Status epilepticus: Refractory and super-refractory
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/neuroindia.NI_958_16
Source of Support: None, Conflict of Interest: None
Status epilepticus (SE) is an important neurological emergency. It is defined as seizures lasting for 5 minutes or more or recurrent seizures without recovery of consciousness to baseline between the attacks. Refractory SE (RSE) is defined as SE persisting despite sufficient dose of benzodiazepines and at least one antiepileptic drug (AED), irrespective of time. Super refractory SE (SRSE) is defined as SE that continues for 24 hours or more after the use of anesthetic therapy, including cases that recur on weaning of the anesthestic agent. RSE occurs in 23%–48% of the patients and SRSE in approximately 22% of the patients with SE. In general, RSE occurs in patients with new-onset seizures rather than in patients with chronic epilepsy. The etiology of RSE in developing countries is dominated by central nervous system (CNS) infections and head injury compared to stroke and drug withdrawal in the developed countries. The treatment of RSE and SRSE is not evidence based. Following benzodiazepines, the second line antiepileptic drugs include sodium valproate, phenytoin, levetiracetam, and anesthetic drugs such as midazolam, phenobarbital, and propofol. Most intravenous anesthetic drugs produce hypotension and respiratory suppression; therefore, patients with RSE are managed in intensive care units (ICUs). In RSE patients, electroencephalogram (EEG) burst suppression with interburst interval of 2–20 s or even flat EEG has been tried. Recently, concerns have been raised on the safety of burst suppression in RSE and SRSE. The paucity of ICUs in developing countries limits the use of these management protocols. There is a need to explore intravenous AEDs with safer cardiovascular and respiratory profile for the management of SE.
Keywords: Burst suppression, refractory status epilepticus, status epilepticus, Status epilepticus in India, super refractory status epilepticus
Status epilepticus (SE) is an important neurological emergency, second only to stroke as a cause of admission to a neurological intensive care unit. The prevalence of SE in the United States has been estimated to be in the range of 18.3–41.0 per 100,000 population., A study from Thailand estimated the incidence of SE as 5.10/100,000 population. In developing countries, the incidence of SE is likely to be higher compared to the developed countries because of higher prevalence of central nervous system (CNS) infections and infestations in the developing countries, whereas stroke and drug withdrawal are the common causes of SE in the developed countries.,,, In the developed countries, SE is managed in the intensive care unit (ICU), whereas in the developing countries, SE is managed in the general ward because of paucity of ICU beds.
Changing definition of status epilepticus
In the 'First International League Against Epilepsy (ILAE) Classification of Seizures,' approved in 1970, SE was defined as a “seizure that persists for a sufficient length of time or is repeated frequently enough to produce a fixed and enduring condition.” In the revised classification of 1981, the definition was minimally changed to a “seizure” that “persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur.” Until 2006, a specific time frame for the definition of SE was not provided in the ILAE definition; however, different studies used progressively shrinking duration of seizures for defining SE. The duration of seizure for defining SE has come down from 30 minutes  to 10 minutes  to 5 minutes. The 30-minute definition of SE is based on the duration of convulsive SE that may lead to permanent neuronal injury. As the majority of seizures are brief, if a seizure persists for more than 5 minutes, it may not remit spontaneously. Recent SE treatment protocols have used a 5-minute definition to minimize both the risk of seizures lasting for 30 minutes, and the adverse outcomes associated with needless optimism of spontaneous remission or self-limited seizures., Animal studies also revealed that permanent neuronal injury  and pharmacoresistance , may occur before the traditional definition of 30 minutes of continuous seizure.
ILAE in 2015 proposed a new definition of SE as a condition resulting either from the failure of mechanisms responsible for seizure termination or from the initiation of mechanisms, which cause abnormally, prolonged seizures (after time point t1). SE can result in long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. In the case of convulsive (tonic–clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. There is limited information available to define t1 and t2 in focal SE, and no information is at present available for absence SE [Table 1]. The likelihood of damage is dependent on the location of the epileptic focus, the intensity of the status, the age of the patient, and other factors. Therefore, ILAE guidelines emphasized that the time limits given are for operational purposes only. These are general approximations, and the timing of onset of cerebral damage will vary considerably in different clinical circumstances.
Types of status epilepticus
Until 1981, as per the ILAE guideline, SE was divided into partial, generalized, or unilateral types, mirroring the seizure classifications., Recently, SE has been classified into 9 types, namely, epilepsia partialis continua (EPC) of Kojevnikov, supplementary motor area, aura continua, dyscognitive focal (psychomotor, complex partial), tonic–clonic, absence, myoclonic, tonic, and subtle SE.
Nonconvulsive status epilepticus
Nonconvulsive SE (NCSE) is commonly reported in critically ill patients admitted in the ICU. EEG monitoring is essential for the diagnosis of NCSE. The EEG criteria for the diagnosis of NCSE in patients without known epileptic encephalopathy includes
In patients with known epileptic encephalopathy
Refractory status epilepticus
Refractory SE is defined as SE which is refractory to two intravenous AEDs, one of which is a benzodiazepine. Some authorities have also defined RSE on the basis of the duration of seizure for 1 or 2 hours., Refractory SE occurs in 23–43% of the patients with SE., The short-term mortality of RSE is approximately three times higher compared to nonrefractory SE. In general, RSE is associated with acute, severe, and potentially fatal underlying etiologies such as encephalitis, massive stroke, or rapidly progressive primary brain tumors, and may be accompanied by severe impairment of consciousness.
Super-refractory status epilepticus
Super-refractory SE (SRSE) is defined as status epilepticus that continues for 24 hours or more after the use of anesthetic therapy, including the cases in whom SE recurs on weaning of anesthesia. It is an uncommon but important clinical problem with a high mortality and morbidity. It was a term used for the first time in the 'Third London–Innsbruck Colloquium on Status Epilepticus' held at Oxford in 2011. The exact incidence of SRSE is unknown because of paucity of prospective studies. In the only prospective study, the incidence of SRSE among 804 episodes of SE was found to be 4%. In the three retrospective studies, incidence of SRSE was found to be 12.2–22% of all episodes of SE.,, In the Indian study, encephalitis as a cause of SE was found to be a determinant of SE progressing to SRSE. In another study, 80% of SRSE lasting for >7 days, had a poor outcome at 1 year of follow up.
New-onset refractory status epilepticus
New-onset RSE (NORSE) is a rare condition characterized by the occurrence of a prolonged period of refractory seizures with no readily identifiable cause in otherwise healthy individuals. It is one of the causes of RSE and SRSE. Initially, the absence of a proven etiology was considered mandatory for the diagnosis of NORSE; however, recent reports have suggested autoimmune encephalitis as a common cause. Unidentified viral infections can also cause of NORSE. As per a recent report, autoimmune encephalitis (paraneoplastic or nonparaneoplastic) is the most commonly identified cause of NORSE; however, half of these patients remain cryptogenic. Outcome of NORSE patients is generally poor but improves during the follow-up, and epilepsy develops in most patients.
Why seizures become refractory?
It is a common clinical experience that the more severe the precipitating insult, the more likely the SE is to become refractory. However, SE also occurs frequently in previously healthy patients without an obvious cause. At the cellular level, 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 SE, 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., As GABA is the principle inhibitory transmitter, reduction in GABAergic activity may be an important reason for seizures to become persistent. The number of glutamatergic receptors at the cell surface also increases. The decreasing GABAergic receptor density may also render the GABAergic drugs (benzodiazepines or barbiturates) inefficient in controlling SE. Mitochondrial failure or insufficiency may also be responsible for the failure of seizure termination. Cellular damage and mitochondrial processes are involved in cell necrosis and apoptosis. Another category of disease triggering persistent SE is an inflammatory condition such as herpes simplex encephalitis (HSE).,,, In a cohort of 93 adult SE patients, 39.8% had CNS infections that included viral encephalitis in 20 (Japanese encephalitis in 4, HSE 3, nonspecific 12), meningitis in 20 (tuberculous 5, pyogenic 3, fungal 1), and the presence of a granuloma in 7 (tuberculoma 5, neurocysticercosis 2). A total of 24.3% patients were refractory to a second and 10.8% were refractory to a third AED. SE caused by viral encephalitis was refractory to a second AED in 36.7% patients and to a third AED in 26.7% patients.
The current guidelines for managing SE are not age specific because the disease pathophysiology of prolonged seizures/SE and the anticonvulsant drug effects on neuronal receptors are the same in infants, children, and adults. A benzodiazepine (specifically IM/IV midazolam, IV lorazepam, or IV diazepam) is recommended as the initial therapy of choice (level A). In prehospital settings or where the three first-line benzodiazepine options are not available, rectal diazepam, intranasal midazolam, or buccal midazolam are reasonable initial alternatives (level B). For second-line therapy, the options include fosphenytoin (level U), valproic acid (level B), and levetiracetam (level U). There is no clear evidence that any one of these options is better than the others. A retrospective study although concludes, that among these drugs, valproate is the most effective in the control of SE [Table 2].
Patients who do not recover to their baseline neurological status within 20–30 min of initiating therapy should undergo continuous EEG monitoring to diagnose ongoing NCSE. There are no evidence-based guidelines for managing RSE and SRSE. Recent recommendations for adults, relying upon limited evidence, suggest that the treatment of RSE should be tailored to the clinical situation. The aim of the treatment of refractory SE is termination of SE as well as minimizing the ICU-related complications. Focal SE without significant impairment of consciousness may be treated conservatively. Early induction of pharmacological coma has been practiced in generalized-convulsive SE using midazolam, propofol, or barbiturates. Several other treatments such as inhalational anesthetic, oral antiepileptic drugs, immunomodulatory compounds, or nonpharmacological approaches (electroconvulsive treatment, hypothermia, ketogenic diet, transcranial magnetic stimulation) have been used in resistant SE. These therapies are anecdotal or based on small case series and their place in therapy is yet to be established.
Ketamine has two theoretical advantages over the conventional anaesthetics. First, it has no cardiac depressant properties and does not cause hypotension. It has a positive sympathomimetic action and has the risk of drug-induced hypertension, although in RSE, this is rarely a consideration. Second, it is potentially neuroprotective because of its strong N-methyl-D-aspartate (NMDA) antagonist action. In prolonged SE, the GABA receptors are internalized and NMDA receptors are present at the cell surface, which propagate seizures by excitotoxicity. Ketamine has been used to control prolonged SE since 2000, although there has been no randomized trial conducted till now.,,
Lacosamide is a new anticonvulsant available in an intravenous formulation. Its cardiorespiratory and systemic side effect profile is reported to be better than other commonly used AEDs. There have been several small studies which have shown the efficacy of intravenous lacosamide in SE., A randomized controlled trial has shown a comparable efficacy and side effect profile in controlling lorazepam resistant SE (Misra et al. 2017).
Ketogenic diet is generally used in severe childhood encephalopathies. The emergency usage of ketogenic diet has also been reported in SE, mostly in children. The first case series published was of six children with SRSE who responded to ketogenic diet. Ketogenic diet successfully controlled SRSE in nine patients with NORSE. It has been suggested that the effectiveness of the ketogenic diet in SRSE may be due to a possible anti-inflammatory action, although conclusive experimental evidence of any such action is lacking.
Recurrent transcranial magnetic stimulation
Recurrent transcranial magnetic stimulation (rTMS) is a potential therapy for RSE. rTMS is a noninvasive technique where pulsed intracranial electrical current is induced by electromagnetic induction. In most patients, a continuous train of low frequency (≤1 Hz) pulses results in cortical suppression, whereas intermittent trains of high frequency (≥5 Hz) pulses result in facilitation of cortical excitability.,,,,,, Several case reports describe rTMS application in medication-refractory focal epilepsy or RSE in non-ICU settings, with mixed results., rTMS is well-tolerated by patients with epilepsy without reports of seizure exacerbation. Seizure suppression can be achieved by low frequency rTMS. The efficacy and safety profile of rTMS in the ICU is not well documented. Hypothetical concerns about interference with ICU electronic equipment may also limit clinical use and warrant further exploration regarding its actual clinical usage.
Electroconvulsive therapy (ECT) is an established treatment in several psychiatric disorders. It consists of applying electrical stimulation to the brain in a mildly anesthetised patient. ECT results in an electrical fit. ECT is markedly efficient, safe, and may be life-saving for patients with refractory mood disorders or schizophrenia. The use of ECT in refractory epilepsy and SE is mentioned in psychiatry practice guidelines. Although no placebo-controlled or open-label study has been published regarding the efficacy and safety of ECT in RSE, a meta-analysis on eight case reports in SE revealed seizure cessation in 80% of the patients and complete recovery in 27%. ECT might be a viable therapeutic option for the most resistant and severe cases of SE. There is a need for clinical trials to assess the usefulness of ECT in RSE.,,,,,,,
Immunological therapies have been reported in several case studies for the treatment of SRSE and most often include steroids, immunoglobulins, and plasma exchange (PLEX). Two case series reviewed adult patients receiving intravenous immunoglobulin (IVIG) for NORSE with no clear etiology. In the first study with five patients, two patients received IVIG with high dose steroids, and in one, only high dose steroid was administered. All three patients recovered without significant neurological deficits. In the other study, seven patients received immunotherapy, and three out of seven received IVIG; five patients died. The two survivors remained in a vegetative state. There is less experience with PLEX compared to steroids and immunoglobulins in SRSE. Out of the two patients with SRSE, one responded and in another, sedation was weaned off.
In case reports, the surgical interventions included focal cortical resection, lobar and multilobar resection, anatomic and functional hemispherectomy, corpus callosotomy, and multiple subpial transection., In a series of surgical intervention following SRSE in three patients, SRSE was successfully terminated in two patients. In a recent case report, thalamic deep brain stimulation in a 17-year-old patient with SRSE was successful.
In RSE and SRSE, burst suppression provides an arbitrary target for the titration of barbiturate or anesthetic treatment [Table 3] with the drug dosing commonly set in a way in which burst suppression is aimed at interburst intervals of 2–30 s or even an isoelectric EEG. The optimal extent of burst suppression is not known. For achieving EEG burst suppression, the patient requires continuous EEG monitoring with mechanical ventilation in the ICU and a facility for blood pressure and blood gas monitoring. This increases both the direct and indirect cost of the treatment. The use of burst suppression is applicable only to ICUs which are equipped with continuous monitoring of vital parameters and have a highly trained manpower. This set up is not available in a majority of secondary-level hospitals in India where most of the SE patients are managed.
Although the use of anesthetic agents in RSE had long been advocated, recent publications have shown a higher morbidity and mortality in this group. This is generally considered to be due to cardiorespiratory depressant effects of these agents, due to which the patients require a prolonged ICU stay and have associated complications., Recently ethical issues have also been raised for patients of prolonged SE in whom the outcome is poor despite aggressive treatment resulting in a burden to the society and on the patient's family.
Developing country's perspective
In the developing countries, the etiology of SE is dominated by CNS infections and trauma, whereas in the developed countries, stroke and drug default are the most common causes. Although there is no systematic prevalence study on SE, the incidence of SE is considered higher in the developing countries due to a higher prevalence of infections and traumatic brain injury. The paucity of ICU beds, lack of mechanical ventilation facility and nursing support are the factors influencing the management and outcome of SE in the developing countries. As majority of the ICU beds are in private hospitals, the patients' financial status influences the treatment decision. The cost of treating SE in a tertiary care government hospital in India was estimated to be Rs 19900 (309.87 $).
The current National Institute of Neurological Disorders and Stroke funded 'Established Status Epilepticus Treatment Trial (ESETT)' trial is comparing the role of intravenous fosphenytoin, levetiracetam, and valproate in children and adults with SE who did not respond to the initial benzodiazepine therapy. ESETT is designed to be a class I randomized control trial that will identify the optimal second therapy for benzodiazepine-resistant status epilepticus.
Although these new developments seem exciting, they need validation in proper trials. Currently, there is no guideline for the management of RSE and SRSE because of the lack of randomized controlled trials., Special circumstances in developing countries mandate that drugs with a lower potential of respiratory suppression and other systemic side effects need to be evaluated for an optimal and a cost effective management of SE.
We thank Mr. Rakesh Kumar Nigam and Mr. Shakti Kumar for secretarial help.
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Conflicts of interest
There are no conflicts of interest
[Table 1], [Table 2], [Table 3]