Super-refractory status epilepticus: An approach to

therapy in this difficult clinical situationSimon Shorvon

UCL Institute of Neurology, University College London, London, United Kingdom

SUMMARY

Super-refractory status epilepticus (SE) is a stage

of refractory SE characterized by unresponsive-

ness to initial anesthetic therapy. It is a new con-

cept that has been the focus of recent basic and

therapeutic work, and is defined as ‘‘SE that con-

tinues or recurs 24 hours or more after the onset

of anesthesia, including those cases in which SE

recurs on the reduction or withdrawl of anesthe-

sia.’’ It is encountered typically, but not exclu-

sively, 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

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 anesthe-

sia, 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.

The choice of therapy for status epilepticus (SE) willdepend greatly on the SE type and the clinical con-text—and particularly on the extent to which the SE islife-threatening. This abstract is largely concerned withtonic–clonic SE, which is the most severe form, and notfor instance nonconvulsive SE or epilepsia partialis con-tinua (EPC), which require totally different therapeuticapproaches.

The protocols for treating the earlier stages of tonic–clonic SE are now well defined, and there is a good degreeof international consensus about these (see for instance,Shorvon et al., 2008, for the consensus report from the 2ndLondon-Innsbruck Colloquium). Refractory SE is definedas SE that has not responded to first-line therapy (benzodi-azepine) or second-line therapy, and which, according tothe treatment protocols, requires the application of generalanesthesia (the conventional choices of anaesthetic areintravenous propofol, intravenous pentobarbital/thiopen-tal, or intravenous midazolam).

Super-refractory status epilepticus can be defined asSE that has continued or recurred despite 24 h of generalanesthesia (Shorvon & Ferlisi, 2011).

Super-refractory SE is a well-recognized clinical prob-lem, which is encountered typically, but not exclusively,in two quite distinctive clinical situations: (1) in patientswith severe acute brain injury and (2) in patients with nohistory of epilepsy in whom SE develops out of the bluewith no overt cause. This latter situation has been con-sidered by some to be a ‘‘syndrome’’ (entitled NORSE:new-onset refractory status epilepticus; Rathakrishnan &Wilder-Smith, 2009), although it seems to this author atleast that a syndromic sobriquet is not meaningful, basedas it is simply on the fact that the SE has occurred withoutany cause found.

Therapy is difficult. There are no randomized or con-trolled studies of therapy. The published evidence baseconsists largely of case reports or small series, and soany recommendations on therapy must be consideredanecdotal at best. The following approaches to therapyhave been recommended:

Anesthesia

In super-refractory SE, continued general anesthesiaremains the bedrock of therapy. It is usual to continueanesthesia for a period of initially 24 h and then slowly toreverse this. If seizures recur, anesthesia is reestablished.This pattern of instituting and withdrawing anesthesia iscontinued in 24–48 h cycles initially and then at 5–7 day

Address correspondence to Simon Shorvon, UCL Institute of Neurol-ogy, Box 5, National Hospital for Neurology and Neurosurgery, QueenSquare, London WC1N 3BG, U.K. E-mail: s.shorvon@ion.ucl.ac.uk

Wiley Periodicals, Inc.ª 2011 International League Against Epilepsy

Epilepsia, 52(Suppl. 8):53–56, 2011doi: 10.1111/j.1528-1167.2011.03238.x

FUTUREPERSPECTIVES,NOVELTHERAPY, ANDINNOVATION

53

cycles. The role of anesthesia is largely to prevent compli-cations and to maintain stable clinical parameters whilethe epilepsy settles down. Whether the anesthetics conferuseful ‘‘antiepileptic’’ action is debatable. Anesthesia isusually administered to the level of ‘‘burst suppression.’’This is an arbitrary decision and in occasional cases focalspikes on electroencephalography (EEG) can be seen tobe breaking through even at this level.1. Conventional anesthesia (propofol, pentobarbital/thio-

pental, or midazolam): The choice of anesthesiadepends largely on side effects (Shorvon, 1994). Propofolis the easiest anesthetic to use from the pharmacokineticand pharmacologic points of view, and pentobarbital/thiopental the most difficult. Propofol carries a particu-lar risk of propofol infusion syndrome (Iyer et al.,2009), especially in children and when used in combi-nation with steroids or catecholamines. Midazolam isassociated with a particular risk of acute tolerance. Allthree anesthetics carry serious problems of hypotensionand cardiac depression, and these are probably mostprominent with the barbiturate anesthetics.

2. Alternative anesthetics: Ketamine is an anesthetic fre-quently 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 conventionalanesthetics: First, it has no cardiac depressant properties(in fact the reverse) and does not cause hypotension;and secondly, it is potentially neuroprotective, becauseit is a strong N-methyl-D-aspartate (NMDA) antagonist,although by the time it is employed, glutaminergic dam-age may already have been incurred. Other anestheticsthat have been reported occasionally in case reports andsmall series to be useful in super-refractory SE includeetomidate and the inhalational anesthetics such asisoflurane and desflurane. In one report of isoflurane ordesflurane given for up to 26 days in seven subjects,with end-tidal volumes of 1.2–5%, four patients hadgood outcomes and three patients died (one of acutehemorrhagic leukoencephalitis, one of bowel infarc-tion, and one remained in a persistent vegetative stateuntil death 5.5 months after the onset of seizures due totoxic encephalopathy). Complications included hypo-tension (7/7), atelectasis (7/7), infections (5/7), para-lytic ileus (3/7), and deep venous thrombosis (2/7)(Mirsattari et al., 2004).

Antiepileptic Drugs

A wide range of antiepileptic drugs have been used inpatients with super-refractory SE in addition to anesthesia.Whether any is superior is unclear, and it is likely that nodrug has strikingly different rates of efficacy than others.The author’s advice is to retain a combination of two orthree antiepileptic drugs at high doses, without switching

too often (as is the usual temptation in a severe case). It issensible where possible to avoid drugs that have a strongallergic potential or that commonly interact with otherdrugs. Other side effects can be troublesome and acutepancreatitis or hepatic or renal failure can be induced withintravenous antiepileptics. High-dose intravenous valpro-ate also carries theoretical risks of platelet and clotting dis-orders and severe hyperammonemia in predisposedpatients.

Magnesium and Other Drugs

Intravenous magnesium retains a unique place and isfrequently given in SE, even in the absence of evidence ofdeficiency (Robakis & Hirsch, 2006; Visser et al., 2011).The infusion is given at doses that increase serum levelfrom 0.81 to 3.5 mM (loading dose and then continuousinfusion). Other drugs that have been used include intrave-nous lidocaine and the old fashioned but highly effectiveintravenous paraldehyde. Verapamil has been reported tohave terminated refractory SE in one patient, and theauthors postulate (without evidence) that this was via aninhibition of p-glycoprotein or other drug transporterprocesses (Schmitt et al., 2010).

Immunotherapy

The most interesting development in the therapy of SEin recent years has been the vogue for initiating immuno-therapy, even in the absence of any evident immunologiccause for the SE. The rationale is that many of the episodeswithout known cause might be due to overt immunologicdisease. The recent discovery that status epilepticus can bedue to anti-NMDA-receptor antibodies and the recogni-tion that this is a common condition has stimulated interestin the possibility that other, as yet undiscovered, antibod-ies may be playing a part in the pathogenesis of SE. Emer-gency treatment is usually attempted with high-dosemethylprednisolone (1 g prednisolone per day), and thenfollowed if there is no response, by one or two courses ofintravenous immunoglobulin (IVIG). If there is aresponse, longer term treatment with steroids, IVIG, andlater other immunomodulatory agents such as cyclophos-phamide or rituximab may be necessary.

Hypothermia

Hypothermia for SE with thiopental anesthesia wasreported in three children with generalized SE in 1984(Orlowski et al., 1984). In this report, moderate hypo-thermia (30–31�C) and anesthesia to the level of burstsuppression was continued for 48–120 h, resulting in thecessation of SE. There has been a recent resurgence ofinterest in this mode of therapy, and Corry et al. (2008)reported four patients with refractory tonic–clonic SE in

Epilepsia, 52(Suppl. 8):53–56, 2011doi: 10.1111/j.1528-1167.2011.03238.x

54

S. Shorvon

whom hypothermia to 30–35�C was achieved for 20–61 husing endovascular cooling; these patients were alsoreceiving barbiturate or benzodiazepine anesthesia. Hypo-thermia is not without its risks, and can cause acid–baseand electrolyte disturbances, disseminated intravascularcoagulation (DIC), coagulation disorders, thrombosis,infection, cardiac arrhythmia, and paralytic ileus (Corryet al., 2008), Nevertheless, it is now applied routinely topatients in super-refractory SE in some units.

Other Physical Treatments

There are individual reports of a range of disparatephysical therapies used to treat super-refractory SE. Theseinclude electroconvulsive therapy (ECT) (an old therapy;Cline & Roos, 2007), transcranial magnetic stimulation(Misawa et al., 2005; Rotenberg et al., 2009), vagus nervestimulation (Winston et al., 2001; De Herdt et al., 2009),and drainage of the cerebrospinal fluid (CSF) (Kohrmannet al., 2006; a very old therapy—see Neligan & Shorvon,2009). Other cases have been treated by emergency neuro-surgery (Lhatoo & Alexopoulos, 2007). An emergencyketogenic 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 chronicstatus syndrome such as EPC, but whether any really havean influence on the course of acute tonic–clonic statusepilepticus is unclear.

In Fig. 1, the author’s recommendations for therapy ofsuper-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 vitalthat the therapy is directed where possible at the underly-ing condition. Indeed, where this is not done, there is a sig-nificant risk of prolonging the SE and rendering it harderto control. The range of conditions that typically cause SEare 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 largelyon the underlying etiology. A recent study looked at thelong-term outcome of 14 patients with SE lasting 7 daysor more (Cooper et al., 2009). Eight patients died duringthe SE or in its aftermath. Six patients survived (medianduration of status epilepticus was 33 days) and despite

Figure 1.

Flow chart summarizing the

author’s approach to the

treatment of super-

refractory 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

Epilepsia, 52(Suppl. 8):53–56, 2011doi: 10.1111/j.1528-1167.2011.03238.x

55

Super-Refractory Status Epilepticus

initial deficits, four of the five patients who could beassessed showed a satisfactory cognitive outcome. It iscommon experience, backed up by this study, that goodrecovery can occur even after prolonged and severe SE andthe neurologist has a role in the intensive care situation toensure that premature withdrawal of care is not contem-plated in the face of super-refractory status epilepticus.

Acknowledgments

This work was undertaken at UCLH/UCL, which received a propor-tion of funding from the Department of Health’s NIHR BiomedicalResearch Centres’ funding scheme.

Disclosures

The author has no conflicts of interest to report in relation to thissubject. I confirm that I have read the Journal’s position on issuesinvolved in ethical publication and affirm that this report is consistentwith these guidelines.

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