia.
clonic status epilepticus at the Ege Overall case fatality was 21%, but
University neurological intensive death could be attributed directly to
care unit from 1988 to 1997. Sev- status epilepticus and/or treatment
enty-two per cent of the study group complication in 10% of the study
had a pre-existing seizure disorder, group. Major determinants of fatal
and antiepileptic drug withdrawal outcomes were: increasing age,
was the most prominent cause of sta- longer duration of status epilepticus
tus epilepticus. The other causes in- before initiation of therapy and cen-
cluded drug toxicity, central nervous tral nervous system infection as a
A. Sagduyu (Y) · S. Tarlaci · H. Sirin system infection, cerebrovascular causal factor.
Ege University, Medical School Hospital, disease, tumour and trauma. Sev-
Neurology Department,
TR-35100 Bornova – Izmir, Turkey enty-three per cent of all patients re- Key words Status epilepticus ·
e-mail: tarlaci @ med.ege.edu.tr sponded to the first-line therapy (di- Causes · Treatment · Case fatality
Tel./Fax: +90-232-388-09-80 azepam and/or phenytoin), and the

Prognosis depends on the time allowed to elapse be-


Introduction tween onset of status epilepticus and initiation of effective
treatment as well as on age, seizure type, aetiology and
Status epilepticus is a common neurological emergency, underlying neurological and systemic condition [3, 8, 10,
causing a wide spectrum of clinical symptoms associated 11, 14, 18, 21].
with significant morbidity and mortality. It has a highly In the present retrospective hospital-based study, we
variable pathophysiological, anatomical and aetiological describe 66 patients treated for generalized status epilepti-
basis. cus at the Ege University neurological ICU of the Neurol-
Despite improvements in the management of patients ogy Department. We evaluated the clinical features, de-
with status epilepticus in advanced neurological intensive mographic data, aetiological and prognostic factors, com-
care units (ICUs), mortality is still high, ranging from 8 to plications and the response to treatment.
32% [2, 3, 8, 14, 18], indicating that there still is a sub-
stantial need to improve measures for both the prevention
and effective management of this syndrome. Patients and methods
Although a new classification with basic subdivisions
based on age has already been proposed [19], status We identified the hospital records of all patients admitted with the
epilepticus is traditionally classified with reference to diagnosis of status epilepticus to the neurological ICU of the Neu-
rology Department, Ege University Medical School Hospital, from
seizure types [7], and the most life-threatening pattern and 1988 to 1997. The majority of the patients were direct referrals to
that requiring the most urgent treatment is the generalized Ege University Hospital and the rest were referred from the com-
tonic-clonic form. munity hospitals around the city. They were all white Turkish peo-
641

ple. Patients’ hospital records were reviewed initially to determine


whether they fulfilled the international classification of epileptic
seizures criteria for status epilepticus [7]. Status epilepticus was
defined as focal or generalized seizures (determined by clinical ob-
servation) that were continuous for at least 30 min, or repeated
generalized seizures without recovery of consciousness between
attacks and continuing for at least 30 min.

Number of patients
Sixty-six patients’ medical records contained information con-
sistent with the diagnosis of status epilepticus. In cases where a pa-
tient had multiple hospital admissions related to status epilepticus,
only the latest admission was taken into consideration.
Seizure types in status epilepticus were defined as partial or
generalized status epilepticus based on the International Classifi-
cation of Seizure Types and types of status epilepticus as defined
by the International League Against Epilepsy [7]. Classification of
seizure types was based on a review of the patient’s total medical
records. The patients who lacked detailed initial admission history
and clear identification of the details of the seizure presentation in
their medical charts were excluded from the study.
All patients’ medical records were evaluated in detail to obtain
the following information: demographic data, details of history of
seizures or epilepsy, previous or coexisting medical problems,
likely aetiologies of status [i.e. alcohol withdrawal, alcohol or drug Idiopathic Post-stroke Trauma Tumour
toxicity, systemic and/or central nervous system (CNS) infections,
antiepileptic drug withdrawal (AEDW), cerebrovascular disease Fig. 1 Aetiologies of primary seizure disorders in patients with a
(CVD), metabolic disorders, tumour, trauma] in both previously history of epilepsy
epileptic and non-epileptic groups, seizure type according to the
status epilepticus causation, clinical response to antiepileptic drug
regimes for status control, need for intubation and mechanical ven-
tilation, the relation between the duration of status epilepticus be-
fore initiation of treatment and the outcome, complications during
Number of patients

status control, predictors of case fatality and prognostic factors.

Treatment protocol
The treatment protocol of generalized status epilepticus was mainly
based upon a commonly used published regime [4]. After standard
initial evaluation, all patients received diazepam (DZP) 10 mg in-
travenous (IV) bolus or 2 mg/min infusion up to 20–30 mg cumu-
lative doses. If the seizures persisted 30 min after the first injection,
phenytoin (DPH) was infused at a dose of 18 mg/kg at a rate of 50
mg/min. If the patients continued to convulse after delivery of
AEDW

CNSI

CVD

Trauma

Tumour

Intoxication

Metabolic

Idiopathic
these drugs, pentobarbital bolus 5 mg/kg was administered at a rate
of 25 mg/min, and the maintenance dose of 2 mg/kg per hour was
infused and that dose adjusted according to the patient’s response.

Statistical methods
Fig. 2 Primary aetiologies of status epilepticus in patients with
If normally distributed, continuous variables were compared using (black bar) and without (white bar) history of epilepsy
the independent sample t test and chi-square test; if not, Mann-
Whitney U test. A P value of less than 0.05 was considered signif-
icant. Odds ratio (OR) and significant levels were calculated along secondary generalization. There were only 3 patients with
with a 95% confidence interval (CI). Analyses were performed simple partial status epilepticus, so they were excluded
with SPSS software for Windows (release 6.1) packages.
from the study, since this group was not large enough for
statistical analysis. Unfortunately, no patient met the crite-
Results ria for complex partial status epilepticus. There was no
significant difference between primary or secondary gen-
Sixty-six patients (28 women and 38 men) with a mean eralized tonic-clonic status epilepticus in terms of demog-
age of 33.9 years (range 6–77) comprised the study group. raphy or causation.
Since our neurological ICU serves mainly adult patients,
all patients were older than 16 years except 5 children of
school age. Nine (14%) patients had more than one episode Aetiology of status and pre-exisiting seizure disorders
of status epilepticus. All patients with generalized status
epilepticus included in the study had only tonic-clonic Forty-eight (73%) of 66 patients had a history of epilepsy,
seizure type; 47 (71%) of them had primary, 19 (29%) had and the most common cause of status epilepticus was an-
642

Table 1 General features of


patients according to antiepi- DZP DZP + DPH DZP + DPH DZP + DPH
leptic drug regimes for status + PB + CLO
control (AEDW antiepileptic
drug withdrawal, CNSI central n 35 (53.0%) 20 (30.3%) 10 (15.2%) 1 (1.5%)
nervous system infection, CVD Sex
cerebrovascular disease, Female 19 14 5
PriGTC primary generalized
tonic-clonic convulsion, Male 16 16 5 1
SecGTC secondary generalized Mean age (years) 32.4 37.1 35.6 6
tonic-clonic convulsion, DZP Previously epileptic 30 12 5 1
diazepam, DPH phenytoin, First seizure 5 8 5
CLO chloralhydrate, PB pento-
barbital) Aetiology of status epilepticus
AEDW 23 5 3 1
CNSI 2 2 3
CVD 1 1
Trauma 1 1
Tumour 1 2 1
Metabolic 1
Drug intoxication 2 1 1
Idiopathic 6 7 1
Type of status epilepticus
SecGTC 8 5 5 1
PriGTC 27 15 5
Need for ventilation 2 6 10
Prognosis
Death 3 7 4
Survivor 32 13 6 1

ticonvulsant drug withdrawal (n = 32) in these patients. received first-line therapy of IV DZP (bolus or infusion):
The other causes included drug toxicity or induction (n = 3), 32 (48%) had status control and survived except for 3 pa-
CNS infection (n = 3), tumour (n = 2), trauma (n = 1), id- tients of whom 1 died of pneumonia after status control
iopathic (n = 7). Drugs implicated as a cause of status and 2 died without status control owing to herniation re-
epilepticus included isoniazid (n = 1) in toxic dosage and sulting from CVD and cardiovascular disease (acute my-
clomipramine (n = 1), penicillin (n = 1) in therapeutic ocardial infarction).
doses. The causes of the pre-existing epilepsy in these 48 There were 20 patients in the second step of therapy
patients were idiopathic in 26 (39%), post-stroke in 7, and seizure control was sustained after administration of
trauma in 8 and tumour in 7, as shown in Fig. 1. adequate doses of IV DPH in addition to DZP in 16 (80%)
In patients without a history of epilepsy (n = 18), the patients, which was 24% of the study group. Of these, 3
primary causes of status epilepticus were CNS infection patients died after seizure control because of underlying
(n = 4), CVD (n = 2), tumour (n = 2), trauma (n = 1), clo- disease (tumour, CNS infection, unidentified). Four pa-
mipramine overdose because of suicidal attempt (n = 1), tients (20%) in this group died without status control be-
metabolic disorder (n = 1), idiopathic (n = 7). Figure 2 cause of cardiac arrest before completing the loading dose
shows the primary cause of status epilepticus in both of DPH. The rest survived without irreversible neurologi-
groups of patients with and without pre-existing seizure cal sequelae.
disorder. In comparing the likely cause of status epilepti- Of 11 patients who were refractory to standard therapy,
cus and the primary seizure disorder in both groups of pa- seizures ended after IV pentobarbital administration in 8
tients, anticonvulsant drug withdrawal was seen to be the (12% of the study group) and after rectal chloralhydrate
main cause of status epilepticus in patients with pre-exist- administration in one case. Two patients had a fatal out-
ing idiopathic epilepsy. come in a short time without status control in the pento-
barbital group owing to pulmonary oedema in 1, and sec-
ondary to severe hypotension in the other. Of the 8 pa-
Response to the treatment tients treated with pentobarbital with sustained seizure
control, 2 died because of unidentified cause in one case
We evaluated the patients’ charts according to the antie- and cardiac arrest in the other. Table 1 illustrates the gen-
pileptic drug regimes for status control. All of the patients eral features of patients according to different antiepilep-
643

Table 2 Profiles of patients


who died during their treat- Pa- Age Pre- Aetiology Seizure Control Need for Cause of death
ment for status epilepticus tient (years) existing of status duration of status ventilation
sex epileptic epilepticus before epilep-
treatment ticus
(h)

1 71/F – CNSI 4 + + Herniation


2 39/M + Tumour 3 + + Herniation
3 72/M + AEDW 0.5 + – Cardiac arrest
4 20/M + CVD 3 – + Herniation
5 19/M – CNSI 2 – + ?
6 61/M + AEDW 5 – + Pulmonary oedema
7 47/M – Idiopathic 4 – – Cardiac arrest
8 34/F – CNSI 4 – + Cardiac arrest
9 19/F + AEDW 3 – – Cardiac arrest
10 17/M + AEDW 2 – – Cardiac arrest
11 77/M + AEDW 5 + + Cardiac failure
12 34/F + AEDW 9 – – Pulmonary oedema
13 60/M – Idiopathic 5 + – ?
14 75/M + AEDW 3 + – Cardiac failure

Table 3 Risk factors for case


fatality (OR odds ratio, CI con- Factor Case fatality
fidence interval)
n [%] OR P-value 95% CI

Age
<45 years 7 12.2
>45 years 7 77.7 2.880 0.011 1.3084–6.3784
Sex
M 4 14.2
F 10 26.6
Seizure duration before treatment
<1h 1 3.0
>1h 13 39.4 2.410 0.0003 1.6622–1.6945
Pre-existing epilepsy
Yes 8 16.7
No 6 33.3
Type of seizure
PriGTC 12 25.5
SecGTC 2 10.5
Aetiology of status epilepticus
AEDW 5 15.6
CNSI 5 71.4 13.881 0.014 1.9444–4.0038
Stroke 1 50.0
Tumour 1 25.0
Idiopathic 2 16.6
Hyperpyrexia
< 38° C 8 16.0
> 38° C 6 37.5
Need for ventilation
No 6 12.5
Yes 8 44.4 1.575 0.004 1.0279–2.4134
644

tic drug regimes. The majority of patients responsive to mine whether a difference in fatality rate existed between
DZP had a history of epilepsy, and AEDW was the main patients with prolonged versus non-prolonged seizure du-
cause of status epilepticus. ration, the data sets were divided into two groups: the pa-
tients whose treatment for status epilepticus started within
1 h (non-prolonged) or later than 1 h (prolonged). Our re-
Complications sults show a clear relation between seizure duration be-
fore initiating therapy and case fatality (OR 2.410; 95%
Complications seen during the management of status CI, 1.6622–1.6945; P = 0.0003).
epilepticus were evaluated in two groups in terms of Among the aetiologies of status epilepticus in patients
severity. Mild events comprising the first group were: gas- with fatal outcome, only CNS infection was associated
trointestinal haemorrhage (2 patients), uraemia (2 pa- with significant case fatality in multivariate analysis (OR
tients), mild elevation of hepatic enzymes (11 patients), 13.881; 95% CI, 1.9444–4.0038; P = 0.014). No specific
pneumonia (4 patients), hypotension owing to DZP/pen- cause was identified from these patients’ cerebrospinal
tobarbital infusion (4 patients), tachycardia (25 patients), fluid (CSF) examinations, so they were all supposed to be
hyperpyrexia (14 patients), leucocytosis (25 patients). Se- viral in origin. Need to intubate was also significantly re-
vere events comprising the second group were: aspiration lated to poor outcome (OR 1.575; 95% CI, 1.0279–
pneumonia and fatal pulmonary failure (2 patients), sig- 2.4134; P = 0.004).
nificant hypotension (systolic blood pressure < 70 mmHg)
owing to pentobarbital infusion (1 patient), hepatic failure
owing to DPH (initially infusion, then oral administration Discussion
in therapeutic doses) (1 patient), bradycardia owing to
cardiovascular insufficiency (pulse rate < 50) (1 patient), The intent of our study was to evaluate our patients with
malign hyperpyrexia owing to underlying disease (CNS generalized status epilepticus, whether primary or sec-
infection and CVD) (2 patients), prolonged apnoea owing ondary, in terms of demographics, aetiology, therapeutic
to DZP infusion (2 patients), significant tachycardia and prognostic factors. Demographic data and the aetiol-
(pulse rate > 180) (5 patients). Of the 5 patients with sig- ogy of status epilepticus did not show a statistical signifi-
nificant tachycardia, 4 developed cardiac arrest during cance in seizure type subgroups, either primary or sec-
DPH infusion before termination of status epilepticus. ondary generalized tonic-clonic convulsion, as has been
The aetiology of status epilepticus was AEDW in 2 and indicated in other reports [8, 10], even though partial with
CNS infection or idiopathic in the rest. Although they secondary generalization was reported as the major
were not autopsied, the cause of death was supposed to be seizure type in the elderly by De Lorenzo et al. [3]. In our
owing to DPH infusion in 3 cases. study, 73% of our patients had pre-existing seizure disor-
der, which was also discordant with the results of the lat-
est population-based survey of status epilepticus [3].
Case fatality AEDW was the main cause of status epilepticus in 66% of
these, which was 48% of the whole study group. In 27%
Fourteen patients (21%) died during their treatment in our of the patients, status was the first epileptic event, and the
neurological ICU, and status control could not be sus- cause of status epilepticus was unidentified in 39% of
tained in 8 (12%) of these patients. Death could be attrib- them. Our results are similar to other reports [1, 2, 5, 6, 10],
uted directly to status epilepticus and/or treatment compli- emphasizing the point that most of the patients presenting
cations in 6 (10%) of them (Table 2), although neu- with status epilepticus in the medical emergency wards
ropathological examination was lacking. have pre-existing epilepsy, which is a consequence of
We performed multiple regression analysis to deter- antiepileptic drug discontinuation in more than half of
mine the potential predictive indicators associated with them. It is also notable that isoniazid, clomipramine and
fatality (Table 3). penicillin might induce status epilepticus in patients with
The mean age was significantly higher in the fatal group epilepsy, and in about 21% of all patients, the cause for
than that of survivors (46.0 and 30.6 years, respectively) status epilepticus could not be identified. Although it is
(P = 0.004). Case fatality for male and female patients commonly reported in the literature [1, 3, 8, 14, 15], there
was 32% and 35%, respectively, and this difference was was no patient with alcohol-related seizures among the
not statistically significant. Case fatality rates did not other likely aetiologies of status epilepticus in our study
show statistically significant differences in patients with group.
and without pre-existing seizure disorder or in patients Almost half of the patients in our study group re-
with primary or secondary type of generalized status epi- sponded succesfully to only IV DZP therapy. Only 3 pa-
lepticus. tients died, but death could not be attributed directly to
We also investigated the effect of duration of status on status epilepticus in them because the cause of death was
outcome before initiating antiepileptic therapy. To deter- clinically clear in 2 non-responders, and the 3rd one died
645

of pneumonia after status control. Of the 31 patients who identified by autopsy. However, severe complications
did not respond to IV DZP, 16 responded to a loading were also seen during the treatment in our study group,
dose of IV DPH. The results show that 68% of our pa- and four patients’ deaths might be attributed to treatment
tients with status epilepticus responded successfully to complications.
initial 10–30 mg IV DZP, followed if necessary by 18 We analysed several determinants of fatal outcome in
mg/kg of DPH. We assume that this therapeutic approach status epilepticus. Our results show statistically signifi-
is probably representative of the standard practice of most cant association of age, duration of status epilepticus and
neurologists [4, 9, 17, 18, 20]. aetiology with case fatality in status epilepticus, and these
Patients who failed to respond to the first two drugs findings are consistent with certain previous observations
were considered to have refractory status epilepticus, and [1, 3, 8, 21]. We found that mean age was significantly
pentobarbital was administered to all except one patient higher in the fatal group, and a poor outcome of status
who received rectal chloralhydrate even though it was not epilepticus was more likely as its duration before initia-
routinely used. Pentobarbital is most widely accepted as a tion of therapy increased. On the other hand, CNS infec-
drug of choice in patients with refractory status epilepti- tion was the only aetiology associated with significant
cus [4, 12, 13, 15, 18, 22], but the high mortality rate in case fatality in multiple regression analysis in our study,
some series [16, 22] may discourage its use. Four patients whereas it was reported to have a comparatively better
died in our study group who received pentobarbital: two prognosis by De Lorenzo and Lowenstein [3, 10]. Towne
during anaesthesia without effective status control, which et al. reported that aetiologies including CNS infection,
might be attributed directly to prolonged status or pento- anoxia and haemorrhage were associated with high mor-
barbital anaesthesia complication; the other two patients’ tality, but in multivariate analysis only anoxia was associ-
deaths were unexpected, because they occurred after sta- ated with significant mortality [21], as also indicated by
tus control and cessation of treatment. Although our study De Lorenzo et al. [3].
group was not large enough to provide a clear idea of the In conclusion, our results indicate that in generalized
efficacy and safety of pentobarbital anaesthesia in status status epilepticus, AEDW is the main cause and seizures
control, we suggest that 50% case fatality in this group can successfully be controlled with first-line therapy
was associated not only with drug complications, but also (DZP and DPH) in about two-thirds of the patients. We
with underlying disease and status duration. also think that pentobarbital infusion is very effective in
Complications seen during the management of status suppressing seizures in refractory status epilepticus. How-
epilepticus in our study group were similar to those in ever, mortality remains unacceptably high, and age, dura-
other reports [1, 8, 14, 18, 21, 22], and most of them were tion of status and underlying disease, especially CNS in-
not serious and were successfully managed in our ICU ex- fection, are the major determinants of fatal outcome.
cept for patients in whom the cause of death could not be

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