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

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: [email protected]

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

Group 1993; Shorvon, 1994; Appleton et al., 2000; SIGN 2003; Introduction Ka¨ lvia¨ inen et al., 2005; Meierkord et al., 2006, 2010; Minicucci The treatment of the earlier phases of tonic–clonic status epilepti- et al., 2006; Holtkamp, 2006, 2007; Shorvon et al., 2008; Aranda cus has been well studied and discussed in recent years. There are et al., 2010; Rossetti, 2010; Rossetti and Lowenstein, 2011). This a number of similar guidelines and protocols published, all of is a well-trodden path which, although based on an inadequate which include the initial use of benzodiazepines, followed by intra- evidence base, is widely accepted and practiced. venous antiepileptic drugs such as phenytoin, phenobarbital or In this article, we focus on the outcome of patients with refractory valproate, and then if necessary the induction of anaesthesia status epilepticus and super-refractory status epilepticus. Refractory (examples include Delgado-Escueta et al., 1984; EFA Working 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. For Permissions, please email: [email protected] Therapies in convulsive status epilepticus Brain 2012: 135; 2314–2328 | 2315 epilepticus requiring general anaesthesia’. Super-refractory status (Rossetti et al., 2011). Apart from this study, the evidence base con- epilepticus is defined as ‘status epilepticus that continues 24 h or sists entirely of single case reports or small series (Table 1). more after the onset of anaesthesia, including those cases in which Furthermore, none of the widely recommended drugs or procedures the status epilepticus recurs on the reduction or withdrawal of an- has been subjected to an adequate systematic review. There are a aesthesia’. Although constituting a minority of cases of status epilep- number of other papers, not considered here, where treatment (often with multiple therapies) is mentioned only in passing, and ticus (10–15% of all those presenting to hospital in status where there are insufficient data to provide any assessment of out- epilepticus develop super-refractory status epilepticus; Novy and come. In papers where data on a particular therapy is focused upon, Rossetti, 2010), appropriate therapy of these cases is poorly studied. and other therapies are mentioned in passing, we have included only The cases considered here are of convulsive status epilepticus and we the therapy with sufficient data. We have considered only therapies have not included non-convulsive cases, except where these evolved aimed primarily at the control of seizures and not therapies used to from a convulsive stage. Anaesthesia is not often required in primarily treat the underlying cause of the status epilepticus (e.g. magnesium in non-convulsive cases, and certainly should not be given early, and magnesium deficiency, pyridoxine in pyridoxine-dependant patients or 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 also been reported but not in recent times, and these will not be Therapy Number of Number of 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 Magnesium 2 3 categorizing outcome Pyridoxine 2 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 S. Shorvon and M. Ferlisi

resulting in the need for a change of therapy (and does not in- midazolam are more recently introduced than the barbiturate an- clude those in whom control was achieved by reintroducing the aesthetics, which have been used in this indication for well over same drug). 50 years, and so the barbiturate outcomes were reported largely (v) Intolerable side-effects: the therapy resulted in side-effects neces- at a time when Intensive Treatment Unit (ITU) practice was not as sitating alternative therapy. well developed as now (about two-thirds of cases between 1980 (vi) Death during the course of the treatment. Some of these deaths and 1999, compared with 510% of propofol and midazolam will be due to the underlying cause, but as it is often impossible to attribute mortality accurately, and as treatment may play a cases); the most severe cases, and those with certain severe aetiol- contributing role in the outcome of these cases, all such deaths ogies, are more likely to be treated with barbiturates; cases that are included in this category (note, deaths occurring after the are unresponsive to midazolam or propofol are nowadays likely to therapy has been discontinued are not included). progress to barbiturate therapy; different treatments are preferred at different ages, for instance children are least likely to be treated Although we have applied this scheme to all cases, a number of dif- with propofol. 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- Control, failure of control and side-effects thetic will inevitably initially control status epilepticus, provided a We found control of refractory and super-refractory status epilep- sufficient dose can be given. If initial failure does occur [Category ticus in 74% (678/920) of the reported cases (Table 2). The rate (ii)], it will be usually because the appropriate dose cannot be reached of initial control on barbiturate was 64%, midazolam 78% and because of side-effects (notably hypotension or cardio-respiratory de- propofol 68%. As mentioned above, an anaesthetic drug will in- pression). It is usual to attempt a dose of anaesthesia that produces evitably control status epilepticus provided the dosage is high the EEG pattern known as ‘burst suppression’, as at this level it is rare enough, and the failure to gain control is usually due to either for any epileptic electrographic activity to be manifest, but often the too low a target dose or dose limitation caused by side-effects. dose required will cause side-effects and cannot be attained. In some reports though, it is possible that therapy was discontinued prema- Side-effects (usually hypotension or cardio-respiratory depression) turely at too low a dose for other reasons. Other types of treatment were reported to require a change in therapy in 3% of patients on are either given as continuing infusions, repeated dosing, or single barbiturates, and 6% on propofol, usually isolated symptoms that one-off therapies. In these cases, the potential for failure of initial could form part of the propofol infusion syndrome. The figures for therapy is higher. For one-off therapies, the category of breakthrough failure on midazolam include a large group from one study (78/ seizures cannot apply, and Category (iv) (withdrawal seizures) is used 306 patients; Hayashi et al., 2007) in whom the reason for failure to include cases in which seizures were initially controlled but rapidly was not reported. returned after the cessation of the one-off therapy.

Breakthrough seizures Results 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- Anaesthetic treatments pofol and 0% on barbiturate (in reports with sufficient detail). These are the best documented of the available therapies. In total, These figures do not include the greater number of patients we found outcome recorded for 192 patients treated with pento- who regained control after relapse by increasing the drug barbital/thiopental, 143 with propofol and 585 with midazolam dosage and therefore not needing a switch of therapy: 7% on [although a single rather briefly documented study (Hayashi midazolam (21/281), 12% on propofol (6/50) and 6% on barbit- et al., 2007) contributed 306 (52%) of the midazolam cases]. urate (3/53). The data on breakthrough seizures are included in These were, as mentioned above, largely anecdotal reports and the Supplementary material. Not all reports provided the level of each drug cannot be compared with the others. Furthermore, a detail required and we recognize that some may not have been number of significant potential biases exist. Propofol and mentioned and that these figures may be artificially low.

Table 2 Overall outcome of anaesthetic therapy

Outcome Thiopental/pentobarbital Midazolam Propofol (n = 192) (n = 585) (n = 143) Control 64% (123/192) 78% (458/585) 68% (97/143) No control ever achieveda 5% (9/192) 16% (93/585) 11% (16/143) Breakthrough seizures 0% (0/192) 3% (19/585) 1% (2/143) Withdrawal seizures 9% (18/192) 51% (2/585) 6% (8/143) Therapy failure because of side-effects 3% (5/192) 51% (1/585) 6% (8/143) Death during therapy 19% (37/192) 2% (12/585) 8% (12/143)

aExcluding 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. Therapies in convulsive status epilepticus Brain 2012: 135; 2314–2328 | 2317

Withdrawal seizures This study cites higher rates of withdrawal and breakthrough seiz- Withdrawal seizures were reported less often on midazolam ures. Methodology differed, however, and we were unable to (0.3%) compared with 6% on propofol and 9% on thiopental/ determine how some figures had been calculated from our own pentobarbital therapy (in reports with sufficient detail). In addition, scrutiny of the same publications. when seizures did occur on tapering or withdrawal, a higher rate of regained control was reported in those patients in whom the Other anaesthetics drug was reintroduced on midazolam (93%) compared The published literature reporting outcome on ketamine infusion with the other two drugs (47% on propofol and 22% on barbit- for super-refractory status epilepticus is very small—with only urate). The data on withdrawal seizures are included in the 17 reported cases, all of which were single case reports except Supplementary material. As with breakthrough seizures, we have one series of seven cases (Bleck et al., 2002). Control was included only reports that provided sufficient level of detail and so achieved in 14 (82%) and it was postulated that the failure of these figures may be artificially low. control in the other three cases was due to insufficient dosage. The documentation of cases was slight and in only 10 were their Death rates during infusion sufficient details of type of status epilepticus or aetiology. Ketamine was used at a late stage in most cases (median duration The reported mortality rates were 19% on thiopental/pentobar- of status prior to the use of ketamine was 672 h with a range bital infusions, 8% on propofol infusions and 2% on midazolam 336–1680 h) and the median duration of therapy was 120 h infusions. Comparison is complicated by the strong potential biases (range 120–336). There was a loss of effect in one case and pos- discussed above, which are likely to inflate the risk for barbiturate, sible neurotoxicity in another. The long-term outcome was poor and also because in some of the older reports on barbiturate with death in seven and severe neurological deficit in three cases. therapy details were vague regarding the timing of death and The infusion dose range was 0.06–7.5 mg/kg/h. some of these deaths may have occurred after the cessation of The outcome of the use of the inhalational anaesthetics isoflur- infusion. In relation to propofol, publication bias is also introduced ane and desflurane is reported in 27 episodes in seven publica- by the inclusion of reports that focus on the ‘propofol infusion tions. Initial control was reported in all cases. However, seizures syndrome’. recurred on withdrawal in 41% and two patients (7%) switched Propofol infusion syndrome is a particular risk in prolonged due to side-effects. As with ketamine, the inhalational anaesthetics infusion in children and in patients co-medicated with steroids were usually used late in the course of status epilepticus (a median or catchecolamines. Iyer et al. (2009) found evidence of duration of status prior to usage of 120 h and range 22–2472 h). propofol infusion syndrome in 45% of 31 patients treated with The median duration of therapy was 45 h (range 1–2040). In the prolonged infusions (mean 67 h) although a very broad definition largest case series, isoflurane and desflurane were used in seven of propofol infusion syndrome was used, which included patients patients, and anaesthesia was maintained for a mean of 11 (range with isolated symptoms such as unexplained hypotension and not 2–26) days (Mirsattari et al., 2004). Four patients had good out- necessarily the full blown syndrome. There is a high morbidity and comes but three patients died subsequently. The therapy also had mortality rate. Because of this risk, Iyer et al. (2009) recommend a high rate of complications including hypotension (7/7), atelec- removal of propofol from their treatment protocol of status tasis (7/7), infections (5/7), paralytic ileus (3/7) and deep venous epilepticus. Other studies have found a lower risk and do not thrombosis (2/7) (Mirsattari et al., 2004). 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). Antiepileptic drug therapy The studies included 920 patients, of all ages and a range It is universally recommended that antiepileptic drug therapy of aetiologies. The median duration of therapy was 53 h (range should be used concurrently with anaesthesia in refractory and 11–1200) on thiopental/pentobarbital, 32 h (range 0.5–432) on super-refractory status epilepticus. However, the published out- propofol and 16 h (range 10–240) on midazolam, perhaps reflect- come of the use of antiepileptics in this situation is restricted to ing the greater severity of the barbiturate cases. All drugs caused 60 cases (in 10 reports) treated with topiramate, 10 (in two complications, most commonly hypotension and respiratory reports) with lacosamide, two (in one report) with pregabalin depression, which can be severe. Other life-threatening complica- and 35 (in eight reports) with levetiracetam. There is no published tions occurred with each of the drugs. The infusion doses var- outcome analysis of any other antiepileptic in refractory or ied considerably from report to report, ranging from 0.5 to super-refractory status epilepticus, despite very widespread usage 20 mg/kg/h for thiopental/pentobarbital, 0.1–24 mg/kg/h for of a large range of drugs. A range of modes of administration propofol and 0.02–1.8 mg/kg/h for midazolam. The median were used including instillation through a percutaneous endo- duration (and range) of the status epilepticus before the onset scopic gastrostomy, nasogastric and rectal administration. of therapy was 16 h (1–720) for thiopental/pentobarbital, 18 h In these small series, topiramate controlled the status in 62% (10–600) for propofol and 4 h for midazolam (0.7–48). (37/60), lacosamide in 10% (1/10), pregabalin in 0% (0/2) and There is one other published study of accumulated data from levetiracetam in 46% (17/35), although the definition of ‘control’ reports of anaesthesia in refractory status epilepticus (Claassen in lacosamide cases [from the report of Goodwin et al. (2011)] et al., 2002) in which 54 cases treated with midazolam, 106 was resolution of electrographic seizures within 4 h, which is a far with barbiturate and 33 with propofol therapy were reported. stricter definition than used for other therapies. These figures, 2318 | Brain 2012: 135; 2314–2328 S. Shorvon and M. Ferlisi coming as they do from small selected series, are not comparable. and pyridoxine is now routinely given in cases of super-refractory One patient died on topiramate and another on lacosamide ther- status epilepticus in young children. In fact, the outcome of ther- apy, and various complications occurred including metabolic acid- apy in non-pyridoxine-dependent patients is reported in only two osis on topiramate, angioedema on lacosamide, and rectal cases, both of whom had low blood levels prior to therapy (one bleeding (during rectal administration) of levetiracetam. Where due to pregnancy and one to malnourishment), and although ini- stated, the median duration of status before the drug was started tial control was achieved in both cases, other therapies were given was 144 h (range 0–720 h) for topiramate, 144 h (range 24–336 h) concurrently and attribution of success to pyridoxine is arguable. for lacosamide, 1632 h (range 744–2520 h) for pregabalin and The infusion of pyridoxine alone carries no risk, although in some 81 h (range 24–288) for levetiracetam. The dose of topiramate countries pyridoxine is only generally available as an infusion used was 2–25 mg/kg/day in children and up to 1600 mg/day in mixed with other vitamins (PabrinexÕ) and this formulation carries adults; of lacosamide was 100–400 mg/day in adults; of pregabalin a small risk of anaphylaxis. The doses used of pyridoxine were was up to 600 mg/day in adults and of levetiracetam 13–70 mg/ 180–600 mg/day. day in children and 250–6000 mg/day in adults. Immunotherapy Hypothermia Another treatment that is widely used in super-refractory status Hypothermia is now routinely used in several centres around the epilepticus is immunotherapy with steroids, intravenous immuno- world for patients in super-refractory status epilepticus. The out- globulins and plasma exchange. Outcome has been reported in come of hypothermia in status epilepticus, however, is reported in only 21 cases in eight reports of patients without identified under- only nine cases in four reports (one from 1984), all of whom lying immunological conditions. Of these, control of status was obtained initial control and seven of the nine recovered. obtained in only 5%. In all cases, other therapies were also intro- Endovascular cooling is the currently the preferred method in duced concurrently and the effects on seizures may be delayed. It adults (but not necessarily children), and was used in four patients is thus difficult definitively to dissect the effects of immunotherapy with external cooling used in the other five. The median duration from that of other treatment. 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- Resective neurosurgery plications including hypotension, electrolyte disturbance, acidosis, We have included resective neurosurgery in our analysis despite disseminated intravascular coagulation, thrombosis and thrombo- the fact that this is in many cases therapy directed at the cause per embolism, infection, bowel ischaemia, shivering and arrhythmias se, because the resection aimed to remove the epileptogenic zone on rewarming. The core temperature in these reports was usually not simply the lesion, and the extent of resection is often greater reduced to 32–35C. 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 Magnesium infusion cases, focal resection was carried out, in three focal resection and Magnesium sulphate infusion is another widely used therapy in multiple subpial transection, in two focal resection and corpus super-refractory status epilepticus although again the published callosectomy, in one multiple subpial transection corpus callosect- evidence base-related outcome is remarkably small. The outcome omy and in eight some form of hemispherectory. Pathology was of only three patients is reported, in one of whom the status identified in 25 cases and non-specific findings in 11. epilepticus was controlled. All patients were young adults, two had mitochondrial disease. The time from the onset of status to Ketogenic diet the prescription of magnesium in these reports was between 144 and 1152 h and therapy was continued for between 48 and 168 h. The use of the 4:1 ketogenic diet to control super-refractory status The infusion rates varied between 2 and 6 g/h, with a target epilepticus has been reported in 14 cases of whom one later serum level in the report of Visser et al. (2011) of 3.5 mEq/l. switched to the modified Atkins diet and one to a 3:1 diet, and However, in the case report by Fisher (1988), levels of magnesium a further two cases in whom the Atkins diet was used from the were raised to extremely high levels (14.2 mEq/l) without con- start. Initial control was observed in 12 of the 14 cases. In one trol of seizures, and levels 48 mEq/l carry significant cardiovascu- case, the therapy was abruptly and inadvertently withdrawn and lar risks. 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 Pyridoxine infusion et al., 2010) were categorized as having FIRES (febrile Intravenous pyridoxine (as the hydrochloride) is an effective treat- infection-related epilepsy syndrome). The diet was used as a last ment in the rare patients with an inborn error of metabolism of resort in these cases, with the median duration of status epilepti- pyridoxine. However, it has also been claimed that intravenous cus before the diet was started of 540 h (range 96–2424). The pyridoxine therapy may be effective in super-refractory status epi- therapy was maintained in the long term in all patients (except the lepticus when no clear deficit in pyridoxine metabolism is present, patient mentioned above) or changed to the modified Atkins diet. Therapies in convulsive status epilepticus Brain 2012: 135; 2314–2328 | 2319

Other physical therapies In our view, it is not possible from these figures to draw any conclusions about whether any specific therapy is responsible for A range of other physical therapies have been reported in recent a particularly high or low rate. Furthermore, long-term mortality is case reports in the treatment of super-refractory status epilepticus. known to be related not so much to the treatment used as to the These include four case reports of patients treated with vagal underlying aetiology (probably the main determinant) and also the nerve stimulation, with final control in all four, although in one duration of status epilepticus. 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 Discussion attribute improvement to the vagal nerve stimulation. One case of deep brain stimulation in the caudal zona incerta, in focal motor The most striking conclusion from this exploration of the literature status epilepticus, is reported with resolution of the seizures. The is the poor quality of the outcome data, which indeed is so inad- outcome of eight patients (in six reports) treated with courses of equate that only broad conclusions can be drawn from this ana- ECT, with resolution of the status epilepticus in seven of the eight lysis. The assessment of each therapy is severely compromised by patients. Three to eight sessions of the ECT were given, with the a number of points. treatment started at a median of 984 h (range 336–2472 h) after (i) The lack of randomized or controlled studies: in this review the onset of the status epilepticus, and with no complications except pneumonia in one case. There is a single convincing we found only a single randomized study, and this failed to report of immediate control of super-refractory status by CSF recruit (see above). Almost all the other studies were either drainage although with subsequent relapse (Korhmann et al., case reports or retrospective series. 2006). Repetitive transcranial magnetic stimulation has been (ii) The small number of individuals treated: many treatments used experimentally and outcome reported in cases of simple par- discussed, even if very widely used in routine practice, are tial status epilepticus and epilepsia partialis continua. Classical based on a very small number of published cases. Indeed, music is another therapy that has been used in non-convulsive apart from the three commonly used anaesthetics (propofol, status epilepticus. Neither of the two latter therapies have been midazolam or pentobarbital/thiopental), none of the treat- reported in convulsive status epilepticus and so are not considered ments reviewed here have a total published outcome data in further here. 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. Long-term outcome Therapies in the super-refractory period of status are In this article, we have focused our outcome assessment on the almost always given in parallel, and assessment of a therapy immediate control of seizures as the primary end-point of each is often complicated by concurrent changes in dosages, or therapy. In a total of 596 cases, the long-term outcome could also physical parameters, of another. be ascertained, divided into five broad categories, and the results (iv) Delay in responses. Reports of responsiveness for some are shown in Table 3. Overall, 35% of the patients died. The therapies include patients who responded days or weeks death rate was higher in patients who had been treated with after the application of treatment. This applies to the studies thiopental/pentobarbital (46%) compared with propofol (36%), of vagal nerve stimulation, ECT, antiepileptic drugs, keto- midazolam (34%) and ketamine (44%) but this likely reflects genic diet neurosurgery and immunotherapy. Furthermore, the potentially severe biases discussed above. The death rate in concomitant therapy is also often changed. This makes treatment of those that had been treated with all other therapies causal attribution very difficult to make. ranged from 0 to 36%, except a rate of 67% in those treated with (v) Some therapies are widely used and yet the published lit- magnesium and a rate of 50% in those treated with levetiracetam. 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 Table 3 Long-term outcome ultimate prognosis depends on factors other than treatment such as age and aetiology (Neligan and Shorvon, 2010, a Outcome n = 596 2011). These further complicate any assessment of individ- Deaths 207 (35%) ual therapies. Severe neurological deficit 79 (13%) Mild neurological deficit 80 (13%) This is all the more regrettable given the severe nature of re- Undefined neurological deficit 22 (4%) fractory status epilepticus, with its mortality rate of 35% and its Recovery to baseline 208 (35%) high morbidity. It is an inescapable conclusion that our current aIn the reports of 596 cases (51% of the total of 1168), the long-term outcome approaches to therapy are based on an inadequate literature was recorded. In the other 575 cases, no long-term outcome data were provided. 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 is lower than often quoted. Although the raw data show a higher treatment approach mortality rate on barbiturate therapy, we consider this difference to be due to selection bias and that there is no reliable support for and protocol marked differences in mortality between treatments. Moreover, mortality in status epilepticus is largely determined by the under- These drawbacks hinder the making of any definitive recommen- lying aetiology (Neligan and Shorvon, 2010) and with modern ITU dations about therapy. A treatment protocol has been suggested practice, iatrogenic mortality rates should be low. The three an- elsewhere (Shorvon and Ferlisi, 2011). Our analysis of outcome aesthetic drugs conventionally used have a number of important does not provide definitive guidance on how appropriate this ap- differences. Their advantages and disadvantages have been re- proach is. However, a number of broad conclusions can be drawn. viewed elsewhere (Shorvon and Ferlisi, 2011), and these findings are summarized in Table 4. Due to the inherent biases in outcome First-line therapy data, comparison of the three drugs can be made only cautiously, This is a therapy that should be applied to every case, in conjunc- but a number of recommendations can be securely made. These tion with the full panoply of ITU care and support and with treat- are summarized in Table 5. ment of the underlying cause (Shorvon and Ferlisi, 2011). Ketamine is reserved as a second-line drug because of the very limited clinical evidence base and the potential neurotoxic effects. Anaesthetics There is also one case report where the development of cerebral General anaesthesia remains the backbone of therapy in refractory atrophy, after status epilepticus, is postulated to have been due to and super-refractory status epilepticus. Our analysis confirms that ketamine therapy (Ubogu et al., 2003), although status epilepticus this is an effective therapy in the majority of cases. Immediate itself can cause cerebral atrophy and this could be an alternative control of refractory status epilepticus is achieved in two-thirds 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 Brain 2012: 135; 2314–2328 | 2321

Table 5 Recommendation for anaesthetic use in refractory and super-refractory status epilepticus (adults)

Anaesthetic Dose Recommendations

Thiopental/ Thiopental: First-line therapy in severe cases. pentobarbital Loading dose: 2–3 mg/kg Avoid in situations where pharmacokinetic interactions would be detrimental. Maintenance dose: 3–5 mg/kg/h Avoid in hepatic disease, myasthenia gravis, porphyria, severe haemorrhage Pentobarbital: or burns, cardiovascular disease, adrenocortical insufficiency. Loading dose: 5–15 mg/kg Maintenance dose: 0.5–3 mg/kg/h Midazolam Loading dose: 0.1–0.2 mg/kg First-line therapy in most cases. Maintenance dose: 0.1–0.4 mg/kg/h Avoid in hepatic or renal disease, myasthenia gravis, porphyria. Propofol Loading dose: 3–5 mg/kg First-line therapy in complex cases where ease of use and pharmacokinetic Maintenance dose: 5–10 mg/kg/h 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. Ketamine Loading dose: 1–3 mg/kg Second-line therapy especially where hypotension or cardiorespiratory Maintenance dose: up to 5 mg/kg/h depression is problematic.

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- Table 6 Suggested approach to antiepileptic drug therapy taining prolonged inhalational anaesthesia in a neurological ITU in refractory status epilepticus setting and in our opinion, these and the high rate of complica- Choice of drug regimen depends on clinical context tions preclude the use of these drugs in most clinical situations. It would be usual initially to reverse anaesthesia every 24–48 h Polytherapy with two antiepileptic drugs and if seizures continue, then to re-establish anaesthesia (cycling). High-dose regimens Avoid frequent switching Such cycles should be repeated several times. If the status con- Favour antiepileptic drugs with low interaction potential tinues to recur, the duration of individual cycles can be increased, Favour antiepileptic drugs with predictable kinetic properties and anaesthesia continued for up to 5 days at a time. The anaes- Favour antiepileptic drugs without renal or hepatic toxicity thesia should be weaned slowly on reversal. This decision needs to Avoid GABAergic antiepileptic drugs 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, (Table 6): (i) polytherapy with no more than two drugs, used at consideration could be given to reversing the anaesthesia alto- high doses. Morbidity will rise with more extensive drug regimes; gether. We know of no data on this point, which deserves further (ii) frequent switches should not be made, as rapid withdrawal can study. exacerbate the tendency for seizures to occur (rebound seizures), increase side-effects, risk allergic reactions and also cause pharma- Antiepileptic therapy cokinetic changes; and (iii) the choice of drug will depend on the Antiepileptic drugs should always be given, so that when the an- clinical context. However, it seems sensible to use powerful anti- aesthetic agent is withdrawn there is adequate antiepileptic cover epileptics; to avoid those with a primarily GABAergic mechanism (in situations where anaesthetics are being continued, the need for of action (e.g. benzodiazepines, barbiturates) as there is evidence antiepileptics is less). There are unfortunately no reliable data sug- of loss of efficacy as status epilepticus becomes more prolonged gesting that any particular antiepileptic drug is better than an- and because the anaesthetic drugs themselves have much more other, nor any evidence concerning regimes or therapeutic powerful GABAergic effects. Where possible, drugs with low inter- approaches. Although many of the antiepileptics are widely action potential and predictable kinetics should be used, and anti- used, the only published literature in super-refractory status epi- epileptics with strong allergenic potential and potential renal or lepticus refers to topiramate (60 cases), levetiracetam (35 cases), hepatic toxicity should be avoided. Levetiracetam, topiramate, pregabalin (2 cases) and lacosamide (10 cases). pregabalin and lacosamide are possible options, given through No conclusions regarding choice of drug can be made on this the nasogastric tube or percutaneous endoscopic gastrostomy. basis. However, by analogy with antiepileptic drug therapy in The target dose should be the high maintenance dose used in other situations, the following recommendations can be made routine oral antiepileptic drug therapy. 2322 | Brain 2012: 135; 2314–2328 S. Shorvon and M. Ferlisi

Second-line therapy Immunological therapy The outcome of therapy with steroids, intravenous immunoglobulin This is a therapy that can be applied in those cases in which first- and plasma exchange, based on this literature review, is poor, with line therapy is not controlling the status epilepticus and should be only 5% of patients gaining control. However, this approach is considered at some point after the initiation of anaesthesia and widely used despite the very limited evidence base, and anecdotal antiepileptic drug therapy. How long after will depend on individ- clinical experience is much more promising. This use is based on ual circumstances, but the longer the seizures persist the worse two theoretical propositions. First, it is possible that some cases of the functional outcome. There are a number of choices and ap- cryptogenic refractory status epilepticus are caused by underlying proaches, and there is no clear guidance about which to choose or occult auto-immune or immunological conditions. This proposition in what order. Based on this review, therapy should be selected is encouraged by the finding of cases due to newly discovered from the following. antibodies including the anti-NMDA receptor antibodies and the voltage-gated potassium antibodies. Second, is the possibility that Hypothermia inflammatory mechanisms occur at the epilepsy focus, resulting in As mentioned above, hypothermia is routinely used in some cen- epileptogenesis, and there is growing experimental evidence of the tres for the treatment of status epilepticus, despite an extremely importance of such inflammation (Vezzani and Ruegg, 2011). small evidence base. It is a therapy that deserves further study, not Thus, in our opinion, a trial of immunological therapy is worthwhile least because of the solid experimental evidence of neuroprotec- as a second-line therapy in patients with super-refractory status tive as well as seizure-terminating properties. However, there are epilepticus, without a history of previous epilepsy and in whom significant complications and serious side-effects, and it is a ther- no aetiology has been found. However, there is an urgent need apy that should be embarked upon only in experienced centres. for more systematic study of this line of therapy. The level of hypothermia is also uncertain, and it has been sug- A typical regimen would be to start therapy with high-dose gested that only mild hypothermia is effective (Rossetti, 2011). In steroids and a course of intravenous immunoglobulin or plasma which cases it should be employed, or at what stage, unfortu- exchange. The steroids should be given for 3 days at a high dose nately is unclear, but it does seem reasonable to consider this as (1 g/day in adults) and continued at lower doses (1 mg/kg/day) a second-line therapy, in resistant cases, with target temperatures for a period of 1 week, and continued if there is a response. In  between 32 and 35 C and the hypothermia continued in the first addition, a course of intravenous immunoglobulin over 5 days, at instance for 24–48 h. 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- Magnesium infusion and pyridoxine infusions venous immunoglobulin can be used. 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 Ketogenic diet sporadic case reports of its clinical use since 1901. The adminis- The ketogenic diet is easy to administer in super-refractory status tration of magnesium in patients with super-refractory status epi- epilepticus, either through the nasogastric tube or percutaneous lepticus that are not responding to therapy carries no major risk, endoscopic gastrostomy. Ready-made solutions with 4:1 commer- although hypotension and PR interval prolongation are reported cial preparation (KetoCal) are most commonly used. The evidence and caution is advised when co-administered with barbiturates or base, however, is very small (12 cases of 4:1 ketogenic diet and benzodiazepines due to a risk of enhanced respiratory depression, two cases of the modified Atkins diet) although the recorded re- and when co-administered with digoxin or calcium channel block- sponse of the cases was convincing. It carries certain risks and is ers. Also, at high doses the neuromuscular blocking effects may contraindicated in cases of pyruvate carboxylase and b-oxidation mask convulsive movements, which can be clinically misleading. It deficiencies. It should, furthermore, probably not be used with seems reasonable to infuse magnesium at a dose 2–6 g/h to obtain propofol anaesthesia or with steroid co-administration. A 4:1 a serum level of 3.5 mmol/l. If this is effective, the infusion should diet with the initial complete avoidance of glucose is recom- be continued, and ceased if ineffective. mended. Details of the administration of the diet can be found In young children, pyridoxine is also widely administered on in Nabbout et al. (2010). 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 Emergency neurosurgery evidence that this is the case. The infusion of pyridoxine alone is In the published cases (36 in total), a good long-term outcome entirely safe, although the infusion of the combined vitamin prep- was reported in 27 (75%). The type of surgery included focal arations (PabrinexÕ) carry a small risk of anaphylaxis. A reasonable resection, multiple subpial transection, corpus callosectomy and dose would be 180–300 mg. hemispherectory (sometimes in combination). Thus, emergency We consider that these therapies should have marginal evidence neurosurgery has, in our opinion, a small place as a second-line of efficacy but as they carry little risk and are relatively easy to therapy in super-refractory status epilepticus, where there is a administer, they should be used as second-line therapies in clear-cut electrographic focus and a lesion causing the epilepsy, super-refractory status epilepticus. but in no other situation. Therapies in convulsive status epilepticus Brain 2012: 135; 2314–2328 | 2323

Third line—last resort therapies Supplementary material The data on these are so deficient that assessing their place is not Supplementary material is available at Brain online. 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. References Aranda A, Foucart G, Ducasse´ JL, Grolleau S, McGonigal A, Valton L. Electroconvulsive therapy Generalized convulsive status epilepticus management in adults: a There are a few reports of effectiveness of ECT, although all pa- cohort study with evaluation of professional practice. Epilepsia 2010; tients had withdrawal or reduction of anaesthesia to allow ECT to 51: 2159–67. 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