New Developments in

Refractory Status
Epilepticus
Sudhir Datar, MD

KEYWORDS
 Status epilepticus  Seizures  Convulsions  Refractory status epilepticus
 Electrographic status

KEY POINTS
 Status epilepticus is a medical emergency and warrants immediate evaluation and
treatment.
 Status epilepticus is conventionally defined as a seizure lasting for more than 5 minutes or
multiple seizures without full recovery of consciousness in between.
 Early treatment aimed at rapid termination of seizures is crucial and may prevent perma-
nent neuronal injury and pharmacoresistance.
 Close monitoring is essential for early detection of systemic complications, especially with
generalized convulsive status epilepticus.
 Use of antiseizure medications, anesthetic drugs when needed, and treatment of the un-
derlying cause when possible are the essential components of patient management.

INTRODUCTION

Annual incidence of status epilepticus (SE) is estimated to be around 6 to 41 per

100,000 population.1–3 Mortality estimates are 14% to 20%, with only half of the
patients returning to their prior baseline.3–6 Of all the patients presenting with SE, be-
tween 20% and 43% develop refractory status epilepticus (RSE) with mortality
approaching 40%.5,7–9
Age, potentially fatal causes, and preexisting comorbidities significantly affect mor-
tality and morbidity.4,10 Prompt recognition and early seizure termination are essential
and may prevent the development of pharmacoresistance. Animal data have
improved the understanding of the underlying pathophysiologic mechanisms respon-
sible for continuation of seizures and for loss of sensitivity to GABA agonists. Outcome

Disclosures: Dr S. Datar has no disclosures.

Section of Neurocritical Care, Departments of Neurology and Anesthesiology, Wake Forest Uni-
versity School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157, USA
E-mail address: [email protected]

Neurol Clin 35 (2017) 751–760

http://dx.doi.org/10.1016/j.ncl.2017.06.010 neurologic.theclinics.com
0733-8619/17/ª 2017 Elsevier Inc. All rights reserved.
752 Datar

is worse with increasing seizure duration.5,11,12 Impact of SE in the form of neuronal

injury and cell death is being increasingly recognized in both generalized convulsive
and nonconvulsive SE.13 More widespread use of continuous electroencephalogram
(EEG) monitoring has shown higher prevalence of SE in the intensive care unit and
inpatient settings than previously thought. This review focuses on recent updates per-
taining to the epidemiology, definitions, pathophysiology, and treatment of patients
with RSE.

DEFINITIONS

SE was previously defined as a continuous seizure lasting for more than 30 minutes or
2 or more seizures without full recovery of consciousness in between. As more data
become available showing long-term neurologic morbidity due to permanent neuronal
injury with prolonged seizures lasting less than 30 minutes, a more operational defini-
tion has now been embraced with the duration of continuous seizure shortened to
more than 5 minutes.14–16 This new definition also makes practical sense in that
most self-terminating seizures last less than 1 to 2 minutes. If a seizure lasts more
than 5 minutes, then it is less likely it will terminate spontaneously.
SE resistant to first- and second-line antiseizure medications, one of which is usu-
ally a benzodiazepine, is termed RSE. If seizures continue beyond 24 hours of anes-
thetic therapy or recur during withdrawal of the anesthetic drugs, then the term
superrefractory status epilepticus (SRSE) is used. SE is also defined based on the
type of seizure; some common examples are (1) generalized convulsive status epilep-
ticus (GCSE), primary or secondary generalized, typically presenting with repeated
tonic, clonic or tonic-clonic seizures; (2) nonconvulsive status epilepticus (NCSE), usu-
ally presenting with alteration of consciousness and either subtle clinical activity (such
as facial twitching, nystagmus) or no clinical activity and EEG showing evidence of
frequent or continuous electrographic seizures; (3) focal SE with or without alteration
of consciousness. For a complete list of all seizure types, readers are referred to the
recent report of the International League Against Epilepsy task force on classification
of SE.17

CAUSE

Causes of seizure and SE commonly encountered in clinical practice are summarized

as follows:
 Ischemic stroke
 Trauma
 Central nervous system tumors
 Meningioma
 Glioblastoma
 Metastatic tumors to the brain
 Low levels of antiseizure medications in patients with previous history of epilepsy
 Posterior reversible encephalopathy syndrome
 Encephalitis
 Infectious (for eg, herpes simplex virus, cytomegalovirus)
 Autoimmune encephalitis
 Intracranial hemorrhage
 Subarachnoid hemorrhage
 Subdural hemorrhage
 Parenchymal hemorrhage
 New Developments in Refractory Status Epilepticus 753

 Metabolic causes
 Hypoglycemia
 Hyponatremia
 Severe hypocalcemia
 Severe hypomagnesemia
 Toxic states
 Illicit drugs, either intoxication or withdrawal
 Alcohol withdrawal
 Serotonin syndrome
 Neuroleptic malignant syndrome
 Malignant hyperthermia
 Idiopathic

FIRST-LINE THERAPY

Benzodiazepines are the first-line drugs of choice for rapid control of seizures. Intra-
venous (IV) lorazepam is usually the preferred agent when venous access is immedi-
ately available based on data from controlled studies.18,19 Intramuscular midazolam
can be used as an alternate treatment when venous access is not available. A random-
ized double-blind noninferiority trial compared intramuscular midazolam to IV loraze-
pam for point-of-care use in the field by paramedics. The study showed that the
median time to treatment was 1.2 minutes for the midazolam group and 4.8 minutes
for lorazepam group; however, duration of convulsions was slightly longer in the mid-
azolam group compared with lorazepam. The investigators concluded that intramus-
cular midazolam is as safe and effective as IV lorazepam for prehospital seizure
cessation.20 A recent meta-analysis of 16 studies found that time to treatment initiation
and time to seizure termination were shorter, with intramuscular midazolam as
compared with other nonvenous medications, which included sublingual lorazepam,
buccal midazolam, and rectal diazepam.21
Resources for providing respiratory and circulatory support should be immediately
available at the time of administration of benzodiazepines because they are known
to cause hypotension and respiratory suppression. It is to be noted that untreated
SE increases the risk of hypotension and respiratory failure as demonstrated in a ran-
domized controlled trial by Alldredge and colleagues.18 In this study, the group
receiving benzodiazepines for treatment of SE had fewer cardiopulmonary complica-
tions (11%) than the placebo group (23%).

SECOND-LINE AGENTS

Commonly used second-line antiseizure medications following treatment with benzo-

diazepines are phenytoin and valproic acid. Because of its widespread availability, low
side-effect profile, and minimum interactions with other drugs, levetiracetam (in
loading doses of up to 4000 mg) has emerged as an additional second-line antiseizure
medication following benzodiazepines, although there are currently insufficient data
regarding its efficacy as a first- or second-line agent. Retrospective observational
studies report an efficacy ranging from 44% to approximately 79% when used in com-
bination with benzodiazepines.22–24 In a retrospective study comparing the efficacy of
phenytoin, valproic acid, and levetiracetam in controlling SE, valproic acid failed to
control SE in 25%, phenytoin in 41%, and levetiracetam in 48% of the episodes. There
was no significant difference in outcome at discharge.23 The established status epilep-
ticus trial (ClinicalTrials.gov Identifier: NCT01960075) is currently enrolling patients
754 Datar

with generalized tonic-clonic seizures with the goal to compare the effectiveness of
phenytoin, valproic acid, and levetiracetam in benzodiazepine refractory SE.25
Small series suggest lacosamide may be an effective initial treatment or add-on
treatment for RSE. In a review by Belcastro and colleagues,26 lacosamide was effective
as initial treatment in 8 of the 16 patients reviewed with post-stroke NCSE. In another
study by Miro and colleagues,27 lacosamide was reported to be efficacious in 65% of
34 patients with RSE. The usual loading dose across most series is 200 to 400 mg over
3 to 5 minutes followed by a maintenance dose of 400 mg divided twice a day. A recent
large review by Hofler and Trinka28 identified a total of 136 episodes of refractory SE
treated with lacosamide across 19 studies (50% nonconvulsive, 31% focal, and
19% convulsive SE). The overall success rate was reported to be 56%. Lacosamide
is generally well tolerated and has a favorable adverse effect profile. Allergic reactions,
hypotension, and atrioventricular blocks with this medication have been reported. All
current data come from small case series and case reports. Further prospective
studies are needed to establish the true efficacy of this drug in SE and RSE.

ANESTHETIC INFUSIONS

Propofol and midazolam are commonly used anesthetic drugs for the induction of
therapeutic coma to treat RSE. Both are GABA agonists and facilitate GABA-
mediated postsynaptic neuronal inhibition. An attractive property of both drugs in
comparison with barbiturates (propofol better than midazolam) is their short half-life,
thus allowing assessment of clinical status within a short period of time after the termi-
nation of the infusion. Midazolam does tend to accumulate in fat deposits, and high
doses for prolonged periods may take longer to metabolize. A randomized, single-
blind, multicenter prospective trial comparing propofol infusion to that of pentobarbital
in patients with RSE was prematurely stopped because of slow recruitment. The study
was underpowered to detect any significant difference in efficacy; however, barbitu-
rate use was associated with significantly longer mechanical ventilation.29 Propofol
is typically used as a loading dose of 1 to 2 mg/kg infused over approximately five mi-
nutes followed by a continuous infusion of 2 to 5 mg/kg/h. A rare, but potentially fatal
adverse effect of high doses of propofol is the propofol infusion syndrome, which pre-
sents with acute onset of cardiovascular collapse.
Midazolam infusion has been shown to be safe and effective in high doses of up to
3 mg/kg/h30 Hypotension occurs at higher doses, but it can be corrected with vaso-
pressors with relative ease and does not lead to worse outcomes.30
Ketamine is emerging as a very useful adjunct to GABA agents. It has been shown
that prolonged seizures are associated with internalization of GABA receptors and
consequent reduced sensitivity to GABA agonists.31 All the conventional anesthetics,
namely propofol, midazolam, and barbiturates, act via GABA receptors. It has also
been shown that during SE there is an increase in surface NMDA receptors, and
glutamate-induced excitatory currents may play a role in ongoing seizure activity
and may contribute to induce excitotoxic neuronal injury.32 In addition, NMDA activa-
tion caused by recurrent seizures can facilitate the loss of GABAergic inhibition.33
Thus, the NMDA antagonist ketamine is an attractive option for the treatment of
RSE from a pathophysiologic perspective. Efficacy of ketamine in controlling seizures
in patients with RSE is approximately 57% according to some series.34,35 Animal
studies suggest a synergistic action of benzodiazepines and ketamine in terminating
SE (ie, lower doses of each medication needed when used in combination as
compared with when either medication is used alone).36 In addition, ketamine has a
favorable hemodynamic profile, and major adverse effects are relatively rare.35
 New Developments in Refractory Status Epilepticus 755

Barbiturate use has declined in recent years with midazolam, propofol, and in some
centers, ketamine being the mainstream anesthetic agents. Pentobarbital and thio-
pental (in Europe) are now used as a last resort. Pentobarbital infusion of 1 to 5 mg/
kg/h is very effective in achieving seizure control. A recent retrospective review of
31 patients with SRSE receiving pentobarbital infusion out of a total of 116 patients
with RSE showed pentobarbital was effective in stopping SE in 90% of the patients.37
However, barbiturates cause frequent side effects, including hypotension in up to 65%
of the cases.38 With their long half-life, barbiturates cause prolonged sedation neces-
sitating increased duration of mechanical ventilation and increased risk of ventilator-
acquired pneumonia.39

CONTINUOUS ELECTROENCEPHALOGRAM MONITORING

Retrospective series examining hospitalized patients with otherwise unexplained

altered mental status and undergoing continuous EEG monitoring report an incidence
of subclinical seizures between 7% and 16% and frequencies of interictal epileptiform
discharges ranging between 10% and 29%.40,41 Patients with electrographic seizures
have been reported to have worse outcomes.42,43 Continuous EEG monitoring should
be obtained in all patients on anesthetic drips. There is a paucity of data regarding
EEG targets to guide the intensity and duration of treatment of RSE with anesthetic
drugs. The recommended endpoint is control of seizures or burst suppression for a
period of 24 to 48 hours followed by gradual weaning of the anesthetic drug.14

POSTANOXIC STATUS EPILEPTICUS

Postanoxic status epilepticus (PSE) due to cardiac arrest deserves special mention.
Because of its unique pathophysiology and frequently poor outcome, PSE has been
excluded from several studies of SE. Most seizures occurring after cardiac arrest
are of myoclonic nature and early myoclonic SE (within 48 hours of the arrest) is asso-
ciated with poor outcome.44–47 The American Academy of Neurology practice param-
eter on prediction of outcome in comatose survivors after cardiopulmonary
resuscitation considers myoclonic SE a very strong predictor of permanent unrespon-
siveness, although this document analyzed studies that predate the era of widespread
use of therapeutic hypothermia and is currently being updated.48 Recent European
Resuscitation Council guidelines advocate using status myoclonus in combination
with other predictors to predict poor outcomes in comatose survivors of cardiac ar-
rest.49 Accumulating evidence suggests that late PSE occurring after return to normo-
thermia in the presence of intact brainstem reflexes, background EEG reactivity, and
preserved cortical responses on somatosentory evoked potentials may be compatible
with a good outcome, and aggressive treatment with antiseizure medications and
therapeutic coma may be justified in such cases.44,46 It is currently unknown whether
PSE inflicts additional damage leading to worse outcomes or whether PSE is merely a
marker of anoxic ischemic brain injury. It is also unknown whether treatment of
PSE can improve outcome. It is hoped that an ongoing Dutch trial, TELSTAR
(ClinicalTrials.gov Identifier: NCT02056236), will shed some light on this. A detailed re-
view of PSE is beyond the scope of this article, and readers can find additional details
elsewhere.

NEW-ONSET REFRACTORY STATUS EPILEPTICUS

New-onset refractory status epilepticus (NORSE) is a rare and challenging disorder

that is not completely understood. It is characterized by treatment-resistant prolonged
756 Datar

seizures in otherwise previously healthy individuals without a history of epilepsy. In a

large retrospective review by Gaspard and colleagues50 examining 130 cases of
NORSE, autoimmune and paraneoplastic encephalitis was the most commonly iden-
tified cause. About half of the cases remained cryptogenic. In this study, mortality was
22%, and 37% developed epilepsy. The role of immunotherapy and anesthetic drugs
remains unclear in this disorder, although these treatment options are frequently used.
Patients have been treated with IV steroids, plasma exchange, IV immunoglobulins,
rituximab, and cyclophosphamide with variable success.51,52 It is possible that the
“cryptogenic” cases are due to currently unknown antibodies, but further research
is needed to improve the understanding of this disorder.

KETOGENIC DIET

The ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet that
has been used since the 1920s for the treatment of childhood refractory epilepsy.
However, the efficacy of KD and another diet, modified Atkins diet (MAD) in adult
cases of RSE and SRSE has not been clearly defined.53 Small case series and case
reports suggest some benefit.54,55 One recent retrospective study of 10 patients
across 4 medical centers showed resolution of SE in all patients achieving ketosis
(90% in this study) in a median of 3 days.56 Because of the labor-intensive nature of
the process and lack of strong data to prove benefit, induction and maintenance of
ketosis are usually reserved as a last resort in patients with SRSE. MAD is more toler-
able than KD and therefore may have better compliance in the long term.

OUTCOME

The status epilepticus severity score has been developed for the prediction of mortal-
ity following SE. It relies on the assessment of age (0 or 2 points, cutoff at 65), previous
history of seizures (1 point if negative, as a surrogate for acute cause), seizure type
(0, 1 or 2 points), and extent of consciousness impairment (1 point if stuporous or
comatose). A score of 0 to 2 is defined as favorable, indicating low risk of death.57
The score has undergone recent external validation; however, the optimal cutoff
was found to be 4 instead of 3 as was originally suggested.58 Further studies are
needed before this tool can be reliably used widely as a research tool and for
prognostication.
Induced coma with anesthetic agents is a universally accepted treatment after fail-
ure of first- and second-line antiseizure medications; however, evidence from random-
ized controlled trials is currently lacking. Recent observational studies have
demonstrated poor outcome with administration of anesthetic agents, apparently in-
dependent from possible confounding factors. In a large single-center observational
review of 467 patients with SE by Marchi and colleagues,6 patients treated with ther-
apeutic coma had a more prolonged hospital stay, higher infection rates, and
increased mortality as compared with patients without therapeutic coma. This effect
was more prominent in patients with complex partial status compared with GCSE
or NCSE in coma. Two other studies also showed increased risk of mortality and
poor outcome with the use of anesthetic drugs in SE.59,60 In a recent study by Alvarez
and colleagues10 examining 236 patients with SE across 2 health care systems, one in
Massachusetts and the other in Switzerland, the investigators did not find any evi-
dence of increased mortality among patients treated with therapeutic coma, but hos-
pital length of stay was longer in this group. The lack of association with mortality in
this study as opposed to previous ones may be explained by better adjustment for
SE refractoriness. Randomized controlled trials testing the impact of therapeutic
 New Developments in Refractory Status Epilepticus 757

coma in SE are needed. With accumulating evidence suggesting neuronal damage

during both GCSE and NCSE with coma, protecting the brain from excitotoxicity using
anesthetic agents, especially for early control of seizures, is standard practice. For
focal SE, the risk-benefit balance is less clear, and it may be reasonable to delay initi-
ation of anesthetic infusions in these patients, opting instead to use additional antisei-
zure medications first.

SUMMARY

The goal of treatment in SE is early seizure control. IV lorazepam is usually the first-line
drug if immediate venous access is available; otherwise, intramuscular midazolam is a
reasonable alternative. Benzodiazepines are then followed by one of the longer-acting
antiseizure medications, most often phenytoin or valproic acid, sometimes levetirace-
tam. The drugs are administered as a bolus loading dose followed by maintenance
doses. The clinician must ensure optimum dosing of the medications before consid-
ering treatment failure.
Following failure of these 2 groups of medications in appropriate doses, anesthetic
infusions, typically propofol or midazolam, are used. Ketamine can be added to
the regimen. Pentobarbital is typically reserved for SRSE not responding to the other
anesthetics. In patients with focal SE, additional antiseizure medications can be
considered in lieu of directly proceeding to early therapeutic coma.
Seizures should be treated while ensuring adequate circulation and respiration, with
mechanical ventilation often needed, and managing the cause of SE. Continuous EEG
monitoring must be used in patients on anesthetic drips. The optimal intensity of treat-
ment with anesthetic drugs and the best EEG targets are not well defined because of
lack of high-quality data. Clinical and electrographic seizure control and burst sup-
pression are both reasonable goals and must be individualized for each patient. A
duration of 24 to 48 hours of electrographic seizure control is generally recommended.
During this time, patients are typically given at least 2 antiseizure medications in op-
timum doses. Drug levels when appropriate can be checked to ensure adequate
serum concentrations needed for seizure control. Anesthetic drips are then gradually
withdrawn over several hours while carefully monitoring the EEG for reemergence of
seizures. If that happens, the patient may need reescalation of anesthetic drugs and
addition/substitution of conventional antiseizure medications. When seizure control
is achieved, anesthetic drips and life support are discontinued as and when appro-
priate. It is not uncommon for patients to end up with polypharmacy, and drug inter-
actions can be a problem; however, these can be minimized by careful selection of
antiseizure medications as they are added to the treatment regimen.

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