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Status epilepticus: Refractory and
super‑refractory
Deepanshu Dubey, Jayantee Kalita, Usha K Misra

Website: Abstract:
www.neurologyindia.com
Status epilepticus (SE) is an important neurological emergency. It is defined as seizures lasting for 5 minutes
DOI: or more or recurrent seizures without recovery of consciousness to baseline between the attacks. Refractory
10.4103/neuroindia. SE (RSE) is defined as SE persisting despite sufficient dose of benzodiazepines and at least one antiepileptic
NI_958_16 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.
PMID: RSE occurs in 23%–48% of the patients and SRSE in approximately 22% of the patients with SE. In general,
xxxx 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.
Key Words:
Burst suppression, refractory status epilepticus, status epilepticus, Status epilepticus in India, super refractory
status epilepticus

Key Messages:
RSE and SRSE are serious neurological emergencies, the management protocols of which have recently been
formalized. Aggressive treatment is required in the intensive care units as the conditions have a 30–40% mortality.

S tatus epilepticus  (SE) is an important

neurological emergency, second only to
stroke as a cause of admission to a neurological
intensive care unit.[1] 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.[1,2] A
study from Thailand estimated the incidence of
Department of SE as 5.10/100,000 population.[3] In developing
Neurology, Sanjay countries, the incidence of SE is likely to be higher
Gandhi Post Graduate compared to the developed countries because of
Institute of Medical higher prevalence of central nervous system (CNS)
Sciences, Lucknow, infections and infestations in the developing
Uttar Pradesh, India countries, whereas stroke and drug withdrawal
are the common causes of SE in the developed
Address for countries.[4‑7] In the developed countries, SE is
correspondence: managed in the intensive care unit (ICU), whereas
Prof. Usha K Misra, in the developing countries, SE is managed in the
Department of Neurology,
general ward because of paucity of ICU beds.
Sanjay Gandhi Post
Graduate Institute of
This is an open access article distributed under the terms of the Creative
Medical Sciences, Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which
Raebareily Road, allows others to remix, tweak, and build upon the work non‑commercially,
Lucknow ‑ 226 014, as long as the author is credited and the new creations are licensed under
Uttar Pradesh, India. the identical terms.
E‑mail: drukmisra@
rediffmail.com For reprints contact: reprints@medknow.com
Changing definition of status epilepticus
In the 'First International League Against Epilepsy
(ILAE) Classification of Seizures,' approved in
1970,[8] 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.”[9] 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[10] to 10 minutes[11]
to 5 minutes.[12] The 30‑minute definition of SE
is based on the duration of convulsive SE that
may lead to permanent neuronal injury.[13] As
How to cite this article: Dubey D, Kalita J, Misra UK.
Status epilepticus: Refractory and super-refractory.
Neurol India 2017;65:S12-7.

S12 © 2017 Neurology India, Neurological Society of India | Published by Wolters Kluwer - Medknow
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Dubey, et al.: Status epilepticus
the majority of seizures are brief, if a seizure persists for more
than 5 minutes, it may not remit spontaneously.[14] 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.[14,15] Animal
studies also revealed that permanent neuronal injury[16] and
pharmacoresistance[17,18] 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.[19] 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.[19]
Types of status epilepticus
Until 1981, as per the ILAE guideline, SE was divided into
partial, generalized, or unilateral types, mirroring the seizure
classifications.[8,20] 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.[19]
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
1. Epileptic discharges  (EDs) >2.5 Hz or EDs  ≤2.5 Hz or
rhythmic delta/theta activity (>0.5 Hz)
AND
2. One of the following: EEG and clinical improvement after
intravenous antiepileptic drug  (AED), or subtle clinical
ictal phenomena with the EEG patterns mentioned above;
or typical spatiotemporal evolution of EEG patterns.
In patients with known epileptic encephalopathy
1. Increase in prominence or frequency of the features
Table 1: t1 and t2 of status epilepticus as per the
ILAE 2015 guidelines
Seizure type t1
Tonic–clonic SE 5 min
Focal SE with impaired consciousness 10 min
Absence status epilepticus 10-15 min
Neurology India | 2017 | Volume 65 | Supplement 1 S13
mentioned above when compared to the baseline with
observable changes in the clinical state, and improvement
of clinical and EEG features with intravenous AEDs is
defined as NCSE.[21]
Refractory status epilepticus
Refractory SE is defined as SE which is refractory to two
intravenous AEDs, one of which is a benzodiazepine.[22]
Some authorities have also defined RSE on the basis of the
duration of seizure for 1 or 2 hours.[23,24] Refractory SE occurs
in 23–43% of the patients with SE.[4,25] The short‑term mortality
of RSE is approximately three times higher compared to
nonrefractory SE.[25] 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.[22]
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.[30] In
the only prospective study, the incidence of SRSE among 804
episodes of SE was found to be 4%.[63] In the three retrospective
studies, incidence of SRSE was found to be 12.2–22% of all
episodes of SE.[60‑62] In the Indian study, encephalitis as a
cause of SE was found to be a determinant of SE progressing
to SRSE.[61] In another study, 80% of SRSE lasting for >7 days,
had a poor outcome at 1 year of follow up.[50]
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.[26] 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.[27]
Unidentified viral infections can also cause of NORSE.[28] 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.[29]
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”
t2
intensifies during SE, and the overall effect is a reduction
30 min
in the number of functional γ‑aminobutyric acid (GABA)
>60 min receptors in the cells affected in the seizure discharge.[31,32]
Unknown As GABA is the principle inhibitory transmitter, reduction
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Dubey, et al.: Status epilepticus

in GABAergic activity may be an important reason for Table 2: Drugs used in SE, their dose, and level of
seizures to become persistent. The number of glutamatergic evidence
receptors at the cell surface also increases. The decreasing Drugs Dose Level of
GABAergic receptor density may also render the GABAergic evidence
drugs (benzodiazepines or barbiturates) inefficient in First line
controlling SE.[33] Mitochondrial failure or insufficiency may IM midazolam 10 mg for >40 kg, 5 mg for 13-40 kg Level A
also be responsible for the failure of seizure termination. (Single dose)
Cellular damage and mitochondrial processes are involved IV lorazepam 0.1 mg/kg/dose max 4 mg/dose Level A
in cell necrosis and apoptosis.[34] Another category of disease May repeat once
triggering persistent SE is an inflammatory condition such IV diazepam 0.15-0.2 mg/kg/dose ma×10 mg/dose Level A
as herpes simplex encephalitis (HSE).[4‑6,35] In a cohort of 93
May repeat once
adult SE patients, 39.8% had CNS infections that included
IV phenobarbital 15 mg/kg/dose (Single dose) Level A
viral encephalitis in 20  (Japanese encephalitis in 4, HSE 3,
Prehospital
nonspecific 12), meningitis in 20 (tuberculous 5, pyogenic 3,
Rectal diazepam 0.2-0.5 mg/kg max 20 mg/ Level B
fungal 1), and the presence of a granuloma in 7 (tuberculoma 5,
Intranasal dose (single)
neurocysticercosis 2). A total of 24.3% patients were refractory
midazolam 0.25 mg/kg
to a second and 10.8% were refractory to a third AED.[4] SE
caused by viral encephalitis was refractory to a second AED in Buccal 0.25-0.5 mg/kg
midazolam
36.7% patients and to a third AED in 26.7% patients.[5]
Second line
Treatment Fosphenytoin 20 mg/kg max 1500 mg Level U
The current guidelines for managing SE are not age Valproic acid 40 mg/kg max 3000 mg Level B
specific because the disease pathophysiology of prolonged Levetiracetam 60 mg/kg max 4500 mg Level U
seizures/SE and the anticonvulsant drug effects on Third Line
neuronal receptors are the same in infants, children, and No clear Level U
adults. A benzodiazepine  (specifically IM/IV midazolam, evidence
IV lorazepam, or IV diazepam) is recommended as the initial IM = Intramuscular, IV = Intravenous
therapy of choice (level A). In prehospital settings or where
the three first‑line benzodiazepine options are not available, properties and does not cause hypotension. It has a positive
rectal diazepam, intranasal midazolam, or buccal midazolam sympathomimetic action and has the risk of drug‑induced
are reasonable initial alternatives  (level B). For second‑line hypertension, although in RSE, this is rarely a consideration.
therapy, the options include fosphenytoin (level U), valproic Second, it is potentially neuroprotective because of its
acid (level B), and levetiracetam (level U). There is no strong N‑methyl‑D‑aspartate (NMDA) antagonist action.
clear evidence that any one of these options is better than In prolonged SE, the GABA receptors are internalized and
the others.[36] A retrospective study although concludes, that NMDA receptors are present at the cell surface, which
among these drugs, valproate is the most effective in the control propagate seizures by excitotoxicity. Ketamine has been used
of SE [Table 2].[37] to control prolonged SE since 2000, although there has been
no randomized trial conducted till now.[39‑41]
Patients who do not recover to their baseline neurological
status within 20–30 min of initiating therapy should undergo Lacosamide
continuous EEG monitoring to diagnose ongoing NCSE.[38] Lacosamide is a new anticonvulsant available in an intravenous
There are no evidence‑based guidelines for managing RSE formulation. Its cardiorespiratory and systemic side effect
and SRSE. Recent recommendations for adults, relying profile is reported to be better than other commonly used AEDs.
upon limited evidence, suggest that the treatment of RSE There have been several small studies which have shown the
should be tailored to the clinical situation. The aim of the efficacy of intravenous lacosamide in SE.[42,43] A randomized
treatment of refractory SE is termination of SE as well as controlled trial has shown a comparable efficacy and side effect
minimizing the ICU‑related complications. Focal SE without profile in controlling lorazepam resistant SE (Misra et al. 2017).
significant impairment of consciousness may be treated
conservatively. Early induction of pharmacological coma Ketogenic diet
has been practiced in generalized‑convulsive SE using Ketogenic diet is generally used in severe childhood
midazolam, propofol, or barbiturates. Several other treatments encephalopathies. The emergency usage of ketogenic diet has
such as inhalational anesthetic, oral antiepileptic drugs, also been reported in SE, mostly in children. The first case series
immunomodulatory compounds, or nonpharmacological published was of six children with SRSE who responded to
approaches (electroconvulsive treatment, hypothermia, ketogenic diet.[44] Ketogenic diet successfully controlled SRSE
ketogenic diet, transcranial magnetic stimulation) have been in nine patients with NORSE.[45] It has been suggested that
used in resistant SE.[22] These therapies are anecdotal or based the effectiveness of the ketogenic diet in SRSE may be due
on small case series and their place in therapy is yet to be to a possible anti‑inflammatory action, although conclusive
established. experimental evidence of any such action is lacking.

Ketamine Recurrent transcranial magnetic stimulation

Ketamine has two theoretical advantages over the Recurrent transcranial magnetic stimulation (rTMS) is a
conventional anaesthetics. First, it has no cardiac depressant potential therapy for RSE. rTMS is a noninvasive technique

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Dubey, et al.: Status epilepticus
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.[46-52] Several case
reports describe rTMS application in medication‑refractory
focal epilepsy or RSE in non‑ICU settings, with mixed
results.[53,54] rTMS is well‑tolerated by patients with epilepsy
without reports of seizure exacerbation.[55] 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.[56]
Electroconvulsive therapy
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.[57] The use of ECT in refractory epilepsy and
SE is mentioned in psychiatry practice guidelines.[58] 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%.[59] 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.[59‑66]
Immunomodulation
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.[66] 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.[67] 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.[68]
Epilepsy surgery
In case reports, the surgical interventions included focal
cortical resection, lobar and multilobar resection, anatomic and
functional hemispherectomy, corpus callosotomy, and multiple
subpial transection.[69,70] In a series of surgical intervention
following SRSE in three patients, SRSE was successfully
terminated in two patients.[70] In a recent case report, thalamic
deep brain stimulation in a 17‑year‑old patient with SRSE was
successful.[71]
Controversies
Burst suppression
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
Neurology India | 2017 | Volume 65 | Supplement 1 S15
Table 3: Drugs used in burst suppression and their
dose and side effects
Drugs Dose Side effects
Loading Maintenance
Midazolam 0.2 mg/kg 0.2-0.6 mg/kg/h Hypotension
Respiratory depression
Tolerance
Propofol 2 mg/kg 2-5(–10) mg/kg/h Hypotension
Respiratory depression
PRIS
Pentobarbital 5 mg/kg 1‑5 mg/kg/h Hypotension
Thiopental 1-2 mg/kg 1-5 mg/kg/h Respiratory depression
PRIS = Propofol related infusion syndrome
suppression is aimed at interburst intervals of 2–30 s or even
an isoelectric EEG.[46] 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.[47] 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.[48,49] 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.[50]
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 $).[47]
Way Forward
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.[51]
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Dubey, et al.: 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.[71,72] 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.
Acknowledgement
We thank Mr. Rakesh Kumar Nigam and Mr. Shakti Kumar
for secretarial help.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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