Documente Academic
Documente Profesional
Documente Cultură
8):5356, 2011
doi: 10.1111/j.1528-1167.2011.03238.x
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:
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
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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
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
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.
References
Bodenant M, Moreau C, Sejourne C, Auvin S, Delval A, Cuisset JM,
Derambure P, Deste A, Defebvre L. (2008) Interest of the ketogenic
diet in a refractory status epilepticus in adults. Rev Neurol (Paris)
164:194199.
Cline JS, Roos K. (2007) Treatment of status epilepticus with electroconvulsive therapy. J ECT 23:3032.
Cooper AD, Britton JW, Rabinstein AA. (2009) Functional and cognitive
outcome in prolonged refractory status epilepticus. Arch Neurol
66:15051509.
Corry JJ, Dhar R, Murphy T, Diringer MN. (2008) Hypothermia for
refractory status epilepticus. Neurocrit Care 9:189197.
De Herdt V, Waterschoot L, Vonck K, Dermaut B, Verhelst H, Van Coster
R, De Jaeger A, Van Roost D, Boon P. (2009) Vagus nerve stimulation
for refractory status epilepticus. Eur J Paediatr Neurol 13:286289.
Francois LL, Manel V, Rousselle C, David M. (2003) Ketogenic regime
as anti-epileptic treatment: its use in 29 epileptic children. Arch Pediatr 10:300306.
Hsieh CY, Sung PS, Tsai JJ, Huang CW. (2010) Terminating prolonged
refractory status epilepticus using ketamine. Clin Neuropharmacol
33:165167.
Iyer VN, Hoel R, Rabinstein AA. (2009) Propofol infusion syndrome in
patients with refractory status epilepticus: an 11-year clinical experience. Crit Care Med 37:30243030.