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Review Article

Status Epilepticus
Address correspondence to
Dr Sara E. Hocker, Mayo Clinic,
200 First Street SW, Rochester,
MN 55905,
hocker.sara@mayo.edu. Sara E. Hocker, MD
Relationship Disclosure:
Dr Hocker has received
personal compensation for
travel and accommodation ABSTRACT
expenses from the
London-Innsbruck Colloquium Purpose of Review: Status epilepticus, which is simultaneously a neurologic and
on Status Epilepticus and systemic emergency, often results in significant disability and may be fatal. This article
Acute Seizures, and presents a pragmatic approach to the evaluation and management of status epilepticus
Dr Hockers institution receives
compensation for her work in adults for the practicing clinician.
as a consultant on the data Recent Findings: Rapid recognition, treatment respecting a written protocol, and
and safety monitoring board careful attention to potential complications may limit sequelae. Studies aimed at earlier
of SAGE Therapeutics.
identification of etiologies in cryptogenic status epilepticus and improving the treat-
Unlabeled Use of
Products/Investigational ment of established status epilepticus are urgently needed to limit the development
Use Disclosure: of refractoriness.
Dr Hocker discusses the Summary: This article reviews the guidelines and up-to-date information on the
unlabeled/investigational use
of lacosamide, levetiracetam, use of both pharmacologic and nonpharmacologic therapies in status epilepticus and
midazolam, propofol, and discusses the shifts in our understanding of the balance between the need for
valproate sodium for the aggressive control of seizures and the risks of treatment. This article also presents a
treatment of status epilepticus.
* 2015, American Academy
suggested approach to the evaluation and management of common types of status
of Neurology. epilepticus and explores future directions.

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INTRODUCTION CLASSIFICATION
Status epilepticus was initially defined by Several classification systems of status
the International League Against Epilepsy epilepticus have been proposed but none
as a seizure that persists for a sufficient have been officially adopted, leading to a
length of time or is repeated frequently number of redundant terms. Generalized
enough that recovery between attacks tonic-clonic status epilepticus is synony-
does not occur.1 Status epilepticus is mous with convulsive status epilepticus.
operationally defined as continuous sei- Nonconvulsive status epilepticus may be
zures lasting at least 5 minutes or recur- broadly divided into generalized non-
rent seizures without complete recovery convulsive status epilepticus and focal
nonconvulsive status epilepticus.7 Gen-
of consciousness between seizures.2 This
eralized nonconvulsive status epilepticus
definition is endorsed by published guide-
is also called electrographic status epi-
lines.3,4 Status epilepticus is both a neu-
lepticus in coma or status in coma, and
rologic and a medical emergency with
focal nonconvulsive status epilepticus is
the potential for significant morbidity also traditionally referred to as simple or
and mortality. The evaluation and man- complex partial status epilepticus. The
agement of status epilepticus in children terms simple and complex refer to the
and infants will not be discussed within preservation and alteration of conscious-
the scope of this review but have been ness, respectively. Another very specific
recently extensively described else- form of focal status epilepticus is epi-
where.5,6 This article presents a prac- lepsia partialis continua, defined as a
tical and up-to-date approach to the continuous clonic muscle twitching of
evaluation and management of status cerebral origin confined to one part of
epilepticus in adults. the body. Epilepsia partialis continua is
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KEY POINTS
not typically accompanied by impair- seizures. They are often prolonged and, h Status epilepticus is
ment of consciousness or dyscognitive thus, can mimic epileptic status epilepti- operationally defined as
features. The Neurocritical Care Society cus. Recognition of nonepileptic status continuous seizures
has recommended classifying status epi- epilepticus is challenging for even exper- lasting at least
lepticus simply as convulsive or non- ienced clinicians as no individual feature 5 minutes or recurrent
convulsive, and this article will respect is sensitive for or specific to the diagno- seizures without
that guideline but also will differenti- sis. Psychogenic status epilepticus should complete recovery of
ate nonconvulsive status epilepticus be considered when: (1) convulsions are consciousness
into focal or generalized nonconvulsive prolonged without accompanying signs between seizures.
status epilepticus.4 Myoclonic status epi- of sympathetic activation, (2) convulsions h The Neurocritical Care
lepticus typically occurs after anoxic- have a start-stop-start quality, (3) bilateral Society has
ischemic injury in the setting of cardiac convulsions are present with preserved recommended
arrest, hanging, or drowning and man- consciousness, (4) pelvic thrusting, ictal classifying status
ifests clinically as sudden brief move- eye closure, ictal crying, or asynchronous epilepticus simply as
ments of the face, trunk, or extremities, or side-to-side head or body movements convulsive
or nonconvulsive.
typically in the setting of coma. The move- are present, or (5) postictal confusion is
ments of a patient with myoclonic status absent between or after convulsions.8 If h Psychogenic status
epilepticus are characteristically arrhyth- mistaken for convulsive status epilepticus, epilepticus should be
mic, multifocal, and triggered or exacer- aggressive treatment of nonepileptic considered when: (1)
convulsions are
bated by external stimuli such as physical status epilepticus may result in signifi-
prolonged without
examination or mechanical ventilation. cant iatrogenic complications. A sim-
accompanying signs of
Nonepileptic, or psychogenic, seizures plification of the classification of status sympathetic activation,
are a psychogenically determined phe- epilepticus is shown in Figure 6-1. The (2) convulsions have a
nomenon in which patients experience remainder of this article will focus on start-stop-start quality,
sudden paroxysmal disturbances of mo- convulsive status epilepticus and both (3) bilateral convulsions
tor, sensory, autonomic, cognitive, or focal and generalized nonconvulsive are present with
emotional functions that mimic epileptic status epilepticus. preserved consciousness,
(4) pelvic thrusting, ictal
eye closure, ictal crying,
or asynchronous or
side-to-side head or body
movements are present,
or (5) postictal confusion
is absent between or
after convulsions.

FIGURE 6-1 Classification of status epilepticus.


NCSE = nonconvulsive status epilepticus.

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Status Epilepticus

KEY POINT
h Patients with prior PATHOPHYSIOLOGY two antiepileptic drugs (AEDs), ranges
epilepsy, elderly Status epilepticus occurs when mecha- from 23% to 48%.18Y20,23Y26 While still
patients, and patients nisms that normally abort a seizure fail, underrecognized, nonconvulsive status
with sepsis are at either because of excessive excitation epilepticus probably affects up to 10%
highest risk for the or ineffective inhibition. Increased ex- of patients with altered mental status27
development of citation can occur as a result of increased and 16% of confused elderly patients in
nonconvulsive glutamate or glutamate analogues, or the hospital.28 Patients with prior epi-
status epilepticus. an increase in other excitatory amino lepsy, elderly patients, and patients with
acids. Decreased inhibition results from sepsis are at highest risk for the develop-
decreased +-aminobutyric acid (GABA), ment of nonconvulsive status epilepticus.
the primary inhibitory neurotransmitter Outcomes are usually worse in pa-
of the brain. GABA-A receptors change tients with status epilepticus of long du-
in number and sensitivity during the ration and those who are medically ill or
course of status epilepticus,9 a phe- have systemic complications. However,
nomenon that has implications for the strongest factor influencing outcome
treatment as drugs that act on GABA is etiology. Common etiologies typically
receptors may be effective early, but fall into one of twelve broad categories
not late, in the course of status epil- (Table 6-1).15,22 Examples of etiologies
epticus. More recently, N-methyl-D- in the other known category include
aspartate (NMDA) receptors have been posterior reversible encephalopathy syn-
shown to accumulate rapidly and in- drome (PRES), prion disease, and electro-
crease glutaminergic excitation during convulsive therapy (ECT), among others.29
status epilepticus. This also has implica-
tions for treatment, as drugs that directly DIAGNOSIS
antagonize NMDA receptors may be The diagnosis of convulsive status
more effective in later stages of status epilepticus is straightforward. The tonic
epilepticus.10 There are likely many other phase is initially prolonged, and the
mechanisms that contribute to the de- clonic movements are violent. The con-
velopment and refractoriness of status vulsive phase is accompanied by a mas-
epilepticus, including mitochondrial sive sympathetic outpouring manifested
failure,11 inflammatory processes result- by pupillary dilatation, tachycardia, hy-
ing in an impaired blood-brain barrier,12Y14 pertension, hyperglycemia, and increased
and changes in gene expression. cerebral blood flow. As status epilepticus
continues, the tonic phase shortens as
EPIDEMIOLOGY the clonic movements disperse and ulti-
The incidence of status epilepticus is mately disappear, sometimes with on-
reported to be between 18 and 41 pa- going nonconvulsive seizure activity. This
tients per year per 100,000 popula- is referred to as subtle status epilepticus
tion.15Y17Approximately 31% to 43% of and is accompanied by metabolic failure
status epilepticus episodes will become with decreased cardiac output, hypogly-
refractory.18Y20 Predictors of refractori- cemia, and decreased cerebral blood
ness include nonconvulsive status epilep- flow.30 To exclude a diagnosis of subtle
ticus, focal motor seizures at onset, and status epilepticus, an EEG should be
delayed diagnosis and treatment.18,19 The obtained if the patient has not returned
mortality of status epilepticus ranges from to his or her baseline within 10 to
19% to 26% and rises with increasing 20 minutes of the cessation of tonic-
age.15,21,22 Mortality of refractory status clonic activity (Case 6-1).
epilepticus, defined as status epilepticus If convulsive activity never occurred
that persists despite administration of or was not observed, identification of
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KEY POINT
status epilepticus in adults appears in h Critically ill adults who
TABLE 6-1 Potential Etiologies several clinically distinguishable forms:
of Status Epilepticus are stuporous or
& Stupor or coma in the setting of a comatose without an
b Anoxic-Ischemic Injury substrate (cerebral atrophy, alternative explanation
medical illness, acute brain injury, require at least a routine
b Antibody Mediated
or exposure to or withdrawal EEG to exclude
Autoimmune from a drug), with generalized nonconvulsive status
epilepticus. If
Paraneoplastic electrographic epileptic activity
epileptiform activity is
b Brain Tumor & Focal nonconvulsive status identified on routine
epilepticus with secondary EEG, the patient should
Metastatic
generalization in which confusion undergo continuous
Primary progresses to stupor or coma, EEG monitoring of
b CNS Infection with generalized electrographic at least several
epileptic activity hours duration.
Abscess/empyema
Meningitis
& Generalized tonic-clonic status
epilepticus that persists until
Viral encephalitis clonic movements disperse and
b Congenital/Hereditary ultimately disappear, despite
persistent electrographic epileptic
b Drug or Alcohol
activity; also called end-stage or
Intoxication subtle status epilepticus
Withdrawal Critically ill adults who are stuporous
b Low Antiepileptic Drug or comatose without an alternative ex-
Levels or Change in planation require at least a routine EEG to
Antiepileptic Drug Regimen exclude nonconvulsive status epilepticus.
b Metabolic Disturbance If epileptiform activity is identified on
routine EEG, the patient should undergo
Acidosis
continuous EEG monitoring of at least
Electrolyte imbalance several hours duration. Examples of this
Hypoglycemia or situation include patients with treated
hyperglycemia severe sepsis who are slow to recover
Organ failure consciousness and those with acute brain
injury who have impaired conscious-
b Other Known Etiologies
ness out of proportion to what would be
That Do Not Fit Into Other
Defined Categories expected based on the severity of the
brain injury.
b Stroke
Focal nonconvulsive status epilepticus
Hemorrhagic is sometimes difficult to recognize as its
Ischemic clinical presentation is highly variable.
Any behavioral, cognitive, sensory, auto-
b Trauma
nomic, or motor function the brain is
b Unknown (Cryptogenic) capable of performing can be observed
CNS = central nervous system. during a focal nonconvulsive seizure or
status epilepticus. The patient is typically
awake and confused and may appear to
generalized nonconvulsive status have somewhat automatic behavior, such
epilepticus requires a high index of as walking or performing simple tasks
suspicion. Generalized nonconvulsive repetitively (eg, turning the faucet on

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Status Epilepticus

Case 6-1
A 61-year-old man with a history of developmental delay and well-controlled epilepsy resulting from a
remote left parietooccipital intraparenchymal hemorrhage was brought to the hospital by his nurse
after developing perseverative speech and irritability followed by several prolonged convulsions,
after which he did not recover consciousness. He had a witnessed generalized tonic-clonic seizure on
arrival to the emergency department and was treated with 4 mg of lorazepam with resolution of
the tonic-clonic activity. He then apparently lost his ability to protect his airway and was intubated
with propofol and rocuronium, after which a stat CT scan was obtained and showed only encephalomalacia
from his prior hemorrhage. On arrival to the neurocritical care unit, he was sedated with propofol and
had subtle eyelid twitching and multifocal arrhythmic myoclonic jerks. The patient exhibited no gaze
deviation or nystagmus. He was treated with an additional 4 mg of lorazepam, and EEG revealed that he
was in subtle status epilepticus. He was then loaded with 20 mg phenytoin equivalents per kg
fosphenytoin, after which the status epilepticus resolved, leaving a polymorphic delta frequency
background. His seizures were previously controlled with levetiracetam 1250 mg 2 times a day so an
additional 1000 mg of levetiracetam was administered empirically after sending blood for a level. Upon
further review with his home nurse, it was discovered that he had had a recent upper respiratory tract
infection and also had recently broken up with his girlfriend. This had produced significant stress and
anxiety, which he was self-treating with extra doses of risperidone (originally prescribed for bipolar disorder).
His levetiracetam level returned at less than 2.0 mcg/mL. Both levetiracetam and fosphenytoin were
continued initially, and he was ultimately discharged home in 3 days on levetiracetam 1500 mg 2 times a day.
Comment. This patient presented with convulsive status epilepticus, and although the convulsions
stopped after administration of lorazepam, he was subsequently sedated and paralyzed for intubation,
impeding clinical monitoring. In this situation, obtaining an emergent EEG despite the resolution of
clinical convulsions is imperative to ensure that the patient has not evolved into nonconvulsive status
epilepticus. While this patient had continued clinical signs of ongoing seizures, electrographic status
epilepticus can occur in the absence of any clinical correlate other than altered consciousness. The
recurrence of multifocal myoclonic jerks was likely a reflection of partial neuromuscular blockade as
the rocuronium cleared. This patients status epilepticus resulted from overuse of risperidone and a
recent respiratory infection, both of which may have lowered the seizure threshold in the setting of
medication noncompliance.

KEY POINT and off). Additional common manifes- The primary aims of the initial evaluation
h The diagnosis of both tations include unresponsiveness, are: (1) stabilization and prevention of
focal and generalized speech arrest, stereotyped automatisms secondary neuronal injury, (2) identifi-
nonconvulsive status cation of acute brain injury or significant
and eye deviation, nystagmus, or blink-
epilepticus requires
ing. The diagnosis of both focal and metabolic derangements that may have
clinical suspicion, EEG
confirmation, and both generalized nonconvulsive status epi- precipitated or contributed to the de-
clinical and lepticus requires clinical suspicion, EEG velopment of status epilepticus, and (3)
electrographic confirmation, and both clinical and elec- screening for markers of systemic injury
improvements following trographic improvements following a to help the clinician anticipate what may
a trial of a fast-acting trial of a fast-acting AED (Table 6-231,32). happen next.
antiepileptic drug. Indications for emergent EEG are listed The priority in the management of
in Table 6-3. status epilepticus, as with any medical
or neurologic emergency, is to ensure
MANAGEMENT OF STATUS that the patients are protecting their
EPILEPTICUS airway, oxygenating and ventilating ad-
Emergency Investigations equately, and hemodynamically stable.
The evaluation and management of status Check a blood sugar and administer
epilepticus must occur simultaneously. thiamine followed by glucose if the

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a
TABLE 6-2 Criteria for the Diagnosis of Nonconvulsive Status Epilepticus

Alteration in consciousness Q5 minutes and any pattern satisfying any of the primary criteria for Q5 minutes
b Primary Criteria
1. Repetitive generalized or focal spikes, sharp waves, spike-and-wave complexes at 3/s.
2. Repetitive generalized or focal spikes, sharp waves, spike-and-wave or sharp-and-slow wave complexes
at 2/s and the secondary criterion.
3. Sequential, rhythmic periodic, or quasiperiodic waves at 1/s and unequivocal evolution in frequency
(gradually increasing or decreasing by at least 1/s, eg, 2/s to 3/s), morphology, or location (gradual
spread into or out of a region involving at least two electrodes). Evolution in amplitude alone is
not sufficient.
b Secondary Criterion
Significant improvement in clinical state or appearance of previously absent normal EEG patterns (such as
posterior-dominant alpha rhythm) temporally coupled to acute administration of rapidly acting antiepileptic
drug. Resolution of the epileptiform discharges leaving diffuse slowing without clinical improvement and
without appearance of previously absent normal EEG patterns would not satisfy the secondary criterion.
a
Data from Young GB, et al, Neurology.31 www.neurology.org/content/47/1/83.short; Chong DJ, Hirsch LJ, J Clin Neurophysiol.32
journals.lww.com/clinicalneurophys/Abstract/2005/04000/Which_EEG_Patterns_Warrant_Treatment_in_the.1.aspx.

a
TABLE 6-3 Indications for Emergent EEG

Neurocritical Care Society


Indication Rationale Guidelines 2012b
Suspected seizures in patients Exclude nonconvulsive status Class I, Level B
with unexplained coma or altered epilepticus
mental status
Otherwise unexplained focal neurologic Exclude nonconvulsive status No recommendation
deficits (eg, aphasia or focal weakness) epilepticus
Recent clinical seizure activity or status Exclude nonconvulsive status Class I, Level B
epilepticus without return to baseline epilepticus; titrate anesthetic
within 10 minutes agent to cessation of electrographic
seizures; monitor for breakthrough
subclinical seizures
Clinical seizure activity is of a Confirm status epilepticus; exclude No recommendation
start-stop-start quality nonepileptic (psychogenic) status
epilepticus
EEG = electroencephalography.
a
Data from Brophy GM, et al, Neurocrit Care.4 link.springer.com/article/10.1007/s12028-012-9695-z.
b
Neurocritical Care Society guidelines use the evidence rating system of the American Heart Association/American College of Cardiology
guidelines:
Class I: Intervention is useful and effective. Treatment benefits clearly exceed risks.
Class IIa: Evidence/expert opinions suggest intervention is useful/effective. Treatment benefits exceed risk.
Class IIb: Strength of evidence/expert opinion about intervention usefulness/effectiveness is less well established. More data are needed;
however, using this treatment when warranted is not unreasonable.
Level A: Adequate evidence is available from multiple, large, randomized clinical trials or meta-analyses
Level B: Limited evidence is available from less rigorous data, including fewer, smaller, randomized trials, nonrandomized studies, and
observational analyses.
Level C: Evidence relies on expert/consensus opinion, case reports, or standard of care.

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Status Epilepticus

KEY POINT
h The threshold to obtain blood sugar is low. If present, fever
should be controlled with acetamino- TABLE 6-4 Initial Laboratory
a lumbar puncture Evaluation in Status
should be low in phen, cooling blankets, and ice packs Epilepticus
patients with epilepsy under the axilla and over the femoral
who have infrequent arteries in the groin. Hypoxemia, hypo- b Etiologic Investigation
breakthrough seizures tension, hypoglycemia, and fever may Glucose
and no alternative each contribute to secondary neuronal
etiology identified for Antiepileptic drug levels
injury by reducing substrate delivery or
their status epilepticus,
increasing metabolic demand. Acid-base disturbances
after obtaining a history,
basic laboratory
The etiology of status epilepticus may Arterial blood gas
investigation, and be readily established in the majority of
Basic metabolic panel
neuroimaging. The cases using a straightforward and step-
wise approach. All patients require a Lactic acid
threshold for lumbar
puncture should be focused history, physical examination, Acute organ failure
even lower in a patient neuroimaging with a noncontrast CT scan Creatinine
presenting with status of the head, and basic laboratory testing
epilepticus with no Blood urea nitrogen
specifically to exclude major acid-base
history of seizures Transaminases (aspartate
disturbances, electrolyte imbalances,
or epilepsy. and alanine aminotransferase)
acute organ failure, and intoxications
(Table 6-4). In patients with known epi- Ammonia
lepsy, AED levels should also be obtained. Electrolyte imbalances
In some cases, the etiology will be readily
Calcium
apparent at this stage. The threshold to
obtain a lumbar puncture should be low Magnesium
in patients with epilepsy who have infre- Phosphorus
quent breakthrough seizures and no Intoxications
alternative etiology for their status epile-
Alcohol level
pticus identified after obtaining a history,
basic laboratory investigation, and neu- Adulterant survey
roimaging. The threshold for a lumbar b Systemic Injury Screening
puncture should be even lower in a pa- Creatine kinase
tient presenting with status epilepticus
Troponin
with no history of seizures or epilepsy.
Any patient with antecedent infectious b CSF (As Indicated)
symptoms or language difficulties, either Cell count
fever or hypothermia, or a suppressed im- Glucose
mune system should undergo CSF analy-
Protein
sis to exclude CNS infection (Table 6-4).
Once an etiology is established, it must Gram stain and bacterial
be immediately corrected. A thorough culture
discussion of the management of vari- Herpes simplex virus PCRa
ous etiologies is beyond the scope of CSF = cerebrospinal fluid; PCR =
this review. It is important to note, how- polymerase chain reaction.
a
ever, that management of any etiology Testing for other infectious agents
may be indicated depending on the
should avoid the use of agents that may clinical scenario.
themselves precipitate seizures or status
epilepticus or lower the threshold for
seizure generation. Common culprits

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KEY POINT
are fluroquinolone antibiotics, often used patient with stress-induced cardiomy- h The majority of patients
in the emergency setting for empiric opathy) (Table 6-5). with de novo status
treatment of community-acquired infec- epilepticus (no prior
Advanced Investigations
tions. Less common examples include history of epilepsy)
cefepime, a third-generation cephalospo- In most cases, the etiology will be es- without a readily
rin frequently used for hospital-acquired tablished after the initial history, labo- identifiable cause
infections, and carbapenems such as ratory evaluation, CT scan, and lumbar become refractory.
meropenem and imipenem. Similarly, if puncture. When the etiology is not
the status epilepticus is thought to be established, the episode of status epi-
caused by drug withdrawal, either recre- lepticus is considered cryptogenic pend-
ational or prescription, the drug should ing further investigations. The majority
be immediately replaced, if possible, by of patients with de novo status epilep-
a parenteral route. ticus (no prior history of epilepsy) with-
The next aim is to screen for systemic out a readily identifiable cause become
injury. Systemic complications in status refractory. Thus, the term new-onset re-
epilepticus involve primarily cardiopul- fractory status epilepticus (NORSE) was
monary, renal, and musculoskeletal in- coined to describe this group of patients
juries. A careful screening physical and who share certain commonalities and yet
laboratory examination can alert the are often found to have varying etiologies.
clinician to systemic complications, pro- Ultimately, many cases of cryptogenic sta-
viding a chance to prevent resultant mor- tus epilepticus and NORSE can be ex-
bidity (eg, from delayed treatment of plained after thorough investigation. A
aspiration pneumonia) or iatrogenic suggested approach to the evaluation
complications from unnecessary inves- of cryptogenic status epilepticus and
tigations (eg, coronary angiography in a NORSE is detailed in Table 6-633 and

TABLE 6-5 Systemic Complications of Status Epilepticus

Screening Diagnostic Tool Systemic Complication Resultant Morbidity


Physical examination Musculoskeletal injuries Bone fractures, bone dislocations,
intracranial hemorrhage, drug
rashes
Urine output and creatine kinase Renal injury Renal failure
Acute tubular necrosis
Rhabdomyolysis
Troponin, ECG Cardiac injury Cardiogenic shock, arrhythmias,
hypoxemia
NonYST-elevation myocardial infarction
Stress-induced cardiomyopathy
Cardiogenic pulmonary edema

Chest x-ray, auscultation of Pulmonary injury Hypoxemia, acute respiratory


the lungs distress syndrome, sepsis
Aspiration
Neurocardiogenic pulmonary edema
Mucous plugging

ECG = electrocardiogram.

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Status Epilepticus

TABLE 6-6 Authors Suggested Approach to the Etiologic Evaluation of Cryptogenic Status
Epilepticus and New-Onset Refractory Status Epilepticus

Diagnostic Test Consider In


Imaging
Brain MRI Patients in whom an etiology is not established after
history, basic laboratory evaluation, brain CT scan,
and lumbar puncture (LP)

)
Chest/abdomen/pelvis CT Patients in whom an etiology is not established after
history, basic laboratory evaluation, brain CT scan,
LP, and brain MRI
Ovarian or testicular ultrasound Patients in whom an etiology is not established after
history, basic laboratory evaluation, head CT scan,
LP, brain MRI, and chest/abdomen/pelvis CT

CSF33
Cell count, glucose, protein, Gram stain
Cytology and flow cytometry
Microbiologic serologies, PCRs, Gram stain and
cultures: herpes simplex virus types 1 and 2,
varicella-zoster virus, Epstein-Barr virus,
cytomegalovirus, human herpes virus 6, enterovirus,
influenza, adenovirus, JC virus, measles, HIV, hepatitis
C virus, West Nile virus, Japanese encephalitis virus,
St Louis encephalitis virus, eastern equine
encephalomyelitis virus, western equine
encephalomyelitis virus, California group virus, Cache Patients in whom an etiology is not established after
Valley virus, Mycoplasma pneumoniae, Mycobacterium history, basic laboratory evaluation, head CT scan,
tuberculosis, Chlamydia species, Bartonella henselae, LP, and brain MRI
cryptococcal antigen, syphilis (rapid plasma reagin),
AND
toxoplasmosis, malaria, Lyme
b Patients in whom history of present illness,
CSF exclusive oligoclonal bands, IgG index
demographics, exposure history, comorbidities, and
and synthesis
family history are potentially suggestive of the
Radioimmunoprecipitation assay: GAD65 diagnosis under consideration
antibody, VGKC antibody
Immunofluorescence assay (tissue immunofluorescence):
ANNA-1, ANNA-2, ANNA-3, PCA-1, PCA-2, PCA-Tr,
amphiphysin antibody, CRMP-5-IgG, AGNA-1
Immunofluorescence assay (cell-binding
immunofluorescence): NMDA receptor antibody,
AMPA receptor antibody, GABA-B receptor antibody
Neuromyelitis optica (aquaporin-4 IgG)
cell-binding assay
Anti-Ma 1 and Anti-Ma 2/Ta antibody
14-3-3 protein
Continued on page 1371

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Diagnostic Test
Serum 33

Microbiologic serologies, PCRs, and cultures: herpes


simplex virus types 1 and 2, varicella-zoster virus,
Epstein-Barr virus, cytomegalovirus, influenza,
adenovirus, JC virus, measles, HIV, hepatitis C virus,
West Nile virus, Japanese encephalitis virus, St Louis
encephalitis virus, eastern equine encephalomyelitis
)
TABLE 6-6 Authors Suggested Approach to the Etiologic Evaluation of Cryptogenic Status
Epilepticus and New-Onset Refractory Status Epilepticus Continued from page 1370

Consider In

virus, western equine encephalomyelitis virus,


Mycoplasma pneumoniae, Chlamydia species,
Bartonella henselae, cryptococcal antigen, syphilis
(rapid plasma reagin ), toxoplasmosis, malaria, Lyme
Nonparaneoplastic autoantibodies: ANA,
double-stranded DNA, lupus anticoagulant,
antiphospholipid, rheumatoid factor, SSA, SSB, ANCA,
thyroid peroxidase, thyroglobulin, transglutaminase,
antigliadin, endomysium
Angiotensin-converting enzyme Patients in whom an etiology is not established
after history, basic laboratory evaluation, CT scan,
Paraneoplastic antibody panel: AchR binding, Anti-Hu LP, and MRI
(ANNA-1), Anti-Ri (ANNA-2), striated muscle, AchR b AND
ganglionic, P/Q-type voltage-gated calcium channel
antibodies, N-type voltage-gated calcium channel Patients in whom history of present illness,
antibody, Anti-Yo (ANNA-3), AGNA-1, PCA-1, PCA-2, demographics, exposure history, comorbidities,
PCA-Tr, amphiphysin, CRMP-5/CV2, VGKC, NMDA and family history are potentially suggestive
Radioimmunoprecipitation assay: P/Q-type calcium of the diagnosis under consideration
channel antibody, N-type calcium channel antibody,
muscle AchR binding antibody, ganglionic AchR
antibody, VGKC antibody, GAD65 antibody
Immunofluorescence assay (tissue immunofluorescence):
ANNA-1, ANNA-2, ANNA-3, PCA-1, PCA-2, PCA-Tr,
amphiphysin antibody, CRMP-5-IgG, AGNA-1
Immunofluorescence assay (cell-binding
immunofluorescence): NMDA receptor antibody,
AMPA receptor antibody, GABA-B receptor antibody
Porphyrins
Heavy metals
Genetic testing (mitochondrial disorders such as POLG1)
Whole body PET scan Patients in whom the above evaluation is nondiagnostic
Angiogram Patients in whom brain MRI, CSF analysis, and/or
serum laboratory evaluation are suggestive of vasculitis

Continued on page 1372

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Status Epilepticus

TABLE 6-6 Authors Suggested Approach to the Etiologic Evaluation of Cryptogenic Status
Epilepticus and New-Onset Refractory Status Epilepticus Continued from page 1371

Diagnostic Test Consider In


Brain SPECT or FDG-PET Patients in whom a thorough evaluation is nondiagnostic
AND
Imaging does not reveal a potential biopsy site
Brain and/or meningeal biopsy Patients in whom a thorough evaluation is nondiagnostic

AND
Any ill-defined lesion is present on MRI (T1 postcontrast,
T2 FLAIR) in a superficial cortical or meningeal location
AchR = acetylcholine receptor; AGNA = antiglial nuclear antibody; AMPA = "-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; ANA =
antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; ANNA = antineuronal nuclear antibody; CRMP-5 = collapsin response
mediator protein-5; CSF = cerebrospinal fluid; CT = computed tomography; DNA = deoxyribonucleic acid; FDG-PET = fluorodeoxyglucose
positron emission tomography; FLAIR = fluid-attenuated inversion recovery; GABA-B = +-aminobutyric acid type B; GAD65 = glutamic acid
decarboxylase 65; HIV = human immunodeficiency virus; IgG = immunoglobulin G; MRI = magnetic resonance imaging; NMDA = N-Methyl-
D-aspartate; PCA = Purkinje cell antibody; PCR = polymerase chain reaction; PET = positron emission tomography; SPECT = single-photon
emission computed tomography; SSA = Sjogren syndrome A; SSB = Sjogren syndrome B; VGKC = voltage-gated potassium channel.

generally begins with an MRI of the brain, A suggested protocol for the pharma-
with and without gadolinium, when no cologic management of status epilepticus
contraindications exist. MRI has a much is shown in Figure 6-2. The initial treat-
higher sensitivity for the identification ment of choice for early status epilepticus
of structural abnormalities than CT. is a benzodiazepine.34,39,40 This has been
endorsed by multiple guidelines3,4 and
Management of Generalized derives from the Veterans Affairs Status
Convulsive Status Epilepticus Epilepticus Cooperative Study Group
Convulsive status epilepticus must be trial, which compared lorazepam, phe-
treated promptly to avoid neuronal injury nobarbital, phenytoin, and diazepam
and the development of refractoriness. plus phenytoin, and demonstrated that
Early treatment has been shown to be lorazepam was significantly more likely
much more effective than late treatment.34 to terminate what the investigators termed
Use of a treatment protocol has been overt status epilepticus than phenytoin
shown to result in better seizure control alone.34 While lorazepam was not signif-
and shorter intensive care unit and icantly more effective than phenobarbital,
hospital length of stay35 and is recom- or diazepam plus phenytoin, it is both
mended by the European Federation of faster and more convenient to administer,
Neurological Societies guideline on which led to its adoption in treatment
the management of status epilepticus protocols as the recommended first-line
in adults.3 Published protocols generally agent for status epilepticus. Lorazepam
divide treatment into early, established, and diazepam were directly compared
and refractory36,37; prehospital, initial, to placebo for the treatment of seizures
and refractory3,38; or urgent, emer- lasting more than 5 minutes in the San
gent, and refractory4 phases, designed Francisco Prehospital Treatment of Status
to aid the clinician in focusing the Epilepticus (PHTSE) study, and they
pharmacologic treatment based on the terminated 59% and 43% of status epilep-
available evidence. ticus episodes, respectively, compared

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KEY POINT
h Uncontrolled status
epilepticus is more likely
than benzodiazepine
administration to result
in hypoxemia or airway
compromise, and the
adequacy of medication
dose is directly related
to efficacy so patients
should not be
underdosed out of
concern for airway safety.

FIGURE 6-2 Suggested algorithm for management of status epilepticus.


IM = intramuscular; IV = intravenous; PE = phenytoin equivalent.
a
All drugs are IV administered except for topiramate, which is orally administered.

with 21% of episodes in the placebo 73% of patients receiving midazolam


group.39 Cardiopulmonary complications and 63% of those treated with loraze-
were less frequent in the benzodiazepine pam.40 Thus, both drugs are acceptable
group compared with the placebo group. options for the initial treatment of status
Uncontrolled status epilepticus is more epilepticus, and the choice should be
likely than benzodiazepine administra- made based on access, making midazolam
tion to result in hypoxemia or airway com- the preferred option in the field and
promise, and the adequacy of medication lorazepam the preferred option when
dose is directly related to efficacy,39,41 IV access is available. The optimal dose
so patients should not be underdosed of each benzodiazepine has not been
out of concern for airway safety. In the systematically studied in the setting of
2012 Rapid Anticonvulsant Medication status epilepticus; however, the rec-
Prior to Arrival Trial (RAMPART), investi- ommended dose in the absence of a
gators randomly assigned 893 patients randomized controlled trial compar-
with convulsive status epilepticus to re- ing doses is 0.1 mg/kg lorazepam ad-
ceive either 10 mg IM midazolam or 4 mg ministered in 2- to 4-mg increments,
IV lorazepam. Seizure termination prior 5 to 10 minutes apart until cessation
to arrival to the hospital was achieved in of seizures, derived from the PHTSE

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Status Epilepticus

KEY POINTS
h Infusion of phenytoin or trial, or 10 mg IM midazolam, derived cardiac arrhythmias may occur during
fosphenytoin is from RAMPART.40 Intranasal or buccal loading. Valproic acid may be infused ra-
frequently associated midazolam and rectal diazepam are pidly and is generally well tolerated, even
with hypotension, alternative options. in critically ill patients. The Neurocritical
especially when infused All patients with convulsive status Care Society guidelines for first-line and
rapidly and in patients epilepticus should be treated with a second-line therapy in status epilep-
with intravascular second-line agent immediately after the ticus are shown in Table 6-7 and this
volume contraction.
first-line agent, whether or not status authors recommended doses are
h A general consensus epilepticus is aborted by benzodiaze- shown in Table 6-8.4
exists among experts It is appropriate to prepare the pa-
pines, to prevent seizure recurrence. A
that treatment of tient for endotracheal intubation and
convulsive refractory
randomized controlled trial comparing
mechanical ventilation, required for ini-
status epilepticus, commonly used AEDs for established sta-
tiation of IV anesthesia, while the second-
defined as status tus epilepticus is needed.42 Some guid-
line agent is infusing and to proceed
epilepticus that fails to ance comes from the Veterans Affairs to a third-line agent if convulsions con-
respond to two Status Epilepticus Cooperative Study
antiepileptic drugs, is
tinue by the end of the infusion. A gen-
Group trial, in which patients who failed eral consensus exists among experts
best achieved with an
anesthetic agent initially
the first-line agent were given a second- that treatment of convulsive refrac-
titrated to cessation of line agent in a predetermined sequence. tory status epilepticus, defined as sta-
convulsions. An When the first drug administered was tus epilepticus that fails to respond to
emergent EEG should a benzodiazepine, second agents were two AEDs, is best achieved with an an-
be obtained to titrate effective in only 3.2% to 7.2% of episodes, esthetic agent initially titrated to cessa-
the infusion to
suggesting that moving very quickly along tion of convulsions. An emergent EEG
electrographic should be obtained to titrate the infu-
seizure control or
the protocol to a continuous IV anes-
sion to electrographic seizure control or
burst suppression. thetic agent in convulsive status epile-
burst suppression. Once seizure control
pticus is appropriate. The preferred is achieved, it is typically maintained for
drugs for second-line treatment of status 24 hours followed by a controlled with-
epilepticus are phenytoin or its prodrug, drawal of the anesthetic agent. It is ad-
fosphenytoin, or valproic acid. Phenytoin visable to have at least two maintenance
was shown to be effective in 43.5% of AEDs at therapeutic doses before at-
episodes of status epilepticus in the tempting to wean the patient from the
Veterans Affairs Status Epilepticus Co- anesthetic agent.
operative Study Group trial. Two small Commonly used anesthetic agents in-
randomized controlled trials have clude midazolam, propofol, and pento-
demonstrated that IV valproic acid is barbital (in some countries, thiopental
also may be available). The agent may be
as effective and possibly superior to
chosen based on the patients comorbid
IV phenytoin as a first-line or second-
conditions and adverse effects associated
line AED.43,44 with each drug (Table 6-9). There are
Infusion of phenytoin or fosphenytoin
insufficient data to suggest superiority
is frequently associated with hypotension, of one agent over another.
especially when infused rapidly and in Seizure recurrence upon weaning of
patients with intravascular volume con- the anesthetic agent should prompt a
traction. When it occurs, administration return to the prior dose that had achieved
of a fluid bolus and slowing the rate of seizure control or the addition or sub-
infusion is generally sufficient to allow stitution of another agent. This stage of
completion of the load. Cardiac moni- status epilepticus is termed super-
toring during infusion is advisable as refractory status epilepticus, or malignant

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KEY POINT

TABLE 6-7 Neurocritical Care Society Guidelines for First-Line and h Ultimately, it is unlikely
Second-Line Antiepileptic Drugs in the Management of that any pharmacologic
Status Epilepticusa or nonpharmacologic
therapy will abort
Treatment Class, Level of Evidenceb super-refractory status
First-line therapy epilepticus without
identification and
Lorazepam Class I, Level A resolution of the
Midazolam Class I, Level A underlying etiology,
although rare cases
Diazepam Class IIa, Level A
have occurred in which
Phenytoin/fosphenytoin Class IIb, Level A the cause is never
identified and the status
Phenobarbital Class IIb, Level A
epilepticus resolves even
Valproate sodium Class IIb, Level A after many weeks
Levetiracetam Class IIb, Level C or months of
super-refractory
Second-line therapy status epilepticus.
Valproate sodium Class IIa, Level A
Phenytoin/fosphenytoin Class IIb, Level B
Midazolam (continuous infusion) Class IIb, Level B
Phenobarbital Class IIb, Level C
Levetiracetam Class IIb, Level C
a
Modified with permission from Brophy GM, et al, Neurocrit Care.4 B 2012 Springer Science +
Business Media LLC. link.springer.com/article/10.1007%2Fs12028-012-9695-z.
b
Neurocritical Care Society guidelines use the evidence rating system of the American Heart
Association/American College of Cardiology guidelines:
Class I: Intervention is useful and effective. Treatment benefits clearly exceed risks.
Class IIa: Evidence/expert opinions suggest intervention is useful/effective. Treatment benefits exceed risk.
Class IIb: Strength of evidence/expert opinion about intervention usefulness/effectiveness is less
well established. More data are needed; however, using this treatment when warranted is
not unreasonable.
Level A: Adequate evidence is available from multiple, large, randomized clinical trials or meta-analyses
Level B: Limited evidence is available from less rigorous data, including fewer, smaller, randomized
trials, nonrandomized studies, and observational analyses.
Level C: Evidence relies on expert/consensus opinion, case reports, or standard of care.

status epilepticus. Other interventions therapy will abort super-refractory status


that may be attempted at this stage epilepticus without identification and
include the use of IV ketamine or resolution of the underlying etiology,
inhaled anesthetic agents such as iso- although rare cases have occurred in
flurane, and nonpharmacologic ap- which the cause is never identified and
proaches such as the ketogenic diet, the status epilepticus resolves even
induced hypothermia, and electrical sti- after many weeks or months of super-
mulation therapies. 45 All of these refractory status epilepticus. A higher
therapies remain unproven, although proportion of patients with NORSE are
there are multicenter retrospective cryptogenic compared with all patients
series supporting the safety of ketamine who present with status epilepticus, and
and the ketogenic diet in this set- it is likely that many of these patients
ting.46,47 Ultimately, it is unlikely that have an antibody-mediated etiology.
any pharmacologic or nonpharmacologic Thus, the author recommends empiric

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Status Epilepticus

TABLE 6-8 Authors Recommended Doses of Commonly Used Medications for the Treatment
of Status Epilepticus

Treatment Dose/Route Rate of Infusion


Lorazepam 0.1 mg/kg IV Up to 4 mg per dose in 5- to 10-minute increments
a
Midazolam 10 mg IM N/A
Diazepam 20 mg rectally or 5Y30 mg IV push 5 mg per dose in 10- to 15-minute increments
Phenytoin 10-15 mg/kg Up to 50 mg/min
Fosphenytoin 18Y20 phenytoin equivalents/kg IV Up to 150 mg/min
a
Valproate sodium 25Y40 mg/kg IV Up to 3 mg/kg/min
a
Levetiracetam 2000Y4000 mg IV Up to 500 mg/min
a
Lacosamide 200Y400 mg IV Infused over 5 minutes
Phenobarbital 20 mg/kg IV Up to 60 mg/min
a
Midazolam 0.2 mg/kg load IV 0.1Y2 mg/kg/h
a
Propofol 1Y2 mg/kg load IV 2Y12 mg/kg/h
Pentobarbital 5Y15 mg/kg load IV administered over 1 hour 0.5Y5 mg/kg/h
Ketamine 1.5Y4.5 mg/kg load IV 2.75Y5 mg/kg/h
IM = intramuscular; IV = intravenous; N/A = not applicable.
a
These drugs are not US Food and Drug Administration (FDA) approved for the treatment of status epilepticus.

KEY POINTS immunosuppression with steroids fol- of consciousness, the risk-to-benefit anal-
h No single variable lowed by plasma exchange or IV immu- ysis generally tips in favor of avoiding
determines the optimal
noglobulin (IVIg) after infection is anesthesia as long as possible. In some
management of
nonconvulsive status
sufficiently excluded in cryptogenic cases. cases, multiple AEDs may be tried be-
epilepticus. Important fore starting a continuous IV anesthetic
variables to consider are Management of Nonconvulsive infusion (Case 6-2).
degree of impairment of Status Epilepticus No single variable determines the
consciousness, etiology, optimal management of nonconvulsive
Two recent retrospective studies sug-
and both the anticipated status epilepticus. Important variables to
gest an association between the use of
risks and benefits of
continuous IV anesthetic drugs and in- consider are degree of impairment of
aggressive treatment.
creased mortality in the setting of status consciousness, etiology, and both the
h Reasons for treatment anticipated risks and benefits of aggres-
failure in patients with
epilepticus after attempting to control
status epilepticus include for known outcome predictors.26,48 sive treatment. The Neurocritical Care
poor drug selection, Endotracheal intubation, mechanical Society guidelines for refractory ther-
inadequate dosing, ventilation, and the prolonged immobil- apy are shown in Table 6-10.4 If con-
delayed recognition, ity associated with anesthetic agents as sciousness is severely impaired due to
incorrect diagnosis (eg, well as the risks associated with indi- nonconvulsive status epilepticus, man-
psychogenic status vidual anesthetic agents are clearly agement does not differ significantly from
epilepticus), failure to
outweighed by both the neurologic that of convulsive status epilepticus
continue maintenance
antiepileptic drugs after and systemic risk associated with except that it may be prudent to wait
aborting status epilepticus, prolonged convulsive seizures. How- longer for the second-line agent to take
and failure to identify and ever, in patients with nonconvulsive sta- effect or, in some cases, pursue trial of
treat the underlying cause. tus epilepticus and some preservation a third nonanesthetic AED before

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TABLE 6-9 Commonly Used Anesthetic Agents Used in Refractory Status Epilepticus

Avoid in the
Following
Drug Mechanism Metabolism Advantages Disadvantages Conditions
Midazolam +-Aminobutyric Hepatic; active Short half-life Hypotension, Hepatic or
acid (GABA) metabolites tachyphylaxis renal failure
potentiation excreted renally (limits prolonged
use), prolonged
elimination
half-life in obese
patients due to
accumulation in
adipose tissue
Propofol GABA agonist, Hepatic Short half-life Hypotension, Hepatic
sodium channel propofol infusion failure,
blockade, syndrome (more inherited
N-methyl-D-aspartate likely with prolonged metabolic
(NMDA) inhibition, use at high doses) disorders
calcium channel
modulation
Pentobarbital GABA potentiation Hepatic Can be used Hypotension, ileus, Hepatic
for prolonged immunosuppression failure
periods (risk of infections),
hepatotoxicity,
metabolic acidosis
due to propylene
glycol toxicity
Ketamine Glutamate and Hepatic; active Unique Hypotension may Hepatic or
NMDA inhibition metabolites mechanism that occur but is not renal failure
excreted renally may be better common
suited to the
malignant (Concern for
stages of status increased intracranial
epilepticus pressure is only
relevant when
ventilation is not
controlled and thus
is not relevant in
refractory status
epilepticus)

proceeding to a continuous anesthetic chogenic status epilepticus), failure to


infusion (Case 6-3). continue maintenance AEDs after abort-
ing status epilepticus, and failure to
WHY DOES TREATMENT FAIL? identify and treat the underlying cause.
Reasons for treatment failure in patients Rarely, in cases of NORSE, the etiology
with status epilepticus include poor drug cannot be identified even after an ex-
selection, inadequate dosing,41 delayed haustive diagnostic evaluation. It is
recognition, incorrect diagnosis (eg, psy- likely that autoantibodies, which have

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Status Epilepticus

Case 6-2
A 78-year-old previously healthy man presented to the emergency department because of spells
that had been occurring for several days and were increasing in frequency. His episodes were now
occurring every 15 minutes, lasting 4 to 5 minutes each, characterized by stereotyped formed visual
hallucinations in the left visual field followed by head and gaze deviation to the left and upward,
progressing to involve difficulty with his speech and ultimately ending with mutism. Following this, he
was confused, and over approximately 10 more minutes, returned to his neurologic baseline. The
patients family reported that prior to the onset of these events he had been having problems with
memory, paranoid thoughts, and increased emotionality. An MRI of his brain performed when the
symptoms began demonstrated an abnormal T2 hyperintensity involving the right posterior temporal
lobe with associated focal enhancement of the cortex and leptomeninges and punctate cortical and
subcortical gradient echo changes. Lorazepam did not impact the frequency of the clinical events.
He was admitted to the neurocritical care unit where EEG monitoring demonstrated seizures
arising from the right hemisphere both between and during the clinical events (Figure 6-3). He was
loaded with 20 mg phenytoin equivalents per kg fosphenytoin, which slowed the frequency of the
clinical seizures but did not impact the subclinical seizures. Subsequent levetiracetam and valproic acid
loading did not affect the frequency of seizures. He was orally loaded with 5 mg per kg of
phenobarbital in divided doses over a 24-hour period and started on maintenance phenobarbital
50 mg 2 times a day, with resolution of the seizures and a gradual return to his baseline mental status.

FIGURE 6-3 Four 15-second scalp EEG pages demonstrating the onset (A, arrow) of right frontocentral onset focal
nonconvulsive status epilepticus, characterized by rhythmic sharp delta discharges. Electrographic discharge
is seen spreading to the right temporal head region (B, box). Subsequently, the discharge evolved in amplitude
and morphology yet remained localized to the right hemisphere (C, box). Finally, the electrographic discharge is seen to settle
with clear ictal offset (D, box). High-pass filter: 1 Hz; low-pass filter: 70 Hz; notch filter: off.

Continued on page 1379


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Continued from page 1378
After excluding CNS infection by CSF analysis, he was empirically treated with steroids for possible
amyloid-"-related angiitis, and after extensive evaluation, the patient was diagnosed with amyloid
angiopathy with amyloid-"-related angiitis.
Comment. This case exemplifies the challenge faced by clinicians attempting to balance the goal of
controlling refractory status epilepticus while avoiding unnecessary exposure to risk. Because this
patient had preserved consciousness, anesthesia was avoided in favor of further attempts at seizure
control with nonanesthetic antiepileptic drugs (AEDs). In this patient, it was the fifth AED that
ultimately controlled the seizures. While the sedating effects of phenobarbital caused marked
drowsiness for approximately 36 hours, the patient did not require intubation and could be
transferred out of the intensive care unit 48 hours following the phenobarbital load.

not yet been identified, play a role in causes seizures to continue despite ini-
the precipitation of status epilepticus tial treatments? What is the optimal
in these patients. pharmacologic approach to established
and refractory status epilepticus? Does
FUTURE DIRECTIONS nonconvulsive status epilepticus cause
Many questions remain in the evalua- clinically significant neuronal injury in
tion, management, and prognosis of humans, and do the risks of aggres-
patients with status epilepticus. What sive treatment outweigh the potential

TABLE 6-10 Neurocritical Care Society Guidelines for Treatment of


Refractory Status Epilepticusa

Treatment Class, Level of Evidenceb


Midazolam Class IIa, Level B
Propofol Class IIb, Level B
Pentobarbital/thiopental Class IIb, Level B
Valproate sodium Class IIa, Level B
Levetiracetam Class IIb, Level C
Phenytoin/fosphenytoin Class IIb, Level C
Lacosamide Class IIb, Level C
Topiramate Class IIb, Level C
Phenobarbital Class IIb, Level C
a
Modified with permission from Brophy GM, et al, Neurocrit Care.4 B 2012 Springer Science +
Business Media LLC. link.springer.com/article/10.1007%2Fs12028-012-9695-z.
b
Neurocritical Care Society guidelines use the evidence rating system of the American Heart
Association/American College of Cardiology guidelines:
Class I: Intervention is useful and effective. Treatment benefits clearly exceed risks.
Class IIa: Evidence/expert opinions suggest intervention is useful/effective. Treatment benefits exceed risk.
Class IIb: Strength of evidence/expert opinion about intervention usefulness/effectiveness is less well
established. More data are needed; however, using this treatment when warranted is not unreasonable.
Level A: Adequate evidence is available from multiple, large, randomized clinical trials or meta-analyses.
Level B: Limited evidence is available from less rigorous data, including fewer, smaller,
randomized trials, nonrandomized studies, and observational analyses.
Level C: Evidence relies on expert/consensus opinion, case reports, or standard of care.

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Status Epilepticus

Case 6-3
A 40-year-old woman was admitted with Pseudomonas urosepsis and acute kidney injury and was
treated with cefepime. Over the first 72 hours of admission she became progressively less responsive
and then had an episode of oxygen desaturation followed by a 1-minute generalized tonic-clonic
seizure. The patient desaturated again 10 minutes later and had an abrupt increase in heart rate to
160 beats per minute lasting 30 seconds and without associated convulsions. Neurology was consulted.
On examination, she was comatose with eye opening only to pain, had intact brainstem reflexes, and
flexion to painful stimulus applied to all four extremities. Levetiracetam 1000 mg IV was administered.
A noncontrast head CT was normal. An emergent EEG demonstrated generalized electrographic
discharges that stopped within seconds of administration of 2 mg of lorazepam (Figure 6-4). She was
then loaded with 20 mg phenytoin equivalents per kg of fosphenytoin and continued on maintenance
doses of both levetiracetam and fosphenytoin. Cefepime was replaced by piperacillin-tazobactam
because of concern that cefepime neurotoxicity could have been responsible for the nonconvulsive
status epilepticus. EEG monitoring was continued, and over the next 24 hours, several generalized
electrographic seizures occurred lasting longer than 5 minutes and were accompanied by an increase
in muscle tone. Each seizure resolved with 2 mg IV lorazepam. Over the subsequent 24 hours, no
further electrographic seizures occurred, and the patients level of consciousness gradually improved.

FIGURE 6-4 Four 15-second EEG pages demonstrating the onset (A, box) of a generalized nonconvulsive electrographic
discharge characterized by high-amplitude 1.5-Hz to 1.75-Hz generalized repetitive sharp waves. The
electrographic discharge is seen to evolve in amplitude and morphology (B). Within seconds following
the administration of 2 mg lorazepam, the continuous repetitive sharp waves stopped (C, blue line) and background
activity consisting of generalized moderate amplitude 2-Hz to 4-Hz delta activity and superimposed generalized
moderate amplitude 10-Hz to 16-Hz mixed alpha-beta activity was seen (D). High-pass filter: 1 Hz; low-pass filter: 70 Hz;
notch filter: off.

Continued on page 1381

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Continued from page 1380
Comment. This patient had generalized nonconvulsive status epilepticus precipitated by sepsis
and cefepime neurotoxicity, which resolved with treatment of the underlying infection, replacement
of cefepime by piperacillin-tazobactam, and treatment with lorazepam, fosphenytoin, and
levetiracetam. In generalized nonconvulsive status epilepticus secondary to medical illness,
intoxication, drug withdrawal, or other toxidrome (ie, cefepime neurotoxicity), treatment of the
cause may be as effective as pharmacologic treatment of the seizures.

benefits in this setting? Future studies evaluation. Curr Opin Pediatr 2014;26(6):655Y661.
doi:10.1097/MOP.0000000000000152.
will need to address these questions,
6. Abend NS, Loddenkemper T. Pediatric status
and collaborative research will likely be epilepticus management. Curr Opin Pediatr
the key to accomplishing this task. 2014;26(6):668Y674. doi:10.1097/
MOP.0000000000000154.

CONCLUSION 7. Kaplan PW. The clinical features, diagnosis,


and prognosis of nonconvulsive status
Status epilepticus is both a medical and epilepticus. Neurologist 2005;11(6):348Y361.
neurologic emergency with significant 8. Avbersek A, Sisodiya S. Does the primary
potential morbidity and mortality. Eval- literature provide support for clinical signs
used to distinguish psychogenic nonepileptic
uation and management are aimed at: seizures from epileptic seizures? J Neurol
(1) stabilization and avoidance of second- Neurosurg Psychiatry 2010;81(7):719Y725.
doi:10.1136/jnnp.2009.197996.
ary injury, (2) rapid control of seizures,
and (3) rapid identification and treatment 9. Kapur J, Macdonald RL. Rapid
seizure-induced reduction of benzodiazepine
of the etiology. Rapid diagnosis of status and Zn2+ sensitivity of hippocampal dentate
epilepticus, treatment respecting a writ- granule cell GABAA receptors. J Neurosci
ten protocol, correction of the underlying 1997;17(19):7532Y7540.

etiology, and attention to potential com- 10. Naylor DE, Liu H, Niquet J, Wasterlain CG.
Rapid surface accumulation of NMDA
plications may limit sequelae. receptors increases glutamatergic excitation
during status epilepticus. Neurobiol Dis
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