Seizures, Status REVIEW ARTICLE


Epilepticus, and C O N T I N U UM A U D I O
INTERVIEW AVAILABLE
ONLINE

Continuous EEG in the

Intensive Care Unit
By Eric S. Rosenthal, MD

ABSTRACT
PURPOSE OF REVIEW: Thisarticle discusses the evolving definitions of seizures
and status epilepticus in the critical care environment and the role of
critical care EEG in both diagnosing seizure activity and serving as a
predictive biomarker of clinical trajectory. CITE AS:
CONTINUUM (MINNEAP MINN)
2021;27(5, NEUROCRITICAL CARE):
RECENT FINDINGS:Initial screening EEG has been validated as a tool to 1321–1343.
predict which patients are at risk of future seizures. However, accepted
definitions of seizures and nonconvulsive status epilepticus encourage a Address correspondence to
Dr Eric S. Rosenthal, Department
treatment trial when the diagnosis on EEG is indeterminate because of of Neurology, Massachusetts
periodic or rhythmic patterns or uncertain clinical correlation. Similarly, General Hospital, 55 Fruit St,
recent data have demonstrated the diagnostic utility of intracranial EEG Lunder 644, Boston, MA 02114,
erosenthal@mgh.harvard.edu.
in increasing the yield of seizure detection. EEG has additionally been
validated as a diagnostic biomarker of covert consciousness, a predictive RELATIONSHIP DISCLOSURE:

biomarker of cerebral ischemia and impending neurologic deterioration, Dr Rosenthal serves on

scientific advisory boards for
and a prognostic biomarker of coma recovery and status epilepticus Ceribell, Inc and UCB, Inc and
resolution. A recent randomized trial concluded that patients allocated to has received personal
compensation for speaking
continuous EEG had no difference in mortality than those undergoing engagements from UCB, Inc.
intermittent EEG but could not demonstrate whether this lack of Dr Rosenthal receives
difference was because of studying heterogeneous conditions, examining research/grant support from
Moberg Analytics, Inc (DoD
a monitoring tool rather than a therapeutic approach, or examining an W81XWH-18-DMRDP-PTCRA)
outcome measure (mortality) perhaps more strongly associated with early and the National Institutes of
withdrawal of life-sustaining therapy than to a sustained response to Health/National Institute of
Neurological Diseases and
pharmacotherapy. Stroke (1R01NS117904,
1R01NS113541, 1K23NS105950,
U54NS100064, DoD
SUMMARY: Seizures and status epilepticus are events of synchronous
W81XWH-BAA-15-1).
hypermetabolic activity that are either discrete and intermittent or,
alternatively, continuous. Seizures and status epilepticus represent the far UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
end of a continuum of ictal-interictal patterns that include lateralized USE DISCLOSURE:
rhythmic delta activity and periodic discharges, which not only predict Dr Rosenthal discusses the
future seizures but may be further classified as status epilepticus on the unlabeled/investigational use of
IV injection of ketamine,
basis of intracranial EEG monitoring or a diagnostic trial of antiseizure midazolam, and propofol for the
medication therapy. In particularly challenging cases, neuroimaging or treatment of seizures.
multimodality neuromonitoring may be a useful adjunct documenting
metabolic crisis. Specialized uses of EEG as a prognostic biomarker have © 2021 American Academy
of Neurology.

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SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU

emerged in traumatic brain injury for predicting language function and

covert consciousness, cardiac arrest for predicting coma recovery, and
subarachnoid hemorrhage for predicting neurologic deterioration due to
delayed cerebral ischemia.

INTRODUCTION

T
his article discusses how to define, diagnose, and manage seizures,
status epilepticus, and indeterminate findings on the ictal-interictal
continuum within the critical care environment. Additionally, the
recent expansion of the utility of continuous EEG as a predictive
biomarker in a variety of critical care populations is discussed, such as
in predicting secondary ischemia after subarachnoid hemorrhage, diagnosing
covert consciousness in patients who are comatose, and predicting neurologic
recovery after structural brain injury or status epilepticus.

DEFINING AND DETECTING SEIZURES AND STATUS EPILEPTICUS IN

THE INTENSIVE CARE UNIT
The detection of seizures in the critical care setting is the subject of much
attention because they are common (found in 10% to 25% of patients recorded),1,2
represent a potentially reversible cause of encephalopathy or coma,3 and are
associated with poor outcome.4-6 The American Clinical Neurophysiology
Society (ACNS) has issued consensus recommendations regarding indications
for prolonged continuous EEG monitoring7:

u Persistently abnormal mental status following generalized convulsive status epilepticus or

other clinically evident seizures
u Acute supratentorial brain injury with altered mental status
u Fluctuating mental status or unexplained alteration of mental status without known acute
brain injury
u EEG patterns along the ictal-interictal continuum such as periodic discharges and
lateralized rhythmic delta activity
u Clinical risk for seizures potentially masked by the requirement for pharmacologic
paralysis during conditions such as extracorporeal membrane oxygenation (ECMO) or
targeted temperature management for cardiac arrest
u Paroxysmal clinical events suspected to be possible seizures

These indications nearly universally include patients with altered mental

status, encephalopathy, coma, or other disorders of consciousness following
traumatic brain injury, spontaneous subdural hematoma, subarachnoid
hemorrhage, intracerebral hemorrhage, meningoencephalitis, brain tumors,
recent neurologic surgery, cardiac arrest, and sepsis, as rates of seizure
exceed 15% among these patients when referred for EEG.4-6 Other
populations with a high risk may include patients with cerebral venous
sinus thrombosis.
Of note, a provider’s suspicion for seizure is likely not a substitute for active
surveillance, as patients not referred for EEG monitoring may be having occult
seizures. For example, in a cohort of patients with subarachnoid hemorrhage
monitored solely as part of an ischemia monitoring protocol to predict delayed

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cerebral ischemia, seizures occurred with a similar rate as in those patients KEY POINTS
referred with a concern for subclinical or clinical seizures (ie, even when the
● Electrographic seizures
provider lacked suspicion for seizure and would not otherwise have ordered and status epilepticus can
an EEG).8 be diagnosed by an
The diagnosis of seizures in the critically ill population has three electroclinical response to
main challenges: antiseizure medication.

● Although most seizures

u Seizures are commonly nonconvulsive, subtle, or obscured by a primary neurologic deficit are detected in the first
or sedation 48 hours of monitoring,
u Seizures may be occult on scalp EEG and only detected by an intracranial electrode shorter-duration monitoring
may be sufficient in patients
u Seizures, as status epilepticus, may only be diagnosed in retrospect after electroclinical without any epileptiform
improvement following treatment abnormalities and
longer-duration monitoring
Current consensus definitions of electrographic and electroclinical seizures may be required in patients
have coalesced around the Salzburg Consensus Criteria9-11 and have been with subarachnoid
hemorrhage.
adopted by the ACNS.12 In the updated 2021 ACNS Standardized Critical Care
EEG Terminology, electrographic seizures are defined as either epileptiform
discharges averaging more than 2.5 Hz for at least 10 seconds or a pattern with
definite evolution and lasting at least 10 seconds. Similarly, electrographic status
epilepticus is defined as an electrographic seizure for at least 10 continuous
minutes or for at least 20% of any 60-minute period.
Other electrographic activity not meeting these criteria may qualify as
“possible” electrographic seizure or electrographic status epilepticus when the
activity consists of periodic discharges, spike-wave activity, or rhythmic delta
activity on the ictal-interictal continuum. Uncertainty about whether
ictal-interictal continuum activity in an individual patient is indeed
nonconvulsive status epilepticus can be resolved, according to the ACNS
Standardized Critical Care EEG Terminology and Salzburg Consensus Criteria,9-12
when the electroclinical activity has a time-locked clinical correlate (eg,
thumb-twitching synchronous with each discharge despite lack of electrographic
evolution) or, alternatively, has combined EEG and clinical improvement
following antiseizure medication.12
The duration of EEG necessary for exhaustive detection of seizures in a
patient remains uncertain, given inherent biases in referring patients to
short-term EEG versus longer-duration continuous EEG monitoring.
However, retrospective research has led to validated risk scores that may be
applied on initial screening EEG to predict which patients will go on to have
seizures detected by continuous EEG monitoring. One method, the 2HELPS2B
score13,14 (FIGURE 6-1) has been tested and validated in separate inpatient
populations, accurately predicting the probability of subsequent seizures
across a range of predicted risk. Overall, 93% of patients with seizures had
detected events in the first 48 hours, and an absence of epileptiform
abnormalities in the first 2 hours was associated with a 72-hour seizure risk
lower than 5%.2 Similarly, in critically ill children with encephalopathy who
were at least 1 year of age, a seizure risk lower than 5% was observed if no prior
seizures were present and no epileptiform discharges and ictal-interictal
continuum patterns were present by 6 hours of recording; 1 day of monitoring
was required if EEG risk factors or prior seizures were evident, and 2 days
were required if both EEG risk factors and prior seizures were evident.15
Specific illnesses, however, may have an increased diagnostic yield from

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SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU

FIGURE 6-1
2HELPS2B risk score system for prediction of subsequent electrographic seizures during
an initial screening EEG. Predicted seizure risk using this tool is well calibrated to the actual
seizure risk observed.
a
Range across the development and validation cohorts.
Data from Struck AF, et al, JAMA Neurol.14

longer-duration monitoring. For example, the median duration until seizure

detection following subarachnoid hemorrhage has been observed to be as long
as 5.6 days, whereas 7.3 days was required to detect 75% of patients
with seizures.8
These risk estimates, however, only apply to the detection of seizures by scalp
EEG. Additional seizures may be detected when recording intracranially by
electrocorticography, using either an orthogonally inserted mini–depth electrode
or a subdural strip electrode (CASE 6-1). Experience using an orthogonal
mini–depth electrode has been reported to increase the yield of seizure detection
from 14.7% to 23.5% in patients with traumatic brain injury16 and from 8% to 38%
in patients with subarachnoid hemorrhage.17 It is not known which scalp EEG
features best predict depth seizures, although the occurrence of depth seizures is
greatest ipsilateral to the side of dominant injury in patients with traumatic
brain injury.16

TREATMENT APPROACHES TO SEIZURES, REFRACTORY STATUS

EPILEPTICUS, AND SUPER-REFRACTORY STATUS EPILEPTICUS
Although the treatment of occult nonconvulsive seizures remains controversial,
antiseizure medication is commonly administered, and clinical trials examining
optimal dosing strategies have typically been performed without a placebo. In
one study, lacosamide was found to be noninferior to fosphenytoin for
controlling nonconvulsive seizures.18 When using fosphenytoin or phenytoin,
therapeutic drug monitoring requires assessment of free phenytoin levels in
patients who are critically ill or the use of more complex correction equations to
estimate a free phenytoin level or else high-magnitude errors can occur when
applying historical correction equations in critically ill patients to estimate free
phenytoin levels.19

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 For convulsive seizures, the treatment approach is more straightforward. KEY POINTS
Benzodiazepines, specifically IV lorazepam or IM midazolam, are first-line
● Seizure detection is
agents,20,21 with IV lorazepam preferred for its rapidity of seizure control if an IV significantly augmented by
catheter is already in place.22 However, benzodiazepines are commonly the implantation of a single
underdosed after status epilepticus,23 despite their use being associated with intraparenchymal or
decreased rates of endotracheal intubation.24 When seizures are refractory to subdural strip electrode.
benzodiazepines, similar rates of terminating established status epilepticus were
● Because of changes in
observed with levetiracetam, fosphenytoin, or valproate. Of note, dosing was protein binding,
robust compared to doses commonly administered, particularly for levetiracetam large-magnitude errors are
(TABLE 6-125).26,27 However, antiseizure medications did not have a high rate of common when estimating
terminating clinically apparent seizures and improving consciousness without free phenytoin applying
standard phenytoin
need for additional antiseizure medication; success rates were approximately correction equations to
52% in children, 44% in adults, and 37% in older adults with established patients who are critically
status epilepticus.26 ill; correction equations
Patients for whom these therapies fail because of continued seizures are adjusting for age, renal
function, hepatic function,
commonly treated with anesthetic seizure suppression or burst suppression; and critical illness are
however, no randomized controlled trials are available to guide drug selection or necessary to avoid
dose. Trends embracing therapies other than traditional anesthetics include significant errors if free
increasing use of IV ketamine25 and ketogenic or low-glycemic diet therapy,28 in phenytoin levels are
unavailable.
addition to rational polytherapy aimed at avoiding the complications of status
epilepticus that are independently associated with mortality at 1 year.29 In the ● High-frequency periodic
absence of comparative effectiveness studies, the selection of antiseizure discharges may be transient
medications in refractory and super-refractory status epilepticus remains when weaning patients from
anesthetic coma following
focused on rational polytherapy targeting different mechanisms of action while
status epilepticus; pausing
managing and preventing complications (TABLE 6-2). and observing the patient
and EEG, evaluating
EEG NEUROMONITORING TO GUIDE LIBERATION FROM ANESTHETIC background activity, and
COMA AFTER STATUS EPILEPTICUS examining for frank seizures
may avoid delaying
EEG is used routinely in the treatment and monitoring of status epilepticus. anesthetic liberation.
Following convulsive status epilepticus, 48% of patients demonstrated persistent
seizures, including 14% with nonconvulsive status epilepticus. Those with
nonconvulsive status epilepticus had a mortality greater than 50% compared
with less than 15% among those without ictal discharges, conferring 1.9-fold risk
of mortality even when adjusted for age and etiology.30 Rapid EEG has not been
used to date in interventional clinical trials in the emergency department; thus,
primary end points in acute status epilepticus clinical effectiveness trials have
been limited to absence of clinically apparent seizures with improved
consciousness and without additional antiseizure medication.26,27 Without an
end point that includes EEG monitoring, patients intubated for neuroimaging or
progression of a structural brain injury have been considered to have failed status
epilepticus therapy regardless of the reason for intubation, a major limitation
given that the rate of intubation has nearly doubled over the past 2 decades.31
In critical care studies of status epilepticus utilizing continuous EEG, an
aggressive approach to anesthetic weaning has demonstrated EEG normalization
and clinical improvement despite initial increases in periodic discharges.32
Although the literature suggests that metabolic crisis is associated with these
high-frequency periodic discharges,33 the emergence of ictal-interictal
continuum activity may be transient in the setting of weaning from anesthetic
coma.34 In this setting, other clinical and quantitative features may be of use to
determine which patients are likely to be liberated from anesthetic coma. For

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SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU

example, in a population without cardiac arrest, unsuccessful anesthetic

liberation after refractory status epilepticus was associated with the presence of
highly epileptiform bursts (multiple discharges in the majority of bursts)35 as
well as with bursts that were monomorphic, exceeded 125 μV amplitude, or
(more often than not) demonstrated epileptiform features.36 A quantitative
approach using spectral power in frequency bands and functional connectivity
measures, including network density, yielded a testing accuracy of 75% in a
holdout cohort and in a secondary external validation cohort, with an area under
the curve of 83% for predicting successful anesthetic liberation. These features
add information about the potential success or failure of a wean up to 12 hours
before a wean is clinically terminated. Thus, many hours before anesthesia
weaning is determined to be a success or failure based on recurrence of status
epilepticus, emerging network connectivity is evident in patients who were

CASE 6-1 A 61-year-old man was admitted to the neurocritical care unit after
craniotomy for aneurysmal subarachnoid hemorrhage. He was comatose,
and continuous EEG monitoring with electrocorticography recording
activity from a 6-contact subdural strip electrode was initiated
immediately after the craniotomy. He was found to have seizures
consisting of periodic discharges with evolution on the subdural strip
electrode while on levetiracetam 500 mg every 12 hours (FIGURE 6-2A). He
had no evident seizures on the scalp EEG channels, which showed only
rhythmic delta activity. After two doses of levetiracetam 1500 mg every
12 hours (FIGURE 6-2B), his EEG improved to an alpha background without
epileptiform activity and his clinical examination had improved to
conversational.

COMMENT This case illustrates the discordant findings between scalp EEG and
intracranial electrocorticography. The scalp EEG showed rhythmic delta
activity, but the subdural strip electrode showed a mix of rhythmic delta
activity with embedded sharp waves as well as periodic discharges with
evolution. Additionally, the case demonstrates how changes over time in
the context of treatment may be interpreted clinically according to the
Salzburg Consensus Criteria.10 Both the rhythmic delta activity on the scalp
and the activity on the strip electrode with evolution resolved after
treatment, coincident with improvement of arousal, orientation, and verbal
functioning. Although this patient’s electroclinical improvement was
consistent with a post hoc diagnosis of nonconvulsive status epilepticus
according to the American Clinical Neurophysiology Society Standardized
Critical Care EEG Terminology and Salzburg Consensus Criteria, clinical
trials are necessary to determine whether antiseizure medication
escalation itself improves clinical outcomes.

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successfully liberated from anesthesia without seizure recurrence.37 Accordingly,
future efforts may be aimed at hastening anesthetic liberation and coma recovery
in patients with status epilepticus based on EEG measures.

BALANCING THE RISKS AND BENEFITS OF TREATING NONCONVULSIVE

SEIZURES AND ICTAL-INTERICTAL CONTINUUM ACTIVITY
When considering the risks of nonconvulsive seizure activity and status
epilepticus, a measure of overall burden (percent prevalence multiplied by time
observed) has been introduced as part of the ACNS Standardized Critical Care
EEG Terminology. When considering the risks of ictal-interictal activity, an
additional measure, index (burden multiplied by the frequency of periodic
discharges or lateralized rhythmic delta activity) can be used as a composite
measure combining both duration and intensity.12

FIGURE 6-2
Continuous EEG monitoring with intracranial electrocorticography from a six-electrode
subdural strip (red boxes) of the patient in CASE 6-1 after craniotomy for aneurysmal
subarachnoid hemorrhage while on levetiracetam 500 mg every 12 hours on hospital day 1 (A)
and on day 2 (B) after two doses of levetiracetam 1500 mg every 12 hours.

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SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU

Nonconvulsive seizures and ictal-interictal continuum activity have

demonstrated an impact on outcome independent of potential confounders such
as disease severity, which itself may be associated with both seizure incidence
and outcome. In multivariate regression analysis, periodic discharges are
associated with an 18.8-fold risk of poor functional outcome on the modified
Rankin Scale in patients with subarachnoid hemorrhage.5 Although one study
demonstrated little difference between brief or prolonged periodic discharges on
functional outcome in a mixed population,38 more recent studies using burden
measures have demonstrated that patients with ischemic stroke with a peak daily
burden of epileptiform activity exceeding 10% have a 23-fold risk of poor
outcome and that the interaction of increasing epileptiform activity burden with
frequency reaching 1.5 Hz conferred a 1.6-fold risk of poor outcome.39 Similarly,
in subarachnoid hemorrhage, the burden of epileptiform activity on the first
day of monitoring and the peak daily burden of epileptiform activity were each
associated with poor functional and cognitive outcomes.40,41 In a cohort of
patients with traumatic brain injury in the INTREPID2566 (Study of NNZ-2566 in
Patients With Traumatic Brain Injury) study, ictal-interictal activity did not have
an association with poor outcome when patients with moderate (including
sub–1.5-Hz lateralized rhythmic delta activity or sub–1.5-Hz generalized periodic
discharges; 45% of patients) and severe ictal-interictal continuum activity (14%
of patients) were grouped together, with the latter underrepresented.42
Given these effects on outcome, antiseizure medication escalation to suppress
events on the ictal-interictal continuum other than generalized rhythmic delta
activity has been investigated, including retrospective studies examining
triphasic-appearing generalized periodic discharges, historically considered
metabolic in origin.3 Recognizing that unequivocal responses to antiseizure
medication escalation (resolution of both the abnormal EEG pattern and
improvement of EEG background or encephalopathy) are common has
encouraged a more proactive approach to treatment. The historic
characterization of triphasic waves as being synonymous with a metabolic
etiology needing treatment of the underlying condition has been updated by data
showing that intervening by treating patients with triphasic discharges with
benzodiazepines or antiseizure medication results in commensurate
electrographic and clinical improvement in a number of patients.3 However,
questions remain about the clinical benefit of routine antiseizure medication
escalation in patients with ictal-interictal continuum activity. One potential

TABLE 6-1 Dosing Administered in the Established Status Epilepticus Treatment Triala

Drug Dose Administration

Levetiracetam 60 mg/kg (maximum 4500 mg) 10-min infusion

Fosphenytoin 20 mg PE/kg (maximum 1500 mg PE) 10-min infusion

Valproate 40 mg/kg (maximum 3000 mg) 10-min infusion

PE = phenytoin sodium equivalent.

a
Data from Gaspard N, et al, Epilepsia.25 and Chamberlain JM, et al, Lancet.26

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strategy is a 48-hour trial of therapy to assess for electrographic response as well KEY POINTS
as sufficient time for a clinical response that may require recovery from a
● The quantified initial or
postictal period. peak burden of
ictal-interictal continuum
POSTACUTE ANTISEIZURE MEDICATION MANAGEMENT activity and electrographic
The negative effects of antiseizure medication on cognition have been seizures are independently
associated with outcome.
demonstrated in subarachnoid hemorrhage and intracerebral hemorrhage.43 As a
result, patients with symptomatic or reversible causes of seizures may be ● Even generalized periodic
considered for withdrawal of antiseizure medications at several weeks following discharges with a triphasic
critical care. These decisions must be balanced against the risks of recurrent morphology, historically
seizures, particularly in patients with seizures attributable to a focal lesion, associated with metabolic
disturbances, may
persistent epileptiform discharges after trauma, or status epilepticus.44,45 One commonly have an
strategy is to perform outpatient EEG after withdrawing seizure medications, electroclinical response to
although it is unclear whether this strategy optimizes the use of antiseizure escalation of antiseizure
medications or cognitive outcomes. medication.

● Electrometabolic status
EEG FOR DETECTION AND PREDICTION OF SECONDARY BRAIN INJURY epilepticus is increasingly
Whether epileptiform activity on the ictal-interictal continuum is a cause or appreciated as
effect of injury and ischemia has been of interest since the specific association of ictal-interictal continuum
activity of high frequency in
generalized or lateralized periodic epileptiform discharges with brain injury was
association with exhaustive
first noted as “paroxysmal high-voltage and rhythmic low-voltage discharges” by metabolic crisis measured
Echlin and colleagues46 following surgical isolation or partial isolation of human by cerebral hyperglycolysis
cortex; by Chatrian and colleagues47-49 beginning in 1952 as periodic lateralized during positron emission
tomography, increasing
epileptiform discharges associated with ischemia, malignancy, or infection; and
lactate to pyruvate ratio
by Alajouanine and colleagues50 in 1955 as generalized and lateralized periodic evident from cerebral
discharges associated with infectious and inflammatory maladies. microdialysis sampling, or
There are multiple potential mechanisms by which epileptiform activity is brain tissue hypoxia
independently associated with poor outcome: (1) association of epileptiform identified during brain tissue
oxygenation monitoring.
activity with exhaustive hypermetabolism and metabolic crisis, (2) association of
epileptiform activity with subsequent cortical spreading depolarization, (3)
association of epileptiform activity with inflammation, and (4) potential
medication toxicity related to escalating antiseizure medication to treat
epileptiform activity.
Numerous modalities have documented the temporal and regional association
of epileptiform activity with exhaustive hypermetabolism and metabolic crisis.
Ictal-interictal activity is associated with regional hyperglycolysis51 that is
frequency dependent33 and decreases with anesthetic burst suppression.51,52 In
patients with subarachnoid hemorrhage, periodic discharges have been shown to
have a regional and temporal frequency-dependent association with decreases in
brain tissue oxygenation53: median partial pressure of brain tissue oxygenation
was 23 mm Hg without periodic discharges, 16 mm Hg when periodic discharges
reached 2.0 Hz, and 14 mm Hg when discharges reached 2.5 Hz.53 In traumatic
brain injury, elevated lactate to pyruvate ratio is associated with either seizures or
periodic discharges16 and subsequent ipsilateral cortical atrophy.6 In
intracerebral hemorrhage, electrographic seizures have been linked to a
subsequent increase in midline shift of 2.7 mm (compared to a decrease of
2.4 mm in patients without seizure over the first 72 hours of admission).54
Patients with in-hospital nonconvulsive seizures after subarachnoid
hemorrhage have a 1.9-fold risk of a systemic inflammatory response syndrome
and higher levels of high-sensitivity C-reactive protein and tumor necrosis factor

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SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU
TABLE 6-2 Antiseizure Medications Commonly Used On-label and Off-label in
Patients Who Are Critically Ill
Drug Proposed mechanism and rationale
Brivaracetam Synaptic vesicle glycoprotein 2A
(SV2A) binding; IV available;
dependable and rapid kinetics; higher
binding affinity than levetiracetam
Carbamazepine Voltage-gated sodium channel
binding, inactivation
Clobazam γ-Aminobutyric acid A (GABAA) partial
agonist selective α1β3γ2 with lower
affinity for α1β2γ2 receptor; increase
in calcium ion conduction; selective
receptor binding to reduce sedative
side effects with increased
antiseizure effects compared to other
benzodiazepines
Lacosamide Sodium channel selective
enhancement of slow inactivation,
collapsin response mediator protein 2
(CRMP-2) binding; IV available;
therapeutic drug monitoring not
routinely required; minimal drug
interactions; noninferior to
fosphenytoin in patients with
nonconvulsive seizures
Levetiracetam Binding to SV2A; partial inhibition of
N-type calcium ion currents; IV
available; therapeutic drug monitoring
not routinely required; highly studied
in status epilepticus
Oxcarbazepine Binding to voltage-gated sodium
channels; inhibition of glutamate
release; easily titrated; less
hyponatremia than carbamazepine;
secondary use in mood disorders
Perampanel Noncompetitive α-Amino-3-hydroxy-
5-methylisoxazole-4-proprionic acid
(AMPA) receptor antagonist; IV
available; unique mechanism
Phenobarbital GABAA receptor β-subunit binding;
increase in calcium ion channel
conduction; IV available; secondary
use in treating alcohol withdrawal;
historic data in status epilepticus
1330
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Monitoring
Complete blood cell count,
liver function tests
Trough levels; complete
blood cell count, liver function
tests/drug reaction with
eosinophilia and systemic
symptoms (DRESS); degraded
by cytochrome P450 (CYP)
3A4; strong, broad enzyme
inducer of CYP3A4
Arousal, hypopnea; degraded
by CYP3A4
ECG PR interval, bradycardia,
heart block
Complete blood cell count,
liver function tests; behavioral
dysfunction
Trough levels; complete
blood cell count, sodium; liver
function tests/DRESS; weakly
induces CYP3A4, weakly
inhibits CYP2C19
DRESS, mood dysfunction;
degraded by CYP3A4
Complete blood cell count,
liver function tests; induces
CYP3A4, CYP2C9, CYP1A2;
degraded by CYP2C9,
CYP2C19, CYP2E1
Considerations
Prior authorization may be
required as outpatient
No long-term IV option;
associated with higher risk of
Stevens-Johnson syndrome in
certain Asian patients with
HLA-B*15:02
Long elimination half-life; use
with caution in patients with
hepatic dysfunction
IV; avoid in second- and
third-degree heart block or sick
sinus syndrome; prior
authorization may be required
as outpatient
IV; dosing in clinical trials higher
than commonly prescribed
No IV option; associated with
higher risk of Stevens-Johnson
syndrome in Asian patients with
HLA-B*15:02, although lower risk
than carbamazepine
May enhance beta activity,
sharpness of EEG
CONTINUED ON PAGE 1331
OCTOBER 2021
CONTINUED FROM PAGE 1330
Drug Proposed mechanism and rationale
Phenytoin/ Blockade of voltage-dependent
fosphenytoin sodium channels; IV available; highly
studied in status epilepticus and
seizure prophylaxis studies of patients
with traumatic brain injury
Topiramate GABAA nonbenzodiazepine receptor
site binding; AMPA and kainate
receptor binding/inhibition;
voltage-dependent sodium channel
binding; IV available; case series in
refractory status epilepticus
Valproate GABA transaminase inhibition and
reduced GABA metabolism;
voltage-gated sodium channel
suppression; IV available; may have
secondary benefit for mood
stabilization or headache
Ketamine Noncompetitive N-methyl-D-
aspartate (NMDA); HCN1 receptor
blockade and commensurate
decrease in AMPA receptor-mediated
transmission; IV dissociative
anesthetic; reduced withdrawal
symptoms; well tolerated without
hemodynamic effects
Midazolam GABAA benzodiazepine binding site;
IV, IM, and intranasal routes; first-line
agent in prehospital setting;
anesthetic third-line agent
Pentobarbital GABAA β-subunit binding; IV
anesthetic third-line agent; silencing
of cerebral metabolism at high doses
Propofol GABAA β2 and β3 receptor subunit
binding. IV anesthetic third-line agent;
rapid onset and offset
ECG = electrocardiogram; EEG = electroencephalogram; IM = intramuscular; IV = intravenous.
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Monitoring
Complete blood cell count,
liver function tests, albumin;
strong, broad enzyme inducer
of CYP3A4, CYP2C9, CYP1A2;
degraded by CYP2C9,
CYP2C19
pH, bicarbonate; weakly
induces CP3A4, weakly
inhibits CYP2C19
Liver function tests, albumin,
amylase/lipase in patients at
high risk; blood cell counts,
albumin; inhibits CYP2C9;
degraded by CYP2A6,
CYP2C9, CYP2C19, CYP2B6
Heart rate, respiratory
function, liver function tests,
laryngospasm; postanesthetic
emergence reaction;
degraded by CYP2B6 and
CYP3A4
Blood pressure, respiratory
function
Heart rate; respiratory
function; complete blood cell
count, liver function tests,
ileus; degraded by CYP2B6,
partially by CYP3A4
Respiratory function; liver
function tests, triglycerides,
creatine kinase, pH, potential
CYP3A4 inhibitor
Considerations
Zero-order kinetics can result in
toxicity; free levels in patients in
the intensive care unit poorly
estimated by historic equations
Alternatives preferred when
possible in patients with
first-term pregnancies
IV; may have effect on platelet
dysfunction even without
thrombocytopenia; free levels
may be needed if
hypoalbuminemia or
concomitant phenytoin/
fosphenytoin therapy;
alternatives preferred when
possible in patients who are
pregnant; consider free levels in
patients with low albumin
Increasing use as earlier option
in patients with refractory
seizures
May require vasopressor
support
Need for vasopressor support;
risk for bowel perforation
May require vasopressor
support; risk for propofol
infusion syndrome in children or
in patients with low body
weight; need for adjusting
nutrition to prevent
hypertriglyceridemia
1331
SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU

receptor 1; a mediation analysis demonstrated that the association between

inflammatory markers and outcome was mediated in part through
nonconvulsive seizures.55 The emergence of new or worsening epileptiform
activity (lateralized rhythmic delta activity, generalized periodic discharges, or
lateralized periodic discharges) was also associated with inflammatory marker
soluble ST2 both in blood and CSF,56 suggesting that inflammation is associated
with ictal-interictal activity in addition to frank electrographic seizures.

EEG ISCHEMIA MONITORING AFTER SUBARACHNOID HEMORRHAGE

Because EEG demonstrates increased delta and decreased alpha activity during
ischemia, continuous EEG has been retrospectively examined for the ability to
predict delayed cerebral ischemia after subarachnoid hemorrhage using
continuous EEG spectral features,57,58 including decreases in the alpha to delta
power ratio57,59,60 or relative alpha power variability.60,61 Specifically, clinically
useful cutoffs in alpha to delta ratio were identified, including six consecutive
recordings with a greater than 10% decrease from baseline (sensitivity 100%,
specificity 76%) and any single measurement with a greater than 50% decrease
(sensitivity 89%, specificity 84%).59 A decrease in relative alpha variability was
100% sensitive but only 50% specific for vasospasm.61
Other findings historically associated with cerebral ischemia include
epileptiform discharges, rhythmic and periodic ictal-interictal continuum
patterns,49,62-64 and isolated alpha suppression.65 In subarachnoid hemorrhage,
new or worsening epileptiform activity has been associated with subsequent
delayed cerebral ischemia.66,67 Using change-point detection, the temporal onset
of brain tissue hypoxia was associated with increases of periodic discharge
frequency exceeding 2.0 Hz, supporting the hypothesis that secondary ischemia
is associated with subarachnoid hemorrhage.53
The findings of spectral frequency change and new epileptiform activity on
continuous EEG have been examined prospectively in both a feasibility study
(demonstrating that more than 90% of delayed cerebral ischemia events
occurred during the mean 6.9 days of continuous EEG monitoring68) and a

TABLE 6-3 Accuracy Results for Continuous EEG Prediction of Delayed Cerebral
Ischemia After Subarachnoid Hemorrhage (n = 103)a

Low risk Medium risk High risk

[risk score = 1] [risk score = 2.5] [risk score = 4]

Sensitivity (%) 91 [81-98] 94 [88-99] 95 [87-99]

Specificity (%) 83 [71-93] 80 [69-90] 77 [36-99]

Pretest probability of delayed cerebral ischemia (%) 37 [25-50] 58 [50-66] 79 [61-92]

Delayed cerebral ischemia risk (continuous EEG deterioration) (%) 76 [58-90] 87 [79-94] 94 [79-100]

Delayed cerebral ischemia risk (no continuous EEG deterioration) (%) 6 [1-13] 10 [2-19] 9 [3-53]

Number needed to monitor 2.6 [2.0-3.8] 3.5 [2.8-4.8] 6.7 [3.6-25.3]

a
Modified with permission from Rosenthal ES, et al, Ann Neurol.67 © 2018 American Neurological Association.

1332 OCTOBER 2021

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diagnostic accuracy study (validating the high sensitivity and specificity of an KEY POINTS
EEG “alarm” in patients with low, medium, or high baseline risk) (TABLE 6-3).67
● Seizure activity is
These EEG alarms were prespecified as a change from baseline consisting of increasingly appreciated as
any of the following not explained by sedation, hydrocephalus, or other clinical associated with an
confounders: (1) 10% decrease in alpha to delta ratio persisting 6 hours or a 50% inflammatory complex
decrease persisting longer than 1 hour, (2) a one-grade decrease in relative alpha of biomarkers in blood
and CSF.
variability over an 8-hour epoch, (3) new focal slowing identified on regional
spectrograms or raw EEG, or (4) new or worsening epileptiform activity. ● A battery of continuous
Because patients with an EEG alarm as described above have a subsequent risk of EEG findings, including
delayed cerebral ischemia of 76% (patients at low risk), 87% (patients at medium decrease in alpha to delta
risk), and 94% (patients at high risk), these methods of ischemia monitoring may ratio of frequency-band
power, one-grade decrease
be useful as patient selection criteria for enrichment strategies in future clinical in relative alpha variability,
trials or as triggers for higher-risk diagnostic or treatment studies such as and new or worsening
cerebral angiography with endovascular vasodilator therapy. Of interest, a epileptiform activity, have
single-center study found that EEG delayed cerebral ischemia biomarkers of new been prospectively
validated as a method of
or worsening epileptiform activity were strongly associated with longitudinal predicting subsequent
functional outcomes following subarachnoid hemorrhage, whereas EEG ischemia in patients with
background deterioration was not.69 This discrepancy may be related to a subarachnoid hemorrhage.
differential response to clinically available interventions. A patient with a
● Cortical spreading
commensurate decrease in both alpha to delta ratio and invasively measured
depolarizations are
cerebral blood flow followed by a response to endovascular intraarterial increasingly being
administration of calcium channel blockers directly at the site of cerebral monitored in clinical
vasospasm is depicted in CASE 6-2. practice as brain activity
associated with unexplained
coma and poor neurologic
CORTICAL SPREADING DEPOLARIZATION MONITORING ACROSS outcome.
ACUTE BRAIN INJURIES
Cortical spreading depolarizations similar to those seen in migraine are present in
acute brain injury. These depolarizations spread slowly and typically have a
magnitude greater in amplitude than seizure activity; when they occur in
vulnerable parenchyma after acute brain injury, they result in severe metabolic
crisis, which is often irreversible when depolarizations occur repeatedly in
clusters. Intracranial electrocorticography has traditionally been required for the
detection of cortical spreading depolarization.70,71 However, evaluation of
examples of simultaneous scalp and subdural electrode recordings suggested that
depression of fast activity over the scalp may be a signature of underlying
spreading depolarization.72 The association of spreading depolarizations with
neurologic deterioration and poor outcome in patients with subarachnoid
hemorrhage, traumatic brain injury,73-76 and surgically managed subdural
hematoma, combined with the reduction of these events by ketamine,77-83 has led
to a trend of both increased clinical use of intracranial monitoring of
low-frequency activity in patients with acute brain injuries and increased interest
in future therapies targeted at treating these events.84

DETECTION OF DELIRIUM, ENCEPHALOPATHY, AND COVERT

CONSCIOUSNESS AND PREDICTION OF COMA RECOVERY
In addition to predicting anesthetic liberation after status epilepticus, EEG has
also gained attention for its ability to diagnose and monitor delirium and
disorders of consciousness in patients who are critically ill and to predict coma
recovery. The depth and severity of delirium is highly correlated with the
prevalence of EEG slowing. The EEG finding most strongly associated with the

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SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU

presence of delirium in one study was a composite of generalized theta or delta

slowing, conferring a tenfold risk (95% confidence interval, 5.3-20.1). Slowing is
present even in patients with delirium who have preserved arousal.85 In clinical
practice, EEG in patients with delirium can be useful to trend improvement from
delirium as an intermediate biomarker of recovery after treatment of potential
underlying causes, such as infection, sedation, toxic-metabolic effects, or
organ dysfunction.
As a tool for patients with disorders of consciousness, EEG is useful to detect
covert consciousness. EEG performed in the background of various stimuli
(audio recordings alternating as a stimulus battery) at a mean of 10 days after

CASE 6-2 A 74-year-old woman presented with a Hunt and Hess Scale grade 4 and
Fisher Scale grade 4 subarachnoid hemorrhage due to a right supraclinoid
internal carotid artery aneurysm. Examination demonstrated delayed
response to commands but no overt focal symptoms of delayed cerebral
ischemia. The patient was considered uncertain to benefit from
catheter-based intraarterial vasodilator therapy. Over a 2-day period, a
depth electrode demonstrated a decline in the alpha to delta ratio that
was concordant with a decline in cerebral blood flow monitoring from
30 mL/100 g/min to 10 mL/100 g/min measured from a nearby probe
(FIGURE 6-3A). Based on these data, the patient was referred for
endovascular intraarterial calcium channel blocker therapy (FIGURE 6-3B),
which was associated with an increase in cerebral blood flow (FIGURE 6-3B)
from 10 mL/100 g/min to 15 mL/100 g/min and concordant emergence of
an EEG alpha rhythm measured from the colocated depth electrode
(FIGURE 6-3B).

COMMENT This case demonstrates that when changes in EEG spectral activity (such as
decrease of the alpha to delta ratio) are concordant with other modalities
(such as cerebral blood flow or brain tissue oxygenation), there may be
increased confidence of vasospasm as a treatable mechanism of
metabolic crisis, manifest as EEG background deterioration.

1334 OCTOBER 2021

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traumatic coma was part of a multimodal assessment, also incorporating
functional MRI (fMRI), that was able to identify cognitive-motor dissociation in
four of 16 subjects and higher-order cortical processing in two additional
patients.86 Patients with EEG differences demonstrated by a machine learning
classifier comparing alternating blocks of auditory stimulation and rest were
more likely to have intact language function as measured by either the Coma
Recovery Scale-Revised or a composite that included fMRI.87 A manual method
examining EEG background had almost as good agreement with the behavioral
language examination as did the machine learning stimulus-based EEG classifier,
and a method employing both background and reactivity had significant

FIGURE 6-3
Findings for the patient in CASE 6-2. A, Depth electrode tracings demonstrate a decline in the
alpha to delta ratio that is discordant with a decline in cerebral blood flow monitoring from
30 mL/100 g/min to 10 mL/100 g/min measured from a nearby probe (sixth tracing from the
top). B, Tracings before (left image) and after (right image) catheter-based intraarterial
vasodilator therapy demonstrate an increase in cerebral blood flow (top image) of
10 mL/100 g/min to 15 mL/100 g/min, concordant with the emergence of an alpha rhythm
measured from the colocated depth electrode (B, bottom tracing).

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SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU

agreement with the composite standard for detecting language function by either
fMRI or behavioral evidence of language.87 In addition to studies of patients with
traumatic brain injury, a prospective study evaluating EEG responses in patients
with a wide variety of acute brain injuries demonstrated that brain activation in
response to auditory stimulation was evident in 15% of 104 patients, conferring
nearly twice the rate (50% compared to 26%) of following commands before
discharge and 4.6-fold odds of achieving a good Glasgow Outcome
Scale-Extended score at 12 months (44% compared to 14%).88 EEG may also be
useful in differentiating patients in an unresponsive wakefulness state from those
in a locked-in state even without preserved eye movements, such that EEG may
demonstrate normal cortical rhythms and reactivity in the locked-in state.89,90
Prognostic information about coma recovery is also evident in patients with
cardiac arrest. Treatment with therapeutic hypothermia significantly affects the
prognostic significance of these findings.91 The occurrence of monomorphic
“identical” bursts has been linked with near uniformly poor outcome in studies
seeking to minimize biases from self-fulfilling prophecies by examining a cohort
in which limitation of life-sustaining therapy did not occur in the first 72 hours,
even though an unfavorable EEG pattern at 12 hours was the factor most strongly
associated with poor outcome.92 A prediction model including the presence of
status epilepticus, suppression-burst pattern alone, and lack of background
reactivity had an area under the curve of 0.92 for predicting poor functional
outcome in a cohort of 373 patients.93 Alternatively, patients with continuous
EEG activity are more likely to respond to antiseizure medication or therapeutic
hypothermia with a resolution of epileptiform activity,94 and the combination of
EEG continuity and lack of anoxic injury on MRI was associated with coma
recovery at a sensitivity of 91% and specificity of 99%. Other more quantitative
tools include a Cerebral Recovery Index (consisting of alpha to delta ratio of
power, standard deviation, coherence in delta activity, Shannon entropy, and
regularity)95-98 and time-varying models containing features of complexity,
category, and connectivity.99
Similarly, in intracerebral hemorrhage, the absence of an anteroposterior
gradient was associated with poor outcome and the presence of stage II sleep
activity was independently associated with good functional outcome.100 In
traumatic brain injury, absence of a posterior dominant rhythm, absence of N2
sleep transients, presence of predominant delta activity, and presence of a
discontinuous background were associated with poor outcome when evident in
the initial 72 hours.42

RESOURCE UTILIZATION
The use of EEG in the emergency and critical care environment has historically
required the availability of both EEG equipment and technologist resources.
The increasing availability of rapid EEG devices that can be placed by physicians
and nurses has enabled EEG placement at a median of 5 minutes, with only
25% of studies requiring greater than 10 minutes before recording could
commence.101 These techniques may also allow for screening neurotelemetry
that may enable examining the rate of seizures in the hyperacute phase as well as
assessing whether ictal-interictal activity is commonly preceded by progression
from sustained seizure activity.102
The use of continuous EEG has increased significantly over time, with critical
care neurophysiologists using quantitative aspects of EEG for seizure detection in

1336 OCTOBER 2021

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over 90% of users, pharmacologic titration to burst suppression in nearly 60% of KEY POINTS
users, and a variety of other uses in 20% to 30% of users, including monitoring
● Covert consciousness is
the depth of sedation, detecting ischemia, detecting vasospasm, and prognosis frequently seen in patients
after cardiac arrest,103 with costs and resource utilization commensurate with who are critically ill with
intermittent EEG. Challenges with the availability and cost of continuous EEG acute brain injury; wider
monitoring compared to intermittent EEG monitoring have led to analyses availability of
stimulus-based EEG
examining differences in yield and outcomes. In patients with cardiac arrest
monitoring (in addition to
undergoing therapeutic hypothermia, for example, a high degree of agreement functional MRI) may not only
was reported between continuous and intermittent EEG methods, and an improve the accuracy of
observational study reported that continuous EEG did not confer a benefit over diagnosing patients with
disorders of consciousness
intermittent EEG in patients with cardiac arrest,104 although decisions to limit
but also improve the
life-sustaining therapy and physician biases may also have explained the lack of information available to
differences. A follow-up randomized controlled trial reported no difference in surrogate decision makers.
outcomes among patients undergoing continuous EEG compared to intermittent
EEG, but the conclusions were limited by a highly heterogeneous population, ● Assessment of the EEG
background rhythm,
lack of a specified treatment protocol during the monitoring, and the potential including sleep features and
for continuous monitoring to inform goals-of-care conversations and thereby continuity, provides
influence the rate of withdrawal of life-sustaining therapy.105 Other studies prognostic information in
reporting improved outcomes when continuous EEG was performed in patients addition to the presence of
activity on the
who were critically ill106 similarly lack an interventional approach to determine ictal-interictal continuum.
whether these effects are related to treatment effects.
● Although one randomized
study concluded that
continuous EEG showed no
CONCLUSION
benefit compared to
The advancement of consistent nomenclature and definitions has improved the intermittent EEG, a definitive
reliability of definitions for seizures, status epilepticus, and indeterminate study would require
patterns on the ictal-interictal continuum. A consolidated approach to diagnosis examining a specific
and management reflecting these many applications of EEG neuromonitoring in population expected to
have a homogeneous
neurocritical care is depicted in FIGURE 6-4. Management of clinically apparent pathophysiology, defining a
and convulsive status epilepticus (FIGURE 6-4A) has evidence-based literature treatment protocol that
guiding management along the continuum of prehospital, emergency, and makes use of
critical care, but continuous EEG may improve diagnostic accuracy and precision neuromonitoring findings,
and controlling for changes
of management at an early phase. Management of encephalopathy, coma, and in life-sustaining treatment
other disorders of consciousness requires a consideration of more diverse resulting from differences in
etiologies and multimodality neuromonitoring to improve diagnostic precision. available prognostic
Monitoring requires serial assessment and iterative management changes information.
(FIGURE 6-4B). Specifically, trends in using adjunctive tools to document both
scalp-negative seizures and the metabolic burden of epileptiform activity have
expanded the recognition that increasing seizure burden and increasing
burden and intensity of periodic and rhythmic patterns on the ictal-interictal
continuum are both associated with cerebral metabolic crisis related to
exhaustive cerebral hypermetabolism. When seizure activity is indeterminate,
intracranial EEG and empiric treatment trials with antiseizure medication have
been used to demonstrate clinical improvement in a substantial portion of
patients, thereby improving diagnostic precision. When seizures are continuous
and refractory in the form of status epilepticus, the current approach is to
optimize antiseizure medications during a structured course of anesthetic
management. Approaches including seizure suppression and burst suppression
with anesthetics have grown to incorporate medications including ketamine as
well as ketogenic or low-glycemic diet therapy and neuromodulation.

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SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU

FIGURE 6-4
EEG monitoring guides the approach to both clinically apparent and convulsive status
epilepticus in the emergency and critical care settings (A) and to a broad differential
diagnosis considered in the evaluation of a patient with encephalopathy, coma, or other
disorder of consciousness (B). Increasing availability of EEG in the emergency setting (A) may
enable more precise management of the patient with established convulsive status
epilepticus by distinguishing pharmacologic sedation, progression to refractory
nonconvulsive seizures, and nonepileptic spells. EEG has numerous roles in patients who are
critically ill with encephalopathy, coma, and disorders of consciousness (B), including
detection of nonconvulsive seizures or nonconvulsive status epilepticus, evaluation for
ictal-interictal continuum activity consistent with possible nonconvulsive status, tissue
dysfunction due to secondary brain injury or delayed cerebral ischemia, and cognitive-motor
dissociation, in which consciousness is only evident through advanced monitoring. For all
these scenarios, complementary multimodality monitoring data can add contextual
information, which can be evaluated along with EEG monitoring for concordance and
iterative response to treatment.
EEG = electroencephalography; FDG CT-PET = fludeoxyglucose computed tomography positron emission
tomography; Rx = pharmacologic management; SAH = subarachnoid hemorrhage; SE = status epilepticus;
TBI = traumatic brain injury.

1338 OCTOBER 2021

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Apart from diagnosing and monitoring seizure activity, other diagnostic roles for
EEG have been demonstrated recently in diverse patient cohorts: monitoring for
ischemia after subarachnoid hemorrhage; diagnosing covert consciousness in
patients who are apparently comatose; and predicting neurologic recovery after
cardiac arrest, primary acute brain injury, or resolution of status epilepticus.

ACKNOWLEDGMENT
This work was supported by a grant from the National Institutes of Health/
National Institute of Neurological Disorders and Stroke (1K23NS105950).

REFERENCES

1 Claassen J, Mayer SA, Kowalski RG, et al.
Detection of electrographic seizures with
continuous EEG monitoring in critically ill
patients. Neurology 2004;62(10):1743-1748.
doi:10.1212/01.wnl.0000125184.88797.62
2 Westover MB, Shafi MM, Bianchi MT, et al. The
probability of seizures during EEG monitoring in
critically ill adults. Clin Neurophysiol 2015;126(3):
463-471. doi:10.1016/j.clinph.2014.05.037
3 O'Rourke D, Chen PM, Gaspard N, et al. Response
rates to anticonvulsant trials in patients with
triphasic-wave EEG patterns of uncertain
significance. Neurocrit Care 2016;24(2):233-239.
doi:10.1007/s12028-015-0151-8
4 Vespa PM, Nuwer MR, Nenov V, et al. Increased
incidence and impact of nonconvulsive and
convulsive seizures after traumatic brain
injury as detected by continuous
electroencephalographic monitoring.
J Neurosurg 1999;91(5):750-760.
doi:10.3171/jns.1999.91.5.0750
5 Claassen J, Hirsch LJ, Frontera JA, et al.
Prognostic significance of continuous EEG
monitoring in patients with poor-grade
subarachnoid hemorrhage. Neurocrit Care 2006;
4(2):103-112. doi:10.1385/NCC:4:2:103
6 Vespa PM, McArthur DL, Xu Y, et al.
Nonconvulsive seizures after traumatic brain
injury are associated with hippocampal
atrophy. Neurology 2010;75(9):792-798.
doi:10.1212/WNL.0b013e3181f07334
7 Herman ST, Abend NS, Bleck TP, et al. Consensus
statement on continuous EEG in critically ill
adults and children, part I: indications.
J Clin Neurophysiol 2015;32(2):87-95.
doi:10.1097/WNP.0000000000000166
8 O'Connor KL, Westover MB, Phillips MT, et al.
High risk for seizures following subarachnoid
hemorrhage regardless of referral bias.
Neurocrit Care 2014;21(3):476-482.
doi:10.1007/s12028-014-9974-y
9 Beniczky S, Hirsch LJ, Kaplan PW, et al. Unified
EEG terminology and criteria for nonconvulsive
status epilepticus. Epilepsia 2013;54(suppl 6):
28-29. doi:10.1111/epi.12270
10 Leitinger M, Beniczky S, Rohracher A, et al.
Salzburg consensus criteria for non-convulsive
status epilepticus—approach to clinical
application. Epilepsy Behav 2015;49:158-163.
doi:10.1016/j.yebeh.2015.05.007
11 Leitinger M, Trinka E, Gardella E, et al. Diagnostic
accuracy of the Salzburg EEG criteria for
non-convulsive status epilepticus: a
retrospective study. Lancet Neurol 2016;15(10):
1054-1062. doi:10.1016/S1474-4422(16)30137-5
12 Hirsch LJ, Fong MWK, Leitinger L, et al. American
Clinical Neurophysiology Society's Standardized
Critical Care EEG Terminology: 2021 version. J Clin
Neurophysiol 2021;38(1):1-29. doi:10.1097/
WNP.0000000000000806
13 Struck AF, Ustun B, Ruiz AR, et al. Association of
an electroencephalography-based risk score
with seizure probability in hospitalized patients.
JAMA Neurol 2017;74(12):1419-1424.
doi:10.1001/jamaneurol.2017.2459
14 Struck AF, Tabaeizadeh M, Schmitt SE, et al.
Assessment of the validity of the 2HELPS2B
score for inpatient seizure risk prediction.
JAMA Neurol 2020;77(4):500-507.
doi:10.1001/jamaneurol.2019.4656
15 Fung FW, Fan J, Vala L, et al. EEG monitoring
duration to identify electroencephalographic
seizures in critically ill children.
Neurology 2020;95(11):e1599-e1608.
doi:10.1212/WNL.0000000000010421
16 Vespa P, Tubi M, Claassen J, et al. Metabolic
crisis occurs with seizures and periodic
discharges after brain trauma. Ann Neurol 2016;
79(4):579-590. doi:10.1002/ana.24606
17 Claassen J, Perotte A, Albers D, et al.
Nonconvulsive seizures after subarachnoid
hemorrhage: multimodal detection and
outcomes. Ann Neurol 2013;74(1):53-64.
doi:10.1002/ana.23859

CONTINUUMJOURNAL.COM 1339

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

SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU
18 Husain AM, Lee JW, Kolls BJ, et al. Randomized
trial of lacosamide versus fosphenytoin for
nonconvulsive seizures. Ann Neurol 2018;83(6):
1174-1185. doi:10.1002/ana.25249
19 Barra ME, Phillips KM, Chung DY, Rosenthal ES. A
novel correction equation avoids
high-magnitude errors in interpreting therapeutic
drug monitoring of phenytoin among critically ill
patients. Ther Drug Monit 2020;42(4):617-625.
doi:10.1097/FTD.0000000000000739
20 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
21 Alldredge BK, Gelb AM, Isaacs SM, et al. A
comparison of lorazepam, diazepam, and
placebo for the treatment of out-of-hospital
status epilepticus. N Engl J Med 2001;345(9):
631-637. doi:10.1056/NEJMoa002141
22 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
23 Sathe AG, Tillman H, Coles LD, et al. Underdosing
of benzodiazepines in patients with status
epilepticus enrolled in established status
epilepticus treatment trial. Acad Emerg Med
2019;26(8):940-943. doi:10.1111/acem.13811
24 Alldredge BK, Lowenstein DH, Simon RP.
Placebo-controlled trial of intravenous
diphenylhydantoin for short-term treatment of
alcohol withdrawal seizures. Am J Med 1989;
87(6):645-648. doi:10.1016/s0002-9343(89)80397-3
25 Gaspard N, Foreman B, Judd LM, et al.
Intravenous ketamine for the treatment of
refractory status epilepticus: a retrospective
multicenter study. Epilepsia 2013;54(8):1498-1503.
doi:10.1111/epi.12247
26 Chamberlain JM, Kapur J, Shinnar S, et al.
Efficacy of levetiracetam, fosphenytoin, and
valproate for established status epilepticus
by age group (ESETT): a double-blind,
responsive-adaptive, randomised controlled
trial. Lancet 2020;395(10231):1217-1224.
doi:10.1016/S0140-6736(20)30611-5
27 Kapur J, Elm J, Chamberlain JM, et al. Randomized
trial of three anticonvulsant medications for
status epilepticus. N Engl J Med 2019;381(22):
2103-2113. doi:10.1056/NEJMoa1905795
28 Cervenka MC, Hocker S, Koenig M, et al. Phase
I/II multicenter ketogenic diet study for adult
superrefractory status epilepticus.
Neurology 2017;88(10):938-943.
doi:10.1212/WNL.0000000000003690
29 Tuppurainen KM, Ritvanen JG, Mustonen H,
Kamppi LS. Predictors of mortality at one year
after generalized convulsive status epilepticus.
Epilepsy Behav 2019;101(pt B):106411.
doi:10.1016/j.yebeh.2019.07.012
1340
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
30 DeLorenzo RJ, Waterhouse EJ, Towne AR, et al.
Persistent nonconvulsive status epilepticus
after the control of convulsive status
epilepticus. Epilepsia 1998;39(8):833-840.
doi:10.1111/j.1528-1157.1998.tb01177.x
31 Alkhachroum AM, Rubinos C, Chatterjee A, et al.
Rates and trends of endotracheal intubation in
patients with status epilepticus. Neurohospitalist
2019;9(4):190-196. doi:10.1177/1941874419830496
32 Rosenthal ES, Claassen J, Wainwright MS, et al.
Brexanolone as adjunctive therapy in
super-refractory status epilepticus. Ann Neurol
2017;82(3):342-352. doi:10.1002/ana.25008
33 Subramaniam T, Jain A, Hall LT, et al. Lateralized
periodic discharges frequency correlates with
glucose metabolism. Neurology 2019;92(7):
e670-e674. doi:10.1212/WNL.0000000000006903
34 Das AS, Lee JW, Rosenthal ES, Vaitkevicius H.
Successful wean despite emergence of
ictal-interictal EEG patterns during the weaning
of prolonged burst-suppression therapy for
super-refractory status epilepticus.
Neurocrit Care 2018;29(3):452-462.
doi:10.1007/s12028-018-0552-6
35 Thompson SA, Hantus S. Highly epileptiform
bursts are associated with seizure recurrence.
J Clin Neurophysiol 2016;33(1):66-71.
doi:10.1097/WNP.0000000000000232
36 Johnson EL, Martinez NC, Ritzl EK. EEG
characteristics of successful burst suppression
for refractory status epilepticus. Neurocrit Care
2016;25(3):407-414. doi:10.1007/s12028-016-0294-2
37 Rubin DB, Angelini B, Shoukat M, et al.
Electrographic predictors of successful weaning
from anaesthetics in refractory status
epilepticus. Brain 2020;143(4):1143-1157.
doi:10.1093/brain/awaa069
38 Ong C, Gilmore E, Claassen J, et al. Impact of
prolonged periodic epileptiform discharges on
coma prognosis. Neurocrit Care 2012;17(1):39-44.
doi:10.1007/s12028-012-9728-7
39 Tabaeizadeh M, Aboul Nour H, Shoukat M, et al.
Burden of epileptiform activity predicts
discharge neurologic outcomes in severe acute
ischemic stroke. Neurocrit Care 2020;32(3):
697-706. doi:10.1007/s12028-020-00944-0
40 De Marchis GM, Pugin D, Meyers E, et al. Seizure
burden in subarachnoid hemorrhage associated
with functional and cognitive outcome.
Neurology 2016;86(3):253-260. doi:10.1212/
WNL.0000000000002281
41 Zafar SF, Postma EN, Biswal S, et al. Effect of
epileptiform abnormality burden on neurologic
outcome and antiepileptic drug management
after subarachnoid hemorrhage. Clin
Neurophysiol 2018;129(11):2219-2227.
doi:10.1016/j.clinph.2018.08.015
42 Lee H, Mizrahi MA, Hartings JA, et al. Continuous
electroencephalography after moderate to
severe traumatic brain injury. Crit Care
Med 2019;47(4):574-582.
doi:10.1097/CCM.0000000000003639
OCTOBER 2021
43 Naidech AM, Kreiter KT, Janjua N, et al. Phenytoin 56 Lissak IA, Zafar SF, Westover MB, et al. Soluble
exposure is associated with functional and ST2 is associated with new epileptiform
cognitive disability after subarachnoid abnormalities following nontraumatic
hemorrhage. Stroke 2005;36(3):583-587. subarachnoid hemorrhage. Stroke 2020;51(4):
doi:10.1161/01.STR.0000141936.36596.1e 1128-1134. doi:10.1161/STROKEAHA.119.028515
44 Kim JA, Boyle EJ, Wu AC, et al. Epileptiform 57 Labar DR, Fisch BJ, Pedley TA, et al. Quantitative
activity in traumatic brain injury predicts EEG monitoring for patients with subarachnoid
post-traumatic epilepsy. Ann Neurol 2018;83(4): hemorrhage. Electroencephalogr Clin
858-862. doi:10.1002/ana.25211 Neurophysiol 1991;78(5):325-332. doi:
10.1016/0013-4694(91)90094-k
45 Chen DF, Kumari P, Haider HA, et al. Association
of epileptiform abnormality on 58 Gollwitzer S, Groemer T, Rampp S, et al. Early
electroencephalography with development of prediction of delayed cerebral ischemia in
epilepsy after acute brain injury. Neurocrit Care subarachnoid hemorrhage based on quantitative
2021. doi:10.1007/s12028-020-01182-0 EEG: a prospective study in adults.
Clin Neurophysiol 2015;126(8):1514-1523.
46 Echlin FA, Arnett V, Zoll J. Paroxysmal high
doi:10.1016/j.clinph.2014.10.215
voltage discharges from isolated and partially
isolated human and animal cerebral cortex. 59 Claassen J, Hirsch LJ, Kreiter KT, et al.
Electroencephalogr Clin Neurophysiol 1952;4(2): Quantitative continuous EEG for detecting
147-164. doi:10.1016/0013-4694(52)90004-7 delayed cerebral ischemia in patients with
poor-grade subarachnoid hemorrhage. Clin
47 Chatrian GE, Vizioli R. [Case of degenerative
Neurophysiol 2004;115(12):2699-2710.
disease of uncertain nosographical
doi:10.1016/j.clinph.2004.06.017
systematization]. Riv Neurol 1952;22:715-720.
60 Rots ML, van Putten MJAM, Hoedemaekers CWE,
48 Chatrian GE, Shaw CM, Leffman H. The
Horn J. Continuous EEG monitoring for early
significance of periodic lateralized epileptiform
detection of delayed cerebral ischemia in
discharges in EEG: an electrographic, clinical and
subarachnoid hemorrhage: a pilot study.
pathological study. Electroencephalogr Clin
Neurocrit Care 2016;24(2):207-216.
Neurophysiol 1964;17:177-193. doi:10.1016/0013-
doi:10.1007/s12028-015-0205-y
4694(64)90149-x
61 Vespa PM, Nuwer MR, Juhasz C, et al. Early
49 Chatrian GE, Shaw CM, Luttrell CN. Focal
detection of vasospasm after acute
electroencephalographic seizure discharges in
subarachnoid hemorrhage using continuous EEG
acute cerebral infarction. Electrographic, clinical,
ICU monitoring. Electroencephalogr Clin
and pathological observations. Neurology 1965;
Neurophysiol 1997;103(6):607-615.
15:123-131. doi:10.1212/wnl.15.2.123
doi:10.1016/s0013-4694(97)00071-0
50 Alajouanine T, Lecasble R, Remond A. Slow
62 Echlin FA, Arnett V, Zoll J. Paroxysmal high
graphic paroxystic elements of periodic
voltage and rhythmic low voltage discharges
occurrence; electrical and clinical correlations [in
from isolated and partially isolated human
French]. Rev Neurol (Paris) 1955;93(2):477-478.
cortex. J Nerv Ment Dis 1952;116(1):65-72.
51 Struck AF, Westover MB, Hall LT, et al. Metabolic
63 Hartings JA, Williams AJ, Tortella FC. Occurrence
correlates of the ictal-interictal continuum:
of nonconvulsive seizures, periodic epileptiform
FDG-PET during continuous EEG. Neurocrit Care
discharges, and intermittent rhythmic delta
2016;24(3):324-331. doi:10.1007/s12028-016-0245-y
activity in rat focal ischemia. Exp Neurol 2003;
52 Akbik F, Robertson M, Das AS, et al. The PET 179(2):139-149. doi:10.1016/s0014-4886(02)00013-4
sandwich: using serial FDG-PET scans with
64 Dreier JP, Major S, Pannek HW, et al. Spreading
interval burst suppression to assess ictal
convulsions, spreading depolarization and
components of disease. Neurocrit Care 2020;
epileptogenesis in human cerebral cortex. Brain
33(3):657-669. doi:10.1007/s12028-020-00956-w
2012;135(pt 1):259-275. doi:10.1093/brain/awr303
53 Witsch J, Frey HP, Schmidt JM, et al.
65 Nuwer MR, Jordan SE, Ahn SS. Evaluation of
Electroencephalographic periodic discharges
stroke using EEG frequency analysis and
and frequency-dependent brain tissue hypoxia
topographic mapping. Neurology 1987;37(7):
in acute brain injury. JAMA Neurol 2017;74(3):
1153-1159. doi:10.1212/wnl.37.7.1153
301-309. doi:10.1001/jamaneurol.2016.5325
66 Kim JA, Rosenthal ES, Biswal S, et al. Epileptiform
54 Vespa PM, O'Phelan K, Shah M, et al. Acute
abnormalities predict delayed cerebral ischemia
seizures after intracerebral hemorrhage: a factor
in subarachnoid hemorrhage. Clin Neurophysiol
in progressive midline shift and outcome.
2017;128(6):1091-1099. doi:10.1016/j.
Neurology 2003;60(9):1441-1446.
clinph.2017.01.016
doi:10.1212/01.wnl.0000063316.47591.b4
67 Rosenthal ES, Biswal S, Zafar SF, et al. Continuous
55 Claassen J, Albers D, Schmidt JM, et al.
electroencephalography predicts delayed
Nonconvulsive seizures in subarachnoid
cerebral ischemia after subarachnoid
hemorrhage link inflammation and
hemorrhage: a prospective study of diagnostic
outcome. Ann Neurol 2014;75(5):771-781.
accuracy. Ann Neurol 2018;83(5):958-969.
doi:10.1002/ana.24166
doi:10.1002/ana.25232

CONTINUUMJOURNAL.COM 1341

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

SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU
68 Muniz CF, Shenoy AV, O'Connor KL, et al. Clinical
development and implementation of an
institutional guideline for prospective EEG
monitoring and reporting of delayed cerebral
ischemia. J Clin Neurophysiol 2016;33(3):217-226.
doi:10.1097/WNP.0000000000000281
69 Lissak IA, Locascio JJ, Zafar SF, et al.
Electroencephalography, hospital complications,
and longitudinal outcomes after subarachnoid
hemorrhage. Neurocrit Care 2021;1-12.
doi:10.1007/s12028-020-01177-x
70 Hartings JA, Shuttleworth CW, Kirov SA, et al. The
continuum of spreading depolarizations in acute
cortical lesion development: examining Leao's
legacy. J Cereb Blood Flow Metab 2017;37(5):
1571-1594. doi:10.1177/0271678X16654495
71 Dreier JP, Fabricius M, Ayata C, et al. Recording,
analysis, and interpretation of spreading
depolarizations in neurointensive care: review
and recommendations of the COSBID research
group. J Cereb Blood Flow Metab 2017;37(5):
1595-1625. doi:10.1177/0271678X16654496
72 Drenckhahn C, Winkler MK, Major S, et al.
Correlates of spreading depolarization in human
scalp electroencephalography. Brain 2012;
135(pt 3):853-868. doi:10.1093/brain/aws010
73 Hartings JA, Watanabe T, Bullock MR, et al.
Spreading depolarizations have prolonged direct
current shifts and are associated with poor
outcome in brain trauma. Brain 2011;134(pt 5):
1529-1540. doi:10.1093/brain/awr048
74 Strong AJ, Macdonald RL. Cortical spreading
ischemia in the absence of proximal vasospasm
after aneurysmal subarachnoid hemorrhage:
evidence for a dual mechanism of delayed
cerebral ischemia. J Cereb Blood Flow Metab
2012;32(2):201-202. doi:10.1038/jcbfm.2011.170
75 Drenckhahn C, Windler C, Major S, et al.
Complications in aneurysmal subarachnoid
hemorrhage patients with and without subdural
electrode strip for electrocorticography. J Clin
Neurophysiol 2016;33(3):250-259.
doi:10.1097/WNP.0000000000000274
76 Hartings JA, Andaluz N, Bullock MR, et al.
Prognostic value of spreading depolarizations in
patients with severe traumatic brain injury.
JAMA Neurol 2020;77(4):489-499.
doi:10.1001/jamaneurol.2019.4476
77 Hertle DN, Dreier JP, Woitzik J, et al. Effect of
analgesics and sedatives on the occurrence of
spreading depolarizations accompanying acute
brain injury. Brain 2012;135(pt 8):2390-2398.
doi:10.1093/brain/aws152
78 Sanchez-Porras R, Santos E, Scholl M, et al. The
effect of ketamine on optical and electrical
characteristics of spreading depolarizations in
gyrencephalic swine cortex.
Neuropharmacology 2014;84:52-61.
doi:10.1016/j.neuropharm.2014.04.018
1342
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
79 Sanchez-Porras R, Zheng Z, Sakowitz OW.
Pharmacological modulation of spreading
depolarizations. Acta Neurochir Suppl 2015;120:
153-157. doi:10.1007/978-3-319-04981-6_26
80 Sanchez-Porras R, Santos E, Scholl M, et al.
Ketamine modulation of the haemodynamic
response to spreading depolarization in the
gyrencephalic swine brain. J Cereb Blood Flow
Metab 2017;37(5):1720-1734.
doi:10.1177/0271678X16646586
81 Carlson AP, Abbas M, Alunday RL, et al.
Spreading depolarization in acute brain injury
inhibited by ketamine: a prospective,
randomized, multiple crossover trial. J Neurosurg
2018;1-7. doi:10.3171/2017.12.JNS171665
82 Reinhart KM, Shuttleworth CW. Ketamine
reduces deleterious consequences of spreading
depolarizations. Exp Neurol 2018;305:121-128.
doi:10.1016/j.expneurol.2018.04.007
83 Santos E, Olivares-Rivera A, Major S, et al. Lasting
s-ketamine block of spreading depolarizations in
subarachnoid hemorrhage: a retrospective
cohort study. Crit Care 2019;23(1):427.
doi:10.1186/s13054-019-2711-3
84 Mohammad LM, Abbas M, Shuttleworth CW,
et al. Spreading depolarization may represent a
novel mechanism for delayed fluctuating
neurological deficit after chronic subdural
hematoma evacuation. J Neurosurg 2020;1-9.
doi:10.3171/2020.1.JNS192914
85 Kimchi EY, Neelagiri A, Whitt W, et al. Clinical
EEG slowing correlates with delirium severity
and predicts poor clinical outcomes.
Neurology 2019;93(13):e1260-e1271.
doi:10.1212/WNL.0000000000008164
86 Edlow BL, Chatelle C, Spencer CA, et al. Early
detection of consciousness in patients with
acute severe traumatic brain injury. Brain 2017;
140(9):2399-2414. doi:10.1093/brain/awx176
87 Chatelle C, Rosenthal ES, Bodien YG, et al. EEG
correlates of language function in traumatic
disorders of consciousness. Neurocrit Care
2020;33(2):449-457. doi:10.1007/s12028-019-
00904-3
88 Claassen J, Doyle K, Matory A, et al. Detection of
brain activation in unresponsive patients with
acute brain injury. N Engl J Med 2019;380(26):
2497-2505. doi:10.1056/NEJMoa1812757
89 Malinowska U, Chatelle C, Bruno MA, et al.
Electroencephalographic profiles for
differentiation of disorders of consciousness.
Biomed Eng Online 2013;12:109.
doi:10.1186/1475-925X-12-109
90 Lesenfants D, Habbal D, Chatelle C, et al. Toward
an attention-based diagnostic tool for patients
with locked-in syndrome. Clin EEG Neurosci 2018;
49(2):122-135. doi:10.1177/1550059416674842
91 Greer DM, Rosenthal ES, Wu O.
Neuroprognostication of hypoxic-ischaemic
coma in the therapeutic hypothermia era.
Nat Rev Neurol 2014;10(4):190-203. doi:10.1038/
nrneurol.2014.36
OCTOBER 2021
92 Hofmeijer J, Tjepkema-Cloostermans MC, van
Putten MJ. Burst-suppression with identical
bursts: a distinct EEG pattern with poor outcome
in postanoxic coma. Clin Neurophysiol 2014;
125(5):947-954. doi:10.1016/j.clinph.2013.10.017
93 Amorim E, Rittenberger JC, Zheng JJ, et al.
Continuous EEG monitoring enhances
multimodal outcome prediction in
hypoxic-ischemic brain injury.
Resuscitation 2016;109:121-126.
doi:10.1016/j.resuscitation.2016.08.012
94 Solanki P, Coppler PJ, Kvaloy JT, et al. Association
of antiepileptic drugs with resolution of
epileptiform activity after cardiac arrest.
Resuscitation 2019;142:82-90.
doi:10.1016/j.resuscitation.2019.07.007
95 Tjepkema-Cloostermans MC, van Meulen FB,
Meinsma G, van Putten MJAM. A Cerebral
Recovery Index (CRI) for early prognosis in
patients after cardiac arrest. Crit Care 2013;17(5):
R252. doi:10.1186/cc13078
96 Ghassemi MM, Amorim E, Pati SB, et al. An
enhanced Cerebral Recovery Index for coma
prognostication following cardiac arrest. Annu
Int Conf IEEE Eng Med Biol Soc 2015;2015:
534-537. doi:10.1109/EMBC.2015.7318417
97 Tjepkema-Cloostermans MC, Hofmeijer J,
Beishuizen A, et al. Cerebral Recovery Index:
reliable help for prediction of neurologic
outcome after cardiac arrest. Crit Care Med 2017;
45(8):e789-e797. doi:10.1097/
CCM.0000000000002412
98 Nagaraj SB, Tjepkema-Cloostermans MC, Ruijter
BJ, et al. The revised Cerebral Recovery Index
improves predictions of neurological outcome
after cardiac arrest. Clin Neurophysiol 2018;
129(12):2557-2566. doi:10.1016/j.clinph.2018.10.004
99 Ghassemi MM, Amorim E, Alhanai T, et al.
Quantitative electroencephalogram trends
predict recovery in hypoxic-ischemic
encephalopathy. Crit Care Med 2019;47(10):
1416-1423. doi:10.1097/CCM.0000000000003840
CONTINUUMJOURNAL.COM
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
100 Purandare M, Ehlert AN, Vaitkevicius H, et al. The
role of cEEG as a predictor of patient outcome
and survival in patients with intraparenchymal
hemorrhages. Seizure 2018;61:122-127.
doi:10.1016/j.seizure.2018.08.014
101 Vespa PM, Olson DM, John S, et al. Evaluating
the clinical impact of rapid response
electroencephalography: the DECIDE
Multicenter Prospective Observational Clinical
Study. Crit Care Med 2020;48(9):1249-1257.
doi:10.1097/CCM.0000000000004428
102 Treiman DM, Walton NY, Kendrick C. A
progressive sequence of
electroencephalographic changes during
generalized convulsive status epilepticus.
Epilepsy Res 1990;5(1):49-60. doi:10.1016/0920-
1211(90)90065-4
103 Swisher CB, Sinha SR. Utilization of quantitative
EEG trends for critical care continuous EEG
monitoring: a survey of neurophysiologists.
J Clin Neurophysiol 2016;33(6):538-544.
doi:10.1097/WNP.0000000000000287
104 Fatuzzo D, Beuchat I, Alvarez V, et al. Does
continuous EEG influence prognosis in patients
after cardiac arrest? Resuscitation 2018;132:
29-32. doi:10.1016/j.resuscitation.2018.08.023
105 Rossetti AO, Schindler K, Sutter R, et al.
Continuous vs routine electroencephalogram in
critically ill adults with altered consciousness
and no recent seizure: a multicenter randomized
clinical trial. JAMA Neurol 2020;77(10):1-8.
doi:10.1001/jamaneurol.2020.2264
106 Hill CE, Blank LJ, Thibault D, et al. Continuous EEG
is associated with favorable hospitalization
outcomes for critically ill patients.
Neurology 2019;92(1):e9-e18.
doi:10.1212/WNL.0000000000006689
1343