REVIEW ARTICLE


Epilepsy Emergencies:
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Status Epilepticus, Acute
CITE AS:
Repetitive Seizures, and
CONTINUUM (MINNEAP MINN)
2019;25(2, EPILEPSY):454–476.
Autoimmune Encephalitis
Address correspondence to By Stephen VanHaerents, MD; Elizabeth E. Gerard, MD
Dr Stephen VanHaerents, 675 N
St Clair, Ste 7-112, Chicago, IL
60611, svanhaer@gmail.com.

RELATIONSHIP DISCLOSURE:
Dr VanHaerents has received
ABSTRACT
research/grant support from the PURPOSE OF REVIEW: Thisarticle reviews epilepsy emergencies, including
Citizens United for Research in status epilepticus, acute repetitive seizures, autoimmune encephalitis, and
Epilepsy, National Institute of
Continued on page 476
the current perspective on their diagnosis and treatment.

UNLABELED USE OF
RECENT FINDINGS: Recent guidelines on the treatment of status epilepticus
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE: from the Neurocritical Care Society in 2012 and the American Epilepsy
Drs VanHaerents and Gerard Society in 2016 highlight areas of consensus in the treatment of status
discuss the unlabeled/
investigational use of
epilepticus as well as areas of uncertainty. The TRENdS (Treatment of
immunosuppressant Recurrent Electrographic Nonconvulsive Seizures) trial is the first
medications for the treatment prospective randomized clinical trial to evaluate the efficacy of IV
of autoimmune encephalitis
(cyclophosphamide, IV antiseizure medications in controlling nonconvulsive seizures on
immunoglobulin, IV continuous EEG. It demonstrated that IV lacosamide is noninferior to
methylprednisolone/ fosphenytoin in this setting. Autoimmune encephalitis is an increasingly
corticosteroids, plasma
exchange, and rituximab) and recognized cause of new-onset seizures or status epilepticus. Recently
the pharmacologic and described scoring systems, the Antibody Prevalence in Epilepsy score and
nonpharmacologic therapies for
the treatment of seizures and
the Response to Immunotherapy in Epilepsy score, can help in the
status epilepticus (convulsive assessment of autoimmune encephalitis.
and nonconvulsive), which
include diazepam, fosphenytoin/
SUMMARY: Status epilepticus, acute repetitive seizures, and autoimmune
phenytoin, levetiracetam,
lorazepam, midazolam, encephalitis are neurologic emergencies. For all these conditions, rapid
phenobarbital, and valproate and appropriate treatment may influence patient prognosis and mitigate
sodium/valproic acid. Drs
VanHaerents and Gerard discuss neuronal injury. For convulsive status epilepticus, there is reasonable
the unlabeled/investigational consensus on the initial steps that need to be taken. There is less
use of several agents for the
agreement about the management of acute repetitive seizures and
treatment of refractory and super-
refractory status epilepticus, nonconvulsive status epilepticus. An increasingly recognized etiology of
which include corticosteroids/ status epilepticus is autoimmune encephalitis, which may not be as rare as
methylprednisolone,
electroconvulsive therapy,
previously thought.
hypothermia, isoflurane, IV
immunoglobulin, ketamine,
ketogenic diet, midazolam,
pentobarbital, propofol, INTRODUCTION

S
thiopental, transcranial tatus epilepticus is an epilepsy emergency with a clear time-
magnetic stimulation, and dependent relationship to morbidity and risk of mortality. However,
vagal nerve stimulation.
status epilepticus is not a single entity; it has a number of different
© 2019 American Academy
forms and a vast array of etiologies. This review will focus on how to
of Neurology. approach status epilepticus, beginning with the most unambiguous

454 APRIL 2019

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

example of status epilepticus, convulsive status epilepticus, and then moving on KEY POINTS
to less clear-cut forms, with repetitive seizures and nonconvulsive status
● Currently, the most
epilepticus. Etiologies will also be discussed, with a special emphasis on commonly accepted
autoimmune encephalitis. definition for convulsive
status epilepticus is either
DEFINITIONS 5 minutes or more of
continuous seizure activity
A number of definitions exist for status epilepticus, which is, in part, because of
or two or more discrete
the limited understanding of its pathophysiologic mechanisms. One simplified seizures between which
way to think of status epilepticus is convulsive or nonconvulsive. The problem there is incomplete recovery
with this distinction is that motor activity with seizures is evolving and dynamic, of consciousness.
making it challenging to completely separate the two entities. This difficulty has
● Refractory status
led to a number of different definitions and guidelines. epilepticus refers to either
A common definition for convulsive status epilepticus is 30 minutes of clinical or electrographic
continuous seizure activity or two or more sequential seizures without full seizures that persist after
recovery of consciousness between the seizures.1 This duration was based on the adequate doses of an initial
benzodiazepine and an
time required to demonstrate neuronal injury in animal models. The definition acceptable second-line
has more recently been revised to incorporate considerations in patient antiseizure drug.
management. Currently, the most commonly accepted definition for convulsive
status epilepticus is either 5 minutes or more of continuous seizure activity or two ● Super-refractory status
epilepticus is defined as
or more discrete seizures between which there is incomplete recovery
status epilepticus that
of consciousness.2 continues or recurs 24 hours
As opposed to convulsive status epilepticus, definitions of nonconvulsive or more after the initiation of
status epilepticus are more controversial. One common definition of anesthetic therapy.
nonconvulsive status epilepticus is a range of conditions in which greater than
30 minutes of recurrent electrographic seizure activity results in nonconvulsive
clinical symptoms.3 Another definition is when electrographic seizure activity
persists for greater than 30 minutes in the absence of visible convulsion.4 With
these varying definitions, a unified definition of status epilepticus proposed by
the Neurocritical Care Society is defined as 5 minutes or longer of continuous
clinical and/or electrographic seizure activity or recurrent seizure activity
without recovery between seizures.5
More recently, further definitions have arisen based on the response to
antiseizure drugs. Refractory status epilepticus refers to either clinical or
electrographic seizures that persist after adequate doses of an initial
benzodiazepine and an acceptable second-line antiseizure drug.6 In super-refractory
status epilepticus, seizures continue to recur 24hours or more after the onset of
anesthetic therapy.7 Of note, definitions of refractory and super-refractory status
epilepticus can apply to either convulsive or nonconvulsive status epilepticus.

TREATMENT OF STATUS EPILEPTICUS

Because status epilepticus is not a single entity and has numerous forms, a vast
array of etiologies, and multiple definitions, one unified treatment algorithm is
not possible. Consequently, treatment should be tailored to both the type and
etiology of status epilepticus. FIGURE 8-1 introduces a simplified framework for
different forms of status epilepticus. It is important to note that, during
prolonged convulsive status epilepticus, the body is often unable to continue to
produce intense motor activity; seizures may continue without overt clinical
signs, although they may generate more subtle jerks of the face, eyes, and
extremities.8 This is typically referred to as postconvulsive nonconvulsive status
epilepticus and is thought to be a continuation of convulsive status epilepticus and

CONTINUUMJOURNAL.COM 455

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

EPILEPSY EMERGENCIES

KEY POINT

● Benzodiazepine therapy
has been well established
as the first-line treatment
for convulsive status
epilepticus.

FIGURE 8-1
Simplified clinical framework for status epilepticus. The purple box represents all forms of
status epilepticus, which can be subdivided into convulsive status epilepticus and
nonconvulsive status epilepticus. It is generally regarded that postconvulsive nonconvulsive
status epilepticus should be treated similarly to convulsive status epilepticus (in orange
boxes). Blue boxes represent more controversial treatment paradigms for nonconvulsive
status epilepticus in patients who are critically ill and in patients who are ambulatory.

to cause continued neuronal injury.8 The article begins with the clinical approach
to convulsive status epilepticus and postconvulsive nonconvulsive status
epilepticus because this has the most clearly defined treatment approaches (in
orange in FIGURE 8-1). Next, more controversial treatment paradigms for
nonconvulsive status epilepticus (in light blue in FIGURE 8-1) will be discussed.

CONVULSIVE STATUS EPILEPTICUS

Ultimately, the goal of treatment for convulsive status epilepticus is to achieve
seizure control as quickly and safely as possible. Unfortunately, even for
convulsive status epilepticus, there are limited rigorous randomized controlled
clinical trials, and therefore, treatment algorithms are based largely on expert
opinion. FIGURE 8-2 compares two common treatment algorithms from the
Neurocritical Care Society in 2012 and the American Epilepsy Society in 2016.5,9
Initial steps should always be to stabilize the patient with special attention to
airway, breathing, and circulation. The physician should administer oxygen
and secure the airway as needed, initiate ECG monitoring, perform finger-stick
glucose, and screen for any immediate life-threatening causes such as meningitis
and intracranial mass lesions. In addition, the physician should attempt IV
access and send blood for electrolytes, hematology, and toxicology screen.5,9
Benzodiazepine therapy has been well established as the first-line treatment for
convulsive status epilepticus. In the US Department of Veterans Affairs
Cooperative Study, a randomized controlled clinical trial of initial IV abortive
therapies for convulsive status epilepticus, IV lorazepam 0.1 mg/kg given at a
rate of 2 mg/min, was superior to IV phenytoin. Another double-blind study
compared IV diazepam 10 mg versus IV lorazepam 4 mg and demonstrated equal
efficacy in seizure termination (76% versus 89%).11 This is helpful when

456 APRIL 2019

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

FIGURE 8-2
Comparison of treatment algorithms for convulsive status epilepticus from the Neurocritical
Care Society and the American Epilepsy Society.
AED = antiepileptic drug; EEG = electroencephalogram; IM = intramuscular; IV = intravenous.
Reprinted with permission from Brophy GM, et al, Neurocrit Care,5 © 2012 Springer Science+Business Media;
and Glauser T, et al, Epilepsy Curr,9 © 2016 American Epilepsy Society.

CONTINUUMJOURNAL.COM 457

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

EPILEPSY EMERGENCIES

managing seizures in the hospital, but the reality is that often status epilepticus
may occur outside of the hospital or at times when there is no IV access. This
was addressed more recently in RAMPART (Rapid Anticonvulsant Medication
Prior to Arrival Trial). In this trial, 10 mg of IM midazolam was found to be
superior to that of 4 mg of IV lorazepam, presumably because of the rate at which
the medication could be administered because it did not require placement
of an IV catheter.12 Of note, one limitation to this study was that the 4-mg dose
of IV lorazepam was approximately half of the typically recommended dose of
0.1 mg/kg in the US Department of Veterans Affairs Cooperative Study.10
Although initial therapy with a benzodiazepine is generally agreed on, when it
should be given is variable. The Neurocritical Care Society 2012 guidelines on
the treatment of status epilepticus recommend immediate IV access and
administration of a benzodiazepine within 0 to 5 minutes.5 Conversely, the
American Epilepsy Society 2016 guidelines recommend giving first-line
benzodiazepine therapy in the first 5 to 20 minutes (ie, once seizures last
5 minutes or more).9
After first-line benzodiazepine therapy, second-line therapy options have
little evidence that any one option is superior to another, and treatment
recommendations are based largely on expert opinion. Historically, phenytoin
and the prodrug fosphenytoin have been the most commonly used second-line
agents based on consensus and without randomized trials to support their
efficacy. Fosphenytoin is typically preferred over phenytoin because it is better
tolerated and because it can be infused more quickly with a decreased risk of
hypotension or infusion site reactions. However, there is insufficient evidence to
conclude that fosphenytoin is more effective than phenytoin.9 Treatment with
either drug requires cardiac monitoring because of a risk of arrhythmias and QT
prolongation.5 Open-label randomized controlled trials have demonstrated that
IV valproate sodium is as effective or more effective than phenytoin when
used as a second-line antiseizure drug in benzodiazepine-refractory convulsive
status epilepticus.9,13,14 In a meta-analysis of 22 studies, the efficacy of valproate
sodium, phenobarbital, and levetiracetam in benzodiazepine-refractory
convulsive status epilepticus was determined to be 75.7%, 73.6%, and 68.5%,
respectively.15 In contrast, phenytoin was estimated to have an efficacy of 50%,
and the authors concluded that this argues against its common use as the drug of
choice in benzodiazepine-refractory status epilepticus. The ongoing ESETT
(Established Status Epilepticus Treatment Trial) will hopefully provide more
clear guidance in the next few years.16 This prospective randomized double-blind
study will compare the efficacy of phenytoin, valproate sodium, and
levetiracetam in the treatment of benzodiazepine-resistant status epilepticus.
Once again, in comparing the two treatment algorithms in FIGURE 8-2, the
main difference is the recommended time points for second-line therapy. In the
Neurocritical Care Society guidelines, administration of a second-line antiseizure
drug is recommended in 5 to 10 minutes, as opposed to the American Epilepsy
Society, which recommends a second antiseizure drug in 20 to 40 minutes. Both
guidelines state that phenytoin, fosphenytoin, valproate sodium, levetiracetam,
and phenobarbital are reasonable choices at this stage with little evidence to
guide the choice between them. The American Epilepsy Society guidelines
recommend the use of phenobarbital only if the other options are not available
because of adverse effects associated with phenobarbital.9 In keeping with the
more aggressive approach recommended by the Neurocritical Care Society,

458 APRIL 2019

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

proceeding directly to IV midazolam after the first-line benzodiazepine is also KEY POINTS
presented as an option at this stage in their guidelines.5
● Both guidelines (from the
After administration of a second-line agent, if seizures persist and the patient Neurocritical Care Society
is in refractory status epilepticus, once again, there is very little evidence to guide and American Epilepsy
therapies. In the two presented treatment guidelines, the dosing and medications Society) state that
do not vary greatly, but the timing varies from 20 to 40 minutes to begin this phenytoin, fosphenytoin,
valproate sodium,
third-line therapy. Both guidelines recommend that IV anesthesia be considered
levetiracetam, and
for continued status epilepticus. They also agree that continuous EEG be started phenobarbital are
to titrate the anesthetic agents. The Neurocritical Care Society guidelines reasonable choices for
recommend titrating anesthesia to burst suppression or seizure suppression on second-line antiseizure
drugs with little evidence
EEG (rather than anesthetic drug levels) but acknowledge that there are
to guide the choice
insufficient data to suggest EEG background is predictive of outcome. between them.
Both the 2012 Neurocritical Care Society and 2016 American Epilepsy Society
guidelines offer a reasonable framework for escalation in treatment of continued ● One proposed clinical
convulsive status epilepticus. However, it is important to emphasize that these definition of acute repetitive
seizures is three or more
algorithms/guidelines may not fit all patients and should not replace a clinician’s seizures within 24 hours for
medical judgment. For example, there may be cases in which it is important to patients whose habitual
initiate intubation and anesthetic sedation in patients before the benchmark time seizure frequency is fewer
outlined by these algorithms. For instance, waiting 20 to 40 minutes or for than three seizures per day.
complete infusion of the second antiseizure medications may not be appropriate
for patients who are not supporting their airway or have continued convulsions
despite infusion of the second-line medication. Early treatment is paramount
when dealing with convulsive status epilepticus because the longer the status
epilepticus lasts, the less effective treatments become.10
As previously stated, super-refractory status epilepticus is defined as status
epilepticus that continues or recurs 24 hours or more after the onset of anesthetic
therapy. It also includes cases in which status epilepticus recurs on the reduction
or withdrawal of anesthesia. Although super-refractory status epilepticus is not
common, it has a high mortality and morbidity, with limited proven therapies. A
recent multicenter trial testing brexanolone, an allosteric modulator of
γ-aminobutyric acid A (GABA-A) receptors, for the treatment of super-refractory
status epilepticus was unable to statistically outperform placebo. Although not
officially published, preliminary data suggested that brexanolone helped 43.9%
of patients wean off a medically induced coma without seizures returning for
24 hours, in contrast to 42.4% of patients given placebo and standard-of-care
treatment.17 At this time, therapy for super-refractory status continues to be
based on clinical reports and opinions. TABLE 8-1 presents some potential
treatments for super-refractory status epilepticus.18

ACUTE REPETITIVE SEIZURES

Acute repetitive seizures is a term typically used in an ambulatory patient with
epilepsy or acute symptomatic seizures whose mental status is relatively
preserved between seizures. One proposed clinical definition of acute repetitive
seizures is three or more seizures within 24 hours for patients whose habitual
seizure frequency is fewer than three seizures per day.19 Acute repetitive seizures
may be used to describe convulsive or nonconvulsive seizures and can be
conceived of as seizure clusters. This pattern is often seen in the context of
frontal lobe epilepsy among other conditions (CASE 8-1). In humans, the
consequences and/or degree of potential neuronal injury of intermittent frequent
seizures as compared with continuous seizure activity of status epilepticus is

CONTINUUMJOURNAL.COM 459

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

EPILEPSY EMERGENCIES

unclear.20 Using an approach as aggressive as that used in status epilepticus may

be associated with unnecessary morbidity.21 Intubation and anesthetic
management of these patients may obscure the clinical examination that is
important in understanding the patient’s response to treatment. Commonly used
treatments include using IV antiseizure medications and oral benzodiazepines
and/or rectal or parenteral benzodiazepines.19 In practice, seizures may not be
aborted immediately after intervention and often decrease over several hours
to days. Seeing an initial response, such as decreased seizure frequency or

TABLE 8-1 Treatment Intervention Options for Super-refractory Status Epilepticusa

Intervention Studied Doses Adverse Effects Clinical Pearls and Considerations

Ketamine Bolus: 0.5–3 mg/kg Tachycardia; acute elevation in
Infusion: 1–10 mg/kg/h blood pressure; ICP elevation; and
theoretical neurotoxic effects
when used for prolonged periods
Use only with great caution if the
patient has an etiology that might
increase ICP (eg, severe brain edema
from anoxic brain injury). Early use of
ketamine may provide better and
faster control of seizures. Consider
in hypotensive patients.

Isoflurane Concentration: 1% to 5% Hypotension requiring IV Likely to stop seizures but not a

vasopressors support; infection; sustained effect. Consider as last-
Infusion: titrate to burst
paralytic ileus; deep vein line therapy.
suppression on EEG
thrombosis; and cognitive
dysfunction with prolonged use

Ketogenic diet 4:1 (the ratio of fat to Hyperlipidemia; weight loss; Compliance is extremely difficult
carbohydrates and contraindicated in pyruvate with long-term use of the diet
protein) carboxylase and beta-oxidation because of social and dietary
deficiency restrictions, cost, and the complexity
involved. Lack of well-designed
trials.

Hypothermia Goal temperature of Coagulation disorders; venous
32°C to 35°C  24 h thrombosis; cardiac arrhythmia;
with rewarming of no electrolyte abnormalities;
more than 0.5°C/h infections; pharmacokinetic and
pharmacodynamic changes; and
acute intestinal ischemia/necrosis
Hypothermia can potentially be used
as an alternative to two or more
unsuccessful EEG burst-suppression
trials. Goal temperature aimed at
appropriate burst-suppression
pattern on EEG.

Electroconvulsive Protocols vary Can induce convulsive and EEG monitoring required. Routine
therapy nonconvulsive status after use not well established. Further
treatment; cognitive impairment; studies are needed.
amnesia; and headache

Transcranial magnetic Can be performed in Rare seizures; headache; Considered a very safe intervention
stimulation the intensive care unit dizziness; and other neurologic and does not require surgery or
setting side effects device implantation. Still
investigational therapy.

Vagal nerve stimulation Surgical implantation Voice hoarseness; infection risk at No strong evidence to support its
the implantation site; and rare use in the acute settings.
bradycardia

EEG = electroencephalogram; ICP = intracranial pressure; IV = intravenous.

a
Modified with permission from Bayrlee A, et al, Curr Neurol Neurosci Rep.18 © 2015 Springer Science+Business Media.

460 APRIL 2019

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

duration, is important when judging if an intervention is having some effect. KEY POINTS
If seizures were to become prolonged, longer than 5 minutes, or the patient fails
● In a patient who is
to demonstrate significant improvement in mental status between seizures, then critically ill, his or her mental
it is reasonable to revert to the algorithms used for status epilepticus. status may be affected by
Acute repetitive seizures can also occur in a patient who is critically ill. These the underlying cause of
seizures typically are detected on continuous EEG monitoring and may have seizures, so it can be
difficult to determine if the
subtle or no clinical signs. The distinction between repetitive electrographic
patient would return to
seizures, which often occur after a primary neurologic injury (eg, stroke, baseline between seizures.
hemorrhage, tumor, or infection), and prolonged or continuous electrographic
seizure activity of status epilepticus is not well defined. In a patient who is ● In a recent randomized
critically ill, his or her mental status may be affected by the underlying cause controlled trial, lacosamide
was noninferior to
of seizures, so it can be difficult to determine if the patient would return to fosphenytoin in the
baseline between seizures. FIGURE 8-4 places a common consensus between the treatment of nonconvulsive
relationship of urgency of treatment and degree of neuronal injury, with single seizures.
seizures causing little if any neuronal injury and generalized convulsive status
epilepticus clearly resulting in significant neuronal injury, with merging seizures
(ie, seizures that wax and wane in amplitude and frequency characteristics, with
one electrographic seizure merging into another) and nonconvulsive status
epilepticus in the middle.22
There is reasonable consensus and some evidence that acute repetitive
seizures, including repetitive electrographic seizures, can initially be managed
with trials of IV antiseizure drugs as opposed to IV anesthesia.21 However, there
are few data on the efficacy of this approach or on which drugs are most
effective. As in convulsive status epilepticus, phenytoin or fosphenytoin has been
the commonly used first-line treatment. A recent study, TRENdS (Treatment of
Recurrent Electrographic Nonconvulsive Seizures), compared the efficacy of
lacosamide with fosphenytoin in the treatment of nonconvulsive seizures.23 This
is the first prospective randomized study of the treatment of nonconvulsive seizures
and the first interventional study to use continuous EEG as a primary study end
point. In this study, nonconvulsive seizures were defined as electrographic seizures
lasting 10 seconds or more with or without clinical accompaniment. Ictal discharges
lasting 30 minutes or more per hour were not included.
Qualifying patients with nonconvulsive seizures were randomly assigned to
receive an initial load of either fosphenytoin, 20 phenytoin equivalents/kg IV, or
lacosamide 400 mg IV. The patient could receive a re-bolus of the initial drug if
seizures recurred during a 6-hour observation period after treatment with the
initial drug and a 2-hour grace period (ie, between 2 and 8 hours after the initial
treatment). Re-bolus dosing was 5 phenytoin equivalents/kg for fosphenytoin and
200 mg for lacosamide. The primary end point was the absence of electrographic
seizures for 24 hours after the initial treatment with the study drug or after the
re-bolus if needed.
Seventy-four patients were randomly assigned, and 62 had sufficient
continuous EEG for analysis. The mean age of enrolled subjects was 63.6 years.
The majority of patients (62%) had concurrent neurologic injury, including
subdural, parenchymal, or subarachnoid hemorrhage; brain tumor; or
toxic-metabolic encephalopathy. Another 31% of enrolled patients had a history
of epilepsy. Initial treatment with IV lacosamide was associated with a cessation
of seizures without recurrence within 24 hours in 63.3% of patients whereas IV
fosphenytoin terminated seizures in 50% of patients. Although the difference
was not sufficient to show superiority of lacosamide over fosphenytoin, the study

CONTINUUMJOURNAL.COM 461

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

EPILEPSY EMERGENCIES

met its primary end point, demonstrating that lacosamide was noninferior to
fosphenytoin in the treatment of nonconvulsive seizures (P=.02). There was no
significant difference in the incidence of treatment-emergent adverse effects or
serious adverse effects between the two groups. Of note, the incidence of
hypotension, arrhythmia, respiratory failure, or multiorgan hypersensitivity was
not different between the two groups (11.4% for fosphenytoin and 13.5% for
lacosamide, P=1.0).

NONCONVULSIVE STATUS EPILEPTICUS

There is no universally accepted definition of nonconvulsive status epilepticus,
and there is no consensus on how to treat it. Not surprisingly, nonconvulsive
status epilepticus is often a challenging diagnosis to make. EEG, although critical
to the evaluation of nonconvulsive status epilepticus, can sometimes be
equivocal. Therefore, in addition to EEG review, an evaluation of the patient’s
clinical state, medical history, and response to antiseizure drugs is often needed
to make the diagnosis. FIGURE 8-5 is an algorithm for the EEG diagnosis of

CASE 8-1 A 20-year-old woman with left frontal lobe epilepsy presented with an
increased frequency of her habitual seizures. Her seizures were well
controlled with levetiracetam until 1 month before when she had a
breakthrough seizure in the setting of sleep deprivation. Two days before
admission, the patient’s mother reported that the patient was sleeping
restlessly, and she started noticing seizures during the day. The patient
would make a facial expression as if she was crying and appear restless
for 20 to 25 seconds. With one of the seizures, she fell to the ground. The
patient was started on clonazepam 0.5 mg 3 times daily, but the
seizures increased in frequency to several times per hour, and the
patient’s mother brought her to the emergency department.
On continuous video-EEG monitoring, the patient was having seizures
every 10 minutes in wakefulness and sleep. Clinically, the seizures were
characterized by an abrupt and involuntary change in the patient’s facial
expression and hypermotor movements. She was aware of the seizures
and was alert throughout. The patient was given lorazepam 2 mg IV and
lacosamide 400 mg IV while she was monitored on cardiac telemetry. She
was continued on lacosamide 200 mg twice daily and levetiracetam
1500 mg twice daily, and clonazepam was increased to 1 mg 3 times
daily. With these interventions, seizures decreased in frequency to once
every 30 minutes and decreased in duration from 15 seconds to 7 to
10 seconds.
Over the next 48 hours, seizures progressively shortened and
decreased in frequency until they resolved. Her seizures were very subtle
on EEG (FIGURE 8-3): They were characterized by rhythmic beta activity
over the left frontocentral region (FIGURE 8-3) and a corresponding
increase in heart rate. An epilepsy-protocol MRI was normal and
unchanged from previous MRIs. The patient was weaned off clonazepam
over the next 2 months. A subsequent inpatient admission confirmed she
was not having clinical or electrographic seizures.

462 APRIL 2019

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

nonconvulsive status epilepticus and is adapted from previously published
criteria.24–26 The algorithm demonstrates one approach to equivocal EEG
patterns that cannot be definitively classified as ictal or not ictal. In these cases, a
response to treatment (typically IV-administered antiseizure drugs) can help
make the diagnosis. The response must include both a positive response in the
clinical state of the patient and the EEG or complete cessation of electrographic
ictal pattern with return of normal background EEG activity.27
Once the diagnosis of nonconvulsive status epilepticus is made, there is often
disagreement on how aggressively to treat it. Ample animal evidence indicates
that continuous nonconvulsive electrographic seizure activity leads to neuronal
damage and the severity increases with time.28–30 Human data on the degree
of injury associated with nonconvulsive status epilepticus can be difficult to
interpret because the etiology of nonconvulsive status epilepticus often
confounds the outcome data. The serum neuron-specific enolase level has been
noted to be elevated with nonconvulsive status epilepticus without other
neurologic injury, indicating some degree of neuronal damage.31 However,

FIGURE 8-3
EEG of the patient in CASE 8-1 showing very subtle seizures characterized by rhythmic beta
activity over the left frontocentral region (arrows) and a corresponding increase in
heart rate.

This is a case of acute repetitive seizures. Patients with frontal lobe COMMENT
seizures are particularly prone to clusters of repetitive seizures when their
sleep is disturbed. Often, this situation can be managed with standing
benzodiazepines, a new antiseizure medication, and letting the patient
catch up on sleep. Seizures may not completely stop after an intervention,
but a decrease in the frequency and duration of seizures is encouraging,
and seizures may continue to resolve over the next day or two. The
morbidity associated with intubation likely outweighs the benefits in these
cases and limits the ability to follow the patient’s clinical examination,
which was particularly important in this case.

CONTINUUMJOURNAL.COM 463

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

EPILEPSY EMERGENCIES

treatment for nonconvulsive

FIGURE 8-4
Graphic representation of the relationship of the
urgency of treatment and the morbidity of
seizures, nonconvulsive status epilepticus, and
convulsive status epilepticus.
SE = status epilepticus; sz = seizure.
Reprinted with permission from Husain AM, Epilepsy
Behav.22 Published by Elsevier Inc.
status epilepticus is not benign.21
Initial treatment approaches
range from trials of additional
antiseizure drugs to intubation
and burst suppression with IV
anesthesia, similar to what is
used in convulsive status
epilepticus. No clinical consensus
exists for how aggressively to
treat nonconvulsive status
epilepticus, but in clinical
practice, the determination is
often based on the patient’s
mental status and clinical course
(CASES 8-2 and 8-3). In all cases,
it is important to address the
underlying etiology.

ETIOLOGY
In adults, status epilepticus occurs in about half of patients as the result of an
acute symptomatic lesion, such as stroke, head trauma, and anoxia. This is then
followed by remote symptomatic lesions and low antiseizure drug levels in
patients with known epilepsy.33–35 In some cases, however, the initial workup
does not reveal a clear etiology. In the management of acute status epilepticus
and recurrent seizures, we often prioritize the control of seizures over the
determination of the cause. However, finding the etiology may have both
therapeutic and prognostic implications. Also, depending on the etiology,
delayed recognition may contribute to a poor outcome in a variety of diseases
that cause status epilepticus.36 Nearly 200 uncommon disorders have been
shown to cause status epilepticus.37

NEW-ONSET REFRACTORY STATUS EPILEPTICUS AND FEBRILE

INFECTION–RELATED EPILEPSY SYNDROME
New-onset refractory status epilepticus (NORSE) is a recently described clinical
presentation that can affect all ages. NORSE occurs in patients without active
epilepsy or other preexisting neurologic disorders and has no clear acute or active
structural, toxic, or metabolic cause.36 Febrile infection–related epilepsy
syndrome (FIRES) is thought to be a subcategory of NORSE that requires a
preceding febrile infection, with fever starting between 2 weeks and 24 hours
before the onset of refractory status epilepticus.36 No known unifying
mechanism exists for cryptogenic NORSE and FIRES, but speculation suggests
that they might be caused by a fulminant inflammatory response in the central
nervous system.38

AUTOIMMUNE ENCEPHALITIS
An increasingly recognized etiology of status epilepticus is autoimmune
encephalitis. In a recent single-center series, among the 570 consecutive patients
with status epilepticus, 2.5% were found to be autoimmune.39 The series found
that, compared with patients with status epilepticus of an infectious cause, the

464 APRIL 2019

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

 KEY POINTS

● No clinical consensus
exists for how aggressively
to treat nonconvulsive
status epilepticus, but in
clinical practice, the
determination is often based
on the patient’s mental
status and clinical course.

● New-onset refractory
status epilepticus (NORSE) is
a recently described clinical
presentation that can affect
all ages and occurs in
patients without active
epilepsy or other preexisting
neurologic disorders and has
no clear acute or active
structural, toxic, or
metabolic cause.

● Febrile infection–related
epilepsy syndrome (FIRES) is
thought to be a subcategory
of new-onset refractory
status epilepticus that
requires a preceding febrile
FIGURE 8-5 infection, with fever starting
Algorithm for the EEG diagnosis of nonconvulsive status epilepticus. Of note, this is a general between 2 weeks and
guideline and does not apply to all scenarios and does not replace clinical judgment. 24 hours before the onset
AED = antiepileptic drug; EEG = electroencephalogram; IV = intravenous; NCSE = nonconvulsive of refractory status
status epilepticus. epilepticus.
Modified with permission from Herman ST, Nonconvulsive Status Elipticus.24 © Spring Publishing
Company, Inc.

patients with autoimmune status epilepticus were younger and had lower
morbidity (return to baseline conditions in 71% versus 32%). However, no
difference in mortality existed between the two groups. Although autoimmune
encephalitis was previously thought of as an extremely rare disease, another
recent population-based comparative study of autoimmune and infectious
encephalitis in Olmsted County, Minnesota, showed that the prevalence and
incidence of autoimmune encephalitis were comparable to infectious
encephalitis, and its detection is increasing over time.40
A small case series of seven patients documented several similarities between
patients with NORSE, including female sex, young age, and a negative
workup.41 In another case series of 11 patients with NORSE, autoantibodies were
identified in seven patients, of which anti–glutamic acid decarboxylase (GAD)
and anti–N-methyl-D-aspartate (NMDA) receptor were most frequent.42 In the
same series of 11 patients, eight were treated with immunotherapy (IV steroids,
immunoglobulins, plasma exchange, or a combination), and four received
chemotherapy. Of the eight patients treated with immunotherapy, six had
favorable outcomes (defined as any outcome other than death, vegetative state,
or inability to take care of oneself ) compared with none of the three patients who
did not receive immunotherapy. Despite the small numbers, this difference in

CONTINUUMJOURNAL.COM 465

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

EPILEPSY EMERGENCIES

CASE 8-2 A 66-year-old right-handed man presented after a fall and was found to
have a left hemispheric subdural hematoma involving the tentorium
(FIGURE 8-6). He had been started on phenytoin on admission for seizure
prophylaxis but had not had clinical seizures. Two days after admission,
he developed an acute fluent aphasia. His neuroimaging had not changed.
His speech was nonsensical, and he could not repeat, name, or follow
commands.
Continuous EEG demonstrated frequent left hemispheric
electrographic seizures recurring every 5 to 10 minutes as illustrated by
quantitative EEG (one of the shortest seizures is depicted in the raw EEG
in FIGURE 8-7). Between seizures, EEG demonstrated left hemispheric
lateralized periodic discharges (LPDs). Aphasia was persistent and not
limited to the time when
seizures occurred.
Electrographic seizure
activity initially responded to
lorazepam 2 mg IV, which was
given at 17:00 (5:00 PM) along
with IV levetiracetam 1 g. The
patient’s aphasia, however,
persisted. Seizures recurred
over the next 24 hours but
were shorter in duration and
less frequent. LPDs also
became infrequent. The patient
was given levetiracetam 1 g
3 times over the next 24 hours
and was subsequently continued
on levetiracetam 1500 mg
2 times a day, and phenytoin
was continued. By the following
FIGURE 8-6
day, rare seizures were seen, Axial noncontrast head CT of the patient in CASE 8-2
and the patient had a pure demonstrating left hemispheric subdural hematoma
anomia. By day 3 of continuous involving the tentorium with mass effect.
EEG recording, the aphasia
had resolved as had seizures
and LPDs.

466 APRIL 2019

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

 FIGURE 8-7
Raw EEG of the patient in CASE 8-2 shows one of the patient’s shortest frequent left
hemispheric electrographic seizures.

This case illustrates one form of nonconvulsive status epilepticus. It would COMMENT
be considered nonconvulsive status (as opposed to acute repetitive
seizures) because of the persistent clinical features (ie, the patient did not
return to baseline between seizures). Of course, the distinction between
the two is less clear because it could be argued that the patient’s brain
injury is a factor in his aphasia. The response to treatment, which paralleled
control of seizures, however, suggests that seizures were contributing to
the patient’s mental status. This is a common occurrence in aphasic status;
aphasia often parallels the control of seizures, but the resolution of aphasia
may occur before or after control of electrographic seizures.32 It is also not
uncommon for seizures to wane over 2 to 3 days. In these cases, it is often
not necessary to intubate patients for control of focal status epilepticus.
Demonstrating an initial response to treatment (a temporary cessation of
seizures or a decrease in frequency or duration) offers promise that the
seizures will come under control.
This case contains data from a previously published article.32

CONTINUUMJOURNAL.COM 467

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

EPILEPSY EMERGENCIES

CASE 8-3 A 45-year-old woman with no

significant past medical history
presented with hallucinations for
2 weeks and episodes of
behavioral arrest with oral
automatisms. Her initial MRI
demonstrated patchy increased
fluid-attenuated inversion
recovery (FLAIR) signal in the left
more than the right temporal
lobes and left orbitofrontal
cortex (FIGURE 8-8) as well left
parietal and occipital lobes. She
was connected to continuous
video-EEG and found to have
FIGURE 8-8
frequent left temporal seizures, Initial coronal fluid-attenuated inversion recovery
which corresponded to oral (FLAIR) MRI of the patient in CASE 8-3 demonstrates
automatisms (FIGURE 8-9), and patchy increased signal in the left and right
bilateral independent lateralized temporal lobes and left orbitofrontal cortex.
Follow-up imaging after immunotherapy with
periodic discharges (FIGURE 8-10). cyclophosphamide and rituximab demonstrated
In the first 24 hours, she marked improvement (not shown).
was started empirically on
acyclovir and given 4 mg
of lorazepam 2 times and fosphenytoin, levetiracetam, and valproate
sodium IV loads without any clear response to therapy. The patient’s mental
status worsened; she became somnolent and only intermittently followed
commands. The patient was intubated for refractory status epilepticus. She
ultimately required both midazolam and phenobarbital to maintain burst
suppression and control electrographic seizures. CSF analysis was notable
for 2 white blood cells/mm3 (98% lymphocytes) and normal protein.

FIGURE 8-9
Continuous video-EEG of the patient in CASE 8-3 demonstrates left temporal seizures that
corresponded to oral automatisms.

468 APRIL 2019

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

FIGURE 8-10
Continuous video-EEG of the patient in CASE 8-3 demonstrates that between the seizures the
patient had bilateral independent lateralized periodic discharges.

Infectious studies, including herpes simplex virus, varicella zoster virus, and
cytomegalovirus polymerase chain reaction (PCR), were negative. CT chest,
abdomen, and pelvis and positron emission tomography (PET) scans were
negative for malignancy. The initial PET scan of the body also included the
brain, and sagittal images showed striking hypermetabolism in the limbic
structures (FIGURE 8-11). Two weeks after presentation, the patient’s serum and
CSF returned positive for anti–glutamic
acid decarboxylase (GAD) antibodies.
All other autoantibodies were negative.
In the first week of admission, the
patient was treated with IV steroids and
as well as two courses of plasma
exchange. The patient demonstrated no
improvement with these interventions.
She continued to acquire additional foci
of FLAIR hyperintensity on MRI and new
hypermetabolic lesions on PET. She
remained in burst suppression on EEG,
with seizures returning during weans of IV
pentobarbital. She was ultimately treated
with cyclophosphamide and rituximab.
One week after rituximab treatment, she FIGURE 8-11
was able to be weaned off her IV Sagittal reconstruction of an axial
acquisition brain positron emission
anesthetics without return of seizures. tomography (PET) scan of the patient
She was weaned off most antiepileptic in CASE 8-3 showing striking
drugs over 2 years and has been seizure hypermetabolism in the limbic
free on phenobarbital. structures.
CONTINUED ON
PAGE 470

CONTINUUMJOURNAL.COM 469

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

EPILEPSY EMERGENCIES

outcome was significant (P=.026).42 Prospective multicenter studies are

necessary to assess the true efficacy of immunotherapy in patients with NORSE.
Recent predictive models have been created for both neural antibody
positivity and immunotherapy response in epilepsy. These studies were not
specific to status epilepticus or NORSE; they included all new-onset seizures and
status that were cryptogenic. The initial prospective study found 20% of
cryptogenic epilepsy cases to be neural antibody seropositive, indicative of a
possible autoimmune cause. The authors evaluated a scoring system to predict
the detection of these antibodies known as the Antibody Prevalence in Epilepsy
(APE) score (TABLE 8-2).43 An APE score of 4 or greater had a sensitivity of
82.6% and a specificity of 82.0% for detecting a positive antibody. In a follow-up
retrospective study of patients with epilepsy at the Mayo Clinic in whom
autoantibody-testing profiles were requested and who received immunotherapy,
a Response to Immunotherapy in Epilepsy (RITE) score was assigned. A
favorable response to immunotherapy was defined as having a greater than
50% reduction of seizure frequency at the first follow-up (TABLE 8-2). A RITE
score of 7 or greater predicted a favorable seizure outcome and had a sensitivity
of 87.5% and specificity of 83.8%.44 Therefore, the use of APE and RITE scores
can aide diagnosis, treatment, and prognostication of autoimmune etiology in
epilepsy and may potentially be useful in identifying an autoimmune etiology
in NORSE.
If there is a concern for a potential autoimmune etiology for seizures or
NORSE, a standard diagnostic algorithm, shown in FIGURE 8-12, can be followed.
The evaluation should be individualized for each patient, and some patients may
not require all the studies shown. However, it is important to emphasize the
possibility that there could be a coexisting malignancy, and if found, it is
important to treat both the tumor and the paraneoplastic disorder simultaneously.

IMMUNE TREATMENT FOR AUTOIMMUNE ENCEPHALITIS

When choosing a treatment strategy for any antibody-associated central nervous
system disorder, it is key to choose objective markers to monitor treatment
response. For patients with NORSE, we would recommend monitoring seizure
frequency (location and duration of the seizures), imaging (brain MRI and/or

CONTINUED FROM
PAGE 469
COMMENT In contrast to CASE 8-2, this case of nonconvulsive status epilepticus
represents one in which intubation and aggressive management with IV
anesthesia are usually indicated. The patient presented at the beginning
of a likely progressive condition (as indicated by inflammatory MRI changes
and clinical deterioration) and was refractory to medications. This is a
case of new-onset refractory status epilepticus (NORSE), ultimately proven
to be of an autoimmune etiology. The patient would have had an Antibody
Prevalence in Epilepsy (APE) score of 6 and a Response to Immunotherapy
in Epilepsy (RITE) score of 8. This case also illustrates the importance of
patience and persistence in cases of autoimmune refractory status
epilepticus because patients can ultimately do very well despite a
prolonged and arduous course.

470 APRIL 2019

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

Components of the Antibody Prevalence in Epilepsy and Response to TABLE 8-2
Immunotherapy in Epilepsy Scoresa,b

Antibody Prevalence in Epilepsy of an Unknown Response to Immunotherapy in Epilepsy

Etiology Score Value Score Value

New-onset, rapidly progressive mental status (+1) New-onset, rapidly progressive mental status (+1)
changes that developed over 1–6 weeks or new- changes that developed over 1–6 weeks or new-
onset seizure activity (within 1 year of evaluation) onset seizure activity (within 1 year of evaluation)

Neuropsychiatric changes; agitation, (+1) Neuropsychiatric changes; agitation, (+1)

aggressiveness, emotional liability aggressiveness, emotional liability

Autonomic dysfunction (sustained atrial
tachycardia or bradycardia, orthostatic
hypotension [≥20 mm Hg decrease in systolic
pressure or ≥10 mm Hg decrease in diastolic
pressure within 3 minutes of standing],
hyperhidrosis, persistently labile blood pressure,
ventricular tachycardia, or cardiac asystole)
(+1) Autonomic dysfunction (sustained atrial (+1)
tachycardia or bradycardia, orthostatic
hypotension [≥20 mm Hg decrease in systolic
pressure or ≥10 mm Hg decrease in diastolic
pressure within 3 minutes of quiet standing],
hyperhidrosis, persistently labile blood pressure,
ventricular tachycardia, or cardiac asystole)

Viral prodrome (rhinorrhea, sore throat, low- (+2) Viral prodrome (rhinorrhea, sore throat, low- (+2)
grade fever) to be scored in the absence of grade fever) only to be scored in the absence
underlying systemic malignancy of underlying malignancy

Facial dyskinesias or faciobrachial dystonic movements (+2) Facial dyskinesias or faciobrachial dystonic movements (+2)

Seizure refractory to at least to two antiseizure (+2) Seizure refractory to at least to two antiseizure (+2)
medications medications

CSF findings consistent with inflammation (+2) CSF findings consistent with inflammation (+2)
(elevated CSF protein >50 mg/dL and/or (elevated CSF protein >50 mg/dL and/or
lymphocytic pleocytosis >5 cells/mm3, if the total lymphocytic pleocytosis >5 cells/mm3, if the total
CSF red blood cell count is <1000 cells/mm3) CSF red blood cell count is <1000 cells/mm3)

Brain MRI showing signal changes consistent (+2) Brain MRI showing signal changes consistent (+2)
with limbic encephalitis (medial temporal with limbic encephalitis (medial temporal
T2-weighted/FLAIR signal changes) T2-weighted/FLAIR signal changes)

Presence of underlying malignancy (excluding (+2) Presence of underlying malignancy (excluding (+2)
cutaneous squamous cell carcinoma, basal cell cutaneous squamous cell carcinoma, basal
carcinoma) cell carcinoma)

Total Initiation of immunotherapy within 6 months (+2)

(maximum: 15) of symptom onset

Detected neural plasma membrane autoantibody (+2)

(NMDA receptor antibody, GABA-A receptor
antibody, GABA-B receptor antibody, AMPA
receptor antibody, DPPX antibody, mGluR1
antibody, mGluR2 antibody, mGluR5 antibody,
LGI1 antibody, or Caspr2 antibody)

Total
(maximum: 19)

a
Reprinted with permission from Dubey D, et al, Epilepsia.44 © 2017 John Wiley and Sons.
b
A Response to Immunotherapy in Epilepsy (RITE) score includes all the components of the Antibody Prevalence in Epilepsy (APE) score and two additional
variables: initiation of immunotherapy within 6 months of symptom onset and presence of plasma membrane autoantibody. An APE score of 4 or greater was
highly suggestive of the presence of an autoantibody. A RITE score of 7 or greater predicted a favorable seizure outcome in response to immunotherapy in a
patient with known or suspected autoimmune epilepsy.
AMPA = amino-3-hydroxy-5-methyl-4-isoxazolepropionic; Caspr2 = contactin-associated protein 2; CSF = cerebrospinal fluid; DPPX = dipeptidyl-
peptidase–like protein-6; FLAIR = fluid-attenuated inversion recovery; GABA = γ-aminobutyric acid; LGI1 = leucine-rich, glioma-inactivated protein 1;
mGluR = metabotropic glutamate receptor; MRI = magnetic resonance imaging; NMDA = N-methyl-D-aspartate.

CONTINUUMJOURNAL.COM 471

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

EPILEPSY EMERGENCIES
KEY POINTS
● In one study, an Antibody
Prevalence in Epilepsy score
of 4 or greater had a
sensitivity of 82.6% and a
specificity of 82.0% for
detecting a positive
antibody.
● In one study, a Response
to Immunotherapy in
Epilepsy score of 7 or
greater predicted favorable
seizure outcome and had a
sensitivity of 87.5% and
specificity of 83.8%.
● When choosing a
treatment strategy for any
antibody-associated central
nervous system disorder, it
is key to choose objective
markers to monitor
treatment response.
472
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
FIGURE 8-12
Diagnostic algorithm for autoimmune encephalitis.
ANA = antinuclear antibody; CSF = cerebrospinal fluid; CT = computed tomography; EEG =
electroencephalography; EGD = esophagogastroduodenoscopy; FLAIR = fluid-attenuated inversion
recovery; GI = gastrointestinal; IgG = immunoglobulin G; MRI = magnetic resonance imaging; PET = positron
emission tomography; TPO = thyroid peroxidase antibody.
Modified with permission from Linnoila J, Pittock SJ, Semin Neurol.45 © 2016 Rights managed by Georg
Thieme Verlag KG.
positron emission tomography [PET]), cognitive testing, and, if present, any
movement disorders or autonomic dysfunction. Additionally, the presence of a
neural autoantibody does not guarantee a good response to treatment. This is
especially true when there is a paraneoplastic antibody and/or intracellular
antigen.45 Cell surface autoantibodies and intracellularly targeted antibodies are
highlighted in TABLE 8-3. Therefore, a successful immune treatment may be
marked by stopping of clinical progression and not necessarily a reversal of
clinical symptoms or signs. The initial goal in treatment is to determine whether
there is a response to immunotherapy. If a positive response is found, then the
authors of this article recommend shifting focus to find the minimal/safest dose
of immunotherapy to maintain the response.45 An initial treatment algorithm is
shown in FIGURE 8-13. Typically, patients are treated with first-line therapies: IV
steroids (five daily doses), IV immunoglobulin (five daily doses), and/or plasma
exchange (five sessions total, every other day). These may be potentially
followed by second-line therapies: rituximab and cyclophosphamide. This is a
reasonable approach in hospitalized patients for the majority of cell surface–
targeted neural autoantibodies. It is important to recognize that full recovery
may take months. Additionally, if the initial response to first-line therapies is
small, particularly in a patient whose symptoms are severe, it is reasonable to
start second-line therapies earlier. When treating a patient with an intracellularly
targeted antibody, cyclophosphamide is generally preferred.45
CONCLUSION
Status epilepticus, acute repetitive seizures, and autoimmune encephalitis are
neurologic emergencies. Rapid identification and treatment of these conditions
APRIL 2019
Cell Surface and Intracellular Targeted Antibodiesa TABLE 8-3

Intracellularly Targeted Antibodies

◆ Antiglial nuclear antibody (sex determining region Y box 1 transcription factor)
◆ Amphiphysin
◆ Antineuronal nuclear antibody 1 (Anti-Hu)
◆ Antineuronal nuclear antibody 2 (Anti-Ri)
◆ Antineuronal nuclear antibody 3
◆ Collapsin response mediator protein 5 (CRMP-5) (anti-CV2)
◆ Glutamic acid decarboxylase (GAD65)
◆ Ma1
◆ Ma2 (Ta)
◆ Purkinje cell cytoplasmic antibody 1 (Anti-Yo)
◆ Purkinje cell cytoplasmic antibody 2
◆ Retinal (cancer-associated retinopathy, melanoma-associated retinopathy)
◆ Striational
◆ Zinc finger protein
Cell Surface Autoantibodies
◆ Acetylcholine receptor (muscle and ganglionic)
◆ α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor
◆ Aquaporin-4
◆ Contactin-associated protein-like 2
◆ Dipeptidyl-peptidase–like protein 6
◆ γ-Aminobutyric acid A receptor
◆ γ-Aminobutyric acid B receptor
◆ Glycine α receptor
◆ Immunoglobulinlike family member 5
◆ Leucine-rich, glioma inactivated 1 (LGI1)
◆ Metabotropic glutamate receptor 1
◆ Metabotropic glutamate receptor 5
◆ Myelin oligodendrocyte glycoprotein
◆ N-methyl-D-aspartic acid receptor
◆ Purkinje cell cytoplasmic antibody Tr (anti–delta/notchlike epidermal growth factor–related)
◆ Voltage-gated calcium channel (P/Q, N-type)
◆ Voltage-gated potassium channel complex

a
Reprinted with permission from Linnoila J, Pittock SJ, Semin Neurol.45 © 2016 Rights managed by Georg
Thieme Verlag KG.

CONTINUUMJOURNAL.COM 473

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

EPILEPSY EMERGENCIES

FIGURE 8-13
Inpatient treatment workflow for autoimmune central nervous system neurologic disorders.
IVIg = intravenous immunoglobulin.
Adapted with permission from Linnoila J, Pittock SJ, Semin Neurol.45
© 2016 Rights managed by Georg Thieme Verlag KG.

may influence patient prognosis. For convulsive status epilepticus, there is

reasonable consensus on the initial steps that need to be taken, but scarce data
exist to direct treatment after benzodiazepine therapy. Even fewer data exist to
inform management of acute repetitive seizures and nonconvulsive status
epilepticus. In these situations, it is important to use clinical judgment to balance
the risk of ongoing seizure activity with the risks related to potential treatments.
In all seizure emergencies, after initial stabilization of the patient, it is important
to recognize and treat the underlying etiology. Autoimmune encephalitis is an
increasingly recognized and important cause of seizures and status epilepticus,
particularly new-onset seizures and status. When confronted with NORSE,
clinicians should maintain a high-level of suspicion for autoimmune encephalitis
and become familiar with its treatments.

REFERENCES

1 Treatment of convulsive status epilepticus. 6 Bleck TP. Refractory status epilepticus.

Recommendations of the Epilepsy Foundation of
America’s Working Group on Status Epilepticus.
JAMA 1993;270(7):854–859.
2 Lowenstein DH, Bleck T, Macdonald RL. It’s time
to revise the definition of status epilepticus.
Epilepsia 1999;40(1):120–122. doi:10.1111/j.
1528-1157.1999.tb02000.x.
3 Walker M, Cross H, Smith S, et al. Nonconvulsive
status epilepticus: Epilepsy Research Foundation
workshop reports. Epileptic Disord 2005;7(3):
253–296.
4 Husain AM. Treatment of Recurrent
Electrographic Nonconvulsive Seizures (TRENdS)
Study. Epilepsia 2013;54(suppl 6):84–88.
doi:10.1111/epi.12287.
5 Brophy GM, Bell R, Claassen J, et al. Guidelines
for the evaluation and management of status
epilepticus. Neurocrit Care 2012;17(1):3–23.
doi:10.1007/s12028-012-9695-z.
Curr Opin Crit Care 2005;11(2):117–120.
doi:10.1097/01.ccx.0000157079.72999.87.
7 Shorvon S, Ferlisi M. The treatment of super-
refractory status epilepticus: a critical review of
available therapies and a clinical treatment
protocol. Brain 2011;134(pt 10):2802–2818.
doi:10.1093/brain/awr215.
8 Treiman DM, Walton NY, Kendrick C. A progressive
sequence of electroencephalographic changes
during generalized convulsive status epilepticus.
Epilepsy Res 2018;5(1):49–60. doi:10.1016/0920-
1211(90)90065-4.
9 Glauser T, Shinnar S, Gloss D, et al. Evidence-
based guideline: treatment of convulsive status
epilepticus in children and adults: report of the
guideline committee of the American Epilepsy
Society. Epilepsy Curr 2016;16(1):48–61.
doi:10.5698/1535-7597-16.1.48.

474 APRIL 2019

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

10 Treiman DM, Meyers PD, Walton NY, et al. A
comparison of four treatments for generalized
convulsive status epilepticus. Veterans Affairs
Status Epilepticus Cooperative Study Group.
N Engl J Med 1998;339(12):792–798. doi:10.1056/
NEJM199809173391202.
11 Leppik IE, Derivan AT, Homan RW, et al. Double-
blind study of lorazepam and diazepam in status
epilepticus. JAMA 1983;249(11):1452–1454.
doi:10.1001/jama.1983.03330350028021.
12 Silbergleit R, Durkalski V, Lowenstein D, et al.
Intramuscular versus intravenous therapy for
prehospital status epilepticus. N Engl J Med 2012;
366(7):591–600. doi:10.1056/NEJMoa1107494.
13 Misra UK, Kalita J, Patel R. Sodium valproate vs
phenytoin in status epilepticus: a pilot study.
Neurology 2006;67(2):340–342. doi:10.1212/01.
wnl.0000224880.35053.26.
14 Agarwal P, Kumar N, Chandra R, et al. Randomized
study of intravenous valproate and phenytoin in
status epilepticus. Seizure 2007;16(6):527–532.
doi:10.1016/j.seizure.2007.04.012.
15 Yasiry Z, Shorvon SD. The relative effectiveness
of five antiepileptic drugs in treatment of
benzodiazepine-resistant convulsive status
epilepticus: a meta-analysis of published
studies. Seizure 2014;23(3):167–174. doi:10.1016/j.
seizure.2013.12.007.
16 Cock HR. Established status epilepticus treatment
Ttrial (ESETT). Epilepsia 2011;52(suppl 8):50–52.
doi:10.1111/j.1528-1167.2011.03237.x.
17 Sage Therapeutics. Sage Therapeutics
reports top-line results from phase 3 STATUS
trial of brexanolone in super-refractory
status epilepticus. investor.sagerx.com/
news-releases/news-release-details/sage-
therapeutics-reports-top-line-results-phase-
3-status-trial. Updated September 12, 2017.
Accessed February 8, 2019.
18 Bayrlee A, Ganeshalingam N, Kurczewski L,
Brophy GM. Treatment of super-refractory
status epilepticus. Curr Neurol Neurosci Rep
2015;15(10):66. doi:10.1007/s11910-015-0589-2.
19 McKee HR, Abou-Khalil B. Outpatient
pharmacotherapy and modes of administration
for acute repetitive and prolonged seizures.
CNS Drugs 2014;29(1):55–70. doi:10.1007/
s40263-014-0219-6.
20 Haut SR, Velísková J, Moshé SL. Susceptibility of
immature and adult brains to seizure effects.
Lancet Neurol 2004;3(10):608–617. doi:10.1016/
S1474-4422(04)00881-6.
21 Hirsch LJ. Finding the lesser of two evils: treating
refractory status epilepticus. Epilepsy Curr 2015;
15(6):313–316. doi:10.5698/1535-7511-15.6.313.
22 Husain AM. Lacosamide in status epilepticus:
update on the TRENdS study. Epilepsy Behav
2015;49:337–339. doi:10.1016/j.yebeh.2015.06.018.
23 Husain AM, Lee JW, Kolls BJ, et al. Randomized
trial of lacosamide vs fosphenytoin for
nonconvulsive seizures. Ann Neurol 2018.
CONTINUUMJOURNAL.COM
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
24 Herman ST. The electroencephalogram of
nonconvulsive status epilepticus. In: Kaplan PW,
Drislane FW, eds. Nonconvulsive status
epilepticus. New York, NY: Demos Medical
Publishing, 2009:41–62.
25 Young GB, Jordan KG, Doig GS. An assessment
of nonconvulsive seizures in the intensive
care unit using continuous EEG monitoring: an
investigation of variables associated with
mortality. Neurology 1996;47(1):83–89. doi:10.1212/
WNL.47.1.83.
26 Chong DJ, Hirsch LJ. Which EEG patterns warrant
treatment in the critically ill? Reviewing the
evidence for treatment of periodic epileptiform
discharges and related patterns. J Clin Neurophysiol
2005;22(2):79–91. doi:10.1097/01.WNP.0000158699.
78529.AF.
27 Kaplan PW. The EEG of status epilepticus. J Clin
Neurophysiol 2006;23(3):221–229. 10.1097/01.wnp.
0000220837.99490.66.
28 Olney JW, Collins RC, Sloviter RS. Excitotoxic
mechanisms of epileptic brain damage.
Adv Neurol 1986;44:857–877.
29 Meldrum BS. Excitotoxicity and selective
neuronal loss in epilepsy. Brain Pathol 1993;3(4):
405–412.
30 Fujikawa DG. The temporal evolution of neuronal
damage from pilocarpine-induced status
epilepticus. Brain Res 1996;725(1):11–22.
doi:10.1016/0006-8993(96)00203-X.
31 Rabinowicz AL, Correale JD, Bracht KA, et al.
Neuron-specific enolase is increased after
nonconvulsive status epilepticus. Epilepsia 1995;
36(5):475–479. doi:10.1111/j.1528-1157.1995.
tb00489.x.
32 Ericson EJ, Gerard EE, MacKen MP, Schuele SU.
Aphasic status epilepticus: electroclinical correlation.
Epilepsia 2011;52(8):1452–1458. doi:10.1111/j.1528-1167.
2011.03084.x.
33 Hesdorffer DC, Logroscino G, Cascino G, et al.
Incidence of status epilepticus in Rochester,
Minnesota, 1965–1984. Neurology 1998;50(3):
735–741. doi:10.1212/WNL.50.3.735.
34 DeLorenzo RJ, Hauser WA, Towne AR, et al. A
prospective, population-based epidemiologic
study of status epilepticus in Richmond, Virginia.
Neurology 1996;46(4):1029–1035. doi:10.1212/
WNL.46.4.1029.
35 Coeytaux A, Jallon P, Galobardes B, Morabia A.
Incidence of status epilepticus in French-
speaking Switzerland: (EPISTAR). Neurology
2000;55(5):693–697. doi:10.1212/WNL.55.5.693.
36 Gaspard N, Hirsch LJ, Sculier C, et al. New-onset
refractory status epilepticus (NORSE) and febrile
infection-related epilepsy syndrome (FIRES):
State of the art and perspectives. Epilepsia 2018;
59(4):745–752. doi:10.1111/epi.14022.
37 Tan RY, Neligan A, Shorvon SD. The uncommon
causes of status epilepticus: a systematic
review. Epilepsy Res 2010;91(2–3):111–122.
doi:10.1016/j.eplepsyres.2010.07.015.
475
EPILEPSY EMERGENCIES
38 Sakuma H, Tanuma N, Kuki I, et al. Intrathecal
overproduction of proinflammatory cytokines
and chemokines in febrile infection-related
refractory status epilepticus. J Neurol Neurosurg
Psychiatry 2015;86(7):820–822. doi:10.1136/jnnp-
2014-309388.
39 Ferlazzo E, Gasparini S, Sueri C, Aguglia U. Status
epilepticus of inflammatory etiology: a cohort
study. Neurology 2016;86(11):1076. doi:10.1212/
WNL.0000000000002508.
40 Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune
encephalitis epidemiology and a comparison to
infectious encephalitis. Ann Neurol 2018;83(1):
166–177. doi:10.1002/ana.25131.
41 Wilder-Smith EP, Lim EC, Teoh HL, et al. The
NORSE (new-onset refractory status epilepticus)
syndrome: defining a disease entity. Ann Acad
Med Singapore 2005;34(7):417–420.
DISCLOSURE
Continued from page 454
Mental Health, National Institute on Aging, National
Institutes of Health, and SAGE Therapeutics.
Dr VanHaerents has received travel honoraria from
NeuroPace and SAGE Therapeutics. Dr Gerard has
received personal compensation as a lecturer for
the Society for Maternal-Fetal Medicine, Society of
OB/GYN Hospitalists, and UCB China and has
476
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
42 Khawaja AM, DeWolfe JL, Miller DW, Szaflarski JP.
New-onset refractory status epilepticus
(NORSE)—the potential role for immunotherapy.
Epilepsy Behav 2015;47:17–23. doi:10.1016/j.
yebeh.2015.04.054.
43 Dubey D, Alqallaf A, Hays R, et al. Neurological
autoantibody prevalence in epilepsy of unknown
etiology. JAMA Neurol 2017;74(4):397–402.
doi:10.1001/jamaneurol.2016.5429.
44 Dubey D, Singh J, Britton JW, et al. Predictive
models in the diagnosis and treatment of
autoimmune epilepsy. Epilepsia 2017;58(7):
1181–1189. doi:10.1111/epi.13797.
45 Linnoila J, Pittock SJ. Autoantibody-associated
central nervous system neurologic disorders.
Semin Neurol 2016;36(4):382–396. doi:10.1055/
s-0036-1585453.
received research/grant support from the
Eleanor Wood-Prince Grant from the Woman’s
Board of Northwestern Memorial Hospital, the
National Institute of Neurological Disorders and
Stroke/National Institutes of Health, SAGE
Therapeutics, and Sunovion Pharmaceutical Inc.
APRIL 2019