Status Epilepticus, Refractory Status Epilepticus, and Super-Refractory Status Epilepticus

REVIEW ARTICLE
Status Epilepticus, 
Refractory Status C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
Epilepticus, and
Super-refractory Status
Epilepticus CITE AS:
By Sarah E. Nelson, MD; Panayiotis N. Varelas, MD, PhD, FNCS, FAAN CONTINUUM (MINNEAP MINN)
2018;24(6, NEUROCRITICAL CARE):
1683–1707.
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVEIbF/e7oEAXuzVwmazllqbBpkQiiGqt6qR5mpPQnj8HzX5DeVo03c0= on 12/06/2018
Address correspondence to
ABSTRACT Dr Sarah E. Nelson, Johns
Hopkins University, 600 N Wolfe
PURPOSE OF REVIEW: Status epilepticus, refractory status epilepticus, and St, Phipps 455, Baltimore, MD
super-refractory status epilepticus can be life-threatening conditions. This 21287, snelso43@jhmi.edu.
article presents an overview of the three conditions and discusses their
RELATIONSHIP DISCLOSURE:
management and outcomes. Dr Nelson receives grant
support from the Johns Hopkins
RECENT FINDINGS: Status epilepticus was previously defined as lasting for Anesthesiology and Critical Care
Medicine (ACCM) Stimulating
30 minutes or longer but now is more often defined as lasting 5 minutes and Advancing ACCM Research
or longer. A variety of potential causes exist for status epilepticus, (StAAR) program. Dr Varelas
refractory status epilepticus, and super-refractory status epilepticus, serves on the board of directors
of the Neurocritical Care
but all three ultimately involve changes at the cellular and molecular Society, on the editorial board
level. Management of patients with status epilepticus generally of Neurocritical Care, and on an
advisory board of Portola
requires several studies, with EEG of utmost importance given the Pharmaceuticals, Inc.
pathophysiologic changes that can occur during the course of status Continued on page 1707
epilepticus. Status epilepticus is treated with benzodiazepines as
first-line antiepileptic drugs, followed by phenytoin, valproic acid, or UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
levetiracetam. If status epilepticus does not resolve, these are followed USE DISCLOSURE:
by an IV anesthetic and then alternative therapies based on limited Drs Nelson and Varelas discuss
data/evidence, such as repetitive transcranial magnetic stimulation, the unlabeled/investigational
use of allopregnanolone, deep
therapeutic hypothermia, immunomodulatory agents, and the ketogenic brain stimulation, desflurane,
diet. Scores have been developed to help predict the outcome of status diazepam, electroconvulsive
epilepticus. Neurologic injury and outcome seem to worsen as the duration therapy, fosphenytoin,
gabapentin, isoflurane, IV
of status epilepticus increases, with outcomes generally worse in immunoglobulin, ketamine,
super-refractory status epilepticus compared to status epilepticus and ketogenic diet, lacosamide,
levetiracetam, lidocaine,
sometimes also to refractory status epilepticus.
lorazepam, methylprednisolone,
midazolam, pentobarbital,
SUMMARY: Status epilepticus can be a life-threatening condition associated phenobarbital, phenytoin,
plasma exchange, propofol,
with multiple complications, including death, and can progress to pyridoxine, thiopental,
refractory status epilepticus and super-refractory status epilepticus. More topiramate, vagal nerve
studies are needed to delineate the best management of these three stimulation, and valproic acid
for the treatment of refractory
entities. status epilepticus.
© 2018 American Academy

of Neurology.
CONTINUUMJOURNAL.COM 1683
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

STATUS EPILEPTICUS
KEY POINTS
INTRODUCTION
S
● While in the past, tatus epilepticus is a common neurologic emergency that requires
tonic-clonic status prompt treatment to decrease morbidity and mortality. Best
epilepticus was defined as management continues to evolve for this condition. This article
continuous seizure activity
or two or more seizures
reviews the current definitions of status epilepticus, refractory status
without recovery of epilepticus, and super-refractory status epilepticus as well as their
consciousness lasting longer epidemiology, etiology, pathophysiology, diagnosis, management, and
than 30 minutes, outcomes. It is important to note that guidelines for the evaluation and treatment
tonic-clonic status
of status epilepticus have been published by the Neurocritical Care Society.1
epilepticus is now defined
as seizure activity lasting Treatment guidelines have also recently been published by the American
5 minutes or longer, with Epilepsy Society, but they stop short of addressing refractory status epilepticus
30 minutes being the cutoff and super-refractory status epilepticus.2
for development of
long-term consequences.
DEFINITIONS
● No standard definition for Typical seizures are fewer than 5 minutes in duration and are self-limited, but
nonconvulsive status those that are longer tend not to resolve on their own.1 Traditionally, status
epilepticus currently exists.
A working definition epilepticus was defined as continuous seizure activity or two or more seizures
differentiates diagnostic without recovery of consciousness lasting longer than 30 minutes. However, status
criteria based on whether epilepticus is now often defined by two time points, t1 and t2, identified as the time
epileptic encephalopathy beyond which seizures are likely to be prolonged and the time beyond which
is present.
seizures lead to long-term consequences, respectively; for tonic-clonic seizures,
● Refractory status t1 is 5 minutes and t2 is 30 minutes, but for focal status epilepticus or absence status
epilepticus is continuous these time points are different or unknown.2,3
seizure activity not Status epilepticus has several subtypes, including convulsive status
controlled by first-line and
epilepticus, epilepsia partialis continua, and nonconvulsive status epilepticus. In
second-line antiepileptic
drugs; it occurs in 9% to 43% convulsive status epilepticus, repetitive tonic-clonic movements occur, followed
of all cases of status by a postictal state. In epilepsia partialis continua, focal neurologic deficits such
epilepticus. as aphasia and motor dysfunction occur as a result of partial seizures, but altered
mental status is not present. Continuous or fluctuating mental status changes
● Super-refractory status
epilepticus is defined either occur in nonconvulsive status epilepticus.2 Although no definitive criteria for
as status epilepticus not nonconvulsive status epilepticus exist, a working definition is listed in
TABLE 5-1.
4,5
controlled by third-line
anesthetic agents or as Refractory status epilepticus is continuous seizure activity not controlled by
status epilepticus continuing
for 24 hours or longer after
first-line and second-line antiepileptic drugs (AEDs).6 Super-refractory status
anesthesia is administered. epilepticus is defined as status epilepticus not controlled by third-line agents.7
The exact incidence and Another definition posits that super-refractory status epilepticus exists if status
associated mortality of epilepticus continues for 24 hours or longer after anesthesia is administered.8
super-refractory status
epilepticus are unknown.
EPIDEMIOLOGY
● The annual incidence of The next section reviews the epidemiology of status epilepticus, refractory status
status epilepticus is
epilepticus, and super-refractory status epilepticus.
approximately 12.6 per
100,000 person-years and is
increasing over time. Seizures Status Epilepticus
or status epilepticus may The pooled crude annual incidence rate of status epilepticus is approximately 12.6
occur in up to 19% of patients
hospitalized in the intensive
per 100,000 person-years.9 In the intensive care unit (ICU) specifically, seizures
care unit. or status epilepticus may occur in up to 19% of patients, although studies
evaluating this frequency are limited by their retrospective nature and different
definitions.10 Of those with status epilepticus, 12% to 43% progress to refractory
status epilepticus and 10% to 15% progress to super-refractory status epilepticus.8
1684 DECEMBER 2018

Status epilepticus incidence appears to peak at ages older than 50 years
(approximately 28.4 per 100,000 per year) and younger than 10 years (14.3 per
100,000 per year) and seems to be greater in African Americans (13.7 per
100,000 per year) compared to whites (6.9 per 100,000 per year) and other
races (7.4 per 100,000 per year).11 Although previous studies found a greater
incidence of status epilepticus in males,12–14 recent estimates suggest that the
rates for both sexes are more similar than previously thought (11.1 per 100,000
person-years in females, 11.3 per 100,000 person-years in males).9 The overall
case fatality rate appears to be close to 15%, with a greater case fatality rate
occurring in the elderly (24.9%) and in patients with refractory status
epilepticus (33.3%).9
The incidence of status epilepticus appears to be increasing over time. In a
study evaluating data from the US National Hospital Discharge Survey, between
1979 and 2010, the incidence of status epilepticus was found to increase from 3.5
per 100,000 per year to 12.5 per 100,000 per year but with no significant change
in in-hospital mortality.11 In a 2015 study that used data from the Centers for
Disease Control and Prevention and the Nationwide Inpatient Sample, status
epilepticus hospitalizations increased by 56.4% from 1999 (8.9 per 100,000
persons) to 2010 (13.9 per 100,000 persons). Mortality also increased over
this same time period, but only by 5.6% (1.8 per 1 million persons to 1.9 per
1 million persons).15
In the United States, 120,000 to 180,000 convulsive status epilepticus
episodes occur annually,16 but the incidence of nonconvulsive status epilepticus
is not as well established.17 Several studies in the late 1990s and early 2000s more
clearly delineated the frequency of seizure types. In a prospective study of status
epilepticus in Richmond, Virginia, seizure types were determined to be
generalized in 74% and partial in 26% of cases.12 A study evaluating status
Criteria for Nonconvulsive Status Epilepticusa TABLE 5-1
Patients Without Epileptic Encephalopathyb

◆ Epileptic discharges greater than 2.5 Hz
OR
◆ Epileptic discharges greater than 2.5 Hz or rhythmic delta/theta activity and one of the
following:
◇ Subtle clinical ictal phenomena during the above EEG patterns
◇ Spatiotemporal evolution
◇ EEG and clinical improvement after IV antiepileptic drugs
Patients With Epileptic Encephalopathyb
◆ Increase in frequency or prominence of the above EEG findings compared to baseline
along with change in clinical state
◆ EEG and clinical improvement with IV antiepileptic drugs
EEG = electroencephalogram; IV = intravenous.

a
Modified with permission from Beniczky S, et al, Epilepsia.4 © 2013 John Wiley and Sons.
b
Epileptic encephalopathy indicates that epileptic activity contributes to behavioral and cognitive
problems in excess of what would be expected from the underlying pathology.5

STATUS EPILEPTICUS
KEY POINT epilepticus in French-speaking Switzerland found that the most common seizure
type was partial (44.8%), followed by generalized tonic-clonic (33.1%).13
● The etiology of status
epilepticus may be divided
into known or symptomatic Refractory and Super-refractory Status Epilepticus
causes and unknown or Refractory status epilepticus occurs in 9% to 43% of all cases of status
cryptogenic causes. In epilepticus.6,7 In one study of 395 patients with refractory status epilepticus
general, acute causes
treated in the ICU, the annual incidence was found to be 3.4 per 100,000.18 As
appear to be more common
than chronic causes. expected, prospective studies19 estimate a lower incidence than retrospective
studies.20–22 Predictors of refractory status epilepticus were lower level of
consciousness and new diagnosis of status epilepticus in one study19 and focal
motor seizures at onset and nonconvulsive status epilepticus in another.21
The exact incidence and associated mortality of super-refractory status
epilepticus have not yet been delineated, likely because of the low number of
patients with this condition and lack of prospective studies.23 One estimate is that
10% to 15% of all in-hospital cases of status epilepticus will evolve into
super-refractory status epilepticus.23 In a 2015 study that used the Finnish
Intensive Care Consortium database, 22% of patients with refractory status
epilepticus were categorized as having super-refractory status epilepticus, with
an annual incidence estimate of 0.7 per 100,000 persons.8 Of 98 patients in West
China diagnosed with status epilepticus, 12.2% had super-refractory status
epilepticus (by comparison, the percentages of patients with nonrefractory
status epilepticus and refractory status epilepticus were 67.3% and 20.4%,
respectively). In this study, convulsive status epilepticus was the main seizure
type in patients with super-refractory status epilepticus (as compared to
nonconvulsive status epilepticus).24
Another study examined 177 patients with convulsive status epilepticus in
India. While 105 (59.3%) patients had nonrefractory status epilepticus, 72
(40.7%) had refractory status epilepticus, of which 30 (16.9% of the total 177)
had super-refractory status epilepticus. Super-refractory status epilepticus was
more common in children and the elderly.25 In a study of patients with status
epilepticus who did not respond to first-line AEDs, seven episodes (20%) met the
authors’ definition of malignant status epilepticus (persistent clinical and/or
electrographic seizure activity that recurred within 5 days of weaning the
maximum dose of IV anesthetics that resulted in EEG burst suppression), which
appears to be similar to the definition of super-refractory status epilepticus.
Patients with malignant status epilepticus were younger than patients with
refractory status epilepticus.26
ETIOLOGY
Status epilepticus may have a structural, infectious, toxic-metabolic, or
autoimmune cause (TABLE 5-2).1 According to the International League Against
Epilepsy, the etiology of status epilepticus may be divided into two groups:
(1) known or symptomatic and (2) unknown or cryptogenic. The symptomatic
group can be subdivided into acute symptomatic, remote symptomatic, and
progressive symptomatic.3 In general, acute causes appear to be more common
than chronic causes.9 The underlying etiology for status epilepticus often
influences the likelihood of a patient’s mortality.15
Interestingly, etiologies seem to vary among different populations. In one
prospective population-based study of 150 patients with status epilepticus
conducted in Germany, the most common etiologies were a remote stroke
1686 DECEMBER 2018

(36.0%) or other remote symptomatic cause (26.7%).14 In a study analyzing
status epilepticus in Richmond, Virginia, the most common etiologies in adults
were low AED levels (34%), remote etiology (24%), and stroke (22%).12 A study
in Switzerland found that status epilepticus due to an acute etiology (eg, traumatic
brain injury, tumor, stroke, metabolic derangement; 62.7%) was more common
than status epilepticus due to a remote etiology (eg, chronic infection, autoimmune
disease, degenerative disease; 28.4%) or due to an unknown etiology (8.7%).13
The etiology of refractory status epilepticus appears to be similar overall
to that of nonrefractory status epilepticus. In one study of 54 patients who
experienced 63 episodes of refractory status epilepticus, low AED levels
(or missed doses) were the most common etiology, followed by metabolic causes
and central nervous system infection.27 Another study found that refractory
status epilepticus was more likely associated with encephalitis and nonrefractory
status epilepticus with low AED levels.20 Similarly, in a study examining the
differences between refractory status epilepticus and nonrefractory status
epilepticus, central nervous system infections were found in greater frequency in
patients with refractory status epilepticus; viral encephalitis, in particular, was
more common in this group.28
The etiology of super-refractory status epilepticus may be different than that
of status epilepticus and refractory status epilepticus.29 Several studies suggest
that encephalitis is a frequent cause of super-refractory status epilepticus
(CASE 5-1).24–26 Encephalitis was the most common etiology in super-refractory
status epilepticus at 66.7% (compared to 12.3% in nonrefractory status
epilepticus) in one study and was found to predict the progression of status
epilepticus to super-refractory status epilepticus.25 It was also identified as an
Possible Causes of Status Epilepticusa TABLE 5-2
Acute Causes
◆ Acute stroke (eg, ischemic stroke, intracerebral hemorrhage)
◆ Head trauma
◆ Central nervous system infections (eg, abscess, meningitis, encephalitis)
◆ Hypoxic brain injury
◆ Posterior reversible encephalopathy syndrome (PRES)
◆ Autoimmune and paraneoplastic etiologies (eg, anti–N-methyl-D-aspartate [NDMA] receptor
encephalitis)
◆ Sepsis
◆ Metabolic disturbances (eg, hypoglycemia, abnormal electrolytes)
◆ Drug withdrawal, toxicity, or noncompliance
Chronic Causes
◆ History of epilepsy (eg, due to noncompliance with antiepileptic drugs)
◆ Brain tumor
◆ Previous brain pathology (eg, due to trauma, stroke, cortical dysplasia)
a
Modified with permission from Brophy GM, et al, Neurocrit Care.1 © 2012 Springer Science+Business
Media, LLC.

STATUS EPILEPTICUS
CASE 5-1 A 24-year-old man presented with fever, nausea, headache, and
generalized tonic-clonic seizures. His past medical history was
unremarkable. He was admitted to the neurocritical care unit, where he
was placed on continuous EEG. CT and MRI of the brain and CSF analysis
(including multiple viral cultures and a paraneoplastic panel) were
unremarkable aside from a mild CSF pleocytosis. Body positron emission
tomography (PET) and testicular ultrasound were normal, but PET of the
brain showed occipital lobe hypometabolism (FIGURE 5-1), and this finding
can be seen in anti–N-methyl-D-aspartate (NMDA) receptor antibody
encephalitis, but despite extensive autoimmune testing he never tested
positive for any antibody.30 He was initially treated with 5 days of
methylprednisolone with no improvement; he was then given five
sessions of plasma exchange.
EEG initially showed electrographic seizures that started in the right
posterior temporal region with subsequent spread first to the rest of the
right hemisphere and then bilaterally (FIGURE 5-2). He had a clinical
correlate of left head deviation, nystagmus, and left face and limb tonic-
clonic activity with some of the seizures, but many had no clear clinical
correlate. He was monitored with continuous EEG for longer than a week
and required multiple medications, including IV levetiracetam,
phenytoin, lacosamide, and phenobarbital. He also required multiple
continuous anesthetic agents, including midazolam, propofol, and
ketamine, to achieve burst suppression. Because additional seizure
control was still needed, he was also started on the ketogenic diet; it was
discontinued 4 days later because of severe metabolic acidosis.
FIGURE 5-1
Positron emission tomography (PET) of the patient in CASE 5-1. The green areas show occipital
lobe hypometabolism, and normal brain metabolism is depicted in black and blue colors.
1688 DECEMBER 2018

FIGURE 5-2
EEG of the patient in CASE 5-1. Seizure onset in the right posterior temporal region (A) with CONTINUED ON
spread to the rest of the right hemisphere (B) and subsequently bilaterally (C). PAGE 1690

STATUS EPILEPTICUS
independent risk factor for malignant status epilepticus (which had a definition
similar to super-refractory status epilepticus in one study, as discussed above).26
In a status epilepticus cohort in China, the most common cause of super-refractory
status epilepticus was acute encephalitis (67.7% of super-refractory status
epilepticus cases).24
The term new-onset refractory status epilepticus (NORSE) has recently emerged
to define patients who have prolonged refractory status epilepticus with no
readily identifiable cause (although an autoimmune or viral encephalitis etiology
may later be found). In a multicenter retrospective study of patients for
whom seizure etiology was not known within 48 hours of admission, out of
675 cases of refractory status epilepticus, 130 cases fulfilled NORSE criteria
(19%). In 47% of these NORSE cases, an etiology was later determined, including
nonparaneoplastic autoimmune (40%), paraneoplastic (30%), and infectious
causes (16%). Anti–N-methyl-D-aspartate (NMDA) receptor antibodies were the
most common causes of both nonparaneoplastic autoimmune and paraneoplastic
etiologies, while herpes viruses (except herpes simplex virus type 1) were the
most frequent infectious cause. Approximately 64% of patients were females,
and 48% were older than 50 years of age. Prodromal symptoms, including
confusion, fever, fatigue, and headache, preceded NORSE onset in 46% of the
cases. Unilateral seizure onset on EEG was more common than bilateral
independent, multifocal, and generalized onsets, and EEG findings did not differ
between patients whose seizure etiology was determined and those whose was
not. MRI abnormalities were found in 62% of cases, most commonly in limbic or
neocortical structures, or both. CSF abnormalities were discovered in 73%, and
no difference was seen in MRI or CSF findings between those with and without
an identified etiology. The type and number of AEDs prescribed for both
cryptogenic and noncryptogenic cases were similar. Status epilepticus duration
was longer in patients whose seizures were of cryptogenic origin (8 days versus
4 days), but ICU and hospital stay duration were similar. Thirty-eight percent
of patients achieved a good or fair outcome (modified Rankin Scale [mRS]
score of 0 to 3) at discharge. Multivariate predictors of both poor outcome
(mRS score of >3) and mortality included the Status Epilepticus Severity Score
CONTINUED FROM After weaning from burst suppression, his EEG showed nearly
PAGE 1689 continuous multifocal sharp waves and diffuse generalized rhythmic
delta activity but no seizures. His examination steadily improved, and
he was successfully extubated a few days later. Antiepileptic drugs
were weaned, and he was eventually discharged on levetiracetam,
lacosamide, and a slow phenobarbital taper as well as oral prednisone for
his presumed diagnosis of autoimmune encephalitis. His EEG before
discharge showed intermittent left temporal slowing.
COMMENT This case illustrates that super-refractory status epilepticus from presumed
encephalitis may respond to immunomodulatory therapy and to multiple
antiepileptic drugs. It may need to be evaluated with extensive laboratory
workup and a PET scan in addition to traditional CSF studies and MRI of the brain.
1690 DECEMBER 2018

(STESS) (refer to the section on prognostic scores and the future of status KEY POINTS
epilepticus research later in this article), status epilepticus duration, and
● Encephalitis appears to
number of complications.31 be a common cause of both
refractory status epilepticus
PATHOPHYSIOLOGY and super-refractory status
At the cellular level, several changes seem to occur that allow a seizure to evolve epilepticus.
into and maintain as status epilepticus. Protein phosphorylation, the release of
● New-onset refractory
neurotransmitters, and the opening and closing of ion channels occur in status epilepticus (NORSE)
milliseconds to seconds after seizure onset. In the next seconds to minutes, has recently emerged as a
changes in receptor trafficking occur, including an increase in excitatory challenging disorder in
α-amino-3-hydroxy-5-methylisoxazole-4 propionic acid (AMPA) and NMDA which the etiology of
refractory status epilepticus
receptors and a decrease in inhibitory γ-aminobutyric acid (GABA)A β2, β3, and is not immediately apparent.
γ2 subunits. Resistance to benzodiazepines with time may be due to modulation
of these GABAA receptors. Next, over minutes to hours, alterations occur in ● Multiple changes at the
neuropeptide expression, including an increase in excitatory substance P and cellular and molecular level
occur in status epilepticus
insufficient presence of inhibitory neuropeptide Y, thus maintaining an excitable as time passes.
state. In the days to weeks after status epilepticus, genetic and epigenetic changes
occur, including alterations in expression of multiple genes. Changes in ● With increasing duration
microRNA regulation and DNA methylation may also occur.10 of seizure activity, the
frequency of systemic
With increasing duration of seizure activity, the frequency of systemic
complications, neurologic
complications, neurologic injury, and mortality increase.16 Neuronal injury injury, and mortality
occurring during status epilepticus has been demonstrated in animals.32 For increase.
example, neuronal injury in the neocortex, thalami, and hippocampi was
demonstrated in baboons in which convulsive seizures were induced.33 Neuronal
injury was also seen when baboons were paralyzed, suggesting that
nonconvulsive status epilepticus can also be harmful.34 In humans, a marker for
neuronal injury, serum neuron-specific enolase, has been shown to be increased
after convulsive and nonconvulsive status epilepticus.10 As demonstrated in
animal models, mechanisms thought to possibly contribute to neuronal injury
and cell death in status epilepticus include excitotoxicity, mitochondrial
dysfunction, necrosis, and apoptosis.10
Neuroimaging may reveal findings in the setting of status epilepticus that
likely reflect the pathophysiology of this condition. CT findings include cortical
edema and sulcal effacement, loss of gray-white matter differentiation, reduced
attenuation, and enhancement. On MRI, findings can include T2 hyperintensity,
restricted diffusion, and apparent diffusion coefficient changes similar to those
seen in a stroke. These changes can occur in the cortex, basal ganglia, thalami,
hippocampi, and corpus callosum.10 Leptomeningeal enhancement and crossed
cerebellar diaschisis (depression in metabolism and blood flow in the cerebellum
contralateral to a supratentorial lesion) can also be seen. Findings may resolve on
follow-up imaging (CASE 5-2), but hippocampal sclerosis and focal atrophy can
persist, thus suggesting permanent neuronal injury.10
DIAGNOSIS
The diagnosis of status epilepticus involves a combination of clinical suspicion as
well as laboratory testing, EEG, and imaging.
General Workup
Convulsive status epilepticus is a clinical diagnosis. When patients present
with suspected status epilepticus, recommended studies include vital signs,

STATUS EPILEPTICUS
CASE 5-2 A 78-year-old woman with a history of hypertension, coronary artery

disease, ischemic stroke with residual right hemiparesis, and a 10-year
history of seizures for which she was taking levetiracetam presented to
the emergency department after experiencing four consecutive
generalized seizures. Per her family, she had not taken her antiepileptic
drugs for 2 days. She was at a family member’s house celebrating her
78th birthday when she had a seizure. She had another seizure when
emergency medical services arrived and another two on the way to the
emergency department.
Her examination was significant for aphasia and right-sided weakness
that was worse than her baseline. She was given IV lorazepam and
levetiracetam while in the emergency department. She then underwent
an MRI of the brain that showed subtle cortical restricted diffusion in the
left parietal lobe involving the superior and inferior parietal lobules. It
also showed restricted diffusion in the posterior left thalamus in the
region of the pulvinar, with subtle corresponding fluid-attenuated
inversion recovery (FLAIR) hyperintensity in the thalamic abnormality, but
with only minimal FLAIR signal change involving the cortex (FIGURE 5-3).
Initial continuous EEG showed occasional brief electrographic seizures
that were maximal over the left hemisphere, frequent generalized
periodic discharges that were maximal over the left hemisphere, diffuse
background slowing in the delta-theta range, and background asymmetry
with higher amplitude and persistent focal slowing over the left
FIGURE 5-3
MRI of the patient in CASE 5-2. Axial diffusion-weighted (A) and fluid-attenuated inversion
recovery (FLAIR) (B) images showing slight restricted diffusion of the left parietal lobe and
left thalamus with corresponding subtle FLAIR abnormalities.
1692 DECEMBER 2018

FIGURE 5-4
EEGs of the patient in CASE 5-2. A, Initial EEG showing frequent generalized periodic
discharges, maximal on the left. B, Follow-up EEG showing left-sided periodic discharges.
hemisphere (FIGURE 5-4A). Her IV levetiracetam dose was increased, and,

with continued seizure activity on EEG, she was also loaded and started
on a maintenance dose of IV phenytoin. Because seizure activity
persisted, phenytoin was discontinued, however, and IV lacosamide and
valproic acid were added.
Follow-up EEG showed left-sided periodic discharges that eventually
decreased in frequency (FIGURE 5-4B). Her examination slowly improved,
and EEG was eventually discontinued. Repeat MRI brain showed that the
previous findings had resolved.
This case of status epilepticus illustrates that EEG does not have to be COMMENT
completely normal to discontinue EEG monitoring, especially if the clinical
examination is improving. In addition, this case demonstrates that
reversible MRI findings can be seen in the setting of status epilepticus.

STATUS EPILEPTICUS
laboratory tests (including complete blood cell count, basic metabolic

panel, calcium, magnesium, and glucose), AED levels (as indicated), head
CT, and EEG.1 Additional studies that may be helpful in determining the cause
of status epilepticus include a toxicology screen, brain MRI, lumbar puncture,
inborn errors of metabolism panel, additional imaging (eg, single-photon
emission CT [SPECT], positron emission tomography (PET) scan, magnetic
resonance spectroscopy), and a paraneoplastic and autoimmune
encephalitis workup.1,35
Electroencephalography
EEG is extremely important in the diagnosis of status epilepticus, especially in
cases of nonconvulsive status epilepticus, which may be suspected clinically
but proven only by EEG. For example, in one study of 570 patients in the ICU
who underwent continuous EEG for detection of subclinical seizures or
unexplained lower level of consciousness, seizures were detected in 19%; 92%
of these patients had only nonconvulsive seizures. Independent predictors for
discovering seizures on EEG were age younger than 18 years, convulsive seizures
before continuous EEG monitoring, coma, and a history of epilepsy.36 One
prospective study in a general hospital setting found that 19% of patients with
status epilepticus had nonconvulsive status epilepticus.37 Forty-seven percent of
patients in a tertiary care center were found to have nonconvulsive status
epilepticus.38 In a study of patients in a general ICU, nonconvulsive status
epilepticus was detected in 8% of patients who were comatose.39 A study of the
neurologic ICU population specifically found that 23 of 170 patients (13.5%) had
nonconvulsive status epilepticus.40
Importantly, studies evaluating the timing of seizures have found that
continuous EEG may not necessarily capture seizures in the first hours after it is
placed. In one study, while continuous EEG detected seizures within the first
24 hours of monitoring in 88% of patients who would eventually have seizures, in
a similar percentage (87%) of patients who were comatose, seizures were more
likely to be detected after more than 24 hours of monitoring, suggesting that
additional monitoring time may be required in patients who are comatose
longer.36 Another study found that approximately 97% of patients who were
hospitalized and noncritically ill had their first seizure within 24 hours of starting
continuous EEG.41
Imaging
The value of CT—and even more so MRI—in revealing a focal lesion as the
cause of status epilepticus has been well demonstrated.42 SPECT has also been
used to detect foci of status epilepticus. In several case series and case
reports of patients with status epilepticus, brain SPECT using technetium
99m–hexamethylpropyleneamine oxime (99mTc-HMPAO) or 99mTc–ethyl
cysteinate dimer (ECD) generally demonstrated focal hyperperfusion in areas
consistent with EEG findings.42–44 Compared to SPECT, PET (especially
PET/CT) can provide better resolution and the ability to perform quantitative
measurements.35 In one study of eight patients with focal status epilepticus,
fludeoxyglucose (FDG)-PET helped to support the diagnosis of status
epilepticus; determine localization of the epileptic focus for planning surgical
treatment; and clarify discordant findings among clinical, MRI, and EEG
findings.45
1694 DECEMBER 2018

MANAGEMENT KEY POINTS
Compared to other neurologic emergencies, such as stroke, treatment of status
● Continuous video-EEG is a
epilepticus is rife with poor-quality data supplied by only a small number of valuable tool given its ability
randomized controlled studies. However, the urgency of treating status to detect nonconvulsive
epilepticus is similar to that of stroke because the response to treatments and the status epilepticus.
prognosis diminishes with elapsed time. Therefore, a staged approach to
● Imaging modalities,
treatment has been advocated, with different drugs used in early (stage I),
including CT, MRI,
established (stage II), refractory (stage III), and super-refractory status single-photon emission CT,
epilepticus (stage IV).46 and positron emission
Several studies suggest that status epilepticus is an emergency that requires tomography, may help in the
immediate treatment. In a study of 48 patients with poor-grade aneurysmal diagnosis and management
of status epilepticus.
subarachnoid hemorrhage in a neurologic ICU with nonconvulsive seizures
who underwent multimodality monitoring, including intracortical EEG, ● Status epilepticus
intracortical seizures were detected in 38% of patients and surface seizures in 8%. requires urgent treatment
Increases in mean arterial pressure, heart rate, respiratory rate, and minute because the response to
treatments and the
ventilation were found to be associated with intracortical seizures, and trends of prognosis diminish with
association with greater intracranial pressure and cerebral perfusion pressure elapsed time. A staged
were seen.47 In a study of 34 patients with moderate to severe traumatic brain approach to treatment has
injury who received multimodality invasive monitoring, 21 patients had either thus been advocated, with
different medications used
pseudoperiodic discharges or seizures, all nonconvulsive. Metabolic crises, as
in early (stage I), established
characterized by elevated cerebral microdialysis lactate to pyruvate ratio and (stage II), refractory (stage
decreased glucose, were time-locked to episodes of pseudoperiodic discharges III), and super-refractory
and seizures.48 These data suggest that nonconvulsive epileptic phenomena may status epilepticus (stage IV).
not be benign.
Initial Management of Status Epilepticus

The efficacy of benzodiazepines as the initial treatment of status epilepticus is
well established. In a four-arm trial comparing (1) lorazepam, (2) phenobarbital,
(3) phenytoin, and (4) diazepam followed by phenytoin, lorazepam was more
successful than phenytoin in aborting status epilepticus in patients with
convulsive status epilepticus and in the combined group of patients with
convulsive status epilepticus and patients with nonconvulsive status epilepticus.
Comparisons among other arms of the trial were not significant.49
The efficacy of out-of-hospital administration of benzodiazepines in status
epilepticus was tested in a randomized trial in which adults with status epilepticus
were randomly assigned to IV lorazepam, IV diazepam, or placebo. The two
benzodiazepines were more successful in aborting status epilepticus by emergency
department arrival than placebo.50 Another study examining out-of-hospital use
of benzodiazepines found that administration of IM midazolam was noninferior to
IV lorazepam in terminating seizures before emergency department arrival in
patients with status epilepticus.51 A smaller and older randomized study found no
difference between the administration of IV diazepam and lorazepam in ending
seizure activity.52 Refer to TABLE 5-3 for recommended dosing of benzodiazepines
as first-line AEDs in status epilepticus.
The value of the other major AEDs used in status epilepticus has also been
investigated. A randomized open-label study of 79 patients with convulsive or
subtle convulsive status epilepticus found that lorazepam and levetiracetam had
similar efficacy in terminating clinical seizures.53 Patients with convulsive status
epilepticus randomly assigned to IV valproic acid or phenytoin experienced a
better seizure termination rate with valproic acid, but no difference was seen

STATUS EPILEPTICUS
between the two medications in terms of seizure freedom at 24 hours.54 A

randomized open-label study of 74 patients with status epilepticus or acute
repetitive seizures (defined as at least two seizures occurring over 5 to 6 hours
different from their usual pattern and not categorized as status epilepticus)
showed that valproic acid and phenytoin were equally efficacious at aborting
seizures, with no rescue medications needed.55 Another study suggested that
phenobarbital works more quickly to terminate generalized convulsive status
epilepticus than the combination of diazepam and phenytoin.56
Approximately 40% of patients with convulsive status epilepticus do not
respond to benzodiazepines and enter stage II (established status epilepticus).
Second-line AED therapy was the topic of two randomized studies. IV valproic
acid and continuous IV diazepam were found to be equally efficacious in one
study,57 while IV valproic acid and phenytoin were found to work similarly in
another study.58 In a meta-analysis of studies of benzodiazepine-resistant status
epilepticus, seizure cessation with valproate (75.7%, 95% confidence interval
63.7% to 84.8%) and phenobarbital (73.6%, 95% confidence interval 58.3% to
TABLE 5-3 Suggested Treatment Algorithm for Status Epilepticus Stages I and IIa,b
Initial Care
◆ Assess airway, breathing, circulation
◆ Monitor vital signs, including oxygenation
◆ Check finger stick blood glucose
◆ Draw metabolic profile, complete blood cell count, toxicology screen, antiepileptic drug
levels
If Seizures Continue, First-line Antiepileptic Drug
◆ Treat with one of the following
◇ IV lorazepam 0.1 mg/kg total dose, can repeat (maximum 4 mg/single dose)
◇ IV diazepam 0.15–0.2 mg/kg total dose, can repeat (maximum 10 mg/single dose)
◇ IM midazolam 10 mg
◆ Alternatives
◇ Rectal diazepam 0.2–0.5 mg/kg (maximum dose 20 mg)
◇ IV phenobarbital 15-20 mg/kg loading dose
◇ Intranasal or buccal midazolam
If Seizures Continue, Second-line Antiepileptic Drug
◆ Treat with one of the following
◇ IV phenytoin or fosphenytoin
◇ IV valproic acid
◇ IV levetiracetam
◇ Others (see TABLE 5-4)
IM = intramuscular; IV = intravenous.
a
Modified with permission from Glauser T, et al, Epilepsy Curr.2 © 2016 American Epilepsy Society.
b
See text for definition of status epilepticus stages.
1696 DECEMBER 2018

84.8%) was higher than with levetiracetam (68.5%, 95% confidence interval
56.2% to 78.7%) or phenytoin (50.2%, 95% confidence interval 34.2% to 66.1%).59
Based on these data, algorithms have been proposed for treating status
epilepticus. A typical algorithm is presented in TABLE 5-3. TABLE 5-4 details
medications (including dosing information and side effects) typically used as
first- and second-line agents to treat status epilepticus.60,61
Generally, the efficacy of each subsequent AED is less than those before it.
One randomized controlled trial that compared four different AED regimens
(phenytoin, lorazepam, phenobarbital, and diazepam followed by phenytoin)
showed that the efficacy of the first AED in aborting convulsive status epilepticus
was 55.5%, efficacy of the second AED 7.0%, and efficacy of the third AED 2.3%.2,49
Of note, the ESETT (Established Status Epilepticus Treatment Trial) study
is ongoing (although currently closed to enrollment for adults) to refine
Second-line Antiepileptic Drugsa TABLE 5-4
Typical Empiric
Medication Initial Dose Maintenance Dose Serious Adverse Effects Notes
Fosphenytoin 20 mg phenytoin 100 mg IV every Arrhythmia, hypotension Phenytoin and valproic

equivalents/kg IV, 8 hours acid interact by
maximum rate up to increasing their free
150 mg phenytoin levels60
equivalents/min
Lacosamide 200–400 mg IV 200 mg IV every PR prolongation, hypotension Minimal drug

12 hours interactions; has not
been used much in status
epilepticus
Levetiracetam 1000–3000 mg IV, up to 500–1500 mg IV Occasional behavioral issues61 Minimal drug interactions
a maximum dose of every 12 hours
4500 mg
Phenobarbital 20 mg/kg IV 50–100 mg IV every Respiratory depression, IV form contains

12 hours hypotension propylene glycol
Phenytoin 20 mg/kg IV 100 mg IV every Arrhythmia, hypotension, IV form contains

8 hours purple glove syndrome propylene glycol;
phenytoin and valproic
acid interact by
increasing their free
levels60
Topiramate 200–400 mg orally 300–1600 mg/d Metabolic acidosis Not available in IV form
orally (divided over
2–4 doses daily)
Valproic acid 20–40 mg/kg IV 500–750 mg IV every Thrombocytopenia, Phenytoin and valproic
8 hours gastrointestinal adverse acid interact by
effects (pancreatitis, increasing their free
hepatotoxicity), levels60
hyperammonemia
IV = intravenous.
a
Modified with permission from Brophy GM, et al, Neurocrit Care.1 © 2012 Springer Science+Business Media, LLC.

STATUS EPILEPTICUS
management of status epilepticus. ESETT is a National Institutes of Health

(NIH)–supported multicenter, randomized, blinded, comparative effectiveness
study of fosphenytoin, valproic acid, and levetiracetam for patients with
benzodiazepine-refractory status epilepticus.16,62
Management of Refractory Status Epilepticus and Super-refractory

Status Epilepticus
Management of refractory status epilepticus is primarily composed of seizure
control, treating the etiology of the seizures, and managing and preventing
complications.63 Interestingly, however, the extent of seizure suppression
needed to treat refractory status epilepticus is not entirely clear. In a
meta-analysis including 193 patients with refractory status epilepticus,
background EEG suppression was associated with fewer breakthrough seizures
as compared to merely suppressing seizures, although it had no effect on
mortality and a greater frequency of hypotension was seen.64 A retrospective
study of 47 patients with refractory status epilepticus showed that the level of
EEG suppression had no effect on outcome.22 However, another study of 63
refractory status epilepticus episodes showed that improved functional outcome
was associated with seizure suppression as compared to burst suppression or
isoelectric background.63
Continuous anesthetic agents are typically used to treat refractory status
epilepticus (TABLE 5-5), and continuous EEG is recommended while these
medications are being used. Although it is not known for how long anesthetic
treatment should be administered to control seizures, a continuous infusion
is typically maintained for 24 to 48 hours before it is weaned.1 In a study of
63 episodes of refractory status epilepticus in 54 patients, however,
anesthetic-induced coma occurred for an average of 11 days.27
The four major IV anesthetics used for refractory status epilepticus are
midazolam, propofol, pentobarbital (thiopental is often used outside the
TABLE 5-5 Continuous Infusions for Refractory Status Epilepticusa
Medication Initial Dose Maintenance Dose Serious Adverse Effects/Drawbacks
Midazolam 0.2 mg/kg 0.05–2 mg/kg/h Respiratory depression, hypotension, tachyphylaxis

after long use
Propofol 1–2 mg/kg 30–200 mcg/kg/min Respiratory depression, hypotension, propofol infusion
loading dose syndrome
Pentobarbital 5–15 mg/kg 0.5–5 mg/kg/h Cardiac and respiratory depression, hypotension, ileus,
loss of neurologic examination at high doses
Thiopental 2–7 mg/kg 0.5–5 mg/kg/h Cardiac and respiratory depression, hypotension
Ketamine 0.5–4.5 mg/kg Up to 5 mg/kg/h Hypertension, arrhythmia, anaphylaxis, pulmonary

edema
Isoflurane Not established End-tidal concentrations Cardiac and respiratory depression, infections
0.8–2% titrated to EEG
EEG = electroencephalography.
a
Data from Brophy GM, et al, Neurocrit Care1 and Hocker S, et al, Neurol Res.63
1698 DECEMBER 2018

United States), and ketamine. Midazolam, propofol, and barbiturates are GABA KEY POINTS
agonists, and propofol may also act as an NMDA antagonist; ketamine is an
● Treating status
NMDA antagonist. All four drugs are primarily metabolized in the liver.7 It is epilepticus generally begins
unclear if the anesthetics with a shorter half-life (midazolam or propofol) should with benzodiazepines
be used before those with a longer half-life (barbiturates). Some algorithms and is followed by IV
include pentobarbital and ketamine as treatment options for refractory status administration of
fosphenytoin, valproic
epilepticus and some algorithms include these drugs only for treatment of
acid, or levetiracetam.
super-refractory status epilepticus, but the ultimate goal is to stop status
epilepticus as soon as possible. In one meta-analysis, pentobarbital appeared to ● The extent of suppression
be associated with decreased breakthrough seizures, less short-term treatment needed to treat refractory
failure, and fewer changes to another medication infusion compared to midazolam status epilepticus (burst
suppression versus merely
and propofol.64 In refractory status epilepticus cases in which barbiturates were suppressing seizures) is
administered, EEG burst or total suppression was achieved more frequently than not known.
in refractory status epilepticus cases without administration of barbiturates.22
However, barbiturates may be linked to a longer hospital stay.22 In a small ● Continuous anesthetic
agents are used to treat
randomized trial of propofol versus pentobarbital, time spent on mechanical refractory status epilepticus
ventilation was longer in patients treated with pentobarbital, but return to baseline and are typically maintained
and mortality were similar.65 One problem with midazolam is that tachyphylaxis for 24 to 48 hours before
can develop, requiring progressively higher doses.63 Another potential problem is being weaned.
propofol infusion syndrome, which is characterized by circulatory collapse, lactic
● Several alternative
acidosis, rhabdomyolysis, and hypertriglyceridemia. It can be a life-threatening therapies can be used in
condition and is typically associated with high doses and long duration of patients with refractory
propofol use.6 status epilepticus and,
Ketamine has recently emerged as an alternative to traditional IV anesthetic especially, super-refractory
status epilepticus, including
agents. However, knowledge about ketamine and its potential usefulness is surgical resection,
limited since it is often added to other continuous infusions.7 A meta-analysis of repetitive transcranial
110 adult patients revealed that ketamine may have helped control refractory magnetic stimulation,
status epilepticus in about 57% of patients.66 A review of 95 patients treated with immunosuppression or
immunomodulation, and
ketamine for refractory status epilepticus or super-refractory status epilepticus the ketogenic diet.
showed that seizures resolved in 68%, but outcomes were variable: good
outcomes were observed in 19 patients (including discharges to home or
rehabilitation), death in 30, and other/unknown deficits in the remaining
patients.67 Although the side effects of ketamine are not well delineated,
concerns include psychiatric symptoms (eg, hallucinations, delirium, dreams) in
awake patients, increased intracranial pressure, increased intraocular pressure,
increased secretion of saliva, arrhythmias, respiratory depression,
and neurotoxicity.67
In addition to general anesthetics, lacosamide has also been tried in refractory
status epilepticus (this drug was not included in the aforementioned meta-
analysis of the drugs used for benzodiazepine-resistant established status
epilepticus).59 The most commonly used IV bolus dose of lacosamide was 200 mg
to 400 mg, followed by a daily dose of approximately 200 mg to 400 mg in a
review of 136 patients with refractory status epilepticus treated with the drug.
This regimen led to control of seizures in 56% of cases of refractory status
epilepticus. Adverse events occurred in 25% of cases; sedation was most
common, followed by hypotension; allergic skin reaction; and one case each of
possible angioedema, pruritus, and third-degree atrioventricular block and
paroxysmal asystole.68
Several other approaches have been attempted in refractory status epilepticus
and even more in super-refractory status epilepticus. Resective neurosurgery can

STATUS EPILEPTICUS
be considered if a definitive seizure focus causing status epilepticus can be

located in a noneloquent brain region.6 Surgeries can include focal, lobar, or
multilobar resection; corpus callosotomy; hemispherectomy; and multiple
subpial transections with or without focal resection. A review of 23 patients
undergoing surgery for refractory status epilepticus showed that 78.3% were
seizure free over a follow-up of 4 months to 5 years.69
Repetitive transcranial magnetic stimulation (rTMS), which provides
intracranial electric current in a noninvasive manner, has also been attempted.
A 2015 systematic review on the use of rTMS in status epilepticus and refractory
status epilepticus identified 11 studies (all case series or case reports) with
21 patients included. In the setting of rTMS, seizure control or reduction
occurred in 71.4%, although seizures recurred in 73.3% of patients who had
initially responded. An adverse event (lower extremity sensory symptoms that
resolved) was reported in only one patient.70
Electroconvulsive therapy has also been used. One systematic review found
14 articles (all retrospective case reports or series) consisting of 19 patients who
underwent electroconvulsive therapy for refractory status epilepticus. In 57.9%
of patients, seizure reduction or control was seen. Four studies discussed adverse
events: Two studies reported no adverse events; in the other two studies, three
patients were described as having transient amnesia or lethargy.71
Therapeutic hypothermia has also been posited as a possible treatment for
refractory status epilepticus and super-refractory status epilepticus. After several
case reports suggested a possible benefit for therapeutic hypothermia in
refractory status epilepticus,6 a 2016 study randomly assigned 270 patients in
the ICU who were on mechanical ventilation and in convulsive status epilepticus
to standard care alone or standard care plus hypothermia (32oC [89.6°F] to 34oC
[93.2°F] for 24 hours). The study did not show better outcomes in the patients
treated with hypothermia (primary outcome was defined as a Glasgow Outcome
Scale score of 5 at 90 days). Interestingly, progression to EEG-confirmed status
epilepticus (a secondary outcome) was more common in the standard care–only
group.72
Immunomodulatory agents, such as plasma exchange, IV immunoglobulin
(IVIg), steroids, and adrenocorticotropic hormone (ACTH), could be considered
in status epilepticus cases suspected to be caused by an immunologic process
after infection is excluded.6 Other adjunctive therapies include IV magnesium,
inhalational anesthetic agents, vagal nerve stimulation, and deep brain
stimulation.1,6,63
The ketogenic diet has recently shown promise as a treatment for
super-refractory status epilepticus. In a 2017 prospective multicenter phase
1/2 study of adult patients with super-refractory status epilepticus treated with
the ketogenic diet, all 15 patients enrolled in the study achieved ketosis after a
median of 2 days on the diet, and 78.6% of patients who completed treatment
with the diet achieved resolution of super-refractory status epilepticus at a
median of 5 days.73 Side effects of the ketogenic diet include metabolic acidosis,
hyperlipidemia, hypoglycemia, constipation, weight loss, and hyponatremia.73
These results suggest the need for future randomized trials to determine the
ketogenic diet’s safety and efficacy in super-refractory status epilepticus.
Allopregnanolone is a neuroactive steroid and positive allosteric modulator of
GABAA receptors that has shown success in reducing seizure activity in multiple
animal models.74 The STATUS (SAGE-547 Treatment as Adjunctive Therapy
1700 DECEMBER 2018

Utilized in Status Epilepticus) trial, a phase 3 randomized, double-blind, KEY POINT
placebo-controlled trial designed to evaluate the efficacy and safety of this
● In some cases, seizures
medication in super-refractory status epilepticus, however, was recently and status epilepticus may
completed and showed no difference between the allopregnanolone and be epiphenomena for severe
placebo arms.75 brain injury rather than the
As previously mentioned, many of the management principles used to treat primary offender. It is
unknown whether treating
refractory status epilepticus are also used for super-refractory status epilepticus.
these conditions will
TABLE 5-6 describes one possible treatment algorithm for refractory status improve outcomes.
epilepticus and super-refractory status epilepticus.
Several complications can occur in status epilepticus that could require
additional attention and management, including the possible need for
tracheostomy, hypotension, arrhythmias, acid-base disorders, renal failure,
thrombocytopenia, pulmonary embolus or deep vein thrombosis, infections such
as pneumonia or sepsis, drug rash, rhabdomyolysis, and critical illness
neuropathy or myopathy.63 Risk factors for these complications include not only
immobility from status epilepticus itself and potentially from IV anesthetic
agents causing coma but also any adverse effects or immunosuppression
resulting from the medications used to treat status epilepticus.63
Finally, it should be acknowledged that limited data exist regarding patients
who are critically ill to guide AED withdrawal after cessation of status epilepticus
or to predict which patients may not tolerate weaning. Although no randomized
controlled trials exist to guide the timing of AED weaning in adults who are
seizure free,76 in the first study evaluating early weaning of AEDs after seizure
cessation in patients who are critically ill, weaning AEDs after seizure cessation
did not lead to more recurrent seizures as compared to not weaning AEDs.77
Recently, independent predictors of drug-resistant epilepsy after convulsive
status epilepticus have been found to include a history of epilepsy, duration of
status epilepticus of 24 hours or more, and cortical or hippocampal abnormalities
on neuroimaging.78
CLINICAL OUTCOMES
Seizures and status epilepticus can lead to poor outcomes; however, it is unclear
whether detecting and treating seizures has an effect on outcomes since, in some
cases, seizures are epiphenomena for severe brain injury rather than the primary
offender.10 Mortality with status epilepticus may reach up to 30% in adults.2
Age older than 60 years, female sex, treatment in smaller-sized hospitals, the
presence of comorbidities (eg, hypertension, diabetes mellitus, previous stroke),
status epilepticus complications (eg, respiratory failure, sepsis), and etiologies
such as status epilepticus postcardiopulmonary resuscitation have been
associated with worse discharge outcomes.79
Outcomes in refractory status epilepticus can be worse, with mortality
reaching 16% to 39%.6 In one study of 54 patients and 63 episodes of refractory
status epilepticus, the mean length of hospital stay was 27.7 days. Poor outcome
at discharge (mRS score of 4 to 6) was noted in 76.2% of patients, and in-hospital
mortality occurred in 31.8%. Mechanical ventilation was required in 90.5% of
patients. Prolonged mechanical ventilation was associated with mortality. Poor
functional outcome was associated with greater CSF white blood cell count, more
days under anesthetic agents, the need for intervention for cardiac arrhythmias,
pneumonia, lack of seizure control on EEG (eg, requiring isoelectric or burst
suppression), and prolonged hospital stay. Seizure control without need for deep

STATUS EPILEPTICUS
TABLE 5-6 Suggested Treatment Algorithm for Refractory Status Epilepticus (Stage III)
and Super-refractory Status Epilepticus (Stage IV)a
Stage III Refractory Status Epilepticus

◆ Patients who are intubated and mechanically ventilated, on complete hemodynamic
support, and under continuous EEG recording
◆ Continue all antiepileptic drugs already started; use IV formulations if available
◆ Anesthetics for 24–48 hours:
◇ Midazolam 0.2 mg/kg IV bolus, which can be repeated every 5–10 minutes up to 2 mg/kg
total and start infusion 0.1–0.2 mg/kg/h OR
◇ Propofol 2 mg/kg IV bolus and 150 mcg/kg/min infusion OR
◇ Thiopental 4 mg/kg IV loading dose and 0.3–0.4 mg/kg/min infusion OR
◇ Pentobarbital 10 mg/kg IV loading dose, which can be repeated to burst suppression
effect (20–30 second suppression interval); start infusion at 1 mg/kg/h and titrate up to
10 mg/kg/h OR
◇ Ketamine 0.5–4.5 mg/kg IV bolus and start infusion up to 5 mg/kg/h
◇ Monitor and aggressively treat hypotension, sepsis, atelectasis or pneumonia, and deep
venous thrombosis; may need total parenteral nutrition
Stage IV.I Super-refractory Status Epilepticus
◆ If seizure control fails or seizures recur after tapering the doses, use the same as above for
longer period (eg, 1 week is suggested by the authors of this Continuum article) or proceed
directly to stage IV.II
Stage IV.II Super-refractory Status Epilepticus
◆ If seizures are still not controlled or recur, use one or more of the following alternative
therapies:
◇ Isoflurane or desflurane or gabapentin or levetiracetam (in acute intermittent porphyria)
◇ Topiramate 300–1600 mg/d per orogastric tube (if no increased stomach residuals)
◇ Magnesium 4 g bolus IV and 2–6 g/h infusion (keep serum levels <6 mEq/L)
◇ Pyridoxine 100–600 mg/d IV or via orogastric tube
◇ Methylprednisolone 1 g/d IV for 5 days, followed by prednisone 1 mg/kg/d orally for 1 week
◇ IVIg 0.4 g/kg/d IV for 5 days
◇ Plasma exchange for 5 sessions
◇ Ketogenic diet 4:1 (fat:carbohydrate and protein grams)
◇ Neurosurgical resection of epileptogenic focus
◇ Electroconvulsive therapy
◇ Vagal nerve stimulation or deep brain stimulation or repetitive transcranial magnetic
stimulation
Stage IV.III Super-refractory Status Epilepticus
◆ If several weaning attempts have failed over a period of weeks, consider an ethics
consultation or palliative care discussion with family or surrogate decision maker based on
patient’s wishes, with subsequent autopsy (if no etiology has been found)
EEG = electroencephalogram; IM = intramuscular; IV = intravenous; IVIg = intravenous immunoglobulin.

a
Modified with permission from Cuero MR, Varelas PN, Curr Neurol Neurosci Rep.23 © 2015 Springer
Science+Business Media, LLC.
1702 DECEMBER 2018

suppression on the EEG (isoelectric or burst suppression) was associated with KEY POINT
good functional recovery. Common complications in this cohort included cardiac
● Up to 50% of patients with
arrhythmias (35%), pulmonary edema (36.7%), acid-base disorders (71.4%), super-refractory status
hypotension (79%), hypoxia (35.7%), and pneumonia (69.6%).27 In another epilepticus die, and
study, fever was found to be the only independent predictor of outcome after outcomes are worse in
adjusting for acute symptomatic etiology, viral encephalitis etiology, fever, super-refractory status
epilepticus compared to
septicemia, and acidosis.28 In one study of 395 patients with refractory status
nonrefractory status
epilepticus treated in an ICU, in-hospital mortality was 7.4% and mortality at epilepticus.
1 year was 25.4%. On multivariate analysis, only the Sequential Organ Failure
Assessment (SOFA) score was independently associated with in-hospital
mortality. In terms of mortality at 1 year, independent predictors were older age,
premorbid nonindependence in activities of daily living, SOFA score, and
development of super-refractory status epilepticus.18
The differences between patients with refractory status epilepticus and
patients with nonrefractory status epilepticus have been investigated. Fever,
septicemia, and acidosis have been more frequently found in patients with
refractory status epilepticus as compared to patients with nonrefractory status
epilepticus.28 Patients with refractory status epilepticus have also been shown to
have a longer duration of seizure activity, mechanical ventilation, neurologic ICU
stay, and hospital stay.20,28 A 2017 meta-analysis found that the case fatality rate
for refractory status epilepticus was greater than the overall status epilepticus
case fatality rate (33% versus 15%).9 Another study also showed greater mortality
in patients with refractory status epilepticus compared to patients with
nonrefractory status epilepticus (42.2% versus 6.2%).28 Although in another
study mortality was similar in patients with nonrefractory status epilepticus and
those with refractory status epilepticus, increased neurologic ICU length of stay,
increased hospital length of stay, and decreased Glasgow Outcome Scale from
admission to discharge were found in patients with refractory status
epilepticus.21
Little has been reported in the literature regarding the outcome of
super-refractory status epilepticus. Long-term mortality of super-refractory
status epilepticus seems to be approximately 30% to 50%. In one study of
87 patients with super-refractory status epilepticus, mortality at 1 year was 36%,8
but mortality reached 50% in another study.24 In yet another status epilepticus
cohort, overall mortality was 19.2%, but mortality was up to 40% in the
super-refractory status epilepticus group, which was significantly greater than in
the nonrefractory status epilepticus (6.7%) group. At 6 months, a Glasgow
Outcome Scale score of 4 to 5 was achieved in 33.3% of patients with
super-refractory status epilepticus, which was significantly less than in patients
with nonrefractory status epilepticus (79.1%) but similar to patients with
refractory status epilepticus (57.1%).25 Compared to patients with refractory
status epilepticus, patients who met the definition of super-refractory status
epilepticus in another study had longer stays in both the neurologic ICU and in the
hospital and were more likely to be functionally dependent at hospital discharge.26
PROGNOSTIC SCORES AND THE FUTURE OF STATUS

EPILEPTICUS RESEARCH
Scores to predict outcome in status epilepticus have recently been developed.
The Status Epilepticus Severity Score (STESS) was first published in 2006. It is
based on four factors: age, seizure type, level of consciousness, and history of

STATUS EPILEPTICUS
seizures.80 A subsequent study found that STESS was a predictor of survival and
ability to achieve baseline clinical condition. This study also suggested that
patients who had favorable STESS scores generally appeared to survive
regardless of whether or not they received coma induction for their status
epilepticus.81 This score was further externally validated in a study of 171 patients
in which the STESS score identified survivors better than nonsurvivors.82 The
Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) was created
using epidemiologic data in hopes of being superior to the STESS score. Points
were developed based on mortality rates in the literature for factors that were
thought to be predictive. Items eventually included in the score were etiology,
age, comorbidities, and EEG findings. This score explained individual mortality
in almost 90% of cases and was found to be superior to STESS.83
More recently, the END-IT score (the letters of which are an acronym for the
score’s components, encephalitis, nonconvulsive status epilepticus, diazepam
resistance, image abnormalities, and tracheal intubation) was created as an
outcome prediction tool in 132 patients with convulsive status epilepticus.
Independent predictors of unfavorable outcome (mRS score of 3 to 6) at
3 months after discharge were encephalitis, nonconvulsive status epilepticus
(defined as subtle status epilepticus in which myoclonic jerks or nystagmus
occurred in insufficiently treated convulsive status epilepticus), diazepam
resistance, imaging abnormalities (unilateral lesions, bilateral lesions, or diffuse
cerebral edema), and intubation. One point was given for each category except
for imaging (in which 1 point was given for unilateral lesions and 2 points for
diffuse cerebral edema or bilateral lesions). The greater the sum of these
categories, the greater the probability of unfavorable outcome. An END-IT score
of 3 or greater seemed to be the cutoff point to provide the best sensitivity and
specificity for predicting unfavorable outcome.84
CONCLUSION
Status epilepticus is a neurologic emergency and can progress to refractory status
epilepticus and super-refractory status epilepticus. Although much progress
has been made in diagnosing and treating status epilepticus, more studies are
needed to delineate optimal management and to improve outcomes.
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DISCLOSURE
Continued from page 1683
Dr Varelas has received personal compensation for Therapeutics, Inc; Marinus Pharmaceuticals, Inc;
speaking engagements for Portola Pharmaceuticals, the National Institutes of Health; the Patient-
Inc and UCB SA and receives publishing royalties Centered Outcomes Research Institute; and Portola
from Springer. Dr Varelas receives research/grant Pharmaceuticals, Inc
support from Bard Pharmaceuticals Limited; Edge

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Criteria for Nonconvulsive Status Epilepticusa TABLE 5-1

Patients Without Epileptic Encephalopathyb

EEG = electroencephalogram; IV = intravenous.

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Possible Causes of Status Epilepticusa TABLE 5-2

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CASE 5-2 A 78-year-old woman with a history of hypertension, coronary artery

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hemisphere (FIGURE 5-4A). Her IV levetiracetam dose was increased, and,

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laboratory tests (including complete blood cell count, basic metabolic

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Initial Management of Status Epilepticus

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between the two medications in terms of seizure freedom at 24 hours.54 A

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Second-line Antiepileptic Drugsa TABLE 5-4

Fosphenytoin 20 mg phenytoin 100 mg IV every Arrhythmia, hypotension Phenytoin and valproic

Lacosamide 200–400 mg IV 200 mg IV every PR prolongation, hypotension Minimal drug

Phenobarbital 20 mg/kg IV 50–100 mg IV every Respiratory depression, IV form contains

Phenytoin 20 mg/kg IV 100 mg IV every Arrhythmia, hypotension, IV form contains

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management of status epilepticus. ESETT is a National Institutes of Health

Management of Refractory Status Epilepticus and Super-refractory

TABLE 5-5 Continuous Infusions for Refractory Status Epilepticusa

Medication Initial Dose Maintenance Dose Serious Adverse Effects/Drawbacks

Midazolam 0.2 mg/kg 0.05–2 mg/kg/h Respiratory depression, hypotension, tachyphylaxis

Ketamine 0.5–4.5 mg/kg Up to 5 mg/kg/h Hypertension, arrhythmia, anaphylaxis, pulmonary

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be considered if a definitive seizure focus causing status epilepticus can be

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Stage III Refractory Status Epilepticus

EEG = electroencephalogram; IM = intramuscular; IV = intravenous; IVIg = intravenous immunoglobulin.

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PROGNOSTIC SCORES AND THE FUTURE OF STATUS

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1706 DECEMBER 2018

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