doi:10.

1093/brain/aws091 Brain 2012: 135; 2314–2328 | 2314

BRAIN
A JOURNAL OF NEUROLOGY

REVIEW ARTICLE
The outcome of therapies in refractory and
super-refractory convulsive status epilepticus
and recommendations for therapy

Downloaded from http://brain.oxfordjournals.org/ at HINARI Colombia Administrative Account on September 19, 2012
Simon Shorvon and Monica Ferlisi

UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK

Correspondence to: Simon Shorvon,

UCL Institute of Neurology,
Queen Square,
London WC1N 3BG, UK
E-mail: s.shorvon@ucl.ac.uk

In a previous paper, we reviewed the range of therapies available for the treatment of super-refractory status epilepticus. Here
we report a review of the outcome of therapies in refractory and super-refractory status epilepticus. Patients (n = 1168) are
reported who had therapy with: thiopental, pentobarbital, midazolam, propofol, ketamine, inhalational anaesthetics (isoflurane,
desflurane), antiepileptic drugs (topiramate, lacosamide, pregabalin, levetiracetam), hypothermia, magnesium, pyridoxine,
immunotherapy, ketogenic diet, emergency neurosurgery, electroconvulsive therapy, cerebrospinal fluid drainage, vagal nerve
stimulation and deep brain stimulation. The outcome parameters reported include control of status epilepticus, relapse on
withdrawal, breakthrough seizures and mortality. Where reported (596 cases), the long-term outcome was found to be death
(35%), severe neurological deficit (13%), mild neurological deficit (13%), undefined deficit (4%) and recovery to baseline
(35%). The quality of reported outcome data is generally poor and the number of cases reported for all non-anaesthetic
therapies is low. Outcome assessment is complicated by changes in co-medication, delay in response and publication bias.
Given these deficits, only broad recommendations can be made regarding optimal therapy. An approach to therapy, divided into
first-line, second-line and third-line therapy, is suggested on the basis of this outcome evaluation. The importance of treatments
directed at the cause of the status epilepticus, and of supportive ITU care is also emphasized.

Keywords: status epilepticus; outcome; refractory epilepsy; morbidity; mortality; therapy

Abbreviations: ITU = intensive treatment unit

Introduction
The treatment of the earlier phases of tonic–clonic status epilepti-
cus has been well studied and discussed in recent years. There are
a number of similar guidelines and protocols published, all of
which include the initial use of benzodiazepines, followed by intra-
venous antiepileptic drugs such as phenytoin, phenobarbital or
valproate, and then if necessary the induction of anaesthesia
(examples include Delgado-Escueta et al., 1984; EFA Working
Group 1993; Shorvon, 1994; Appleton et al., 2000; SIGN 2003;
Kälviäinen et al., 2005; Meierkord et al., 2006, 2010; Minicucci
et al., 2006; Holtkamp, 2006, 2007; Shorvon et al., 2008; Aranda
et al., 2010; Rossetti, 2010; Rossetti and Lowenstein, 2011). This
is a well-trodden path which, although based on an inadequate
evidence base, is widely accepted and practiced.
In this article, we focus on the outcome of patients with refractory
status epilepticus and super-refractory status epilepticus. Refractory
status epilepticus is defined for the purposes of this article as ‘status

Received October 20, 2011. Revised January 13, 2012. Accepted January 28, 2012. Advance Access publication May 9, 2012
ß The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
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Therapies in convulsive status epilepticus Brain 2012: 135; 2314–2328 | 2315

epilepticus requiring general anaesthesia’. Super-refractory status
epilepticus is defined as ‘status epilepticus that continues 24 h or
more after the onset of anaesthesia, including those cases in which
the status epilepticus recurs on the reduction or withdrawal of an-
aesthesia’. Although constituting a minority of cases of status epilep-
ticus (10–15% of all those presenting to hospital in status
epilepticus develop super-refractory status epilepticus; Novy and
Rossetti, 2010), appropriate therapy of these cases is poorly studied.
The cases considered here are of convulsive status epilepticus and we
have not included non-convulsive cases, except where these evolved
from a convulsive stage. Anaesthesia is not often required in primarily
non-convulsive cases, and certainly should not be given early, and
(Rossetti et al., 2011). Apart from this study, the evidence base con-
sists entirely of single case reports or small series (Table 1).
Furthermore, none of the widely recommended drugs or procedures
has been subjected to an adequate systematic review. There are a
number of other papers, not considered here, where treatment
(often with multiple therapies) is mentioned only in passing, and
where there are insufficient data to provide any assessment of out-
come. In papers where data on a particular therapy is focused upon,
and other therapies are mentioned in passing, we have included only
the therapy with sufficient data. We have considered only therapies
aimed primarily at the control of seizures and not therapies used to
treat the underlying cause of the status epilepticus (e.g. magnesium in
magnesium deficiency, pyridoxine in pyridoxine-dependant patients or

Downloaded from http://brain.oxfordjournals.org/ at HINARI Colombia Administrative Account on September 19, 2012
the response to treatment in these cases may well differ. In this art- immunotherapy in identifiable immunological disease).
icle, the publications reporting successful outcome of anaesthetic Outcome at the refractory and super-refractory stages of status
drugs do not always specify the time of anaesthesia, and so might epilepticus can be categorized into one of the following six categories
possibly include some patients who have refractory not (one successful category and five types of failure).
super-refractory status epilepticus (by the definitions used in this
(i) Successful therapy: the status epilepticus is completely
article). However, for all failures of anaesthetics (by definition), and
controlled by the therapy, without breakthrough or withdrawal
for all the other therapies administered, the therapies were used at
seizures, or discontinuation due to side-effects, or death during
the stage of super-refractory status epilepticus.
the therapy.
A number of therapies are in current usage and the literature (ii) Initial failure: the therapy failed to control status epilepticus at all.
reporting these therapies has been reviewed in detail elsewhere (iii) Breakthrough seizures: recurrence of status epilepticus during the
(Shorvon and Ferlisi, 2011). The current review aims to accom- treatment, despite initial control, resulting in the need for a change
pany the previous paper and provide a synthesis, from this pub- of therapy [and does not include those cases in which seizures
lished literature from 1981, of the outcome of these therapies. The recurred and control was gained by increasing the dose—these
therapies considered include thiopental, pentobarbital, midazolam, cases are included in Category (i)].
propofol, ketamine, inhalational anaesthetics (isoflurane, desflur- (iv) Withdrawal seizures: recurrence of status epilepticus during or
ane), antiepileptic drugs (topiramate, lacosamide, pregabalin, leve- immediately after the tapering or withdrawal of the therapy,
tiracetam), hypothermia, magnesium, pyridoxine, immunotherapy,
ketogenic diet, emergency neurosurgery, electroconvulsive therapy
(ECT), CSF drainage, vagal nerve stimulation and deep brain Table 1 The published literature on treatment outcomes
stimulation. Therapy with the following older drug therapies has
Therapy Number of Number of
also been reported but not in recent times, and these will not be
published published
considered further: chloral, bromide, paraldehyde, etomidate, lig- papers reporting cases in which
nocaine, and a variety of other barbiturate and benzodiazepines outcome data outcome data
such as bromethol, hexobarbital, methohexital, butallylonal, seco- are provided
barbital, amylobarbital, diethylamine barbiturate, nitraepam, clor- Pentobarbital/thiopental 23 192
azepate and clonazepam. Propofol 24 143
Midazolam 20 585
Ketamine 7 17
Inhalational anaesthetics 7 27
Method of assessing and Hypothermia 4 9

categorizing outcome Magnesium

Pyridoxine
2
2
3
2
Details of the literature used as the basis of this review are published Immunotherapy 8 21
elsewhere (Shorvon and Ferlisi, 2011, including the associated Ketogenic diet 4 14
Supplementary material). Of these 159 papers, 121 published since Vagal nerve stimulation 4 4
1981 reported outcome data in 1061 patients in sufficient detail. Deep brain stimulation 1 1
These papers form the evidence base of this review and are listed in ECT 6 8
Appendix 1. Details of the analysis of each paper are provided in the Emergency neurosurgery 15 36
Supplementary material. We also analysed an additional 21 papers CSF drainage 1 2
reporting outcome of 107 patients with super-refractory status epilep- Topiramate 10 60
ticus treated with antiepileptic drugs (topiramate, levetiracetam, preg- Levetiracetam 8 35
abalin and lacosamide) making a total of 1168 patients studied. It is Pregabalin 1 2
Lacosamide 2 10
salutary to note that there is only one randomized or controlled study
of any of these therapies (a trial comparing thiopental and propofol)
All patients had received more than one therapy, but we have included in this table
requiring 150 patients for adequate power but which managed to only the therapies highlighted in individual papers. The anaesthetic reports include
recruit only 24 patients and therefore failed to reach any conclusions patients with refractory and super-refractory status epilepticus.
2316 | Brain 2012: 135; 2314–2328
resulting in the need for a change of therapy (and does not in-
clude those in whom control was achieved by reintroducing the
same drug).
(v) Intolerable side-effects: the therapy resulted in side-effects neces-
sitating alternative therapy.
(vi) Death during the course of the treatment. Some of these deaths
will be due to the underlying cause, but as it is often impossible
to attribute mortality accurately, and as treatment may play a
contributing role in the outcome of these cases, all such deaths
are included in this category (note, deaths occurring after the
therapy has been discontinued are not included).
Although we have applied this scheme to all cases, a number of dif-
ferences between the types of therapy exist. All anaesthetic drugs, if
used in high enough doses, will result in a depth of anaesthesia suf-
ficient to abolish seizure activity. In this sense, any effective anaes-
thetic will inevitably initially control status epilepticus, provided a
sufficient dose can be given. If initial failure does occur [Category
(ii)], it will be usually because the appropriate dose cannot be reached
because of side-effects (notably hypotension or cardio-respiratory de-
pression). It is usual to attempt a dose of anaesthesia that produces
the EEG pattern known as ‘burst suppression’, as at this level it is rare
for any epileptic electrographic activity to be manifest, but often the
dose required will cause side-effects and cannot be attained. In some
reports though, it is possible that therapy was discontinued prema-
turely at too low a dose for other reasons. Other types of treatment
are either given as continuing infusions, repeated dosing, or single
one-off therapies. In these cases, the potential for failure of initial
therapy is higher. For one-off therapies, the category of breakthrough
seizures cannot apply, and Category (iv) (withdrawal seizures) is used
to include cases in which seizures were initially controlled but rapidly
returned after the cessation of the one-off therapy.
Results
Anaesthetic treatments
These are the best documented of the available therapies. In total,
we found outcome recorded for 192 patients treated with pento-
barbital/thiopental, 143 with propofol and 585 with midazolam
[although a single rather briefly documented study (Hayashi
et al., 2007) contributed 306 (52%) of the midazolam cases].
These were, as mentioned above, largely anecdotal reports and
each drug cannot be compared with the others. Furthermore, a
number of significant potential biases exist. Propofol and
Table 2 Overall outcome of anaesthetic therapy
Outcome Thiopental/pentobarbital
(n = 192)
Control 64% (123/192)
No control ever achieveda 5% (9/192)
Breakthrough seizures 0% (0/192)
Withdrawal seizures 9% (18/192)
Therapy failure because of side-effects 3% (5/192)
Death during therapy 19% (37/192)
a
Excluding those who died without control who are included in the ‘death during therapy’ category, and those who switched because of side-effects
who are included in the ‘therapy failure because of side-effects’ category.
S. Shorvon and M. Ferlisi
midazolam are more recently introduced than the barbiturate an-
aesthetics, which have been used in this indication for well over
50 years, and so the barbiturate outcomes were reported largely
at a time when Intensive Treatment Unit (ITU) practice was not as
well developed as now (about two-thirds of cases between 1980
and 1999, compared with 510% of propofol and midazolam
cases); the most severe cases, and those with certain severe aetiol-
ogies, are more likely to be treated with barbiturates; cases that
are unresponsive to midazolam or propofol are nowadays likely to
progress to barbiturate therapy; different treatments are preferred
at different ages, for instance children are least likely to be treated
with propofol.
Downloaded from http://brain.oxfordjournals.org/ at HINARI Colombia Administrative Account on September 19, 2012
Control, failure of control and side-effects
We found control of refractory and super-refractory status epilep-
ticus in 74% (678/920) of the reported cases (Table 2). The rate
of initial control on barbiturate was 64%, midazolam 78% and
propofol 68%. As mentioned above, an anaesthetic drug will in-
evitably control status epilepticus provided the dosage is high
enough, and the failure to gain control is usually due to either
too low a target dose or dose limitation caused by side-effects.
Side-effects (usually hypotension or cardio-respiratory depression)
were reported to require a change in therapy in 3% of patients on
barbiturates, and 6% on propofol, usually isolated symptoms that
could form part of the propofol infusion syndrome. The figures for
failure on midazolam include a large group from one study (78/
306 patients; Hayashi et al., 2007) in whom the reason for failure
was not reported.
Breakthrough seizures
Once control was achieved, breakthrough seizures, defined here
as seizures recurring after initial control and requiring switching of
therapy, occurred at a rate of 3% on midazolam, 1.3% on pro-
pofol and 0% on barbiturate (in reports with sufficient detail).
These figures do not include the greater number of patients
who regained control after relapse by increasing the drug
dosage and therefore not needing a switch of therapy: 7% on
midazolam (21/281), 12% on propofol (6/50) and 6% on barbit-
urate (3/53). The data on breakthrough seizures are included in
the Supplementary material. Not all reports provided the level of
detail required and we recognize that some may not have been
mentioned and that these figures may be artificially low.
Midazolam Propofol
(n = 585) (n = 143)
78% (458/585) 68% (97/143)
16% (93/585) 11% (16/143)
3% (19/585) 1% (2/143)
51% (2/585) 6% (8/143)
51% (1/585) 6% (8/143)
2% (12/585) 8% (12/143)
Therapies in convulsive status epilepticus
Withdrawal seizures
Withdrawal seizures were reported less often on midazolam
(0.3%) compared with 6% on propofol and 9% on thiopental/
pentobarbital therapy (in reports with sufficient detail). In addition,
when seizures did occur on tapering or withdrawal, a higher rate
of regained control was reported in those patients in whom the
drug was reintroduced on midazolam (93%) compared
with the other two drugs (47% on propofol and 22% on barbit-
urate). The data on withdrawal seizures are included in the
Supplementary material. As with breakthrough seizures, we have
included only reports that provided sufficient level of detail and so
these figures may be artificially low.
Death rates during infusion
The reported mortality rates were 19% on thiopental/pentobar-
bital infusions, 8% on propofol infusions and 2% on midazolam
infusions. Comparison is complicated by the strong potential biases
discussed above, which are likely to inflate the risk for barbiturate,
and also because in some of the older reports on barbiturate
therapy details were vague regarding the timing of death and
some of these deaths may have occurred after the cessation of
infusion. In relation to propofol, publication bias is also introduced
by the inclusion of reports that focus on the ‘propofol infusion
syndrome’.
Propofol infusion syndrome is a particular risk in prolonged
infusion in children and in patients co-medicated with steroids
or catchecolamines. Iyer et al. (2009) found evidence of
propofol infusion syndrome in 45% of 31 patients treated with
prolonged infusions (mean 67 h) although a very broad definition
of propofol infusion syndrome was used, which included patients
with isolated symptoms such as unexplained hypotension and not
necessarily the full blown syndrome. There is a high morbidity and
mortality rate. Because of this risk, Iyer et al. (2009) recommend
removal of propofol from their treatment protocol of status
epilepticus. Other studies have found a lower risk and do not
consider the use of propofol to be contraindicated provided
there is careful monitoring, especially if the duration of infusion
does not exceed 48 h (e.g. Power et al., 2011).
The studies included 920 patients, of all ages and a range
of aetiologies. The median duration of therapy was 53 h (range
11–1200) on thiopental/pentobarbital, 32 h (range 0.5–432) on
propofol and 16 h (range 10–240) on midazolam, perhaps reflect-
ing the greater severity of the barbiturate cases. All drugs caused
complications, most commonly hypotension and respiratory
depression, which can be severe. Other life-threatening complica-
tions occurred with each of the drugs. The infusion doses var-
ied considerably from report to report, ranging from 0.5 to
20 mg/kg/h for thiopental/pentobarbital, 0.1–24 mg/kg/h for
propofol and 0.02–1.8 mg/kg/h for midazolam. The median
duration (and range) of the status epilepticus before the onset
of therapy was 16 h (1–720) for thiopental/pentobarbital, 18 h
(10–600) for propofol and 4 h for midazolam (0.7–48).
There is one other published study of accumulated data from
reports of anaesthesia in refractory status epilepticus (Claassen
et al., 2002) in which 54 cases treated with midazolam, 106
with barbiturate and 33 with propofol therapy were reported.
Brain 2012: 135; 2314–2328 | 2317
This study cites higher rates of withdrawal and breakthrough seiz-
ures. Methodology differed, however, and we were unable to
determine how some figures had been calculated from our own
scrutiny of the same publications.
Other anaesthetics
The published literature reporting outcome on ketamine infusion
for super-refractory status epilepticus is very small—with only
17 reported cases, all of which were single case reports except
one series of seven cases (Bleck et al., 2002). Control was
achieved in 14 (82%) and it was postulated that the failure of
control in the other three cases was due to insufficient dosage.
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The documentation of cases was slight and in only 10 were their
sufficient details of type of status epilepticus or aetiology.
Ketamine was used at a late stage in most cases (median duration
of status prior to the use of ketamine was 672 h with a range
336–1680 h) and the median duration of therapy was 120 h
(range 120–336). There was a loss of effect in one case and pos-
sible neurotoxicity in another. The long-term outcome was poor
with death in seven and severe neurological deficit in three cases.
The infusion dose range was 0.06–7.5 mg/kg/h.
The outcome of the use of the inhalational anaesthetics isoflur-
ane and desflurane is reported in 27 episodes in seven publica-
tions. Initial control was reported in all cases. However, seizures
recurred on withdrawal in 41% and two patients (7%) switched
due to side-effects. As with ketamine, the inhalational anaesthetics
were usually used late in the course of status epilepticus (a median
duration of status prior to usage of 120 h and range 22–2472 h).
The median duration of therapy was 45 h (range 1–2040). In the
largest case series, isoflurane and desflurane were used in seven
patients, and anaesthesia was maintained for a mean of 11 (range
2–26) days (Mirsattari et al., 2004). Four patients had good out-
comes but three patients died subsequently. The therapy also had
a high rate of complications including hypotension (7/7), atelec-
tasis (7/7), infections (5/7), paralytic ileus (3/7) and deep venous
thrombosis (2/7) (Mirsattari et al., 2004).
Antiepileptic drug therapy
It is universally recommended that antiepileptic drug therapy
should be used concurrently with anaesthesia in refractory and
super-refractory status epilepticus. However, the published out-
come of the use of antiepileptics in this situation is restricted to
60 cases (in 10 reports) treated with topiramate, 10 (in two
reports) with lacosamide, two (in one report) with pregabalin
and 35 (in eight reports) with levetiracetam. There is no published
outcome analysis of any other antiepileptic in refractory or
super-refractory status epilepticus, despite very widespread usage
of a large range of drugs. A range of modes of administration
were used including instillation through a percutaneous endo-
scopic gastrostomy, nasogastric and rectal administration.
In these small series, topiramate controlled the status in 62%
(37/60), lacosamide in 10% (1/10), pregabalin in 0% (0/2) and
levetiracetam in 46% (17/35), although the definition of ‘control’
in lacosamide cases [from the report of Goodwin et al. (2011)]
was resolution of electrographic seizures within 4 h, which is a far
stricter definition than used for other therapies. These figures,
2318 | Brain 2012: 135; 2314–2328
coming as they do from small selected series, are not comparable.
One patient died on topiramate and another on lacosamide ther-
apy, and various complications occurred including metabolic acid-
osis on topiramate, angioedema on lacosamide, and rectal
bleeding (during rectal administration) of levetiracetam. Where
stated, the median duration of status before the drug was started
was 144 h (range 0–720 h) for topiramate, 144 h (range 24–336 h)
for lacosamide, 1632 h (range 744–2520 h) for pregabalin and
81 h (range 24–288) for levetiracetam. The dose of topiramate
used was 2–25 mg/kg/day in children and up to 1600 mg/day in
adults; of lacosamide was 100–400 mg/day in adults; of pregabalin
was up to 600 mg/day in adults and of levetiracetam 13–70 mg/
day in children and 250–6000 mg/day in adults.
Hypothermia
Hypothermia is now routinely used in several centres around the
world for patients in super-refractory status epilepticus. The out-
come of hypothermia in status epilepticus, however, is reported in
only nine cases in four reports (one from 1984), all of whom
obtained initial control and seven of the nine recovered.
Endovascular cooling is the currently the preferred method in
adults (but not necessarily children), and was used in four patients
with external cooling used in the other five. The median duration
of status prior to the initiation of hypothermia was 744 h
(range 48–1440), and the median duration of therapy was 61 h
(range 20–288). In the reported cases, there were significant com-
plications including hypotension, electrolyte disturbance, acidosis,
disseminated intravascular coagulation, thrombosis and thrombo-
embolism, infection, bowel ischaemia, shivering and arrhythmias
on rewarming. The core temperature in these reports was usually
reduced to 32–35 C.
Magnesium infusion
Magnesium sulphate infusion is another widely used therapy in
super-refractory status epilepticus although again the published
evidence base-related outcome is remarkably small. The outcome
of only three patients is reported, in one of whom the status
epilepticus was controlled. All patients were young adults, two
had mitochondrial disease. The time from the onset of status to
the prescription of magnesium in these reports was between 144
and 1152 h and therapy was continued for between 48 and 168 h.
The infusion rates varied between 2 and 6 g/h, with a target
serum level in the report of Visser et al. (2011) of 3.5 mEq/l.
However, in the case report by Fisher (1988), levels of magnesium
were raised to extremely high levels (14.2 mEq/l) without con-
trol of seizures, and levels 48 mEq/l carry significant cardiovascu-
lar risks.
Pyridoxine infusion
Intravenous pyridoxine (as the hydrochloride) is an effective treat-
ment in the rare patients with an inborn error of metabolism of
pyridoxine. However, it has also been claimed that intravenous
pyridoxine therapy may be effective in super-refractory status epi-
lepticus when no clear deficit in pyridoxine metabolism is present,
S. Shorvon and M. Ferlisi
and pyridoxine is now routinely given in cases of super-refractory
status epilepticus in young children. In fact, the outcome of ther-
apy in non-pyridoxine-dependent patients is reported in only two
cases, both of whom had low blood levels prior to therapy (one
due to pregnancy and one to malnourishment), and although ini-
tial control was achieved in both cases, other therapies were given
concurrently and attribution of success to pyridoxine is arguable.
The infusion of pyridoxine alone carries no risk, although in some
countries pyridoxine is only generally available as an infusion
mixed with other vitamins (PabrinexÕ ) and this formulation carries
a small risk of anaphylaxis. The doses used of pyridoxine were
180–600 mg/day.
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Immunotherapy
Another treatment that is widely used in super-refractory status
epilepticus is immunotherapy with steroids, intravenous immuno-
globulins and plasma exchange. Outcome has been reported in
only 21 cases in eight reports of patients without identified under-
lying immunological conditions. Of these, control of status was
obtained in only 5%. In all cases, other therapies were also intro-
duced concurrently and the effects on seizures may be delayed. It
is thus difficult definitively to dissect the effects of immunotherapy
from that of other treatment.
Resective neurosurgery
We have included resective neurosurgery in our analysis despite
the fact that this is in many cases therapy directed at the cause per
se, because the resection aimed to remove the epileptogenic zone
not simply the lesion, and the extent of resection is often greater
than the extent of the lesion. Thirty-six cases are reported, and in
33 the surgery resulted in control of the status epilepticus. In 21
cases, focal resection was carried out, in three focal resection and
multiple subpial transection, in two focal resection and corpus
callosectomy, in one multiple subpial transection corpus callosect-
omy and in eight some form of hemispherectory. Pathology was
identified in 25 cases and non-specific findings in 11.
Ketogenic diet
The use of the 4:1 ketogenic diet to control super-refractory status
epilepticus has been reported in 14 cases of whom one later
switched to the modified Atkins diet and one to a 3:1 diet, and
a further two cases in whom the Atkins diet was used from the
start. Initial control was observed in 12 of the 14 cases. In one
case, the therapy was abruptly and inadvertently withdrawn and
the epilepsy relapsed and the patient died. The age of the patients
ranged between 4 and 49 years. The aetiology was established in
three cases, and an additional nine (from a single report; Nabbout
et al., 2010) were categorized as having FIRES (febrile
infection-related epilepsy syndrome). The diet was used as a last
resort in these cases, with the median duration of status epilepti-
cus before the diet was started of 540 h (range 96–2424). The
therapy was maintained in the long term in all patients (except the
patient mentioned above) or changed to the modified Atkins diet.
Therapies in convulsive status epilepticus
Other physical therapies
A range of other physical therapies have been reported in recent
case reports in the treatment of super-refractory status epilepticus.
These include four case reports of patients treated with vagal
nerve stimulation, with final control in all four, although in one
patient pentobarbital was weaned 48 h before implantation and
the status appeared to be resolving on the evening before the
implantation (Patwardhan et al., 2005), and in the others the
reported effect of vagal nerve stimulation was delayed with
other therapies also given, rendering it impossible definitively to
attribute improvement to the vagal nerve stimulation. One case of
deep brain stimulation in the caudal zona incerta, in focal motor
status epilepticus, is reported with resolution of the seizures. The
outcome of eight patients (in six reports) treated with courses of
ECT, with resolution of the status epilepticus in seven of the eight
patients. Three to eight sessions of the ECT were given, with the
treatment started at a median of 984 h (range 336–2472 h) after
the onset of the status epilepticus, and with no complications
except pneumonia in one case. There is a single convincing
report of immediate control of super-refractory status by CSF
drainage although with subsequent relapse (Korhmann et al.,
2006). Repetitive transcranial magnetic stimulation has been
used experimentally and outcome reported in cases of simple par-
tial status epilepticus and epilepsia partialis continua. Classical
music is another therapy that has been used in non-convulsive
status epilepticus. Neither of the two latter therapies have been
reported in convulsive status epilepticus and so are not considered
further here.
Long-term outcome
In this article, we have focused our outcome assessment on the
immediate control of seizures as the primary end-point of each
therapy. In a total of 596 cases, the long-term outcome could also
be ascertained, divided into five broad categories, and the results
are shown in Table 3. Overall, 35% of the patients died. The
death rate was higher in patients who had been treated with
thiopental/pentobarbital (46%) compared with propofol (36%),
midazolam (34%) and ketamine (44%) but this likely reflects
the potentially severe biases discussed above. The death rate in
treatment of those that had been treated with all other therapies
ranged from 0 to 36%, except a rate of 67% in those treated with
magnesium and a rate of 50% in those treated with levetiracetam.
Table 3 Long-term outcome
Outcomea n = 596
Deaths 207 (35%)
Severe neurological deficit 79 (13%)
Mild neurological deficit 80 (13%)
Undefined neurological deficit 22 (4%)
Recovery to baseline 208 (35%)
a
In the reports of 596 cases (51% of the total of 1168), the long-term outcome
was recorded. In the other 575 cases, no long-term outcome data were provided.
Brain 2012: 135; 2314–2328 | 2319
In our view, it is not possible from these figures to draw any
conclusions about whether any specific therapy is responsible for
a particularly high or low rate. Furthermore, long-term mortality is
known to be related not so much to the treatment used as to the
underlying aetiology (probably the main determinant) and also the
duration of status epilepticus.
Discussion
The most striking conclusion from this exploration of the literature
Downloaded from http://brain.oxfordjournals.org/ at HINARI Colombia Administrative Account on September 19, 2012
is the poor quality of the outcome data, which indeed is so inad-
equate that only broad conclusions can be drawn from this ana-
lysis. The assessment of each therapy is severely compromised by
a number of points.
(i) The lack of randomized or controlled studies: in this review
we found only a single randomized study, and this failed to
recruit (see above). Almost all the other studies were either
case reports or retrospective series.
(ii) The small number of individuals treated: many treatments
discussed, even if very widely used in routine practice, are
based on a very small number of published cases. Indeed,
apart from the three commonly used anaesthetics (propofol,
midazolam or pentobarbital/thiopental), none of the treat-
ments reviewed here have a total published outcome data in
more than 40 patients, and most in less than 10 patients.
This is an extraordinary state of affairs.
(iii) Co-medication and changing doses of co-medication.
Therapies in the super-refractory period of status are
almost always given in parallel, and assessment of a therapy
is often complicated by concurrent changes in dosages, or
physical parameters, of another.
(iv) Delay in responses. Reports of responsiveness for some
therapies include patients who responded days or weeks
after the application of treatment. This applies to the studies
of vagal nerve stimulation, ECT, antiepileptic drugs, keto-
genic diet neurosurgery and immunotherapy. Furthermore,
concomitant therapy is also often changed. This makes
causal attribution very difficult to make.
(v) Some therapies are widely used and yet the published lit-
erature is extremely small. Where this is the case, the small
number is likely to represent very considerable publication
bias.
(vi) Finally, refractory status epilepticus is heterogeneous and its
ultimate prognosis depends on factors other than treatment
such as age and aetiology (Neligan and Shorvon, 2010,
2011). These further complicate any assessment of individ-
ual therapies.
This is all the more regrettable given the severe nature of re-
fractory status epilepticus, with its mortality rate of 35% and its
high morbidity. It is an inescapable conclusion that our current
approaches to therapy are based on an inadequate literature
with large potential biases.
2320 | Brain 2012: 135; 2314–2328 S. Shorvon and M. Ferlisi

of cases, and the rate of breakthrough and withdrawal seizures

Recommendations for
treatment approach
and protocol
These drawbacks hinder the making of any definitive recommen-
dations about therapy. A treatment protocol has been suggested
elsewhere (Shorvon and Ferlisi, 2011). Our analysis of outcome
does not provide definitive guidance on how appropriate this ap-
proach is. However, a number of broad conclusions can be drawn.
First-line therapy
is lower than often quoted. Although the raw data show a higher
mortality rate on barbiturate therapy, we consider this difference
to be due to selection bias and that there is no reliable support for
marked differences in mortality between treatments. Moreover,
mortality in status epilepticus is largely determined by the under-
lying aetiology (Neligan and Shorvon, 2010) and with modern ITU
practice, iatrogenic mortality rates should be low. The three an-
aesthetic drugs conventionally used have a number of important
differences. Their advantages and disadvantages have been re-
viewed elsewhere (Shorvon and Ferlisi, 2011), and these findings
are summarized in Table 4. Due to the inherent biases in outcome

This is a therapy that should be applied to every case, in conjunc-
tion with the full panoply of ITU care and support and with treat-
ment of the underlying cause (Shorvon and Ferlisi, 2011).
Anaesthetics
General anaesthesia remains the backbone of therapy in refractory
and super-refractory status epilepticus. Our analysis confirms that
this is an effective therapy in the majority of cases. Immediate
control of refractory status epilepticus is achieved in two-thirds
Downloaded from http://brain.oxfordjournals.org/ at HINARI Colombia Administrative Account on September 19, 2012
data, comparison of the three drugs can be made only cautiously,
but a number of recommendations can be securely made. These
are summarized in Table 5.
Ketamine is reserved as a second-line drug because of the very
limited clinical evidence base and the potential neurotoxic effects.
There is also one case report where the development of cerebral
atrophy, after status epilepticus, is postulated to have been due to
ketamine therapy (Ubogu et al., 2003), although status epilepticus
itself can cause cerebral atrophy and this could be an alternative
explanation in this case.

Table 4 Advantages and disadvantages of anaesthetics used in status epilepticus

Thiopental/ Advantages:
pentobarbital strong antiepileptic action;
long clinical experience;
tendency to lower core temperature; and
theoretical neuroprotective effects.
Disadvantages:
problematic pharmacokinetics—zero-order kinetics, profound tendency to accumulation, long recovery time,
hepatic metabolism, autoinduction, drug–drug interactions;
hypotension, cardio-respiratory depression; and
pancreatic and hepatic toxicity.
Midazolam Advantages:
antiepileptic action; and
only benzodiazepine with pharmacokinetic properties suitable for prolonged infusion without accumulation.
Disadvantages:
may be less effective than other anaesthetics;
hypotension, cardio-respiratory depression;
risk of hepatic and renal impairment; and
risk of tolerance and breakthrough seizures (probably overestimated).
Propofol Advantages:
excellent pharmacokinetic properties including very rapid onset and recovery even after prolonged infusion allowing
ease of control of anaesthesia;
no drug interactions; and
less hypotension and cardio-respiratory depression than barbiturate or midazolam anaesthesia.
Disadvantages:
propofol infusion syndrome, especially in children;
pain at the injection site; and
difficulty in differentiating drug-induced involuntary movements and seizures.
Ketamine Advantages:
no cardiodepressant or hypotensive action; and
anti-glutaminergic action.
Disadvantages:
very limited published experience; and
possible neurotoxicity.
Therapies in convulsive status epilepticus
Table 5 Recommendation for anaesthetic use in refractory and super-refractory status epilepticus (adults)
Anaesthetic Dose
Thiopental/ Thiopental:
pentobarbital
Loading dose: 2–3 mg/kg
Maintenance dose: 3–5 mg/kg/h
Pentobarbital:
Loading dose: 5–15 mg/kg
Maintenance dose: 0.5–3 mg/kg/h
Midazolam Loading dose: 0.1–0.2 mg/kg
Maintenance dose: 0.1–0.4 mg/kg/h
Propofol Loading dose: 3–5 mg/kg
Maintenance dose: 5–10 mg/kg/h
Ketamine Loading dose: 1–3 mg/kg
Maintenance dose: up to 5 mg/kg/h
The doses reflect our clinical practice, but higher doses are sometimes quoted in the literature, for instance midazolam 0.2–0.6 mg/kg/h and ketamine up to 7.5 mg/kg/h
(Rossetti and Lowenstein, 2011).
There are formidable technical and logistical difficulties in main-
taining prolonged inhalational anaesthesia in a neurological ITU
setting and in our opinion, these and the high rate of complica-
tions preclude the use of these drugs in most clinical situations.
It would be usual initially to reverse anaesthesia every 24–48 h
and if seizures continue, then to re-establish anaesthesia (cycling).
Such cycles should be repeated several times. If the status con-
tinues to recur, the duration of individual cycles can be increased,
and anaesthesia continued for up to 5 days at a time. The anaes-
thesia should be weaned slowly on reversal. This decision needs to
be tailored to individual circumstances. Prolonged anaesthesia car-
ries increasing iatrogenic risks, and skilled ITU care and monitoring
for complications is mandatory. It is possible that in very pro-
longed status epilepticus (weeks or months) that the risks of an-
aesthesia exceed the risks of seizures and in this situation,
consideration could be given to reversing the anaesthesia alto-
gether. We know of no data on this point, which deserves further
study.
Antiepileptic therapy
Antiepileptic drugs should always be given, so that when the an-
aesthetic agent is withdrawn there is adequate antiepileptic cover
(in situations where anaesthetics are being continued, the need for
antiepileptics is less). There are unfortunately no reliable data sug-
gesting that any particular antiepileptic drug is better than an-
other, nor any evidence concerning regimes or therapeutic
approaches. Although many of the antiepileptics are widely
used, the only published literature in super-refractory status epi-
lepticus refers to topiramate (60 cases), levetiracetam (35 cases),
pregabalin (2 cases) and lacosamide (10 cases).
No conclusions regarding choice of drug can be made on this
basis. However, by analogy with antiepileptic drug therapy in
other situations, the following recommendations can be made
Brain 2012: 135; 2314–2328 | 2321
Recommendations
First-line therapy in severe cases.
Avoid in situations where pharmacokinetic interactions would be detrimental.
Avoid in hepatic disease, myasthenia gravis, porphyria, severe haemorrhage
or burns, cardiovascular disease, adrenocortical insufficiency.
First-line therapy in most cases.
Avoid in hepatic or renal disease, myasthenia gravis, porphyria.
First-line therapy in complex cases where ease of use and pharmacokinetic
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properties are important.
Use where other drugs cause problematic hypotension.
Avoid prolonged infusion (448 h) especially at high doses and in children.
Caution with concurrent steroid or catecholamine therapy.
Second-line therapy especially where hypotension or cardiorespiratory
depression is problematic.
Table 6 Suggested approach to antiepileptic drug therapy
in refractory status epilepticus
Choice of drug regimen depends on clinical context
Polytherapy with two antiepileptic drugs
High-dose regimens
Avoid frequent switching
Favour antiepileptic drugs with low interaction potential
Favour antiepileptic drugs with predictable kinetic properties
Favour antiepileptic drugs without renal or hepatic toxicity
Avoid GABAergic antiepileptic drugs
(Table 6): (i) polytherapy with no more than two drugs, used at
high doses. Morbidity will rise with more extensive drug regimes;
(ii) frequent switches should not be made, as rapid withdrawal can
exacerbate the tendency for seizures to occur (rebound seizures),
increase side-effects, risk allergic reactions and also cause pharma-
cokinetic changes; and (iii) the choice of drug will depend on the
clinical context. However, it seems sensible to use powerful anti-
epileptics; to avoid those with a primarily GABAergic mechanism
of action (e.g. benzodiazepines, barbiturates) as there is evidence
of loss of efficacy as status epilepticus becomes more prolonged
and because the anaesthetic drugs themselves have much more
powerful GABAergic effects. Where possible, drugs with low inter-
action potential and predictable kinetics should be used, and anti-
epileptics with strong allergenic potential and potential renal or
hepatic toxicity should be avoided. Levetiracetam, topiramate,
pregabalin and lacosamide are possible options, given through
the nasogastric tube or percutaneous endoscopic gastrostomy.
The target dose should be the high maintenance dose used in
routine oral antiepileptic drug therapy.
2322 | Brain 2012: 135; 2314–2328
Second-line therapy
This is a therapy that can be applied in those cases in which first-
line therapy is not controlling the status epilepticus and should be
considered at some point after the initiation of anaesthesia and
antiepileptic drug therapy. How long after will depend on individ-
ual circumstances, but the longer the seizures persist the worse
the functional outcome. There are a number of choices and ap-
proaches, and there is no clear guidance about which to choose or
in what order. Based on this review, therapy should be selected
from the following.
Hypothermia
As mentioned above, hypothermia is routinely used in some cen-
tres for the treatment of status epilepticus, despite an extremely
small evidence base. It is a therapy that deserves further study, not
least because of the solid experimental evidence of neuroprotec-
tive as well as seizure-terminating properties. However, there are
significant complications and serious side-effects, and it is a ther-
apy that should be embarked upon only in experienced centres.
The level of hypothermia is also uncertain, and it has been sug-
gested that only mild hypothermia is effective (Rossetti, 2011). In
which cases it should be employed, or at what stage, unfortu-
nately is unclear, but it does seem reasonable to consider this as
a second-line therapy, in resistant cases, with target temperatures
between 32 and 35 C and the hypothermia continued in the first
instance for 24–48 h.
Magnesium infusion and pyridoxine infusions
The widespread use of magnesium infusion is based on the proven
efficacy of magnesium in eclamptic seizures, and also supported
by a small body of experimental work. Indeed, there have been
sporadic case reports of its clinical use since 1901. The adminis-
tration of magnesium in patients with super-refractory status epi-
lepticus that are not responding to therapy carries no major risk,
although hypotension and PR interval prolongation are reported
and caution is advised when co-administered with barbiturates or
benzodiazepines due to a risk of enhanced respiratory depression,
and when co-administered with digoxin or calcium channel block-
ers. Also, at high doses the neuromuscular blocking effects may
mask convulsive movements, which can be clinically misleading. It
seems reasonable to infuse magnesium at a dose 2–6 g/h to obtain
a serum level of 3.5 mmol/l. If this is effective, the infusion should
be continued, and ceased if ineffective.
In young children, pyridoxine is also widely administered on
the basis that deficiency may be difficult to detect and can be
disastrous if overlooked. Furthermore, it is possible that there is
effectiveness in the absence of deficiency, although there is little
evidence that this is the case. The infusion of pyridoxine alone is
entirely safe, although the infusion of the combined vitamin prep-
arations (PabrinexÕ ) carry a small risk of anaphylaxis. A reasonable
dose would be 180–300 mg.
We consider that these therapies should have marginal evidence
of efficacy but as they carry little risk and are relatively easy to
administer, they should be used as second-line therapies in
super-refractory status epilepticus.
S. Shorvon and M. Ferlisi
Immunological therapy
The outcome of therapy with steroids, intravenous immunoglobulin
and plasma exchange, based on this literature review, is poor, with
only 5% of patients gaining control. However, this approach is
widely used despite the very limited evidence base, and anecdotal
clinical experience is much more promising. This use is based on
two theoretical propositions. First, it is possible that some cases of
cryptogenic refractory status epilepticus are caused by underlying
occult auto-immune or immunological conditions. This proposition
is encouraged by the finding of cases due to newly discovered
antibodies including the anti-NMDA receptor antibodies and the
voltage-gated potassium antibodies. Second, is the possibility that
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inflammatory mechanisms occur at the epilepsy focus, resulting in
epileptogenesis, and there is growing experimental evidence of the
importance of such inflammation (Vezzani and Ruegg, 2011).
Thus, in our opinion, a trial of immunological therapy is worthwhile
as a second-line therapy in patients with super-refractory status
epilepticus, without a history of previous epilepsy and in whom
no aetiology has been found. However, there is an urgent need
for more systematic study of this line of therapy.
A typical regimen would be to start therapy with high-dose
steroids and a course of intravenous immunoglobulin or plasma
exchange. The steroids should be given for 3 days at a high dose
(1 g/day in adults) and continued at lower doses (1 mg/kg/day)
for a period of 1 week, and continued if there is a response. In
addition, a course of intravenous immunoglobulin over 5 days, at
a dose of 0.4 g/kg/day, or plasma exchange, can be tried. If there
is a response, long-term steroids and repeated courses of intra-
venous immunoglobulin can be used.
Ketogenic diet
The ketogenic diet is easy to administer in super-refractory status
epilepticus, either through the nasogastric tube or percutaneous
endoscopic gastrostomy. Ready-made solutions with 4:1 commer-
cial preparation (KetoCal) are most commonly used. The evidence
base, however, is very small (12 cases of 4:1 ketogenic diet and
two cases of the modified Atkins diet) although the recorded re-
sponse of the cases was convincing. It carries certain risks and is
contraindicated in cases of pyruvate carboxylase and b-oxidation
deficiencies. It should, furthermore, probably not be used with
propofol anaesthesia or with steroid co-administration. A 4:1
diet with the initial complete avoidance of glucose is recom-
mended. Details of the administration of the diet can be found
in Nabbout et al. (2010).
Emergency neurosurgery
In the published cases (36 in total), a good long-term outcome
was reported in 27 (75%). The type of surgery included focal
resection, multiple subpial transection, corpus callosectomy and
hemispherectory (sometimes in combination). Thus, emergency
neurosurgery has, in our opinion, a small place as a second-line
therapy in super-refractory status epilepticus, where there is a
clear-cut electrographic focus and a lesion causing the epilepsy,
but in no other situation.
Therapies in convulsive status epilepticus
Third line—last resort therapies
The data on these are so deficient that assessing their place is not
possible. At present, they should be reserved for consideration in
those very resistant cases where first and second-line therapies
have proved ineffective. With more experience, it is possible
that some will become second-line therapies.
Electroconvulsive therapy
There are a few reports of effectiveness of ECT, although all pa-
tients had withdrawal or reduction of anaesthesia to allow ECT to
be given and it is possible that this in itself resulted in the reso-
lution of the status epilepticus, not least as between—three and
eight sessions were required to control the seizures and the
response was therefore observed after days of therapy.
Nevertheless, this is a therapy used in several centres worldwide
and should be considered as a third-line treatment, and where
used, daily sessions should be given for between 3 and 8 days.
Cerebrospinal fluid drainage and other therapies
There is one modern report of two episodes of CSF drainage in the
same patient. The first procedure was highly effective (Korhmann
et al., 2006). Exactly how such a therapy would result in control
of status epilepticus is unclear, but it is possible it removes inflam-
matory or other compounds from the CSF or, less likely, acts via
changes of intracranial pressure dynamics. It is a therapy that was
widely used up until the 1940s at least, and was reported to be
‘serviceable’ by S.A. Kinnier Wilson in his textbook Neurology
(1940). It would be worth considering at least, as a last resort
therapy, in severe super-refractory status epilepticus.
In relation to vagal nerve stimulation, deep brain stimulation
and repetitive transcranial magnetic stimulation, there is, in our
opinion, no clear evidence of any efficacy from these therapies,
each of which has drawbacks and hazards and so can not be
recommended at present.
Treatment directed at the cause of the
status epilepticus, and ITU therapy
In all patients, treatment directed at the cause of the status is vital
and the long-term outcome is to a large extent dependent on this.
Skilled ITU care is also vital, with EEG monitoring and in some
cases intracranial pressure monitoring (Schmutzhardt and
Pfausler, 2011; Smith, 2011). There are no studies of the value
of neuroprotectants and these would be worth pursuing in the
future.
Funding
This work was undertaken at UCLH/UCL and Imperial College/
Imperial College Healthcare both of whom received a proportion
of funding from the Department of Health’s NIHR Biomedical
Research Centres funding scheme.
Brain 2012: 135; 2314–2328 | 2323
Supplementary material
Supplementary material is available at Brain online.
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Appendix 1
Details of the literature used as the basis of this review are pub-
lished elsewhere (Shorvon and Ferlisi, 2011). Of these 159 papers,
121 published since 1981 reported outcome data in 1061 patients
in sufficient detail. These papers form the evidence base of this
review and are listed below:
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levetiracetam in critically ill children with status epilepticus
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