European Journal of Neurology 2006, 13: 445–450 doi:10.1111/j.1468-1331.2006.01397.

EFNS TASK FORCE ARTICLE

EFNS guideline on the management of status epilepticus

H. Meierkorda, P. Boonb, B. Engelsenc, K. Göcked, S. Shorvone, P. Tinuperf and M. Holtkampa
a
Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany; bDepartment of Neurology, Ghent University Hospital,
Ghent, Belgium; cDepartment of Neurology, Haukeland University Hospital, Bergen, Norway; dDeutsche Epilepsievereinigung e.V., Berlin,
Germany; eInstitute of Neurology, University College London, London, UK; and fDepartment of Neurological Sciences, University of
Bologna, Bologna, Italy

Keywords: The objective of the current paper was to review the literature and discuss the degree
generalised convulsive of evidence for various treatment strategies for status epilepticus (SE) in adults. We
status epilepticus, non- searched MEDLINE and EMBASE for relevant literature from 1966 to January 2005.
convulsive status epilepti- Furthermore, the Cochrane Central Register of Controlled Trials (CENTRAL) was
cus, refractory status sought. Recommendations are based on this literature and on our judgement of the
epilepticus, treatment relevance of the references to the subject. Recommendations were reached by
informative consensus approach. Where there was a lack of evidence but consensus
Received 31 August 2005 was clear we have stated our opinion as good practice points. The preferred treatment
Accepted 8 September 2005 pathway for generalised convulsive status epilepticus (GCSE) is intravenous (i.v.)
administration of 4 mg of lorazepam or 10 mg of diazepam directly followed by 15–
18 mg/kg of phenytoin or equivalent fosphenytoin. If seizures continue for more than
10 min after first injection another 4 mg of lorazepam or 10 mg of diazepam is
recommended. Refractory GCSE is treated by anaesthetic doses of midazolam,
propofol or barbiturates; the anaesthetics are titrated against an electroencephalogram
burst suppression pattern for at least 24 h. The initial therapy of non-convulsive SE
depends on the type and the cause. In most cases of absence SE, a small i.v. dose of
lorazepam or diazepam will terminate the attack. Complex partial SE is initially
treated such as GCSE, however, when refractory further non-anaesthetising
substances should be given instead of anaesthetics. In subtle SE i.v. anaesthesia is
required.

continuing after such failure is termed refractory SE

Background
and represents an even more difficult clinical problem.
Drug treatment approaches in this situation are
Incidence, mortality and morbidity
based on retrospective series, case reports and expert
Generalised convulsive status epilepticus (GCSE) and opinions. The goal of this paper is to summarise
non-convulsive status epilepticus (NCSE) are important published treatment options for generalised convulsive
neurological conditions potentially associated with and NCSE. Post-anoxic myoclonus is not considered in
significant mortality and morbidity rates. Annual inci- this guideline since there is no agreement regarding its
dence rates of GCSE range between 3.6 and 6.6 per epileptic nature. The focus of this article is on critical
100 000 and of NCSE between 2.6 and 7.8 per 100 000 care situations in adults and SE in children is not
[1–3]. Mortality and morbidity rates of SE are heavily considered.
influenced by the underlying aetiology and it is, there-
fore, difficult to give reliable figures for the condition
Mechanisms
itself [1,4,5]. In particular, mortality of NCSE after
profound brain damage is high and usually to the injury The basic processes generating SE may be seen as a
itself [5]. However, there is general agreement that failure of the normal mechanisms that terminate sei-
immediate and effective treatment is required. First-line zures. Reduced inhibition and persistent excessive
anticonvulsants like benzodiazepines and phenytoin excitation create interactions that produce and sustain
fail to terminate SE in 31–50% of cases [6–8]. SE ongoing seizure activity. Pronounced excitation via
glutamate analogues leads to prolongation of seizures
[9] and GABA antagonists such as picrotoxin and bic-
Correspondence: Hartmut Meierkord, Department of Neurology,
Charité – Universitätsmedizin Berlin, Schumannstrase 20/21, 10117
uculline may also provoke SE [10], both impairing the
Berlin, Germany (tel.: +49 30 450 56 01 05; fax: +49 30 450 56 09 32; usual mechanism by which seizures terminate. During
e-mail: [email protected]). prolonged seizure activity dynamic changes in GABAA

Ó 2006 EFNS 445

446 H. Meierkord et al.

receptor function has been described resulting in pro- Consequently, Lowenstein et al. [26] have proposed an
gressive receptor insensitivity [11]. Absence SE with operational definition of SE that is based on a duration
3-Hz spike-wave discharges are induced by excessive of 5 min [20]. Currently, clinical studies are based on
inhibition [12]. This form of SE does not lead to the 5 min [21], 10 min [6,7] or 30 min [2,22] of ongoing
neuronal injury seen with excessive excitation [13]. epileptic activity to define SE. The diagnosis of NCSE is
based on a change in behaviour and/or mentation from
baseline and an associated electroencephalogram
Search strategy
(EEG) with epileptiform discharges [23]. Currently,
One member of the Task Force Panel (HM) searched there is no generally accepted duration of electro-clin-
available published reports from 1966 to 2005 using the ical alterations incorporated in the diagnostic criteria of
database MEDLINE and EMBASE (last search in NCSE.
January 2005). The search was limited to papers pub- NCSE includes subtypes such as absence status,
lished in English. The subject term Ôstatus epilepticusÕ complex partial SE and subtle generalised SE. The
was combined with the terms Ôcontrolled clinical trialÕ, latter evolves from overt GCSE and is characterised by
Ôrandomised controlled trialÕ (RCT), Ômulticentre studyÕ, coma and ongoing electrographic seizure activity
meta analysisÕ and Ôcross over studyÕ. Furthermore, the without any or with subtle convulsive movements [6].
Cochrane Central Register of Controlled Trials Absence SE with 3-Hz spike-wave discharges is a more
(CENTRAL) was sought. Finally, the websites of the benign type of SE and is not further considered in this
World Health Organisation (WHO), the International paper.
League against Epilepsy (ILAE) and the American An appropriate definition of refractory SE also is still
Neurological Association (ANA) were explored to look missing. The failure of two [7,24] or three [25,26] anti-
for additional information. convulsants has been suggested in combination with a
minimal duration of the condition of 1 h [7,27], 2 h
[24,28] or regardless of the time that has elapsed since
Evaluation of published literature
onset [22,26].
The evidence for therapeutic interventions (class I–IV)
and the rating of recommendations (level A–C) were
Results
classified by using the definitions previously reported
[14].
Literature and data on treatment

Initial treatment of generalised convulsive status

Methods for reaching consensus
epilepticus
The other members of the task force read the first draft High-level evidence for the initial pharmacological
of the recommendations and discussed changes treatment of GCSE has been given in three RCTs that
(informative consensus approach). Where there was a are indicated below. In 384 patients with GCSE,
lack of evidence but consensus was clear we have stated intravenous (i.v.) administration of 0.1 mg/kg of
our opinion as good practice points (GPP). lorazepam was successful in 64.9% of cases, 15 mg/kg
of phenobarbital in 58.2%, and 0.15 mg/kg of diaze-
pam followed by 18 mg/kg phenytoin in 55.8%; the
Definitions
efficacy of these anticonvulsants was not significantly
The time that has to evolve to define ongoing epileptic different [6] (Class I). The same trial has shown that
activity as Ôstatus epilepticusÕ is as yet not generally in pairwise comparison initial monotherapy with
agreed upon. The Commission on Classification and 18 mg/kg phenytoin is significantly less effective than
Terminology of the ILAE defines SE as Ôa seizure [that] administration of lorazepam. Another RCT has
persists for a sufficient length of time or is repeated focussed on the pre-hospital treatment of GCSE per-
frequently enough that recovery between attacks does formed by paramedics [21] (Class I). Patients were
not occurÕ [15]. Experimental studies have shown irre- administered 2 mg of i.v. lorazepam, 5 mg of i.v. dia-
versible neuronal damage after about 30 min of con- zepam, or placebo, the injection of identical doses of
tinuing epileptic activity [16]. Therefore, this time benzodiazepines was repeated when seizures continued
window has been adopted by the majority of authors for more than 4 min. Lorazepam terminated SE in
[1,2,17]. On the other hand some clinical data indicate 59.1% of cases and was as effective as diazepam
that spontaneous cessation of generalised convulsive (42.6%). Both drugs were significantly superior to the
seizures is unlikely after 5 min [18,19] and, therefore, administration of placebo (21.1%). An earlier RCT on
acute treatment with anticonvulsants is required. 81 episodes of all clinical forms of SE compared i.v.

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 Guideline on the management of status epilepticus 447

administration of 4 mg of lorazepam vs. 10 mg of recommend general anaesthesia to obtain burst sup-

diazepam, which were repeated when seizures continued pression on the EEG (i.e. the absence of electrographic
or recurred after 10 min [29] (Class I). In episodes of seizure activity) if initial therapy has not controlled the
GCSE with or without focal onset (n ¼ 39) 13 episodes SE within 1–2 h. However, there are no studies com-
responded to lorazepam after the first administration paring anaesthetic therapy with continuing non-anaes-
and three after the second whilst three episodes did not thetising anticonvulsants. The therapeutic decision is
respond. With diazepam 14 episodes responded to the based on the type of SE, comorbidity and prognostic
first administration and two to the second whilst four issues. This is of special relevance in patients with non-
episodes did not respond. convulsive forms of SE since the risks of anaesthesia
(e.g. arterial hypotension, gastroparesis, immunosup-
Initial treatment of non-convulsive status epilepticus pression, etc.) may be greater than the risks of ongoing
The pharmacological treatment of subtle SE has been non-convulsive epileptic activity [32]. In view of the lack
addressed in a RCT with 134 patients [6] (Class I). The of controlled studies, the decision on further treatment
i.v. administration of lorazepam (0.1 mg/kg), diazepam is based on a few retrospective studies and expert
(0.15 mg/kg) followed by phenytoin (18 mg/kg), phe- opinions. Retrospective studies have analysed the fur-
nobarbital (18 mg/kg) and phenytoin (18 mg/kg) ter- ther treatment options after failure of initial anticon-
minated SE in 8–24% of cases only. Success rates were vulsants [7]. It should be noted that treatment pathways
not significantly different between the drugs or drug were naturally influenced by multiple variables such as
combinations tested. However, key criterion for study aetiology, age and comorbidity. In 26 episodes of RSE,
entry was the evidence of subtle SE at the time of after failure of first- and second-line drugs, 23 episodes
evaluation, regardless of prior treatment. Though not were treated with a third-line drug that was non-
further specified, it can be assumed that in some of the anaesthetising in all but one case. In 12 of these epi-
patients, anticonvulsants have been administered sodes, seizures were controlled, but 11 patients needed
before. Further RCT or other prospective data focus- further treatment [7] (class IV). These data indicate that
sing on the treatment of subtle or other forms of NCSE the majority of patients with SE refractory to initial
are missing. Even retrospective studies usually do not anticonvulsants was treated with further non-anaes-
address this frequent subgroup of SE. thetising anticonvulsants which were successful in
approximately half of the patients. However, these data
Side effects of initial treatment of status epilepticus did not differentiate between GCSE and NCSE.
Safety issues of the common initial anticonvulsants The lowest class of evidence available is based on
have been compared in patients with generalised con- expertsÕ opinions. Two surveys have been performed,
vulsive SE as well as in patients with non-convulsive one on the treatment of GCSE amongst American
subtle SE [6] (Class I). In GCSE hypoventilation was neurologists [33] and another on the management of
observed in 10–17% of cases, hypotension in 26–34%, refractory GCSE and CPSE amongst epileptologists
and cardiac arrhythmias in 2–7%. These side effects and critical care neurologists in Austria, Germany and
were more frequent in subtle SE and ranged between 3 Switzerland [34]. American neurologists did not agree
and 59% of cases. Distribution of side effects was not on how to proceed in pharmacological treatment of SE
significantly different in patients treated with loraze- after failure of benzodiazepines and phenytoin or fos-
pam, diazepam followed by phenytoin, phenobarbital phenytoin: more than 80% would not directly proceed
and phenytoin in overt and subtle SE. Out-of-hospital to an anaesthetic (43% administer phenobarbital and
administration of benzodiazepines compared to placebo 16% valproic acid), whilst 19% would directly admin-
did not result in more complications such as arterial ister anaesthetic [33] (class IV). However, this survey
hypotension, cardiac dysrhythmia or respiratory inter- did not include the management of refractory CPSE.
vention [21] (Class I). These side effects occurred in The European survey revealed that after failure of
10.6% of patients treated with lorazepam, 10.3% of benzodiazepines and phenytoin two-thirds of the par-
patients treated with diazepam and 22.5% of patients ticipants would administer in GCSE as well as in CPSE
given placebo. another non-anaesthetising anticonvulsant, the major-
ity of participants preferred phenobarbital. Immediate
Refractory status epilepticus administration of an anaesthetic was preferred by 35%
The rationale for treating refractory SE with anaes- in GCSE and by 16% in CPSE [34] (class IV). Three-
thesia is that prolonged electrographic seizure activity, fourths of the experts did not administer anaesthetics in
in experimental animal models, results in brain damage refractory CPSE at all, whilst all did at some time point
[30,31]. To what extent this occurs in human SE is not in GCSE. Administration of anaesthetics was withheld
known, but it is for this reason that most authorities in CPSE: more than 60% of the participants administer

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448 H. Meierkord et al.

anaesthetics not earlier than 60 min after onset of status assessment and control of the airways and of ventila-
compared to only 21% of participants waiting that long tion, arterial blood gas monitoring to see if there is
in GCSE. metabolic acidosis and hypoxia requiring immediate
treatment through airway management and supple-
Further non-anaesthetising anticonvulsants mental oxygen, ECG and blood pressure monitoring.
Though phenobarbital has been assessed in the initial Other measures include i.v. glucose and thiamine as
anticonvulsive treatment [6] of SE, sufficient data on the required, emergency measurement of antiepileptic drug
efficiency of the substance after failure of benzodiaze- levels, electrolytes and magnesium, a full haematologi-
pines and phenytoin/fosphenytoin are missing. Doses of cal screen, and measures of hepatic and renal function.
20 mg/kg infused at a rate of 30–50 mg/min are used. The cause of the status should be identified urgently
The role of i.v. valproic acid in the treatment of SE is and may require treatment in its own right (GPP).
yet to be defined. Valproic acid is a non-sedating sub-
stance that has not caused hypotension or respiratory Initial pharmacological treatment of GCSE and NCSE
suppression and has been reported to be effective in The initial therapy of NCSE depends on the type and
generalised convulsive and NCSE [35] (class IV). In a the cause. Subtle SE evolving from GCSE is refractory
retrospective study that included 63 patients, efficacy by nature and its further treatment is described below.
rates of 63% and favourable tolerance of rapid admin- Complex partial SE should be treated initially as
istration ranging from 200 to 500 mg/min were reported GCSE. The preferred treatment pathway is i.v.
[36] (class IV). Loading doses of 25–45 mg/kg [37] (class administration of 4 mg of lorazepam, this dose is
IV) and infusion rates up to 6 mg/kg/min have been repeated if seizures continue for more than 10 min
suggested [38] (class IV). However, at present, there is after first injection. If necessary, additional phenytoin
inadequate data to justify its use before phenytoin. (15–18 mg/kg) or equivalent fosphenytoin is recom-
mended. Alternatively, 10 mg of diazepam directly
Anaesthetising anticonvulsants followed by 15–18 mg/kg of phenytoin or equivalent
Most authorities recommend administering anaesthetic fosphenytoin can be given, if seizures continue for
agents to a depth of anaesthesia which produces a burst more than 10 min after injection another 10 mg of
suppression pattern in the EEG [34] (class IV) or an diazepam is recommended. If necessary, additional
isoelectric EEG [39]. Studies are needed in this area, as lorazepam (4–8 mg) should be administered (Level A
these issues give rise to ethically highly problematic rating).
decisions.
Barbiturates, midazolam and propofol are commonly General management of refractory status epilepticus
used in refractory SE [34] (class IV). There have been no GCSE that does not respond to initial anticonvulsant
RCTs comparing these treatment options. A systematic substances needs to be treated on an intensive care unit
review of drug therapy for refractory SE including (GPP).
barbiturates, midazolam and propofol assessed data on
193 patients from 28 retrospective trials in an attempt Pharmacological treatment for refractory GCSE and
to clarify this issue [40] (class IV). Pentobarbital was subtle status epilepticus
more effective than either propofol or midazolam in In GCSE and subtle SE we suggest to proceed imme-
preventing breakthrough seizures (12 vs. 42%). How- diately to the infusion of anaesthetic doses of midazo-
ever, in most studies barbiturates were titrated against lam, propofol or barbiturates because of the increasing
an EEG burst suppression pattern whilst midazolam risk of brain and systemic damage. Due to poor evi-
and propofol were administered to obtain EEG seizure dence we cannot recommend which of the anaesthetic
cessation. Accordingly, side effects such as arterial substances should be administered first. We recommend
hypotension were significantly more frequently seen the titration of the anaesthetic against an EEG burst
with pentobarbital compared to midazolam and prop- suppression pattern. This goal should be maintained for
ofol (77 vs. 34%). Overall mortality was 48% but there at least 24 h. Simultaneously, antiepileptic the chronic
was no association between drug selection and the risk medication the patient will be treated with in future
of death. should be initiated (GPP).
Barbiturates: To start with thiopental is administered
as a 100–200 mg of bolus over 20 s then further 50 mg
Recommendations
of boluses every 2–3 min until seizures are controlled,
General initial management infusion 3–5 mg/kg/h. Pentobarbital (the first meta-
General management approaches in generalised con- bolite of thiopental) is marketed in the USA as the
vulsive, complex partial and subtle SE should include: alternative to thiopental and is given as a bolus dose of

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 Guideline on the management of status epilepticus 449

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