Epilepsia, 52(Suppl.

8):5356, 2011
doi: 10.1111/j.1528-1167.2011.03238.x

FUTURE PERSPECTIVES, NOVEL THERAPY, AND INNOVATION

Super-refractory status epilepticus: An approach to

therapy in this difficult clinical situation
Simon Shorvon
UCL Institute of Neurology, University College London, London, United Kingdom

(2) in patients with no history of epilepsy in whom

status epilepticus develops out of the blue with no
overt cause. There are a variety of treatments
used, almost entirely based on open observational
studies or case reports. Therapy includes anesthesia, antiepileptic drug therapy, hypothermia and
ICU therapy, other medical, immunological, and
physical therapies. In this review, the range of
possible therapies is outlined and an approach to
therapy is discussed.
KEY WORDS: Anesthesia, Antiepileptic drugs,
Hypothermia, Intensive care unit, Magnesium.

SUMMARY
Super-refractory status epilepticus (SE) is a stage
of refractory SE characterized by unresponsiveness to initial anesthetic therapy. It is a new concept that has been the focus of recent basic and
therapeutic work, and is defined as SE that continues or recurs 24 hours or more after the onset
of anesthesia, including those cases in which SE
recurs on the reduction or withdrawl of anesthesia. It is encountered typically, but not exclusively, in two quite distinctive clinical situations:
(1) in patients with severe acute brain injury, and

Super-refractory SE is a well-recognized clinical problem, which is encountered typically, but not exclusively,
in two quite distinctive clinical situations: (1) in patients
with severe acute brain injury and (2) in patients with no
history of epilepsy in whom SE develops out of the blue
with no overt cause. This latter situation has been considered by some to be a syndrome (entitled NORSE:
new-onset refractory status epilepticus; Rathakrishnan &
Wilder-Smith, 2009), although it seems to this author at
least that a syndromic sobriquet is not meaningful, based
as it is simply on the fact that the SE has occurred without
any cause found.
Therapy is difficult. There are no randomized or controlled studies of therapy. The published evidence base
consists largely of case reports or small series, and so
any recommendations on therapy must be considered
anecdotal at best. The following approaches to therapy
have been recommended:

The choice of therapy for status epilepticus (SE) will

depend greatly on the SE type and the clinical contextand particularly on the extent to which the SE is
life-threatening. This abstract is largely concerned with
tonicclonic SE, which is the most severe form, and not
for instance nonconvulsive SE or epilepsia partialis continua (EPC), which require totally different therapeutic
approaches.
The protocols for treating the earlier stages of tonic
clonic SE are now well defined, and there is a good degree
of international consensus about these (see for instance,
Shorvon et al., 2008, for the consensus report from the 2nd
London-Innsbruck Colloquium). Refractory SE is defined
as SE that has not responded to first-line therapy (benzodiazepine) or second-line therapy, and which, according to
the treatment protocols, requires the application of general
anesthesia (the conventional choices of anaesthetic are
intravenous propofol, intravenous pentobarbital/thiopental, or intravenous midazolam).
Super-refractory status epilepticus can be defined as
SE that has continued or recurred despite 24 h of general
anesthesia (Shorvon & Ferlisi, 2011).

Anesthesia
In super-refractory SE, continued general anesthesia
remains the bedrock of therapy. It is usual to continue
anesthesia for a period of initially 24 h and then slowly to
reverse this. If seizures recur, anesthesia is reestablished.
This pattern of instituting and withdrawing anesthesia is
continued in 2448 h cycles initially and then at 57 day

Address correspondence to Simon Shorvon, UCL Institute of Neurology, Box 5, National Hospital for Neurology and Neurosurgery, Queen
Square, London WC1N 3BG, U.K. E-mail: s.shorvon@ion.ucl.ac.uk
Wiley Periodicals, Inc.
2011 International League Against Epilepsy

53

54
S. Shorvon
cycles. The role of anesthesia is largely to prevent complications and to maintain stable clinical parameters while
the epilepsy settles down. Whether the anesthetics confer
useful antiepileptic action is debatable. Anesthesia is
usually administered to the level of burst suppression.
This is an arbitrary decision and in occasional cases focal
spikes on electroencephalography (EEG) can be seen to
be breaking through even at this level.
1. Conventional anesthesia (propofol, pentobarbital/thiopental, or midazolam): The choice of anesthesia
depends largely on side effects (Shorvon, 1994). Propofol
is the easiest anesthetic to use from the pharmacokinetic
and pharmacologic points of view, and pentobarbital/
thiopental the most difficult. Propofol carries a particular risk of propofol infusion syndrome (Iyer et al.,
2009), especially in children and when used in combination with steroids or catecholamines. Midazolam is
associated with a particular risk of acute tolerance. All
three anesthetics carry serious problems of hypotension
and cardiac depression, and these are probably most
prominent with the barbiturate anesthetics.
2. Alternative anesthetics: Ketamine is an anesthetic frequently described as a potentially useful therapy,
although published experience is minimal (Pruss &
Holtkamp, 2008; Martin & Kapur, 2009; Hsieh et al.,
2010). It has two advantages over the conventional
anesthetics: First, it has no cardiac depressant properties
(in fact the reverse) and does not cause hypotension;
and secondly, it is potentially neuroprotective, because
it is a strong N-methyl-D-aspartate (NMDA) antagonist,
although by the time it is employed, glutaminergic damage may already have been incurred. Other anesthetics
that have been reported occasionally in case reports and
small series to be useful in super-refractory SE include
etomidate and the inhalational anesthetics such as
isoflurane and desflurane. In one report of isoflurane or
desflurane given for up to 26 days in seven subjects,
with end-tidal volumes of 1.25%, four patients had
good outcomes and three patients died (one of acute
hemorrhagic leukoencephalitis, one of bowel infarction, and one remained in a persistent vegetative state
until death 5.5 months after the onset of seizures due to
toxic encephalopathy). Complications included hypotension (7/7), atelectasis (7/7), infections (5/7), paralytic ileus (3/7), and deep venous thrombosis (2/7)
(Mirsattari et al., 2004).

Antiepileptic Drugs
A wide range of antiepileptic drugs have been used in
patients with super-refractory SE in addition to anesthesia.
Whether any is superior is unclear, and it is likely that no
drug has strikingly different rates of efficacy than others.
The authors advice is to retain a combination of two or
three antiepileptic drugs at high doses, without switching
Epilepsia, 52(Suppl. 8):5356, 2011
doi: 10.1111/j.1528-1167.2011.03238.x

too often (as is the usual temptation in a severe case). It is

sensible where possible to avoid drugs that have a strong
allergic potential or that commonly interact with other
drugs. Other side effects can be troublesome and acute
pancreatitis or hepatic or renal failure can be induced with
intravenous antiepileptics. High-dose intravenous valproate also carries theoretical risks of platelet and clotting disorders and severe hyperammonemia in predisposed
patients.

Magnesium and Other Drugs

Intravenous magnesium retains a unique place and is
frequently given in SE, even in the absence of evidence of
deficiency (Robakis & Hirsch, 2006; Visser et al., 2011).
The infusion is given at doses that increase serum level
from 0.81 to 3.5 mM (loading dose and then continuous
infusion). Other drugs that have been used include intravenous lidocaine and the old fashioned but highly effective
intravenous paraldehyde. Verapamil has been reported to
have terminated refractory SE in one patient, and the
authors postulate (without evidence) that this was via an
inhibition of p-glycoprotein or other drug transporter
processes (Schmitt et al., 2010).

Immunotherapy
The most interesting development in the therapy of SE
in recent years has been the vogue for initiating immunotherapy, even in the absence of any evident immunologic
cause for the SE. The rationale is that many of the episodes
without known cause might be due to overt immunologic
disease. The recent discovery that status epilepticus can be
due to anti-NMDA-receptor antibodies and the recognition that this is a common condition has stimulated interest
in the possibility that other, as yet undiscovered, antibodies may be playing a part in the pathogenesis of SE. Emergency treatment is usually attempted with high-dose
methylprednisolone (1 g prednisolone per day), and then
followed if there is no response, by one or two courses of
intravenous immunoglobulin (IVIG). If there is a
response, longer term treatment with steroids, IVIG, and
later other immunomodulatory agents such as cyclophosphamide or rituximab may be necessary.

Hypothermia
Hypothermia for SE with thiopental anesthesia was
reported in three children with generalized SE in 1984
(Orlowski et al., 1984). In this report, moderate hypothermia (3031C) and anesthesia to the level of burst
suppression was continued for 48120 h, resulting in the
cessation of SE. There has been a recent resurgence of
interest in this mode of therapy, and Corry et al. (2008)
reported four patients with refractory tonicclonic SE in

55
Super-Refractory Status Epilepticus

Figure 1.
Flow chart summarizing the
authors approach to the
treatment of superrefractory status epilepticus.
Note: In parallel to the
treatment of seizures
outlined, emergency therapy
should also be directed
where possible at the
underlying cause of the SE.
ICU, intensive care unit;
AEDs, antiepileptic drugs.
Epilepsia ILAE

whom hypothermia to 3035C was achieved for 2061 h

using endovascular cooling; these patients were also
receiving barbiturate or benzodiazepine anesthesia. Hypothermia is not without its risks, and can cause acidbase
and electrolyte disturbances, disseminated intravascular
coagulation (DIC), coagulation disorders, thrombosis,
infection, cardiac arrhythmia, and paralytic ileus (Corry
et al., 2008), Nevertheless, it is now applied routinely to
patients in super-refractory SE in some units.

Other Physical Treatments

There are individual reports of a range of disparate
physical therapies used to treat super-refractory SE. These
include electroconvulsive therapy (ECT) (an old therapy;
Cline & Roos, 2007), transcranial magnetic stimulation
(Misawa et al., 2005; Rotenberg et al., 2009), vagus nerve
stimulation (Winston et al., 2001; De Herdt et al., 2009),
and drainage of the cerebrospinal fluid (CSF) (Kohrmann
et al., 2006; a very old therapysee Neligan & Shorvon,
2009). Other cases have been treated by emergency neurosurgery (Lhatoo & Alexopoulos, 2007). An emergency
ketogenic diet has also been reported to be successful
(Francois et al., 2003; Bodenant et al., 2008). These thera-

pies are most convincing when used against a chronic

status syndrome such as EPC, but whether any really have
an influence on the course of acute tonicclonic status
epilepticus is unclear.
In Fig. 1, the authors recommendations for therapy of
super-refractory SE are summarized in a flow chart.

Treatment of the Underlying

Condition and Long-Term
Outcome
Although efforts are made to control seizures, it is vital
that the therapy is directed where possible at the underlying condition. Indeed, where this is not done, there is a significant risk of prolonging the SE and rendering it harder
to control. The range of conditions that typically cause SE
are different from those that result in ordinary epilepsy,
and this topic was reviewed recently (Tan et al., 2010).
The prognosis of super-refractory SE depends largely
on the underlying etiology. A recent study looked at the
long-term outcome of 14 patients with SE lasting 7 days
or more (Cooper et al., 2009). Eight patients died during
the SE or in its aftermath. Six patients survived (median
duration of status epilepticus was 33 days) and despite
Epilepsia, 52(Suppl. 8):5356, 2011
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56
S. Shorvon
initial deficits, four of the five patients who could be
assessed showed a satisfactory cognitive outcome. It is
common experience, backed up by this study, that good
recovery can occur even after prolonged and severe SE and
the neurologist has a role in the intensive care situation to
ensure that premature withdrawal of care is not contemplated in the face of super-refractory status epilepticus.

Acknowledgments
This work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Healths NIHR Biomedical
Research Centres funding scheme.

Disclosures
The author has no conflicts of interest to report in relation to this
subject. I confirm that I have read the Journals position on issues
involved in ethical publication and affirm that this report is consistent
with these guidelines.

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