Professional Documents
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Epilepsy Emergencies
Address correspondence to
Dr Stephen Hantus, Cleveland
Clinic, 9500 Euclid Avenue
#S51, Cleveland, OH 44195,
Stephen Hantus, MD hantus@gmail.com.
Relationship Disclosure:
Dr Hantus reports no disclosure.
Unlabeled Use of
ABSTRACT Products/Investigational
Purpose of Review: Epilepsy emergencies include acute repetitive seizures and Use Disclosure:
Dr Hantus reports no disclosure.
status epilepticus. Their prognosis depends on the etiology of the seizures and the
* 2016 American Academy
time spent in status epilepticus. This review discusses the current perspective on the of Neurology.
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.
KEY POINTS
DEFINITION OF STATUS ber of patients diagnosed with status
h Nonconvulsive status
EPILEPTICUS epilepticus over the past 10 years and
epilepticus, which may
have no clinical Status epilepticus has traditionally an increase in the number of inpatient
manifestations and is been defined as 30 minutes of contin- hospitalizations for status epilepticus,
only detectable through uous seizure activity or multiple sei- particularly in elderly patients
video-EEG monitoring, zures without return to neurologic intubated in the intensive care unit
is increasingly baseline. This definition was devel- (ICU).3 Rather than a true increase in
being recognized. oped to coincide with data suggesting the occurrence of status epilepticus,3
h A patients prognosis is irreversible damage to neurons after this shift in epidemiology may reflect
dependent on the continuous seizure activity in animals the increased detection of non-
underlying etiology of and in vitro. However, this definition convulsive status epilepticus in ICU
and time spent in is useful only in the retrospective patients with the growing use of con-
status epilepticus. identification of patients. A working tinuous EEG monitoring. A number of
h Seizures lasting longer definition must be able to identify large consecutive patient studies have
than 5 minutes are less patients within time to treat and identified nonconvulsive seizures in 8%
likely to end without an possibly prevent irreversible damage.1 to 34% of patients with altered mental
external intervention Typical seizures last up to 3 to status in the ICU.4Y6 Additional factors
and should be 5 minutes before being stopped by potentially contributing to the in-
considered status
the intrinsic inhibitory mechanisms of creased documented incidence of sta-
epilepticus for all
the brain. Seizures lasting longer than tus epilepticus include the aging of
practical purposes;
therefore, they need to
5 minutes are less likely to end without the population and the implementa-
be emergently treated. an external intervention and should be tion of a less-rigid working definition of
considered status epilepticus for all status epilepticus.
h Rather than a true
practical purposes; thus, they need to
increase in the
be emergently treated. Refractory sta- PATHOPHYSIOLOGY
occurrence of status
epilepticus, the shift in tus epilepticus is defined as seizures Status epilepticus represents the per-
epidemiology of status that continue despite first- and second- sistence of abnormal excitation and
epilepticus seen in the line treatments. Super-refractory status the ineffective recruitment of inhibi-
past 10 years may epilepticus occurs when third-line tion.7 Excitation can come from many
reflect increased agents (IV anesthetics) fail and pre- sources, such as an established epi-
detection of sents particular challenges discussed leptogenic circuit from preexisting
nonconvulsive status later in this article. epilepsy, excitation from the region
epilepticus in intensive surrounding a structural lesion, or
care unit patients with EPIDEMIOLOGY diffuse excitation from a toxic/meta-
the growing utilization
The incidence of status epilepticus bolic state. These limbic and cortical
of continuous
reportedly ranges from 10 per 100,000 inputs feed into the perforant pathway
EEG monitoring.
to 40 per 100,000 in various databases.2 along the parahippocampal gyrus and
A peak incidence occurs at younger to the neurons in the dentate gyrus.
than 10 years of age (14.3 per 100,000) The dentate is often the brake for
and at older than 50 years of age (28.4 excitatory activity, but when over-
per 100,000), with the highest mortal- whelmed, excitatory activity feeds
ity in the elderly population.2 Status back to the hippocampus and then
epilepticus may be the initial presenta- back to the parahippocampal gyrus,
tion of chronic epilepsy in up to 30% creating a self-amplifying reverberating
of patients, whereas an acute symp- circuit that perpetuates status epilep-
tomatic etiology for status epilepticus ticus. This pathophysiology can often
occurs in 40% to 50% of cases. A 2015 be suspected when the brain MRI of a
evaluation of large national patient patient in status epilepticus shows a
databases showed an increasing num- low level of restricted diffusion in the
174 www.ContinuumJournal.com February 2016
KEY POINTS
h Acute repetitive seizures (ranging from several minutes up to etiology of the status epilepticus should
represent an escalation 24 hours). These seizures represent immediately be sought. The most com-
in severity, are less likely an escalation in severity, are less likely mon etiologies include seizure break-
to remit without to remit without treatment, and may throughs in the context of a known
treatment, and may lead lead to status epilepticus and neuronal chronic epilepsy, acute structural le-
to status epilepticus and damage.10 Acute repetitive seizures sions, or acute metabolic derangements.
neuronal damage. are thought to present a similar risk Nonconvulsive seizures present a
Acute repetitive seizures of seizure-related neuronal damage as much more difficult diagnostic chal-
are thought to present a prolonged seizures and require lenge. Patients with altered mental
similar risk of prompt medical intervention, typically status in the critical care setting have
seizure-related neuronal
with benzodiazepines.11 In patients in a risk for nonconvulsive seizures that
damage as prolonged
the critical care setting, acute repeti- is proportional to the severity of the
seizures and require
prompt medical
tive seizures often occur as elec- altered mental status. Patients in coma
intervention, typically trographic seizures and little in the have the highest risk of nonconvulsive
with benzodiazepines. way of apparent clinical signs. These status epilepticus at 30% to 40%.
electrographic seizures typically occur Finding a patient with altered mental
h Acute repetitive seizures
in the critical care
after a primary neurologic injury of status greater than expected for his or
setting have often some kind (eg, stroke, hemorrhage, her underlying condition should raise
been equated to status tumor, infection). The relative signifi- concern for nonconvulsive status
epilepticus since cance of this intermittent frequent epilepticus. Patients with primary neu-
patients do not return seizure pattern as compared to the rologic pathology (eg, hemorrhage,
to a baseline function prolonged continuous electrographic tumor, stroke, central nervous system
in between their acute seizure activity of traditional status infection, and anoxia) have the
repetitive seizures. epilepticus is unknown. Although the highest risk of seizures.13 A CT scan
h Finding a patient with consequences of acute repetitive sei- of the head to evaluate for a high-risk
altered mental status zures are not well understood, they primary neurologic pathology is the
that is worse than should be treated promptly as they typical first step in diagnosis. A brain
expected for his or her pose a significant risk for the develop- MRI is required to evaluate for the full
underlying condition ment of status epilepticus.12 In fact, range of structural pathology that
should raise concern from a pragmatic perspective, acute could be the cause for seizures or
for nonconvulsive
repetitive seizures in the critical care status epilepticus, but given the length
status epilepticus.
setting have often been equated to of the procedure, it may be deferred
h Patients at risk for status epilepticus since patients do not until the status epilepticus is ade-
status epilepticus based return to a baseline function in be- quately treated. If any concern of
on clinical criteria
tween their acute repetitive seizures. infection, possible meningitis, or en-
(eg, altered mental
Therefore, treatment recommenda- cephalitis exists, a lumbar puncture
status, high-risk
neurologic pathology,
tions made in the remainder of this should be performed, but it should
subtle clinical jerks) article apply to both status epilepticus also not delay initial treatment. Pa-
should be urgently and acute repetitive seizures. tients at risk for status epilepticus
recorded on continuous based on clinical criteria (eg, altered
EEG monitoring. DIAGNOSIS mental status, high-risk neurologic
The diagnosis of generalized convul- pathology, subtle clinical jerks) should
sive status epilepticus is fairly straight- be urgently recorded on continuous
forward and based on clinical seizure EEG monitoring; guidelines have been
activity. Generalized convulsive status established for this monitoring.14
epilepticus should be treated without
delay. Once some type of treatment TREATMENT
has been initiated and the intense The treatment of status epilepticus
motor convulsions are controlled, the should aim to achieve seizure control
176 www.ContinuumJournal.com February 2016
TABLE 9-1 General Dosing Recommendations for the Most Common First-, Second-, and
Third-Line Medications Used in the Treatment of Status Epilepticus
KEY POINTS
h Ensuring that the coma with seizures diagnosed on con- line agents should be initiated in a
patient is transitioned to tinuous EEG, or a patient who is post- time-dependent fashion, and continu-
a sustainable regimen of transplant with sudden decline in ous EEG is needed to titrate the
rational antiepileptic mental status), he or she should re- medication to burst suppression and
drug polytherapy is ceive 0.1 mg/kg lorazepam followed to monitor for seizure activity. Once a
critical to avoid seizure immediately by a third-line agent (IV third-line agent is administered, little
recurrence after midazolam, propofol, or pentobarbital) likelihood exists of observing any
discontinuation if seizures continue. A third-line agent is motor activity with seizures, but it
of IV status typically readily available in the ICU and can still occur, even in the setting of
epilepticus treatment. is usually sufficient to terminate the burst suppression.
h Early treatment should status epilepticus. Traditional second- Choices for third-line agents are
be emphasized based line AEDs can then be initiated with less largely based on availability and co-
on data showing that urgency to provide the treatment cover- morbid conditions. Propofol is often
status epilepticus age necessary to prevent the return of available in the ICU and has a short
treatment becomes less
seizures when the patient is weaned off half-life. However, it can lower blood
effective the longer the
anesthesia. Ensuring that the patient is pressure, and high doses given for
episode of status
epilepticus lasts.
transitioned to a sustainable regimen of more than 48 hours can be associated
rational AED polytherapy is critical to with propofol infusion syndrome,
avoid seizure recurrence after discontin- which leads to congestive heart fail-
uation of IV status epilepticus treatment. ure, lactic acidosis, hypertriglyc-
eridemia, and rhabdomyolysis. Thus,
REFRACTORY STATUS propofol is often used as an initial drug
EPILEPTICUS because of its rapid effect, but patients
Seizures that continue despite first- are either weaned off the drug after 24
and second-line therapies are consid- hours or transitioned to another agent
ered refractory status epilepticus. Re- such as pentobarbital. Midazolam is
fractory status epilepticus should be often used as the initial choice for a
promptly treated with an IV anesthetic third-line agent since it has less impact
agent (third-line agent, eg, propofol, on blood pressure and is often effective.
midazolam, or pentobarbital) adminis- Midazolam is less effective with
tered quickly with the goal of having prolonged use and requires an increase
the third-line agent established as in dose for the same effect because of
soon as possible from the onset of degradation of the GABA receptors
status epilepticus. Early treatment during status epilepticus.20 When it is
should be emphasized based on data used as an initial drug, patients are
showing that status epilepticus treat- often weaned off the midazolam after
ment becomes less effective the lon- 48 to 72 hours or transitioned to
ger the episode of status epilepticus pentobarbital. Pentobarbital has a long
lasts.15 Some evidence also exists that half-life and takes a number of hours to
nonconvulsive seizures (which tend to reach a therapeutic level, but it is very
last much longer than convulsive reliable in its ability to achieve burst
seizures) are more difficult to treat, suppression. It does have increased
with a 15% response to the first morbidity because of the prolonged
medication, while generalized convul- duration of pentobarbital-associated
sive status epilepticus has a 55% comas; these typically last at least a
response rate overall to the first week, potentially increasing the risk for
medication and a 60% to 70% re- deep venous thrombosis/pulmonary
sponse rate when the medication is embolism, myocardial depression/
given in the prehospital setting. Third- reduced cardiac output, and ileus
180 www.ContinuumJournal.com February 2016
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.
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.
Continued on page 183
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 deep venous thrombosis/pulmonary KEY POINT
nonconvulsive seizures on continuous embolism, and other common ICU h Patients who have
EEG is the major diagnostic challenge. complications. Remaining in a pro- prolonged status
epilepticus have
If the seizures are not recognized, longed state of coma, even if the
significant risk for acute
the patient may have a worse cogni- seizures are being suppressed, leads to
organ failure,
tive outcome because of prolonged significant complications. Critical illness polyneuropathy, sepsis,
nonconvulsive status epilepticus. polyneuropathy and myopathy affect deep venous thrombosis/
However, the seizures are unlikely 30% to 50% of critically ill patients and pulmonary embolism,
to respond to treatment until the are frequent complications in status and other common
underlying cause of the metabolic epilepticus that may prevent weaning intensive care
disturbance (eg, sepsis, liver failure) patients from the ventilator and con- unit complications.
is corrected (Case 9-2). Patients with tribute to morbidity.22 Early rehabilita-
an autoimmune or paraneoplastic eti- tion in the ICU has been noted
ology may also continue to have re- to improve outcomes with critical
fractory seizures until the underlying illness neuromyopathy. Sepsis is also a
condition is addressed (Case 9-3). frequent complication in patients with
status epilepticus. Patients with de-
COMPLICATIONS creased neurologic function have higher
Patients who have prolonged status risk for infections, and many episodes of
epilepticus have significant risk for acute status epilepticus begin with a violent
organ failure, polyneuropathy, sepsis, seizure and aspiration of oral contents
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.
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.
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.
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.
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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