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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.
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
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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.
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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-
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KEY POINTS
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.
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KEY POINT
h The use of IV
antiepileptic drugs is
generally preferred for
management of status
epilepticus, as oral
medications may not
be absorbed.
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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
NA
12 hours
Hepatic
Midazolama
NA
2Y6 hours
Hepatic; active
metabolites
excreted renally
Diazepam
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
9Y16 hours
Hepatic
Levetiracetama
2000Y4000 mg
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
2Y5 mg/kg/h
10 minutesY2.5 hours
Hepatic
Ketamine
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KEY POINT
h Modern treatment of
status epilepticus should
emphasize time to
treatment rather than
a certain sequence
of medications.
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KEY POINTS
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-
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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
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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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).
KEY POINT
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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
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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.
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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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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FIGURE 9-7
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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Epilepsy Emergencies
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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