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Review Article

Epilepsy Emergencies
Stephen Hantus, MD
ABSTRACT
Purpose of Review: Epilepsy emergencies include acute repetitive seizures and
status epilepticus. Their prognosis depends on the etiology of the seizures and the
time spent in status epilepticus. This review discusses the current perspective on the
diagnosis and treatment of status epilepticus and acute repetitive seizures in the
intensive care unit.
Recent Findings: Current data on the treatment of status epilepticus emphasize
early treatment over the choice of antiepileptic drug. The Rapid Anticonvulsant
Medication Prior to Arrival Trial (RAMPART) data support the efficacy of prehospital
treatment using faster routes of benzodiazepine administration. As additional
antiepileptic drugs have become available in an IV formulation, their use in status
epilepticus has increased, with little data to guide their administration. Recent
publications have also stressed the changing epidemiology of status epilepticus in
the United States, with a rise in incidence without much change in overall mortality.
This rise is likely related to improved diagnostic capabilities with better availability
and usage of continuous EEG in the intensive care unit and to the aging of the
patient population.
Summary: Acute repetitive seizures and status epilepticus are neurologic
emergencies that are being increasingly diagnosed and treated in the modern
era. Rapid treatment may influence patient prognosis, future cognitive outcomes,
and the long-term potential for developing epilepsy. However, little is known about
the mechanisms that perpetuate seizure activity, and our ability to intervene and
prevent this condition remains limited. Preventing complications during the
treatment of status epilepticus plays a large role in prognosis and the chance of
treatment success.

Address correspondence to
Dr Stephen Hantus, Cleveland
Clinic, 9500 Euclid Avenue
#S51, Cleveland, OH 44195,
hantus@gmail.com.
Relationship Disclosure:
Dr Hantus reports no disclosure.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Dr Hantus reports no disclosure.
* 2016 American Academy
of Neurology.

Continuum (Minneap Minn) 2016;22(1):173190.

INTRODUCTION
Status epilepticus is a neurologic emergency with a time-dependent impact on
morbidity and mortality. Generalized
convulsive status epilepticus is easily
diagnosed as patients initially have
generalized convulsions without return
to neurologic baseline. However, as
motor convulsions proceed, patients
may cease to have overt motor features
and status epilepticus may only manifest as subtle jerks of the face, eyes, and
extremities. Nonconvulsive status
epilepticus, which may have no clinical
manifestations and is only detectable
through video-EEG monitoring, is also
Continuum (Minneap Minn) 2016;22(1):173190

increasingly being recognized. In all


forms, prognosis is dependent on the
underlying etiology and time spent in
status epilepticus. Making the diagnosis
is critical and not always straightforward, especially in the critical care
setting, when seizures most often
occur without apparent clinical signs.
Preventing complications of status
epilepticus and its treatment and
maintaining patients overall health
during and after the treatment of status
epilepticus contribute greatly to reducing patient morbidity and mortality,
but often present multiple challenges
that should not be overlooked.
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173

Epilepsy Emergencies
KEY POINTS

h Nonconvulsive status
epilepticus, which may
have no clinical
manifestations and is
only detectable through
video-EEG monitoring,
is increasingly
being recognized.

h A patients prognosis is
dependent on the
underlying etiology of
and time spent in
status epilepticus.

h Seizures lasting longer


than 5 minutes are less
likely to end without an
external intervention
and should be
considered status
epilepticus for all
practical purposes;
therefore, they need to
be emergently treated.

h Rather than a true


increase in the
occurrence of status
epilepticus, the shift in
epidemiology of status
epilepticus seen in the
past 10 years may
reflect increased
detection of
nonconvulsive status
epilepticus in intensive
care unit patients with
the growing utilization
of continuous
EEG monitoring.

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DEFINITION OF STATUS
EPILEPTICUS
Status epilepticus has traditionally
been defined as 30 minutes of continuous seizure activity or multiple seizures without return to neurologic
baseline. This definition was developed to coincide with data suggesting
irreversible damage to neurons after
continuous seizure activity in animals
and in vitro. However, this definition
is useful only in the retrospective
identification of patients. A working
definition must be able to identify
patients within time to treat and
possibly prevent irreversible damage.1
Typical seizures last up to 3 to
5 minutes before being stopped by
the intrinsic inhibitory mechanisms of
the brain. Seizures lasting longer than
5 minutes are less likely to end without
an external intervention and should be
considered status epilepticus for all
practical purposes; thus, they need to
be emergently treated. Refractory status epilepticus is defined as seizures
that continue despite first- and secondline treatments. Super-refractory status
epilepticus occurs when third-line
agents (IV anesthetics) fail and presents particular challenges discussed
later in this article.
EPIDEMIOLOGY
The incidence of status epilepticus
reportedly ranges from 10 per 100,000
to 40 per 100,000 in various databases.2
A peak incidence occurs at younger
than 10 years of age (14.3 per 100,000)
and at older than 50 years of age (28.4
per 100,000), with the highest mortality in the elderly population.2 Status
epilepticus may be the initial presentation of chronic epilepsy in up to 30%
of patients, whereas an acute symptomatic etiology for status epilepticus
occurs in 40% to 50% of cases. A 2015
evaluation of large national patient
databases showed an increasing num-

ber of patients diagnosed with status


epilepticus over the past 10 years and
an increase in the number of inpatient
hospitalizations for status epilepticus,
particularly in elderly patients
intubated in the intensive care unit
(ICU).3 Rather than a true increase in
the occurrence of status epilepticus,3
this shift in epidemiology may reflect
the increased detection of nonconvulsive status epilepticus in ICU
patients with the growing use of continuous EEG monitoring. A number of
large consecutive patient studies have
identified nonconvulsive seizures in 8%
to 34% of patients with altered mental
status in the ICU.4Y6 Additional factors
potentially contributing to the increased documented incidence of status epilepticus include the aging of
the population and the implementation of a less-rigid working definition of
status epilepticus.
PATHOPHYSIOLOGY
Status epilepticus represents the persistence of abnormal excitation and
the ineffective recruitment of inhibition.7 Excitation can come from many
sources, such as an established epileptogenic circuit from preexisting
epilepsy, excitation from the region
surrounding a structural lesion, or
diffuse excitation from a toxic/metabolic state. These limbic and cortical
inputs feed into the perforant pathway
along the parahippocampal gyrus and
to the neurons in the dentate gyrus.
The dentate is often the brake for
excitatory activity, but when overwhelmed, excitatory activity feeds
back to the hippocampus and then
back to the parahippocampal gyrus,
creating a self-amplifying reverberating
circuit that perpetuates status epilepticus. This pathophysiology can often
be suspected when the brain MRI of a
patient in status epilepticus shows a
low level of restricted diffusion in the

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mesial temporal structures on


diffusion-weighted imaging. This MRI
change may also present as cortical
ribboning in focal status epilepticus.
This restricted diffusion is typically
reversible in 2 to 5 days after the
seizure activity is terminated.8
Understanding the pathophysiology
of status epilepticus may lead to future
treatment options. The first and very
rapid changes in status epilepticus
involve protein phosphorylation, opening and closure of ion channels,
and release of neurotransmitters and
modulators. Essentially all current
antiepileptic drugs (AEDs) work at this
level by either interacting with ion
channels or possibly affecting the release of neurotransmitters in synaptic
vesicles. Later changes affect receptor
trafficking, with inhibitory receptors
being removed from the synaptic cleft
and excitatory neurotransmitters being
reinforced. ,-Aminobutyric acid (GABA)
receptors are endocytosed into clathrincoated pits and degraded in endosomes
with progressive seizures. Glutamate
receptors are recruited to the synaptic
cleft and likely play a role in the
maladaptive changes that perpetuate
status epilepticus.9 With increasing
time spent in status epilepticus, additional changes involve neuropeptide
modulators. Poorly understood processes lead to continued seizures and
eventually spontaneous epileptogenicity.
CLASSIFICATION
The simplest way to classify status
epilepticus is as convulsive or
nonconvulsive. However, the motor
activity with seizures is a dynamic
process, and these two classes are
not completely separate. Generalized
convulsive status epilepticus has pronounced convulsive motor activity
that typically involves tonic contractures followed by clonic jerking that
are classically recognized as seizure
Continuum (Minneap Minn) 2016;22(1):173190

activity. These generalized convulsive


activities are classified as generalized
convulsive status epilepticus if they
persist for more than 5 minutes. After
a period of time spent in generalized
convulsive status epilepticus, the body
is no longer able to produce intense
motor activity and instead generates
more subtle jerks of the face, eyes, and
extremities. With the less-intense motor
activity, the seizures are typically called
nonconvulsive, although they are often
identical to generalized convulsive status epilepticus on EEG recordings.
Classifying the mental status of a
patient in status epilepticus is a similar
challenge. If a conscious patient suddenly becomes unconscious with a seizure, the ictal phenomenon is easily
recognized as a seizure with altered
awareness. However, if a comatose patient develops the same electrographic
seizure, it is often referred to as seizures
with no clinical signs because the
patients preexisting poor mental status
complicates the ascertainment of a
seizure-specific alteration of consciousness. Despite these challenges, the
classification of convulsive and nonconvulsive seizures is important. Convulsive status epilepticus appears to
be more rapidly damaging to the patient and should therefore be aggressively treated. Being aware of the
subtleties of nonconvulsive status
epilepticus provides a critical heightened awareness for this diagnostic possibility. Without such increased attention,
nonconvulsive status epilepticus can
be completely missed if not suspected
and then looked for on continuous
EEG monitoring.

KEY POINTS

h The simplest way to


classify status
epilepticus is as convulsive
or nonconvulsive.
However, the motor
activity with seizures is a
dynamic process, and
these two classes are not
completely separate.

h Convulsive status
epilepticus appears to
be more rapidly damaging
to the patient than
nonconvulsive status
epilepticus and should
therefore be aggressively
treated. Being aware
of the subtleties of
nonconvulsive status
epilepticus provides a
critical heightened
awareness for this
diagnostic possibility.

ACUTE REPETITIVE SEIZURES


In patients with known epilepsy, acute
repetitive seizures are described as an
abrupt increase in seizure frequency
compared to the baseline seizure load,
often over a short period of time
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175

Epilepsy Emergencies
KEY POINTS

h Acute repetitive seizures


represent an escalation
in severity, are less likely
to remit without
treatment, and may lead
to status epilepticus and
neuronal damage.
Acute repetitive seizures
are thought to present a
similar risk of
seizure-related neuronal
damage as prolonged
seizures and require
prompt medical
intervention, typically
with benzodiazepines.

h Acute repetitive seizures


in the critical care
setting have often
been equated to status
epilepticus since
patients do not return
to a baseline function
in between their acute
repetitive seizures.

h Finding a patient with


altered mental status
that is worse than
expected for his or her
underlying condition
should raise concern
for nonconvulsive
status epilepticus.

h Patients at risk for


status epilepticus based
on clinical criteria
(eg, altered mental
status, high-risk
neurologic pathology,
subtle clinical jerks)
should be urgently
recorded on continuous
EEG monitoring.

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(ranging from several minutes up to


24 hours). These seizures represent
an escalation in severity, are less likely
to remit without treatment, and may
lead to status epilepticus and neuronal
damage.10 Acute repetitive seizures
are thought to present a similar risk
of seizure-related neuronal damage as
prolonged seizures and require
prompt medical intervention, typically
with benzodiazepines.11 In patients in
the critical care setting, acute repetitive seizures often occur as electrographic seizures and little in the
way of apparent clinical signs. These
electrographic seizures typically occur
after a primary neurologic injury of
some kind (eg, stroke, hemorrhage,
tumor, infection). The relative significance of this intermittent frequent
seizure pattern as compared to the
prolonged continuous electrographic
seizure activity of traditional status
epilepticus is unknown. Although the
consequences of acute repetitive seizures are not well understood, they
should be treated promptly as they
pose a significant risk for the development of status epilepticus.12 In fact,
from a pragmatic perspective, acute
repetitive seizures in the critical care
setting have often been equated to
status epilepticus since patients do not
return to a baseline function in between their acute repetitive seizures.
Therefore, treatment recommendations made in the remainder of this
article apply to both status epilepticus
and acute repetitive seizures.
DIAGNOSIS
The diagnosis of generalized convulsive status epilepticus is fairly straightforward and based on clinical seizure
activity. Generalized convulsive status
epilepticus should be treated without
delay. Once some type of treatment
has been initiated and the intense
motor convulsions are controlled, the

etiology of the status epilepticus should


immediately be sought. The most common etiologies include seizure breakthroughs in the context of a known
chronic epilepsy, acute structural lesions, or acute metabolic derangements.
Nonconvulsive seizures present a
much more difficult diagnostic challenge. Patients with altered mental
status in the critical care setting have
a risk for nonconvulsive seizures that
is proportional to the severity of the
altered mental status. Patients in coma
have the highest risk of nonconvulsive
status epilepticus at 30% to 40%.
Finding a patient with altered mental
status greater than expected for his or
her underlying condition should raise
concern for nonconvulsive status
epilepticus. Patients with primary neurologic pathology (eg, hemorrhage,
tumor, stroke, central nervous system
infection, and anoxia) have the
highest risk of seizures.13 A CT scan
of the head to evaluate for a high-risk
primary neurologic pathology is the
typical first step in diagnosis. A brain
MRI is required to evaluate for the full
range of structural pathology that
could be the cause for seizures or
status epilepticus, but given the length
of the procedure, it may be deferred
until the status epilepticus is adequately treated. If any concern of
infection, possible meningitis, or encephalitis exists, a lumbar puncture
should be performed, but it should
also not delay initial treatment. Patients at risk for status epilepticus
based on clinical criteria (eg, altered
mental status, high-risk neurologic
pathology, subtle clinical jerks) should
be urgently recorded on continuous
EEG monitoring; guidelines have been
established for this monitoring.14
TREATMENT
The treatment of status epilepticus
should aim to achieve seizure control

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as promptly and as safely as possible.


Treatment recommendations are limited
by the paucity of rigorous randomized
controlled clinical trials comparing various therapies. In the following sections,
the general treatment recommendations are first reviewed (Table 9-1), and
then some pragmatic treatment approaches based on the clinical setting
of the status epilepticus presentation
are discussed.
Standard Status Epilepticus
Treatment Protocol
The initial treatment protocol of status
epilepticus has been established by the
US Department of Veterans Affairs (VA)
Cooperative Study randomized controlled clinical trial in which IV lorazepam
0.1 mg/kg given at a rate of 2 mg/min
was superior as compared to IV phenytoin as the first-line therapy in aborting
status epilepticus. In the VA Cooperative
Study, 64.9% of status epilepticus events
were first aborted with IV lorazepam as
opposed to 43.5% with IV phenytoin,
establishing the superiority of IV lorazepam as first-line therapy.15 Beyond this
Class I evidence favoring IV lorazepam,
treatment recommendations have been
essentially based on anecdotal evidence
and small case series.
The recommended second-line therapy includes phenytoin/fosphenytoin at
20 mg/kg. IV phenytoin had the lowest
efficacy in the VA study (43.5%) when
compared to lorazepam and phenobarbital but became the drug of choice for
second-line therapy because it has a lesssedating side effect profile compared to
phenobarbital, which had 58.2% efficacy
in the study. IV phenytoin carries a
significant risk for infusion site reactions
and cardiac arrhythmias, particularly
with rapid infusions. These risks are
significantly lower with fosphenytoin,
so it is therefore recommended to use
IV fosphenytoin whenever possible, particularly when using a peripheral IV line.
Continuum (Minneap Minn) 2016;22(1):173190

However, since both fosphenytoin and


phenytoin carry some risk of cardiac
arrhythmias, hypotension, and liver induction, newer AEDs currently available
in IV formulation (eg, levetiracetam,
valproate, lacosamide) have also been
used as second-line therapy. Sufficient
evidence does not exist to support a
particular sequence of medications to be
given, and medication choices are
based on comorbid conditions, side
effects, and opinions.16 No randomized
controlled trial has specifically evaluated the efficacy of different sequences
of IV AEDs, but available evidence
suggests some degree of efficacy
for IV valproate, levetiracetam, and
lacosamide. Additional medications,
such as topiramate, zonisamide, and
felbamate, can be given orally if the
intestines are able to support absorption. Since ileus is a frequent complication of status epilepticus, the use of
IV AEDs is generally preferred, as oral
medications may not be absorbed.
If status epilepticus persists after
treatment with first- and second-line
therapy, transfer to the ICU for initiation of third-line therapy with IV anesthetics is recommended. Options for
third-line therapy include propofol,
midazolam, and pentobarbital. Specific
considerations related to each medication are later discussed in the section
on ICU treatment.

KEY POINT

h The use of IV
antiepileptic drugs is
generally preferred for
management of status
epilepticus, as oral
medications may not
be absorbed.

Tailored Status Epilepticus


Treatment Recommendations
Clinically, patients first present in
status epilepticus in three distinct
scenarios: (1) prehospital, (2) emergency department or inpatient, and
(3) ICU. To optimize the clinical utility
of this section on treatment recommendations, unique considerations related to each of these settings is
discussed.
Regardless of the setting, modern
treatment of status epilepticus should
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177

Epilepsy Emergencies

TABLE 9-1 General Dosing Recommendations for the Most Common First-, Second-, and
Third-Line Medications Used in the Treatment of Status Epilepticus
Medication

Loading Dose

Maintenance

Half-Life

Metabolism

Lorazepam

0.1 mg/kg at a rate


of 2 mg/min

NA

12 hours

Hepatic

Midazolama

0.2 mg/kg, initial


dose of 10 mg IM

NA

2Y6 hours

Hepatic; active
metabolites
excreted renally

Diazepam

0.2 mg/kg at a rate


of 5 mg/min

NA

20Y100 hours

Hepatic

Phenytoin

20 mg/kg IV at a rate
of 50 mg/minb; may
rebolus with another
10 mg/kg as needed

100 mg IV given
every 6 to 8 hours

10Y15 hours

Hepatic

Fosphenytoin

20 mg PE/kg IV at a
rate of 150 mg PE/minc;
may rebolus with
another 10 mg PE/kg
as needed

100 mg IV given
every 6 to 8 hours

10Y15 hours

Hepatic

Valproatea

20Y40 mg/kg

4Y6 mg/kg given


every 6 hours

9Y16 hours

Hepatic

Levetiracetama

2000Y4000 mg

10Y15 mg/kg given


every 12 hours

7Y11 hours

Renal excretion

Lacosamidea

200Y400 mg

200Y300 mg given
every 12 hours

13 hours

95% Renal
excretion

1Y2 mg/kg

2Y10 mg/kg/h

Rapid distribution:
2Y4 minutes

Hepatic

First line

Second line

Third line
Propofola

Risk of infusion
syndrome over
5 mg/kg/h for
more than 48 hours

Slower distribution:
30Y60 minutes
Terminal elimination:
3Y12 hours

Midazolam

0.2 mg/kg

0.1Y2 mg/kg/h

2Y6 hours

Hepatic; active
metabolites
excreted renally

Pentobarbital

5Y10 mg/kg

0.5Y5 mg/kg/h

15Y50 hours

Hepatic

1.5 mg/kg repeated


every 5 minutes up
to a dose of 4.5 mg/kg

2Y5 mg/kg/h

10 minutesY2.5 hours

Hepatic

Ketamine

IM = intramuscular; IV = intravenous; NA = not applicable; PE = phenytoin equivalent.


a
Not US Food and Drug Administration (FDA) approved for the indication of status epilepticus.
b
IV must be 18 gauge or larger and must be placed in the antecubital fossa or more proximal to prevent subcutaneous infusion/necrosis
(purple glove syndrome) and venosclerosis.
c
While fosphenytoin can be given at a faster rate than phenytoin, it does not exert its therapeutic effect any faster. Fosphenytoin is a
prodrug that is converted to phenytoin in the liver before exerting any therapeutic effect.

178

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emphasize time to treatment rather


than a certain sequence of medications. In addition to the initial treatment managing the underlying
etiology, treating seizure-related complications and preventing seizure recurrence are critical. Rapid treatment
for status epilepticus depends on the
clinical context.
Prehospital Treatment
The Rapid Anticonvulsant Medications
Prior to Arrival Trial (RAMPART) demonstrated better efficacy for IM
midazolam than for the standard IV
lorazepam because of speed and ease
of administration (ie, the IM route did
not require an IV line placement).17,18
IM midazolam (10 mg) was administered by auto-injector and stopped
seizures prior to emergency department arrival in 73.4% of patients,
compared to IV lorazepam (4 mg)
which stopped seizures prior to emergency department arrival in 63.4% of
patients. Other routes of administration that do not require IV access are
also being used for prehospital termination of status epilepticus, including intranasal midazolam, buccal midazolam,
and rectal diazepam.19 While the early
administration of a benzodiazepine
should be emphasized and the success
of non-IV formulations has been shown,
it is important to keep in mind that
26.5% of patients in the RAMPART trial
did not stop seizing prior to emergency
department arrival, so placement of an
IV by emergency response personnel
and prompt transport to a controlled
clinical environment remain paramount.
Emergency Department/
Inpatient Treatment
In the emergency department or hospital ward, the patient may already
have an IV line established; if not,
expert assistance can be sought to
establish one rapidly. In the inpatient
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setting, IV access will be needed


eventually for AEDs and support regardless and will be a goal of the care
team. One limitation to the RAMPART
study is that only a relatively modest
dose of IV lorazepam (4 mg) was used.
While this is typically a generous initial
dose, it is about half of the typical
0.1 mg/kg dose recommended for the
treatment of status epilepticus based
on the VA Cooperative Study.15 This
modest dose was necessary in the
prehospital phase because of the
possibility of respiratory compromise.
However, for inpatient use, the full
0.1 mg/kg of lorazepam can be administered at 2 mg/min as the recommended
first-line therapy to best terminate
status epilepticus.
After the full dose of benzodiazepine, second-line therapy with IV AEDs
should be considered. As alluded to
earlier, the purely academic proposals
of one ideal AED treatment sequence
versus another (eg, fosphenytoin versus
other IV AEDs) are faced with the
logistic challenges of real clinical practice, including delays in transporting
AEDs from the hospital pharmacy to
the inpatient ward, potentially delaying
availability for use in the treatment of a
given patients status epilepticus. The
point to highlight here is that the
treatment of an acutely convulsing
patient should not be delayed waiting
on a medication. If a patient remains in
convulsive status epilepticus after receiving 0.1 mg/kg IV lorazepam and the
clinical team is facing logistic delays in
obtaining the traditional second-line
agents (IV AEDs), immediate intubation
and transfer to the ICU should be
considered for the safe initiation of a
third-line agent (anesthesia).
Intensive care unit treatment. If a
patient is already in the ICU at the
onset of status epilepticus (eg, a
patient who is postoperative, a patient
with an intracranial hemorrhage and

KEY POINT

h Modern treatment of
status epilepticus should
emphasize time to
treatment rather than
a certain sequence
of medications.

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179

Epilepsy Emergencies
KEY POINTS

h Ensuring that the


patient is transitioned to
a sustainable regimen of
rational antiepileptic
drug polytherapy is
critical to avoid seizure
recurrence after
discontinuation
of IV status
epilepticus treatment.

h Early treatment should


be emphasized based
on data showing that
status epilepticus
treatment becomes less
effective the longer the
episode of status
epilepticus lasts.

coma with seizures diagnosed on continuous EEG, or a patient who is posttransplant with sudden decline in
mental status), he or she should receive 0.1 mg/kg lorazepam followed
immediately by a third-line agent (IV
midazolam, propofol, or pentobarbital)
if seizures continue. A third-line agent is
typically readily available in the ICU and
is usually sufficient to terminate the
status epilepticus. Traditional secondline AEDs can then be initiated with less
urgency to provide the treatment coverage necessary to prevent the return of
seizures when the patient is weaned off
anesthesia. Ensuring that the patient is
transitioned to a sustainable regimen of
rational AED polytherapy is critical to
avoid seizure recurrence after discontinuation of IV status epilepticus treatment.
REFRACTORY STATUS
EPILEPTICUS
Seizures that continue despite firstand second-line therapies are considered refractory status epilepticus. Refractory status epilepticus should be
promptly treated with an IV anesthetic
agent (third-line agent, eg, propofol,
midazolam, or pentobarbital) administered quickly with the goal of having
the third-line agent established as
soon as possible from the onset of
status epilepticus. Early treatment
should be emphasized based on data
showing that status epilepticus treatment becomes less effective the longer the episode of status epilepticus
lasts.15 Some evidence also exists that
nonconvulsive seizures (which tend to
last much longer than convulsive
seizures) are more difficult to treat,
with a 15% response to the first
medication, while generalized convulsive status epilepticus has a 55%
response rate overall to the first
medication and a 60% to 70% response rate when the medication is
given in the prehospital setting. Third-

180

line agents should be initiated in a


time-dependent fashion, and continuous EEG is needed to titrate the
medication to burst suppression and
to monitor for seizure activity. Once a
third-line agent is administered, little
likelihood exists of observing any
motor activity with seizures, but it
can still occur, even in the setting of
burst suppression.
Choices for third-line agents are
largely based on availability and comorbid conditions. Propofol is often
available in the ICU and has a short
half-life. However, it can lower blood
pressure, and high doses given for
more than 48 hours can be associated
with propofol infusion syndrome,
which leads to congestive heart failure, lactic acidosis, hypertriglyceridemia, and rhabdomyolysis. Thus,
propofol is often used as an initial drug
because of its rapid effect, but patients
are either weaned off the drug after 24
hours or transitioned to another agent
such as pentobarbital. Midazolam is
often used as the initial choice for a
third-line agent since it has less impact
on blood pressure and is often effective.
Midazolam is less effective with
prolonged use and requires an increase
in dose for the same effect because of
degradation of the GABA receptors
during status epilepticus.20 When it is
used as an initial drug, patients are
often weaned off the midazolam after
48 to 72 hours or transitioned to
pentobarbital. Pentobarbital has a long
half-life and takes a number of hours to
reach a therapeutic level, but it is very
reliable in its ability to achieve burst
suppression. It does have increased
morbidity because of the prolonged
duration of pentobarbital-associated
comas; these typically last at least a
week, potentially increasing the risk for
deep venous thrombosis/pulmonary
embolism, myocardial depression/
reduced cardiac output, and ileus

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complicating nutrition and any oral


medication use. Typically, the patient
is weaned off the third-line agent after
24 to 48 hours. If seizures recur, the
patient is placed back into seizure
suppression with the third-line agent
for 3 to 7 days with intermittent
weaning of the medication to assess
for seizure control.
ADDRESSING THE UNDERLYING
ETIOLOGY
Since 50% of status epilepticus cases
involve an acute symptomatic etiology
(eg, hemorrhage, stroke, encephalitis)
and others include exacerbations of

chronic etiologies (eg, tumor, remote


stroke, traumatic brain injury), addressing the underlying etiology must
occur concurrently with terminating
the seizure activity. For example, a subdural hematoma that has caused cerebral edema and seizures may proceed
to herniation without prompt intervention.21 Simply stopping the seizures in
this case would not benefit the patient, and the seizures would likely stay
refractory until the hematoma is evacuated and the cerebral edema and hydrocephalus controlled (Case 9-1).
Patients with underlying metabolic
encephalopathies are also at risk

KEY POINT

h Since 50% of status


epilepticus cases involve
an acute symptomatic
etiology (eg,
hemorrhage, stroke,
encephalitis) and
others include
exacerbations of chronic
etiologies (eg, tumor,
remote stroke,
traumatic brain injury),
addressing the
underlying etiology
must occur concurrently
with terminating the
seizure activity.

Case 9-1
A 62-year-old man with a history of atrial fibrillation presented to the emergency department
with the sudden onset of a severe headache. In the emergency department, he began to have
difficulty speaking. His CT scan showed a left hemisphere subdural hematoma (Figure 9-1A),
and he was admitted to the neurosurgery service. Overnight, he became progressively less responsive
and had a clinical seizure (generalized tonic-clonic per the nurses description). He was taken
to the operating room for an emergent left subdural evacuation. After the surgery, he remained
lethargic and was not able to follow commands. He had a repeat CT scan postoperatively that

FIGURE 9-1

CT scans of the patient in Case 9-1. A, Initial CT scan shows left hemisphere
subdural hematoma. B, Postoperative repeat CT scan shows resolution of the
subdural hematoma and lessening of midline shift.

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Epilepsy Emergencies

Continued from page 181


showed resolution of the subdural hematoma and lessening of his midline shift (Figure 9-1B).
Continuous EEG showed frequent seizures arising over the left hemisphere, which were treated
with lorazepam and levetiracetam (Figure 9-2). Quantitative EEG was used in this case, with
several hours displayed graphically at the bedside, allowing titration of antiepileptic drugs to his
EEG to ensure the seizures were stopped and avoid overmedicating the patient (Figure 9-3). After
the antiepileptic drugs were administered, the seizures resolved and he woke up slowly over the
next 48 hours.

FIGURE 9-2

EEG of the patient in Case 9-1 shows an electrographic seizure evolving over the left hemisphere maximum in
the left frontocentral region.

Comment. This case demonstrates status epilepticus in the setting of an acute symptomatic
lesion. His mental status could very well be attributed to his subdural hematoma, its worsening,
and then the surgery. The electrographic seizures would have been missed without continuous EEG
monitoring, and he may have had a poor cognitive outcome that might have been blamed on
the subdural hematoma in the absence of EEG data. With treatment, his seizures were stopped
quickly and he made a full recovery.

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Continued from page 182

FIGURE 9-3

Studies of the patient in Case 9-1 show the left hemisphere electrographic seizure (right panel) and the
corresponding quantitative EEG with multiple seizure detections (left panel).

for status epilepticus, and identifying


nonconvulsive seizures on continuous
EEG is the major diagnostic challenge.
If the seizures are not recognized,
the patient may have a worse cognitive outcome because of prolonged
nonconvulsive status epilepticus.
However, the seizures are unlikely
to respond to treatment until the
underlying cause of the metabolic
disturbance (eg, sepsis, liver failure)
is corrected (Case 9-2). Patients with
an autoimmune or paraneoplastic etiology may also continue to have refractory seizures until the underlying
condition is addressed (Case 9-3).
COMPLICATIONS
Patients who have prolonged status
epilepticus have significant risk for acute
organ failure, polyneuropathy, sepsis,
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deep venous thrombosis/pulmonary


embolism, and other common ICU
complications. Remaining in a prolonged state of coma, even if the
seizures are being suppressed, leads to
significant complications. Critical illness
polyneuropathy and myopathy affect
30% to 50% of critically ill patients and
are frequent complications in status
epilepticus that may prevent weaning
patients from the ventilator and contribute to morbidity.22 Early rehabilitation in the ICU has been noted
to improve outcomes with critical
illness neuromyopathy. Sepsis is also a
frequent complication in patients with
status epilepticus. Patients with decreased neurologic function have higher
risk for infections, and many episodes of
status epilepticus begin with a violent
seizure and aspiration of oral contents

KEY POINT

h Patients who have


prolonged status
epilepticus have
significant risk for acute
organ failure,
polyneuropathy, sepsis,
deep venous thrombosis/
pulmonary embolism,
and other common
intensive care
unit complications.

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Epilepsy Emergencies

Case 9-2
A 66-year-old woman with a history of cirrhosis, portal hypertension, and esophageal varices presented with
nausea, vomiting, and abdominal pain. She was diagnosed with a small-bowel obstruction and admitted to
the internal medicine service. She became progressively less responsive and then started to have subtle facial
twitching. She had an MRI of her brain that was reported as showing changes consistent with hyperammonemia,
which was managed with lactulose (Figure 9-4). She was placed on continuous EEG because of her altered
mental status and the facial twitching. She had five to seven seizures per hour recorded from the left and
right hemispheres (Figure 9-5). She was given 0.1 mg/kg lorazepam and loaded with 2000 mg IV
levetiracetam but continued to have seizures. She was then loaded with 400 mg IV lacosamide and placed
on a propofol drip; her seizures became less frequent but continued. She was finally placed on a midazolam
drip, and her seizures were terminated. She was maintained on midazolam for 48 hours and then weaned
off with no return of her seizures. She remained unresponsive for several days after the midazolam was
stopped, and the medical team discharged her to hospice care with the intention of comfort care. Over the
next week in hospice, she began to speak, follow commands, and move her extremities.

FIGURE 9-4

Axial brain MRI (A, fluid-attenuated inversion recovery [FLAIR]; B,


diffusion-weighted imaging) of the patient in Case 9-2 shows restricted diffusion
involving the insular and cingulate cortices and thalamus bilaterally consistent
with hyperammonemia.

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Continued from page 184

FIGURE 9-5

EEG of the patient in Case 9-2 shows five to seven seizures per hour recorded from the left and right hemispheres.

Comment. This case illustrates that status epilepticus can present without a primary neurologic
injury, but may be secondary to any of a number of systemic or metabolic disturbances. It is also worth
noting that this patients medications were chosen specifically based on her liver dysfunction (no
valproate or phenytoin was used), but given the refractory nature of her seizures, she required
third-line agents (propofol and midazolam) to control her seizures. Given her liver dysfunction, it
could be expected that she would take longer to wake up after she was weaned off the medications
and that she would require lower doses of medications because of her altered metabolism. The point
to make is that delayed mental status recovery and slowed metabolism of pharmacologic status
epilepticus treatment should be anticipated in patients with severe metabolic dysfunction and should
be taken into account when making decisions about long-term care.

into the lungs. With prolonged status


epilepticus, skin breakdown from
decubitus ulcers can also be a source
of sepsis. Deep venous thrombosis and
pulmonary emboli are potentially lifethreatening complications and are also
common in patients with prolonged
immobility and decreased mental status.
Subcutaneous heparin, mechanical calf
compression, and frequent monitoring
with ultrasound are all recommended to
prevent these complications.
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OUTCOMES
Little is known about long-term outcomes of status epilepticus. Some
reports associate the length of
electrographic seizures with a poor
neurologic outcome, as well as diffuse
brain atrophy with prolonged seizures
(Case 9-3).23 Studies on patients after
convulsive status epilepticus suggest
they may have memory loss, psychiatric
issues (eg, paranoia, hallucinations, loss
of executive function), and chronic
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185

Epilepsy Emergencies

Case 9-3
A 22-year-old man presented to the emergency department several times over the course of a month with
agitation. He finally barricaded himself in his house; the police brought him to a psychiatric unit, where
he was given haloperidol. He became progressively obtunded over the next 2 days and was transferred to
the intensive care unit where he required intubation for airway protection. In the intensive care unit,
his EEG showed giant delta waves with overlying beta (Figure 9-6). He had a lumbar puncture and
neuroimaging with the initial results being unremarkable. Over the next week, his EEG began to show
evolving electrographic seizures that were refractory to lorazepam, fosphenytoin, levetiracetam, and
lacosamide (Figure 9-7). He was started on IV midazolam and then IV pentobarbital. He was weaned off
pentobarbital after 1 week, and the seizures returned. He was placed back on pentobarbital and given a
course of methylprednisolone and IVIg. He had a fluorodeoxyglucose positron emission tomography
(FDG-PET) scan that was consistent with limbic encephalitis (Figure 9-8, middle panel). His CSF was
positive for N-methyl-D-aspartate (NMDA) receptor antibodies. He had multiple courses of plasma
exchange and cyclophosphamide with continued seizures. A brain MRI demonstrated some global
atrophy that progressed during his stay, particularly in the first 2 months (Figure 9-9). He was then
started on a course of rituximab and was able to be successfully weaned off pentobarbital without
seizures. Repeat FDG-PET after rituximab showed a resolution of the limbic encephalitis on day 99
(Figure 9-8). After the seizures stopped, he remained in a stuporous state with no noted physical
movements except for rapid eye fluttering. He was discharged to rehabilitation and after 5 months was
able to speak and follow commands, with 3/5 weakness and spasticity in all four extremities. Six months
later, he had made a full recovery; he was able to drive again 2 years after the onset of the illness,
but had some residual contractions in his hands.

FIGURE 9-6

EEG of the patient in Case 9-3 shows giant delta waves with overlying beta.

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Continued from page 186

FIGURE 9-7

EEG of the patient in Case 9-3 shows evolving seizures.

FIGURE 9-8

Imaging of the patient in Case 9-3. Left, Axial fluid-attenuated inversion recovery (FLAIR) MRI at the time of the limbic
encephalitis. Middle, Fluorodeoxyglucose positron emission tomography (FDG-PET) scan shows hypermetabolism in
the region of the bilateral mesial temporal structures (arrows), consistent with limbic encephalitis. Right, Repeat
FDG-PET after rituximab shows a resolution of the limbic encephalitis on day 99 of his hospital stay.

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187

Epilepsy Emergencies

Continued from page 187

FIGURE 9-9

Axial brain MRIs of the patient in Case 9-3, which demonstrate global atrophy
that progressed during his hospital stay, particularly in the first 2 months.

Comment. This case demonstrates that addressing the underlying etiology is paramount to stopping
status epilepticus. This patients seizures were refractory to all medications given, and even after the
diagnosis of NMDA receptor encephalitis was made, multiple rounds of immunosuppressive activity
were unsuccessful until seizure freedom was finally achieved after treatment with rituximab. This
case also demonstrates that long-term refractory status epilepticus can be survived and have a
favorable prognosis.

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February 2016

epilepsy as sequelae. Studies on


nonconvulsive seizures are less robust,
but existing data suggest that 60% of
patients with fewer than 10 hours of
nonconvulsive seizures were able to
return home, while 10 to 20 hours of
nonconvulsive status epilepticus was
associated with permanent disability
(50%) and more than 20 hours was
associated with death in 85% of patients.23 Additional prospective trials
are needed to determine the outcome
of status epilepticus, especially in the
case of nonconvulsive status epilepticus.
It is clear that etiology, management of
complications, and time spent in status
epilepticus are the major determinants
of short-term prognosis, but modifying
these variables to the patients benefit is
more challenging. It remains unclear at
this time if some etiologies (especially
acute symptomatic causes) that are associated with acute repetitive seizures
have status epilepticus as a result of
worsening of the underlying etiology, or
if the presence of seizures contributes
to the worsening of the underlying
etiology. Regardless, the recommendation at this time, based on consensus
statement and some evidence, is to
treat nonconvulsive seizures aggressively with time to seizure termination
being the most important goal.16
CONCLUSION
Status epilepticus is a major neurologic
emergency and requires diagnostic vigilance and rapid response to prevent
morbidity and mortality. Early treatment should be emphasized over
choice of medication, with prehospital
treatment showing the highest efficacy.
Established status epilepticus and
nonconvulsive status epilepticus tend
to be refractory and pose significant
treatment challenges. An epidemiologic shift in the identification of
status epilepticus in the inpatient
population has occurred based on
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the use and availability of continuous


EEG. More data are required to determine the long-term benefits of
this increased detection and treatment of status epilepticus in the
inpatient population.
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