The Treatment of Super-refractory Status Epilepticus

A Critical Review of Available Therapies and a Clinical Treatment Protocol

Simon Shorvon; Monica Ferlisi

Disclosures

Brain. 2011;134(10):2802-2818. 

In This Article

Abstract and Introduction

Abstract

Super-refractory status epilepticus is defined as status epilepticus that continues or recurs 24 h or more after the onset of anaesthetic therapy, including those cases where status epilepticus recurs on the reduction or withdrawal of anaesthesia. It is an uncommon but important clinical problem with high mortality and morbidity rates. This article reviews the treatment approaches. There are no controlled or randomized studies, and so therapy has to be based on clinical reports and opinion. The published world literature on the following treatments was critically evaluated: anaesthetic agents, anti-epileptic drugs, magnesium infusion, pyridoxine, steroids and immunotherapy, ketogenic diet, hypothermia, emergency resective neurosurgery and multiple subpial transection, transcranial magnetic stimulation, vagal nerve stimulation, deep brain stimulation, electroconvulsive therapy, drainage of the cerebrospinal fluid and other older drug therapies. The importance of treating the identifying cause is stressed. A protocol and flowchart for managing super-refractory status epilepticus is suggested. In view of the small number of published reports, there is an urgent need for the establishment of a database of outcomes of individual therapies.

Introduction

Tonic–clonic status epilepticus is a medical emergency. Treatment is aimed at stopping seizures largely in order to avoid cerebral damage and other morbidity.

All contemporary protocols take a staged approach to treatment (Fig. 1). Typically, in Stage 1 (early status epilepticus), therapy is with benzodiazepines. If seizures continue despite this therapy, the patient is said to be in Stage 2 (established status epilepticus) and therapy is with intravenous anti-epileptic drugs such as phenytoin, phenobarbital or valproate. If seizures continue despite this treatment for up to 2 h, the patient is said to be in Stage 3 (refractory status epilepticus) and general anaesthesia is usually recommended, at a dose that results in EEG burst suppression (a level of anaesthesia at which all seizure activity is usually controlled). It is interesting in passing to note that anaesthesia has been recommended since the mid-19th century, and John Hughlings Jackson (who is commemorated in this issue of Brain) for instance writes that 'chloral is the best drug; and if the fits are very frequent, etherisation will help' (Hughlings Jackson, 1888).

Figure 1.

The stages of treatment of status epilepticus. It is universal practice to stage therapy of status epilepticus. A typical protocol is summarized above. If Stage 1 therapy is ineffective after 30 min, Stage 2 therapy is initiated, and if this is ineffective within 2 h, Stage 3 therapy with general anaesthesia is instituted. Status epilepticus that has either not responded or has recurred 24 h after the initiation of anaesthetic therapy can be considered to have reached the stage of 'super-refractory status epilepticus'. IV = intravenous.

A protocol such as this (albeit with variations) has been recommended on numerous occasions in the past three decades (Delgado-Escueta et al., 1984; EFA Working Group, 1993; Shorvon, 1994; Appleton et al., 2000; SIGN, 2003; Meierkord et al., 2006, 2010; Minicucci et al., 2006; Shorvon et al., 2008).

In most patients, this treatment regimen is sufficient to control the seizures. In some though seizures continue or recur. Super-refractory status epilepticus is defined as status epilepticus that continues or recurs 24 h or more after the onset of anaesthetic therapy, including those cases that recur on the reduction or withdrawal of anaesthesia. It was a term used first in the Third London-Innsbruck Colloquium on status epilepticus held in Oxford on 7–9th April 2011 (Shorvon and Trinka, 2011).

Super-refractory status epilepticus is not uncommonly encountered in neurointensive care, but its exact frequency is not known. In the only prospective study, 22% of all the cases with status epilepticus (29 of 108 cases) admitted to hospital failed to respond to first and second lines of therapy, and of these, 41% (12 cases) required coma induction (however, it should be noted that only 47 of the 108 patients had convulsive status epilepticus and presumably it is mainly in these in whom coma induction was needed). Other retrospective studies have shown that 12–43% of the cases with status epilepticus become refractory (Lowenstein and Aldredge, 1993; Mayer et al., 2002; Holtkamp et al., 2005; Rosetti et al., 2005). In the series of 35 patients of Holtkamp et al. (2005), seven (20%) recurred within 5 days of tapering the anaesthetic drug and in all other studies at least 50% of those requiring anaesthesia will become super-refractory. From these published findings, it can be estimated that ~15% of all the cases with status epilepticus admitted to hospital will become super-refractory. All neurologists are likely to be involved with the care of patients with super-refractory status epilepticus, or consulted by their intensivist colleagues about how best to proceed in this situation. The treatment of this issue is a terra incognita from the point of view of evidence-based medicine, yet a landscape where action is required. This review outlines available approaches for treatment and medical management of patients in what can be a dire clinical predicament.

Why Does Status Epilepticus Become Super-refractory?

This question is obviously crucial to successful management. It is a common clinical experience that the more severe the precipitating insult (for instance, in status epilepticus after trauma infection or stroke), the more likely is the status epilepticus to become super-refractory. However, super-refractory status epilepticus also occurs frequently in previously healthy patients without obvious cause.

In all these cases, the processes that normally terminate seizures have proved insufficient (for review, see Lado and Moshe, 2008). At a cellular level, one of the most interesting recent discoveries has been the recognition that receptors on the surface of axons are in a highly dynamic state, moving onto (externalization), away from (internalization) and along the axonal membrane. This 'receptor trafficking' intensifies during status epilepticus, and the overall effect is a reduction in the number of functional γ-aminobutyric acid (GABA) receptors in the cells affected in the seizure discharge (Arancibia and Kittler, 2009; Smith and Kittler, 2010). As GABA is the principle inhibitory transmitter, this reduction in GABAergic activity may be an important reason for seizures to become persistent. Furthermore, the number of glutaminergic receptors at the cell surface increases, and the reduction in the density of the GABA receptors is itself triggered it seems by activation of the glutaminergic receptor systems. Why this should happen is unknown, and from the epilepsy point of view is certainly maladaptive. This loss of GABAergic receptor density is also the likely reason for the increasing ineffectiveness of GABAergic drugs (such as benzodiazepines or barbiturates) in controlling seizures as the status epilepticus becomes prolonged (Macdonald and Kapur, 1999). It has also been repeatedly shown that the extracellular ionic environment, which can change in status epilepticus, may be an important factor in perpetuating seizures, and the normally inhibitory GABA(A)-mediated currents may become excitatory with changes in extracellular chloride concentrations (Lamsa and Taira, 2003).

Other cellular events might also be important. Mitochondrial failure or insufficiency may be one reason for the failure of seizure termination and cellular damage and mitochondrial processes are involved in cell necrosis and apoptosis (Cock et al., 2002). Another category of disease triggering persistent status epilepticus is inflammatory disease (Tan et al., 2010), and inflammatory processes may be important in the persistence of status epilepticus. The opening of the blood–brain barrier almost certainly plays a major role in the perpetuation of seizures, due to a variety of possible mechanisms (Friedman and Dingledine, 2011), and this may be especially the case in status epilepticus due to inflammation (Marchi et al., 2011). This may explain the benefits of steroids in the therapy of status epilepticus. Leakage of the blood–brain barrier will also lead to higher potassium levels and excitation (David et al., 2009). No genetic mechanism has been identified to explain the failure of seizure termination although massive changes in gene expression occur within minutes of the onset of status epilepticus.

At a systems level, it has been suggested rather fascinatingly and counter intuitively that status epilepticus results from a failure to synchronize seizure activity (Schindler et al., 2007a, b; Walker, 2011), and that the lack of synchrony somehow prevents seizure termination.

These mechanisms influence strategies for therapy. However, often overriding is the importance of establishing cause of the status epilepticus, for emergency therapy directed at the cause may be crucial in terminating the episode (for review of the influence of aetiology on prognosis, see Neligan and Shorvon, 2011).

Cerebral Damage Induced by Status Epilepticus

The cerebral damage of status epilepticus includes neuronal cell necrosis, gliosis and network reorganization. The classic work by Meldrum and colleagues (1973a, b) suggested that the major initiating process causing cell death was excitotoxicity (as opposed to anoxia or hypoglycaemia for instance; for review see Meldrum, 1991). The process is driven by massive glutaminergic receptor over-activity, which accompanies continuous seizures. This causes calcium influx into the cells that triggers a cascade of harmful processes resulting in necrosis or apoptosis. This cascade is usually initiated after a few hours of continuous seizure activity, and it is because of this that the recommendation is made to initiate anaesthesia after seizures have persisted for >1–2 h. The processes induced by this cascade, however, may occur rapidly over minutes or take weeks to take full effect, and these include mitochondrial dysfunction, oxidative stress, release of neurotrophins and neurohormones, inflammatory reactions, dendritic remodelling, neuromodulation, immunosuppression and the activation of several molecular signalling pathways that mediate programmed death (Löscher and Brandt, 2010). In the longer term, structure changes and histological changes include neurogenesis and angiogenesis (Pitkanen and Lukasiuk, 2009, 2011).

To prevent excitotoxicity, all electrographic activity should be suppressed and so anaesthesia is usually recommended to be administered at a dose that achieves the level of EEG burst suppression (a depth of anaesthesia that has usually been found sufficient to stop EEG epileptic activity; Amzica, 2011). A number of neuroprotective strategies have been suggested to prevent the consequences of the excitotoxicity cascade, and some have been incorporated into therapy (for instance, hypothermia, barbiturate, steroids and ketamine), although how these influence outcome clinically is not known.

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