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Status Epilepticus,
Refractory Status C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
Epilepticus, and
Super-refractory Status
Epilepticus CITE AS:
By Sarah E. Nelson, MD; Panayiotis N. Varelas, MD, PhD, FNCS, FAAN CONTINUUM (MINNEAP MINN)
2018;24(6, NEUROCRITICAL CARE):
1683–1707.
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVEIbF/e7oEAXuzVwmazllqbBpkQiiGqt6qR5mpPQnj8HzX5DeVo03c0= on 12/06/2018
Address correspondence to
ABSTRACT Dr Sarah E. Nelson, Johns
Hopkins University, 600 N Wolfe
PURPOSE OF REVIEW: Status epilepticus, refractory status epilepticus, and St, Phipps 455, Baltimore, MD
super-refractory status epilepticus can be life-threatening conditions. This 21287, snelso43@jhmi.edu.
article presents an overview of the three conditions and discusses their
RELATIONSHIP DISCLOSURE:
management and outcomes. Dr Nelson receives grant
support from the Johns Hopkins
RECENT FINDINGS: Status epilepticus was previously defined as lasting for Anesthesiology and Critical Care
Medicine (ACCM) Stimulating
30 minutes or longer but now is more often defined as lasting 5 minutes and Advancing ACCM Research
or longer. A variety of potential causes exist for status epilepticus, (StAAR) program. Dr Varelas
refractory status epilepticus, and super-refractory status epilepticus, serves on the board of directors
of the Neurocritical Care
but all three ultimately involve changes at the cellular and molecular Society, on the editorial board
level. Management of patients with status epilepticus generally of Neurocritical Care, and on an
advisory board of Portola
requires several studies, with EEG of utmost importance given the Pharmaceuticals, Inc.
pathophysiologic changes that can occur during the course of status Continued on page 1707
epilepticus. Status epilepticus is treated with benzodiazepines as
first-line antiepileptic drugs, followed by phenytoin, valproic acid, or UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
levetiracetam. If status epilepticus does not resolve, these are followed USE DISCLOSURE:
by an IV anesthetic and then alternative therapies based on limited Drs Nelson and Varelas discuss
data/evidence, such as repetitive transcranial magnetic stimulation, the unlabeled/investigational
use of allopregnanolone, deep
therapeutic hypothermia, immunomodulatory agents, and the ketogenic brain stimulation, desflurane,
diet. Scores have been developed to help predict the outcome of status diazepam, electroconvulsive
epilepticus. Neurologic injury and outcome seem to worsen as the duration therapy, fosphenytoin,
gabapentin, isoflurane, IV
of status epilepticus increases, with outcomes generally worse in immunoglobulin, ketamine,
super-refractory status epilepticus compared to status epilepticus and ketogenic diet, lacosamide,
levetiracetam, lidocaine,
sometimes also to refractory status epilepticus.
lorazepam, methylprednisolone,
midazolam, pentobarbital,
SUMMARY: Status epilepticus can be a life-threatening condition associated phenobarbital, phenytoin,
plasma exchange, propofol,
with multiple complications, including death, and can progress to pyridoxine, thiopental,
refractory status epilepticus and super-refractory status epilepticus. More topiramate, vagal nerve
studies are needed to delineate the best management of these three stimulation, and valproic acid
for the treatment of refractory
entities. status epilepticus.
CONTINUUMJOURNAL.COM 1683
KEY POINTS
INTRODUCTION
S
● While in the past, tatus epilepticus is a common neurologic emergency that requires
tonic-clonic status prompt treatment to decrease morbidity and mortality. Best
epilepticus was defined as management continues to evolve for this condition. This article
continuous seizure activity
or two or more seizures
reviews the current definitions of status epilepticus, refractory status
without recovery of epilepticus, and super-refractory status epilepticus as well as their
consciousness lasting longer epidemiology, etiology, pathophysiology, diagnosis, management, and
than 30 minutes, outcomes. It is important to note that guidelines for the evaluation and treatment
tonic-clonic status
of status epilepticus have been published by the Neurocritical Care Society.1
epilepticus is now defined
as seizure activity lasting Treatment guidelines have also recently been published by the American
5 minutes or longer, with Epilepsy Society, but they stop short of addressing refractory status epilepticus
30 minutes being the cutoff and super-refractory status epilepticus.2
for development of
long-term consequences.
DEFINITIONS
● No standard definition for Typical seizures are fewer than 5 minutes in duration and are self-limited, but
nonconvulsive status those that are longer tend not to resolve on their own.1 Traditionally, status
epilepticus currently exists.
A working definition epilepticus was defined as continuous seizure activity or two or more seizures
differentiates diagnostic without recovery of consciousness lasting longer than 30 minutes. However, status
criteria based on whether epilepticus is now often defined by two time points, t1 and t2, identified as the time
epileptic encephalopathy beyond which seizures are likely to be prolonged and the time beyond which
is present.
seizures lead to long-term consequences, respectively; for tonic-clonic seizures,
● Refractory status t1 is 5 minutes and t2 is 30 minutes, but for focal status epilepticus or absence status
epilepticus is continuous these time points are different or unknown.2,3
seizure activity not Status epilepticus has several subtypes, including convulsive status
controlled by first-line and
epilepticus, epilepsia partialis continua, and nonconvulsive status epilepticus. In
second-line antiepileptic
drugs; it occurs in 9% to 43% convulsive status epilepticus, repetitive tonic-clonic movements occur, followed
of all cases of status by a postictal state. In epilepsia partialis continua, focal neurologic deficits such
epilepticus. as aphasia and motor dysfunction occur as a result of partial seizures, but altered
mental status is not present. Continuous or fluctuating mental status changes
● Super-refractory status
epilepticus is defined either occur in nonconvulsive status epilepticus.2 Although no definitive criteria for
as status epilepticus not nonconvulsive status epilepticus exist, a working definition is listed in
TABLE 5-1.
4,5
controlled by third-line
anesthetic agents or as Refractory status epilepticus is continuous seizure activity not controlled by
status epilepticus continuing
for 24 hours or longer after
first-line and second-line antiepileptic drugs (AEDs).6 Super-refractory status
anesthesia is administered. epilepticus is defined as status epilepticus not controlled by third-line agents.7
The exact incidence and Another definition posits that super-refractory status epilepticus exists if status
associated mortality of epilepticus continues for 24 hours or longer after anesthesia is administered.8
super-refractory status
epilepticus are unknown.
EPIDEMIOLOGY
● The annual incidence of The next section reviews the epidemiology of status epilepticus, refractory status
status epilepticus is
epilepticus, and super-refractory status epilepticus.
approximately 12.6 per
100,000 person-years and is
increasing over time. Seizures Status Epilepticus
or status epilepticus may The pooled crude annual incidence rate of status epilepticus is approximately 12.6
occur in up to 19% of patients
hospitalized in the intensive
per 100,000 person-years.9 In the intensive care unit (ICU) specifically, seizures
care unit. or status epilepticus may occur in up to 19% of patients, although studies
evaluating this frequency are limited by their retrospective nature and different
definitions.10 Of those with status epilepticus, 12% to 43% progress to refractory
status epilepticus and 10% to 15% progress to super-refractory status epilepticus.8
CONTINUUMJOURNAL.COM 1685
KEY POINT epilepticus in French-speaking Switzerland found that the most common seizure
type was partial (44.8%), followed by generalized tonic-clonic (33.1%).13
● The etiology of status
epilepticus may be divided
into known or symptomatic Refractory and Super-refractory Status Epilepticus
causes and unknown or Refractory status epilepticus occurs in 9% to 43% of all cases of status
cryptogenic causes. In epilepticus.6,7 In one study of 395 patients with refractory status epilepticus
general, acute causes
treated in the ICU, the annual incidence was found to be 3.4 per 100,000.18 As
appear to be more common
than chronic causes. expected, prospective studies19 estimate a lower incidence than retrospective
studies.20–22 Predictors of refractory status epilepticus were lower level of
consciousness and new diagnosis of status epilepticus in one study19 and focal
motor seizures at onset and nonconvulsive status epilepticus in another.21
The exact incidence and associated mortality of super-refractory status
epilepticus have not yet been delineated, likely because of the low number of
patients with this condition and lack of prospective studies.23 One estimate is that
10% to 15% of all in-hospital cases of status epilepticus will evolve into
super-refractory status epilepticus.23 In a 2015 study that used the Finnish
Intensive Care Consortium database, 22% of patients with refractory status
epilepticus were categorized as having super-refractory status epilepticus, with
an annual incidence estimate of 0.7 per 100,000 persons.8 Of 98 patients in West
China diagnosed with status epilepticus, 12.2% had super-refractory status
epilepticus (by comparison, the percentages of patients with nonrefractory
status epilepticus and refractory status epilepticus were 67.3% and 20.4%,
respectively). In this study, convulsive status epilepticus was the main seizure
type in patients with super-refractory status epilepticus (as compared to
nonconvulsive status epilepticus).24
Another study examined 177 patients with convulsive status epilepticus in
India. While 105 (59.3%) patients had nonrefractory status epilepticus, 72
(40.7%) had refractory status epilepticus, of which 30 (16.9% of the total 177)
had super-refractory status epilepticus. Super-refractory status epilepticus was
more common in children and the elderly.25 In a study of patients with status
epilepticus who did not respond to first-line AEDs, seven episodes (20%) met the
authors’ definition of malignant status epilepticus (persistent clinical and/or
electrographic seizure activity that recurred within 5 days of weaning the
maximum dose of IV anesthetics that resulted in EEG burst suppression), which
appears to be similar to the definition of super-refractory status epilepticus.
Patients with malignant status epilepticus were younger than patients with
refractory status epilepticus.26
ETIOLOGY
Status epilepticus may have a structural, infectious, toxic-metabolic, or
autoimmune cause (TABLE 5-2).1 According to the International League Against
Epilepsy, the etiology of status epilepticus may be divided into two groups:
(1) known or symptomatic and (2) unknown or cryptogenic. The symptomatic
group can be subdivided into acute symptomatic, remote symptomatic, and
progressive symptomatic.3 In general, acute causes appear to be more common
than chronic causes.9 The underlying etiology for status epilepticus often
influences the likelihood of a patient’s mortality.15
Interestingly, etiologies seem to vary among different populations. In one
prospective population-based study of 150 patients with status epilepticus
conducted in Germany, the most common etiologies were a remote stroke
Acute Causes
◆ Acute stroke (eg, ischemic stroke, intracerebral hemorrhage)
◆ Head trauma
◆ Central nervous system infections (eg, abscess, meningitis, encephalitis)
◆ Hypoxic brain injury
◆ Posterior reversible encephalopathy syndrome (PRES)
◆ Autoimmune and paraneoplastic etiologies (eg, anti–N-methyl-D-aspartate [NDMA] receptor
encephalitis)
◆ Sepsis
◆ Metabolic disturbances (eg, hypoglycemia, abnormal electrolytes)
◆ Drug withdrawal, toxicity, or noncompliance
Chronic Causes
◆ History of epilepsy (eg, due to noncompliance with antiepileptic drugs)
◆ Brain tumor
◆ Previous brain pathology (eg, due to trauma, stroke, cortical dysplasia)
a
Modified with permission from Brophy GM, et al, Neurocrit Care.1 © 2012 Springer Science+Business
Media, LLC.
CONTINUUMJOURNAL.COM 1687
CASE 5-1 A 24-year-old man presented with fever, nausea, headache, and
generalized tonic-clonic seizures. His past medical history was
unremarkable. He was admitted to the neurocritical care unit, where he
was placed on continuous EEG. CT and MRI of the brain and CSF analysis
(including multiple viral cultures and a paraneoplastic panel) were
unremarkable aside from a mild CSF pleocytosis. Body positron emission
tomography (PET) and testicular ultrasound were normal, but PET of the
brain showed occipital lobe hypometabolism (FIGURE 5-1), and this finding
can be seen in anti–N-methyl-D-aspartate (NMDA) receptor antibody
encephalitis, but despite extensive autoimmune testing he never tested
positive for any antibody.30 He was initially treated with 5 days of
methylprednisolone with no improvement; he was then given five
sessions of plasma exchange.
EEG initially showed electrographic seizures that started in the right
posterior temporal region with subsequent spread first to the rest of the
right hemisphere and then bilaterally (FIGURE 5-2). He had a clinical
correlate of left head deviation, nystagmus, and left face and limb tonic-
clonic activity with some of the seizures, but many had no clear clinical
correlate. He was monitored with continuous EEG for longer than a week
and required multiple medications, including IV levetiracetam,
phenytoin, lacosamide, and phenobarbital. He also required multiple
continuous anesthetic agents, including midazolam, propofol, and
ketamine, to achieve burst suppression. Because additional seizure
control was still needed, he was also started on the ketogenic diet; it was
discontinued 4 days later because of severe metabolic acidosis.
FIGURE 5-1
Positron emission tomography (PET) of the patient in CASE 5-1. The green areas show occipital
lobe hypometabolism, and normal brain metabolism is depicted in black and blue colors.
CONTINUUMJOURNAL.COM 1689
independent risk factor for malignant status epilepticus (which had a definition
similar to super-refractory status epilepticus in one study, as discussed above).26
In a status epilepticus cohort in China, the most common cause of super-refractory
status epilepticus was acute encephalitis (67.7% of super-refractory status
epilepticus cases).24
The term new-onset refractory status epilepticus (NORSE) has recently emerged
to define patients who have prolonged refractory status epilepticus with no
readily identifiable cause (although an autoimmune or viral encephalitis etiology
may later be found). In a multicenter retrospective study of patients for
whom seizure etiology was not known within 48 hours of admission, out of
675 cases of refractory status epilepticus, 130 cases fulfilled NORSE criteria
(19%). In 47% of these NORSE cases, an etiology was later determined, including
nonparaneoplastic autoimmune (40%), paraneoplastic (30%), and infectious
causes (16%). Anti–N-methyl-D-aspartate (NMDA) receptor antibodies were the
most common causes of both nonparaneoplastic autoimmune and paraneoplastic
etiologies, while herpes viruses (except herpes simplex virus type 1) were the
most frequent infectious cause. Approximately 64% of patients were females,
and 48% were older than 50 years of age. Prodromal symptoms, including
confusion, fever, fatigue, and headache, preceded NORSE onset in 46% of the
cases. Unilateral seizure onset on EEG was more common than bilateral
independent, multifocal, and generalized onsets, and EEG findings did not differ
between patients whose seizure etiology was determined and those whose was
not. MRI abnormalities were found in 62% of cases, most commonly in limbic or
neocortical structures, or both. CSF abnormalities were discovered in 73%, and
no difference was seen in MRI or CSF findings between those with and without
an identified etiology. The type and number of AEDs prescribed for both
cryptogenic and noncryptogenic cases were similar. Status epilepticus duration
was longer in patients whose seizures were of cryptogenic origin (8 days versus
4 days), but ICU and hospital stay duration were similar. Thirty-eight percent
of patients achieved a good or fair outcome (modified Rankin Scale [mRS]
score of 0 to 3) at discharge. Multivariate predictors of both poor outcome
(mRS score of >3) and mortality included the Status Epilepticus Severity Score
CONTINUED FROM After weaning from burst suppression, his EEG showed nearly
PAGE 1689 continuous multifocal sharp waves and diffuse generalized rhythmic
delta activity but no seizures. His examination steadily improved, and
he was successfully extubated a few days later. Antiepileptic drugs
were weaned, and he was eventually discharged on levetiracetam,
lacosamide, and a slow phenobarbital taper as well as oral prednisone for
his presumed diagnosis of autoimmune encephalitis. His EEG before
discharge showed intermittent left temporal slowing.
COMMENT This case illustrates that super-refractory status epilepticus from presumed
encephalitis may respond to immunomodulatory therapy and to multiple
antiepileptic drugs. It may need to be evaluated with extensive laboratory
workup and a PET scan in addition to traditional CSF studies and MRI of the brain.
DIAGNOSIS
The diagnosis of status epilepticus involves a combination of clinical suspicion as
well as laboratory testing, EEG, and imaging.
General Workup
Convulsive status epilepticus is a clinical diagnosis. When patients present
with suspected status epilepticus, recommended studies include vital signs,
CONTINUUMJOURNAL.COM 1691
FIGURE 5-3
MRI of the patient in CASE 5-2. Axial diffusion-weighted (A) and fluid-attenuated inversion
recovery (FLAIR) (B) images showing slight restricted diffusion of the left parietal lobe and
left thalamus with corresponding subtle FLAIR abnormalities.
This case of status epilepticus illustrates that EEG does not have to be COMMENT
completely normal to discontinue EEG monitoring, especially if the clinical
examination is improving. In addition, this case demonstrates that
reversible MRI findings can be seen in the setting of status epilepticus.
CONTINUUMJOURNAL.COM 1693
Electroencephalography
EEG is extremely important in the diagnosis of status epilepticus, especially in
cases of nonconvulsive status epilepticus, which may be suspected clinically
but proven only by EEG. For example, in one study of 570 patients in the ICU
who underwent continuous EEG for detection of subclinical seizures or
unexplained lower level of consciousness, seizures were detected in 19%; 92%
of these patients had only nonconvulsive seizures. Independent predictors for
discovering seizures on EEG were age younger than 18 years, convulsive seizures
before continuous EEG monitoring, coma, and a history of epilepsy.36 One
prospective study in a general hospital setting found that 19% of patients with
status epilepticus had nonconvulsive status epilepticus.37 Forty-seven percent of
patients in a tertiary care center were found to have nonconvulsive status
epilepticus.38 In a study of patients in a general ICU, nonconvulsive status
epilepticus was detected in 8% of patients who were comatose.39 A study of the
neurologic ICU population specifically found that 23 of 170 patients (13.5%) had
nonconvulsive status epilepticus.40
Importantly, studies evaluating the timing of seizures have found that
continuous EEG may not necessarily capture seizures in the first hours after it is
placed. In one study, while continuous EEG detected seizures within the first
24 hours of monitoring in 88% of patients who would eventually have seizures, in
a similar percentage (87%) of patients who were comatose, seizures were more
likely to be detected after more than 24 hours of monitoring, suggesting that
additional monitoring time may be required in patients who are comatose
longer.36 Another study found that approximately 97% of patients who were
hospitalized and noncritically ill had their first seizure within 24 hours of starting
continuous EEG.41
Imaging
The value of CT—and even more so MRI—in revealing a focal lesion as the
cause of status epilepticus has been well demonstrated.42 SPECT has also been
used to detect foci of status epilepticus. In several case series and case
reports of patients with status epilepticus, brain SPECT using technetium
99m–hexamethylpropyleneamine oxime (99mTc-HMPAO) or 99mTc–ethyl
cysteinate dimer (ECD) generally demonstrated focal hyperperfusion in areas
consistent with EEG findings.42–44 Compared to SPECT, PET (especially
PET/CT) can provide better resolution and the ability to perform quantitative
measurements.35 In one study of eight patients with focal status epilepticus,
fludeoxyglucose (FDG)-PET helped to support the diagnosis of status
epilepticus; determine localization of the epileptic focus for planning surgical
treatment; and clarify discordant findings among clinical, MRI, and EEG
findings.45
CONTINUUMJOURNAL.COM 1695
TABLE 5-3 Suggested Treatment Algorithm for Status Epilepticus Stages I and IIa,b
Initial Care
◆ Assess airway, breathing, circulation
◆ Monitor vital signs, including oxygenation
◆ Check finger stick blood glucose
◆ Draw metabolic profile, complete blood cell count, toxicology screen, antiepileptic drug
levels
If Seizures Continue, First-line Antiepileptic Drug
◆ Treat with one of the following
◇ IV lorazepam 0.1 mg/kg total dose, can repeat (maximum 4 mg/single dose)
◇ IV diazepam 0.15–0.2 mg/kg total dose, can repeat (maximum 10 mg/single dose)
◇ IM midazolam 10 mg
◆ Alternatives
◇ Rectal diazepam 0.2–0.5 mg/kg (maximum dose 20 mg)
◇ IV phenobarbital 15-20 mg/kg loading dose
◇ Intranasal or buccal midazolam
If Seizures Continue, Second-line Antiepileptic Drug
◆ Treat with one of the following
◇ IV phenytoin or fosphenytoin
◇ IV valproic acid
◇ IV levetiracetam
◇ Others (see TABLE 5-4)
IM = intramuscular; IV = intravenous.
a
Modified with permission from Glauser T, et al, Epilepsy Curr.2 © 2016 American Epilepsy Society.
b
See text for definition of status epilepticus stages.
Typical Empiric
Medication Initial Dose Maintenance Dose Serious Adverse Effects Notes
Levetiracetam 1000–3000 mg IV, up to 500–1500 mg IV Occasional behavioral issues61 Minimal drug interactions
a maximum dose of every 12 hours
4500 mg
Topiramate 200–400 mg orally 300–1600 mg/d Metabolic acidosis Not available in IV form
orally (divided over
2–4 doses daily)
Valproic acid 20–40 mg/kg IV 500–750 mg IV every Thrombocytopenia, Phenytoin and valproic
8 hours gastrointestinal adverse acid interact by
effects (pancreatitis, increasing their free
hepatotoxicity), levels60
hyperammonemia
IV = intravenous.
a
Modified with permission from Brophy GM, et al, Neurocrit Care.1 © 2012 Springer Science+Business Media, LLC.
CONTINUUMJOURNAL.COM 1697
Propofol 1–2 mg/kg 30–200 mcg/kg/min Respiratory depression, hypotension, propofol infusion
loading dose syndrome
Pentobarbital 5–15 mg/kg 0.5–5 mg/kg/h Cardiac and respiratory depression, hypotension, ileus,
loss of neurologic examination at high doses
Thiopental 2–7 mg/kg 0.5–5 mg/kg/h Cardiac and respiratory depression, hypotension
Isoflurane Not established End-tidal concentrations Cardiac and respiratory depression, infections
0.8–2% titrated to EEG
EEG = electroencephalography.
a
Data from Brophy GM, et al, Neurocrit Care1 and Hocker S, et al, Neurol Res.63
CONTINUUMJOURNAL.COM 1699
CLINICAL OUTCOMES
Seizures and status epilepticus can lead to poor outcomes; however, it is unclear
whether detecting and treating seizures has an effect on outcomes since, in some
cases, seizures are epiphenomena for severe brain injury rather than the primary
offender.10 Mortality with status epilepticus may reach up to 30% in adults.2
Age older than 60 years, female sex, treatment in smaller-sized hospitals, the
presence of comorbidities (eg, hypertension, diabetes mellitus, previous stroke),
status epilepticus complications (eg, respiratory failure, sepsis), and etiologies
such as status epilepticus postcardiopulmonary resuscitation have been
associated with worse discharge outcomes.79
Outcomes in refractory status epilepticus can be worse, with mortality
reaching 16% to 39%.6 In one study of 54 patients and 63 episodes of refractory
status epilepticus, the mean length of hospital stay was 27.7 days. Poor outcome
at discharge (mRS score of 4 to 6) was noted in 76.2% of patients, and in-hospital
mortality occurred in 31.8%. Mechanical ventilation was required in 90.5% of
patients. Prolonged mechanical ventilation was associated with mortality. Poor
functional outcome was associated with greater CSF white blood cell count, more
days under anesthetic agents, the need for intervention for cardiac arrhythmias,
pneumonia, lack of seizure control on EEG (eg, requiring isoelectric or burst
suppression), and prolonged hospital stay. Seizure control without need for deep
CONTINUUMJOURNAL.COM 1701
TABLE 5-6 Suggested Treatment Algorithm for Refractory Status Epilepticus (Stage III)
and Super-refractory Status Epilepticus (Stage IV)a
CONTINUUMJOURNAL.COM 1703
seizures.80 A subsequent study found that STESS was a predictor of survival and
ability to achieve baseline clinical condition. This study also suggested that
patients who had favorable STESS scores generally appeared to survive
regardless of whether or not they received coma induction for their status
epilepticus.81 This score was further externally validated in a study of 171 patients
in which the STESS score identified survivors better than nonsurvivors.82 The
Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) was created
using epidemiologic data in hopes of being superior to the STESS score. Points
were developed based on mortality rates in the literature for factors that were
thought to be predictive. Items eventually included in the score were etiology,
age, comorbidities, and EEG findings. This score explained individual mortality
in almost 90% of cases and was found to be superior to STESS.83
More recently, the END-IT score (the letters of which are an acronym for the
score’s components, encephalitis, nonconvulsive status epilepticus, diazepam
resistance, image abnormalities, and tracheal intubation) was created as an
outcome prediction tool in 132 patients with convulsive status epilepticus.
Independent predictors of unfavorable outcome (mRS score of 3 to 6) at
3 months after discharge were encephalitis, nonconvulsive status epilepticus
(defined as subtle status epilepticus in which myoclonic jerks or nystagmus
occurred in insufficiently treated convulsive status epilepticus), diazepam
resistance, imaging abnormalities (unilateral lesions, bilateral lesions, or diffuse
cerebral edema), and intubation. One point was given for each category except
for imaging (in which 1 point was given for unilateral lesions and 2 points for
diffuse cerebral edema or bilateral lesions). The greater the sum of these
categories, the greater the probability of unfavorable outcome. An END-IT score
of 3 or greater seemed to be the cutoff point to provide the best sensitivity and
specificity for predicting unfavorable outcome.84
CONCLUSION
Status epilepticus is a neurologic emergency and can progress to refractory status
epilepticus and super-refractory status epilepticus. Although much progress
has been made in diagnosing and treating status epilepticus, more studies are
needed to delineate optimal management and to improve outcomes.
REFERENCES
1 Brophy GM, Bell R, Claassen J, et al. Guidelines 4 Beniczky S, Hirsch LJ, Kaplan PW, et al. Unified
for the evaluation and management of status EEG terminology and criteria for nonconvulsive
epilepticus. Neurocrit Care 2012;17(1):3–23. status epilepticus. Epilepsia 2013;54(suppl 6):
doi:10.1007/s12028-012-9695-z. 28–29. doi:10.1111/epi.12270.
2 Glauser T, Shinnar S, Gloss D, et al. Evidence- 5 Berg AT, Berkovic SF, Brodie MJ, et al. Revised
based guideline: treatment of convulsive status terminology and concepts for organization of
epilepticus in children and adults: report of the seizures and epilepsies: report of the ILAE
guideline committee of the American Epilepsy Commission on Classification and Terminology,
Society. Epilepsy Curr 2016;16(1):48–61. 2005–2009. Epilepsia 2010;51(4):676–685.
doi:10.5698/1535-7597-16.1.48. doi:10.1111/j.1528-1167.2010.02522.x.
3 Trinka E, Cock H, Hesdorffer D, et al. A definition 6 Rossetti AO, Lowenstein DH. Management of
and classification of status epilepticus—report of refractory status epilepticus in adults: still more
the ILAE Task Force on classification of status questions than answers. Lancet Neurol 2011;
epilepticus. Epilepsia 2015;56(10):1515–1523. 10(10):922–930. doi:10.1016/S1474-4422(11)70187-9.
doi:10.1111/epi.13121.
CONTINUUMJOURNAL.COM 1705
35 Sarikaya I. PET studies in epilepsy. Am J Nucl Med 49 Treiman DM, Meyers PD, Walton NY, et al. A
Mol Imaging 2015;5(5):416–430. comparison of four treatments for generalized
convulsive status epilepticus. Veterans Affairs
36 Claassen J, Mayer SA, Kowalski RG, et al.
Status Epilepticus Cooperative Study Group.
Detection of electrographic seizures with
N Engl J Med 1998;339(12):792–798. doi:10.1056/
continuous EEG monitoring in critically ill
NEJM199809173391202.
patients. Neurology 2004;62(10):1743–1748.
doi:10.1212/01.WNL.0000125184.88797.62. 50 Alldredge BK, Gelb AM, Isaacs SM, et al. A
comparison of lorazepam, diazepam, and
37 Dunne JW, Summers QA, Stewart-Wynne EG.
placebo for the treatment of out-of-hospital
Non-convulsive status epilepticus: a prospective
status epilepticus. N Engl J Med 2001;345(9):
study in an adult general hospital. Q J Med 1987;
631–637. doi:10.1056/NEJMoa002141.
62(238):117–126. doi:10.1093/oxfordjournals.
qjmed.a068084. 51 Silbergleit R, Durkalski V, Lowenstein D, et al.
Intramuscular versus intravenous therapy for
38 Rudin D, Grize L, Schindler C, et al. High
prehospital status epilepticus. N Engl J Med 2012;
prevalence of nonconvulsive and subtle status
366(7):591–600. doi:10.1056/NEJMoa1107494.
epilepticus in an ICU of a tertiary care center: a
three-year observational cohort study. Epilepsy 52 Leppik IE, Derivan AT, Homan RW, et al. Double-
Res 2011;96(1–2):140–150. doi:10.1016/j.eplepsyres. blind study of lorazepam and diazepam in status
2011.05.018. epilepticus. JAMA 1983;249(11):1452–1454.
39 Towne AR, Waterhouse EJ, Boggs JG, et al. 53 Misra UK, Kalita J, Maurya PK. Levetiracetam versus
Prevalence of nonconvulsive status epilepticus lorazepam in status epilepticus: a randomized,
in comatose patients. Neurology 2000;54(2): open labeled pilot study. J Neurol 2012;259(4):
340–345. doi:10.1212/WNL.54.2.340. 645–648. doi:10.1007/s00415-011-6227-2.
40 Laccheo I, Sonmezturk H, Bhatt AB, et al. Non- 54 Misra UK, Kalita J, Patel R. Sodium valproate vs
convulsive status epilepticus and non-convulsive phenytoin in status epilepticus: a pilot study.
seizures in neurological ICU patients. Neurocrit Neurology 2006;67(2):340–342. doi:10.1212/01.
Care 2015;22(2):202–211. doi:10.1007/s12028- wnl.0000224880.35053.26.
014-0070-0.
55 Gilad R, Izkovitz N, Dabby R, et al. Treatment
41 Betjemann JP, Nguyen I, Santos-Sanchez C, et al. of status epilepticus and acute repetitive
Diagnostic yield of electroencephalography in a seizures with i.v. valproic acid vs phenytoin.
general inpatient population. Mayo Clin Proc Acta Neurol Scand 2008;118(5):296–300.
2013;88(4):326–331. doi:10.1016/j.mayocp. doi:10.1111/j.1600-0404.2008.01097.x.
2012.12.013.
56 Shaner DM, McCurdy SA, Herring MO, Gabor AJ.
42 Bauer J, Stefan H, Huk WJ, et al. CT, MRI and Treatment of status epilepticus: a prospective
SPECT neuroimaging in status epilepticus with comparison of diazepam and phenytoin versus
simple partial and complex partial seizures: phenobarbital and optional phenytoin.
case report. J Neurol 1989;236(5):296–299. Neurology 1988;38(2):202–207. doi:10.1212/
doi:10.1007/BF00314460. WNL.38.2.202.
43 Tatum WO, Alavi A, Stecker MM. Technetium- 57 Chen WB, Gao R, Su YY, et al. Valproate versus
99m-HMPAO SPECT in partial status epilepticus. diazepam for generalized convulsive status
J Nucl Med 1994;35(7):1087–1094. epilepticus: a pilot study. Eur J Neurol 2011;18(12):
1391–1396. doi:10.1111/j.1468-1331.2011.03420.x.
44 Kutluay E, Beattie J, Passaro EA, et al. Diagnostic
and localizing value of ictal SPECT in patients 58 Agarwal P, Kumar N, Chandra R, et al.
with nonconvulsive status epilepticus. Epilepsy Randomized study of intravenous valproate and
Behav 2005;6(2):212–217. doi:10.1016/j.yebeh. phenytoin in status epilepticus. Seizure 2007;
2004.12.001. 16(6):527–532. doi:10.1016/j.seizure.2007.04.012.
45 Siclari F, Prior JO, Rossetti AO. Ictal cerebral 59 Yasiry Z, Shorvon SD. The relative effectiveness
positron emission tomography (PET) in focal of five antiepileptic drugs in treatment of
status epilepticus. Epilepsy Res 2013;105(3): benzodiazepine-resistant convulsive status
356–361. doi:10.1016/j.eplepsyres.2013.03.006. epilepticus: a meta-analysis of published
studies. Seizure 2014;23(3):167–174. doi:10.1016/
46 Trinka E, Kälviäinen R. 25 Years of advances in the
j.seizure.2013.12.007.
definition, classification and treatment of status
epilepticus. Seizure 2017;44:65–73. doi:10.1016/ 60 Perucca E, Hebdige S, Frigo GM, et al. Interaction
j.seizure.2016.11.001. between phenytoin and valproic acid: plasma
protein binding and metabolic effects. Clin
47 Claassen J, Perotte A, Albers D, et al. Nonconvulsive
Pharmacol Ther 1980;28(6):779–789. doi:10.1038/
seizures after subarachnoid hemorrhage:
clpt.1980.235.
Multimodal detection and outcomes. Ann Neurol
2013;74(1):53–64. doi:10.1002/ana.23859. 61 Cramer JA, De Rue K, Devinsky O, et al. A
systematic review of the behavioral effects of
48 Vespa P, Tubi M, Claassen J, et al. Metabolic
levetiracetam in adults with epilepsy, cognitive
crisis occurs with seizures and periodic
disorders, or an anxiety disorder during clinical
discharges after brain trauma. Ann Neurol 2016;
trials. Epilepsy Behav 2003;4(2):124–132.
79(4):579–590. doi:10.1002/ana.24606.
doi:10.1016/S1525-5050(03)00005-2.
DISCLOSURE
Continued from page 1683
Dr Varelas has received personal compensation for Therapeutics, Inc; Marinus Pharmaceuticals, Inc;
speaking engagements for Portola Pharmaceuticals, the National Institutes of Health; the Patient-
Inc and UCB SA and receives publishing royalties Centered Outcomes Research Institute; and Portola
from Springer. Dr Varelas receives research/grant Pharmaceuticals, Inc
support from Bard Pharmaceuticals Limited; Edge
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