Status Epilepticus in Pediatric Emergency: Article Review

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Status epilepticus in the pediatric emergency department
Article in Clinical Pediatric Emergency Medicine · March 2015
DOI: 10.1016/j.cpem.2015.01.001
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Abstract:
Status epilepticus is a common pediatric neurologic condition that often
presents to the emergency department. Prior neurologic abnormalities
or preexisting epilepsy are significant
risk factors for the development of
status epilepticus, although younger
children more commonly present with
either an acute symptomatic or febrile etiology. Prolonged seizure duration is associated with the
development of resistance to anticonvulsants and the potential for
permanent neurologic injury. Treatment strategies should focus on rapid
administration of appropriate antiepileptic medications, with benzodiazepines used as the first-line agent.
Nonconvulsive and subclinical status
epilepticus may be difficult to identify.
A high index of suspicion should be
maintained for nonconvulsive status
epilepticus, particularly in encephalopathic and critically ill children.
Treatment of refractory status epilepticus often requires intensive care
unit admission and the involvement
of a neurologist. Initial diagnostic
evaluation should include a broad
differential and be focused on treatable causes, including central nervous system infections, electrolyte
and metabolic disorders, and trauma.
Keywords:
status epilepticus; subclinical status
epilepticus; nonconvulsive status
epilepticus; refractory status
epilepticus; anticonvulsant
Department of Pediatrics, Division of
Neurology, Ann & Robert H. Lurie Children's
Hospital of Chicago, Northwestern University
Feinberg School of Medicine, Chicago, IL;
Ruth D. & Ken M. Davee Pediatric
Neurocritical Care Program, Ann & Robert H.
Lurie Children's Hospital of Chicago,
Northwestern University Feinberg School of
Medicine, Chicago, IL.
Status Epilepticus
in the Pediatric
Emergency
Department
S
Jonathan E. Kurz, MD, PhD,
Joshua Goldstein, MD
tatus epilepticus (SE) is a common, life-threatening
neurologic emergency, characterized by persistent,
continuous seizure activity. It is commonly encountered
by pediatric emergency care providers; 6 to 7% of
patients presenting to the emergency department (ED) with
seizure are in SE, 1,2 and there are approximately 3.1 million
pediatric ED visits in the United States for seizure yearly. 3
Prolonged seizures carry a significant risk of mortality, estimated
to be 3% among pediatric patients. 4,5 Status epilepticus additionally predisposes patients to short- and long-term neurologic
morbidities, including recurrent SE, cognitive deficits, and
neurodevelopmental delays. 4,6,7 Animal models suggest that
resistance to anticonvulsant therapy develops as the duration of
seizure increases. 8 Early recognition of SE and appropriate
treatment by prehospital and emergency care providers may
therefore improve chances for rapid seizure control and reduce
subsequent morbidity and mortality.
CLASSIFICATION AND PATHOPHYSIOLOGY
Status epilepticus is characterized by continuous clinical and/
or electrographic seizure activity, or episodes of recurrent seizure
activity without recovery between seizures. There is considerable
variability in the duration of continuous seizures required to meet
the threshold for SE in clinical trials and treatment guidelines.
Current practices favor a shorter duration of continuous seizures
being defined as SE, based on the typical duration of individual
seizures and animal data suggesting increased risk for
STATUS EPILEPTICUS IN THE PEDIATRIC EMERGENCY DEPARTMENT / KURZ AND GOLDSTEIN • VOL. 16, NO. 1 37
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VOL. 16, NO. 1 • STATUS EPILEPTICUS IN THE PEDIATRIC EMERGENCY DEPARTMENT / KURZ AND GOLDSTEIN
Reprint requests and correspondence:
Joshua Goldstein, MD, Ann and Robert H.
Lurie Children's Hospital of Chicago, Division
of Child Neurology, No. 51, 225 E. Chicago
Ave, Chicago, IL 60614.
[email protected] (J.E. Kurz),
[email protected] (J. Goldstein)
1522-8401
© 2015 Published by Elsevier Inc.
pharmacoresistance and neuronal injury with increasing seizure duration. 9,10
Most seizures are self-limited, brief events. In
adult epilepsy monitoring units, video and subdural
electrode monitoring of patients with secondarily
generalized seizures demonstrated a mean clinical
and electrographic duration of less than 2 minutes. 11
Another study of adult seizure duration documented
mean seizure durations of 130 seconds or less,
depending on seizure type. 12 Most seizures in
children are similarly brief and self-limited. Among
children with new-onset seizure, 76% of seizures
were brief, with a mean duration of 3.6 minutes; the
remainder lasted more than 30 minutes. 13 Seizures
lasting more than 10 to 15 minutes are less likely to
stop spontaneously 13 and may signify a failure of the
mechanisms that typically terminate a seizure.
These longer events are more likely to progress to
the self-sustaining and continuous seizures of SE.
Data from animal models show that experimentally
induced seizures become self-sustaining between 15
and 30 minutes. After this point, a self-perpetuating
circuit presumably develops, sustaining seizure activity for hours without further stimulation. 14 Although
extrapolation of animal data to clinical practice is
imprecise, a continuous seizure in humans is thought
to involve both failure of the typical endogenous
mechanisms leading to seizure termination and
development of self-sustaining seizure activity.
Numerous neurophysiologic and biochemical
changes are postulated to play a role in the initiation
of SE. For example, synaptic expression and subunit-specific trafficking of g-aminobutyric acid type A
(GABAA) receptors changes with increasing seizure
duration. 15 The resultant change in GABA-nergic
inhibitory neurotransmission may help sustain ongoing seizure activity. In addition, seizure-induced
changes in GABA receptor subunit composition
may decrease response to anticonvulsant therapies
by altering receptor sensitivity to benzodiazepines. 16
In animal models, as seizure duration increases,
resistance to anticonvulsant medications develops. 8
Similarly, in a study of pediatric patients, delay
between seizure onset and treatment in the ED was
associated with an increase in the risk of seizures
lasting more than 60 minutes. 17 These data support
aggressive treatment of seizures at earlier timepoints, before the development of self-sustaining
seizures and pharmacoresistance impairs the efficacy
of abortive anticonvulsive therapy.
Seizure-induced neuronal injury may also occur
during SE. In an animal model of pilocarpine-induced
SE, dead neurons begin to appear in the hippocampus
after 20 minutes of continuous seizure activity, and
mild damage is present in multiple brain regions by 40
minutes. 18 Similarly, in primate studies, evidence of
brain injury was present after 45 to 60 minutes of
continuous seizure. 19 Neuronal injury may be due to
both ischemic 19 and excitotoxic 20 mechanisms.
Evidence for seizure-induced brain injury in human
studies is less detailed, and the exact time-point at
which injury begins to occur is not well defined. 21
There is limited magnetic resonance imaging (MRI)
evidence that suggests that prolonged seizures cause
cerebral atrophy. In addition, some authors have
postulated that decreases in measured mortality in
pediatric SE over the past 4 decades are due to earlier
and more effective treatment of SE, implying that
morbidity and mortality in prolonged seizure may be
duration dependent. 22
In consideration of the short typical duration of
self-limited seizures, the potential for pharmacoresistance with longer events, and the potential for
seizure-induced neuronal injury that may occur
with a longer duration of continuous seizures, the
threshold duration of seizure defined as SE in
clinical trials and treatment guidelines has been
repeatedly revised. Earlier definitions specified
1-hour or 30-minute time-points; 23,24 the 30-minute
definition continues to be used extensively in
clinical research. More recently, other authors, 25
as well as recent guidelines from the Neurocritical
Care Society, 9 have proposed defining SE as 5
minutes of continuous seizure. In addition, some
authors propose a category of “early” or “impending” SE at 5 minutes of continuous seizure, for the
purpose of initiating early treatment, while maintaining the 30 minute time-point as a threshold for
“established” SE for the purpose of epidemiologic
studies. 26 Regardless of the definition used, it is
reasonable to begin pharmacologic treatment at 5
minutes of continuous seizure, in an attempt to abort
the seizure prior to the development of physiologic
changes that limit response to treatment or promote
neuronal injury. In addition to avoiding brain injury,
prompt treatment of continuous seizures may
shorten recovery time, reduce morbidity, and
reduce the need for intensive care admission. 7,27
STATUS EPILEPTICUS IN THE PEDIATRIC EMERGENCY DEPARTMENT / KURZ AND GOLDSTEIN • VOL. 16, NO. 1 39
Status epilepticus can be classified by semiology
into convulsive (CSE) and nonconvulsive SE
(NCSE). Convulsive SE typically is characterized
by generalized tonic-clonic convulsions and mental
status impairment, although myoclonic SE and
tonic SE also can present in certain clinical
situations. Focal motor SE (epilepsia partialis
continua) is generally considered to be a separate
entity from CSE and is not covered by this review.
Nonconvulsive SE has been defined as a range of
conditions in which electrographic seizure activity is
prolonged and results in nonconvulsive clinical symptoms, 28 coupled with a proposed minimal seizure
duration of 30 minutes. Nonconvulsive SE can be
associated with subtle motor manifestations or can be
entirely subclinical, presenting only with a clouding of
alertness, confusion, or a change in mental status.
EPIDEMIOLOGY
Status epilepticus is one of the most common
pediatric neurologic emergencies, with an incidence
of 17 to 38 per 100 000 in children. 4,29 The
incidence of pediatric SE is age dependent; reported
incidences are as high as 51 to 156 per 100 000 in
the first year of life 4,29 and lowest among adolescents. Most epidemiologic studies of SE have used a
30-minute time-point as the definition of SE;
including children that present with prolonged
seizures in the 5- to 29-minute range would likely
result in higher incidences. The mean age of
children presenting with SE is 4.4 years. Most of
these cases are convulsive SE. 30
Prior neurologic conditions are a risk factor for
developing SE. Fifty-six to 60% of children presenting with SE are neurologically normal beforehand,
whereas the remainder have a preexisting neurologic abnormality. 4,30 These remote symptomatic
causes of SE are less common in younger children
(who more commonly present with febrile or acute
symptomatic SE) and more common in older
children and adolescents. In one study, 60% of
children older than 5 years with SE had a prior
neurologic abnormality, compared with only 21% of
children younger than 2 years. 30
Preexisting epilepsy is a risk factor for developing
SE. Approximately 10% of children with childhood-onset epilepsy will experience at least one
episode of SE. 31 In an analysis of 2 large cohorts of
children with SE, 45% had a history of one or more
unprovoked afebrile seizures. 30 Among children
with chronic epilepsy, a major risk factor for
developing SE is having experienced prior episodes
of SE; 32 occurrence of SE is more than 20-fold
higher in children with a history of SE than in those
TABLE 1. Etiologies of status epilepticus.
Febrile SE
Presents between 6 mo and 6 y of age
Should rule out infectious causes
Acute symptomatic
Infectious
- Bacterial meningitis
- Viral encephalitis (including herpes simplex)
Metabolic
- Hypoglycemia and hyperglycemia
- Hyponatremia and hypernatremia
- Hypocalcemia
- Hypomagnesemia
Toxicologic
Trauma
- Epidural, subdural, or subarachnoid hemorrhage
- Intraparenchymal hemorrhage
Vascular
- Arterial ischemic stroke
- Central sinus venous thrombosis
Preexisting epilepsy
Medication withdrawal or noncompliance
Concurrent infection
Remote symptomatic
Prior central nervous system (CNS) trauma, stroke, cortical
malformation, other preexisting CNS abnormality
without. Patients with a history of seizure clustering
are also more likely to experience SE. 32 The risk of
recurrent episodes of SE is highest in children with
remote symptomatic etiologies and those with
progressive neurologic disease. 33
ETIOLOGIES AND DIAGNOSTIC WORKUP
On initial assessment of patients with SE, emergency providers should maintain a broad differential
diagnosis. Causes of SE can be separated into febrile
SE, acute symptomatic, remote symptomatic, and
idiopathic or cryptogenic (Table 1). During acute
evaluation and treatment, providers should have a
particular focus on identifying reversible causes of
SE, such as electrolyte disturbances, hypoglycemia,
and for patients already on antiepileptic drugs
(AED), subtherapeutic medication levels. Acute
evaluations should also be focused on identifying
potential underlying etiologies that are life-threatening or will require a change in acute management, such as central nervous system (CNS)
infection, trauma, or stroke (Table 2).
Febrile seizures are the most common form of
pediatric seizure, affecting 2 to 4% of children in the
United States and Western Europe. 34 Presenting
between 6 months and 6 years of age, most of these
40
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TABLE 2. Initial studies for status epilepticus
without identified etiology.
Serum electrolytes (sodium, magnesium, calcium) and glucose
Computed tomography of head
Complete blood count
Antiepileptic drug levels (if applicable)
Lumbar puncture (if febrile or concern for CNS infection)
Consider urine or serum toxicology (if ingestion history or cause
not identified)
events are simple febrile seizures, or, single, nonfocal events lasting less than 10 minutes occurring
in otherwise healthy children. However, febrile SE
(defined as duration N 30 minutes) represents 5% of
all febrile seizures, and febrile SE is the underlying
etiology for approximately one quarter of all
episodes of childhood SE. Febrile SE accounts for
more than two thirds of SE occurring in children
between 1 and 2 years of age. 30 These seizures can
be very prolonged; in one study, 24% of episodes of
febrile SE lasted longer than 2 hours. 35 Ninety
percent of patients in febrile SE required an AED to
terminate the seizures, with patients requiring an
average of 2 medications. 36 Most of febrile SE is
convulsive, and most seizures have some focal
features. 35 As with other etiologies of SE, prompt
treatment should be initiated to limit neurologic
morbidity in febrile SE. Prolonged febrile seizure
can lead to acute hippocampal injury detectable on
MRI, with increased risk for the development of
mesial temporal sclerosis. 37 Although common,
febrile SE is a diagnosis of exclusion, and other
causes of prolonged seizure with fever, including
CNS infection, should be excluded. Cerebrospinal
fluid (CSF) analysis in children after febrile SE is
typically normal, 38 and CSF pleocytosis should
raise a concern for CNS infection or another
medical explanation.
Central nervous system infection is a common
etiology of SE in children. Meningoencephalitis or
encephalitis, either bacterial or viral, can lead to SE.
A documented CNS infection was reported on
average in 12.8% of children with SE in one
meta-analysis. 39 In a series of 24 children with SE
and fever, bacterial meningitis was detected in 17%
of the febrile group, none of whom exhibited typical
signs of meningismus. 40 Another report documented acute bacterial meningitis in 11% of children
presenting with first ever febrile SE. 4 Given these
data, lumbar puncture (LP) and CNS imaging should
be obtained in the setting of SE and fever at any age,
unless an LP is contraindicated or another etiology
is clearly identified. Empiric treatment with antibiotics and acyclovir should be considered until CSF
analysis excludes herpes encephalitis or bacterial
meningitis as a possibility.
Among children with preexisting epilepsy, medication noncompliance or withdrawal is a frequent
cause of SE. Even children with well-controlled
epilepsy can experience prolonged seizures after
missing medication doses. Among children taking
AEDs who experienced SE, 32% had low serum
levels in one analysis. 39 In children with epilepsy
who are taking AEDs, obtaining serum levels
should be considered if available. A careful
medication history should be obtained to determine if there are missed doses or recent medication changes.
Electrolyte abnormalities such as hyponatremia,
or metabolic abnormalities such as hyperglycemia
or hypoglycemia, can play a role in pediatric SE.
Hypocalcemia may present as SE in neonates. In
studies of the diagnostic yield of these studies,
electrolyte or glucose abnormalities have been
reported in 6% of children with SE on average. 39
Status epilepticus induced by electrolyte abnormalities may be refractory to treatment until the
underlying metabolic disturbance is corrected.
Evaluation of electrolytes and glucose should be
obtained on all children presenting with SE. Toxic
ingestion may be suggested by the history and
should also be considered in cases with unknown
etiology. Toxic ingestion is documented in 3.6% of
reported cases of SE. 39 Serum and urine toxicology
may be helpful in establishing a diagnosis in these
cases. Urine toxicology screening tests typically evaluate only for drugs of abuse; if ingestion of a specific
agent is suggested by the history, specific serum
toxicologic testing for that agent may be more useful.
Seizures and SE can be the presenting symptom
of traumatic brain injury. Although trauma may be
suggested by the history or examination, in some
cases, the history may be unclear. In particular, in
cases of nonaccidental trauma, the initial history
may be incomplete or inaccurate. Nonaccidental
injury in infants is strongly associated with the
development of prolonged seizure activity. 41 Clinicians should be observant for any external findings
that are suggestive of traumatic injury. In cases
where a clear etiology of SE cannot be identified,
neuroimaging should be obtained once the child is
stabilized and the seizures are controlled. These
studies are reasonably high yield in this setting; in
one study of patients with new-onset seizure
presenting as SE, neuroimaging (computed tomography [CT] or MRI) was diagnostic of an underlying
etiology in 30% of patients and directed management
STATUS EPILEPTICUS IN THE PEDIATRIC EMERGENCY DEPARTMENT / KURZ AND GOLDSTEIN • VOL. 16, NO. 1 41
in 24%. 42 Although MRI identified abnormalities not
detected by CT, these were mostly lesions associated
with a remote, rather than acute symptomatic cause.
Computed tomography is generally appropriate as an
acute imaging modality for patients presenting with
SE. Limited-sequence rapid MRI protocols are available in some centers and may also be considered for
initial imaging.
Vascular lesions, such as arterial ischemic stroke
or central sinus venous thrombosis, may present as
seizure or SE. 43 A persistent new focal neurologic
finding should raise a high suspicion for stroke,
although prolonged seizure with a subsequent Todd
paralysis may mimic stroke-like symptoms. Patients
with new focal neurologic findings all require
neuroimaging as part of their evaluation. Computed
tomographic imaging of the brain may be helpful in
identifying acute ischemic stroke and intracranial
hemorrhage, although subtle or hyperacute ischemic lesions may require repeat imaging to identify.
MRI with diffusion-weighted imaging provides superior evaluation for ischemia, particularly small
infarcts or lesions in the posterior fossa. MRI should
be considered as part of a patient's evaluation for SE
once the patient is stable enough for the longer
imaging procedure, particularly if there is a high
suspicion for stroke or structural lesion not identified on CT.
Remote symptomatic causes, such as occult prior
CNS injury, cortical dysplasia, or vascular malformations (in the absence of acute hemorrhage), also
may present as SE. Identification of these causes
may require imaging with MRI or more detailed
laboratory evaluation. Because these remote causes
are generally not acutely reversible, this evaluation
may continue outside the emergent setting. Similarly, other acute symptomatic etiologies, such as
CNS autoimmune conditions, may require extensive serologic testing to identify as part of an ongoing
workup after the patient has left the ED.
ACUTE TREATMENT
Although guidelines and practice parameters
regarding the acute management of SE are available, 9 there is no universally accepted treatment
paradigm for pediatric SE, and protocols can vary
between institutions. 44 Despite this, there is agreement on common principles of treatment of SE,
including the need for rapid and appropriate
therapy to terminate seizures (Figure 1). As with
any critically ill patient, the first steps in management should be assessment of vital signs, airway,
breathing, and circulation. The airway should be
secured, first with noninvasive maneuvers (midline
positioning, jaw thrust, or chin tilt) and with more
invasive measures if necessary. Oxygen should be
provided, intravenous (IV) access obtained, and any
hemodynamic instability addressed. Reassessment
of airway, breathing, and circulation and vital signs
should continue throughout the acute treatment of
SE, and providers should remain alert for changes
induced both by prolonged seizure and by adverse
effects of therapy. Many AEDs are sedating and may
lead to an inability to maintain a safe airway,
potentially requiring further intervention; prolonged
seizure may induce an encephalopathy with a similar
potential effect. Benzodiazepines and barbiturates
can suppress respiratory drive. Several medications,
particularly barbiturates, can induce hypotension. As
discussed above, diagnostic workup should begin
concurrently with acute treatment. A glucose check
should be obtained during the initial assessment.
Most treatment protocols advocate a stepwise
approach to anticonvulsant therapy in CSE. Anticonvulsant therapy should begin after 5 minutes of
continuous seizure activity. Benzodiazepines are
generally given as the first-line agent, followed by a
loading dose of an IV AED, most commonly fosphenytoin. It is important to avoid excessive time intervals
between medications, underdosing of medications, or
provision of medications via an inappropriate route.
First-Line Treatment
Intravenous lorazepam is the preferred agent for
initial therapy of SE. Data from adult studies suggest
that IV lorazepam is superior to IV diazepam and IV
phenytoin alone for control of SE, 45 although one
pediatric randomized clinical trial suggests that IV
diazepam and lorazepam may be equivalent in
children. 46 Lorazepam should be given at a dose of
0.1 mg/kg IV (at a rate of up to 2 mg/min) to a
maximum dose of 2 to 4 mg. If IV access is not
available or will require a significant delay in therapy,
numerous other benzodiazepine dosage routes are
available. Midazolam can be administered via intramuscular, buccal, or intranasal routes; buccal or
intranasal dosing is 0.2 to 0.5 mg/kg up to a maximal
dose of 10 mg. 47,48 Diazepam is the preferred
medication for rectal administration. Rectal dosing
ranges from 0.2 to 0.5 mg/kg, depending on age. 49
Benzodiazepine therapy should be provided promptly
and at an adequate dose.
Importantly, frequent small or subtherapeutic doses
of benzodiazepines should be avoided, as this will delay
time to adequate serum concentrations of anticonvulsant. Instead, 1 or 2 doses of benzodiazepine should be
provided at a therapeutic dose, to allow for more timely
administration of a second agent if needed.
42
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Figure 1. Algorithm for initial therapy of status epilepticus.
Second-Line Treatments
After initial therapy with benzodiazepines, the next
phase of management is an IV loading dose of an AED.
There are 2 goals of this phase of therapy: terminating
ongoing seizure activity and rapidly producing
therapeutic serum concentrations of an AED for
ongoing seizure control after SE is terminated.
Intravenous fosphenytoin is most commonly used
as the agent of choice for second-line therapy in
pediatric SE. Fosphenytoin is a water-soluble prodrug
that is converted to phenytoin by serum and tissue
alkaline phosphatase within 10 minutes of administration. Phenytoin acts at neuronal voltage-gated
sodium channels to limit repetitive firing of action
potentials. In both adult and pediatric randomized
controlled trials, a phenytoin-diazepam combination
was equivalent to lorazepam in terminating SE as a
first-line agent. 45,50 In a study of 3 second-line agents
in SE, the efficacy of phenytoin was not statistically
different from valproic acid or levetiracetam. 51 As
compared with phenytoin, fosphenytoin infusion is
less likely to induce cardiac arrhythmias and has a
lower risk of causing tissue necrosis if extravasation
occurs. 52 Fosphenytoin is dosed in phenytoin equivalents (PE). A typical loading dose in SE is 20 mg PE/
kg IV, which should provide a serum total phenytoin
level of approximately 20 μg/mL. Some protocols
STATUS EPILEPTICUS IN THE PEDIATRIC EMERGENCY DEPARTMENT / KURZ AND GOLDSTEIN • VOL. 16, NO. 1 43
advocate a second dose of 5 to 10 mg PE/kg in children
with persistent seizures after the initial loading dose.
Other IV AEDs have also been studied as acute
therapy for CSE as alternatives to phenytoin.
Valproic acid (VPA) is an AED with several proposed
mechanisms, including action at T-type calcium
channels, voltage-gated sodium channels, and
GABA receptors. Valproic acid presents several
advantages in the setting of CSE: it can be rapidly
administered via IV and is efficacious against a
broad variety of seizure types (including primary
generalized epilepsy), and loading doses are generally well tolerated. Two randomized controlled trials
(primarily with adult patients) have been reported
comparing efficacy of VPA to phenytoin in the
treatment of acute SE. Both trials demonstrated that
VPA was equivalent or superior to phenytoin in
achieving seizure control. 53,54 In a retrospective
review of VPA loading for SE and repetitive seizures
in pediatric patients, VPA was similarly effective in
controlling seizures and was not associated with
significant adverse effects. 55 Based on these data, IV
loading doses of VPA are a reasonable alternative to
phenytoin for second-line therapy in acute SE. This
may be particularly true in patients with primary
generalized epilepsy or in cases where phenytoin is
contraindicated (such as patients with sodium
channelopathies or documented phenytoin allergy).
Loading doses in the range of 20 to 40 mg/kg are
typically reported. Limitations to the acute use of
VPA include the potential for hepatotoxicity, hyperammonemia, pancreatitis, and teratogenicity. The
risk for VPA-induced hepatotoxicity is highest for
children younger than 2 years receiving VPA as
polytherapy, 56 and caution should be used in this
age group. Valproic acid should be avoided in
children with preexisting hepatic failure, pancreatitis, or mitochondrial disease. Valproic acid therapy
is also associated with development of congenital
malformations, particularly if given during the first
trimester, 57 and should be avoided in pregnant
patients.
Phenobarbital is the most commonly used AED in
neonatal SE, based on established practice. Studies
regarding the use of phenobarbital in neonatal
seizures report similar efficacy to phenytoin, although less than 50% of seizures in neonates were
controlled with monotherapy of either agent. 58
Bolus doses of IV phenobarbital can also be used
for control of SE in older children and adults, with
efficacy similar to that of phenytoin or VPA. 45,58
Loading doses in neonates and older children are
typically 20 mg/kg IV, which should yield a plasma
level of approximately 20 mg/L. A loading dose can be
repeated after 15 to 20 minutes if seizures are
not controlled. Phenobarbital acts by enhancing
GABA-mediated inhibitory neurotransmission. Adverse effects of phenobarbital are possible with
loading doses in SE, 59 including excessive sedation,
respiratory depression, and hypotension, which may
play a factor in the choice of phenobarbital as a
second-line medication outside of neonatal SE.
Levetiracetam is a newer AED that offers several
theoretical advantages in the treatment of SE. It is
available in an IV formulation, has minimal interaction with other medications and a benign side-effect profile, and is a broad-spectrum agent that
may be effective against both primary generalized
and focal seizures. Evidence for its efficacy in the
acute treatment of SE is limited, however, one
randomized, controlled pilot study evaluated levetiracetam as a first-line agent at 20 mg/kg, enrolling
79 patients between the ages of 1 and 75 years.
Levetiracetam was found to be equally efficacious as
compared with lorazepam. 60 Further evidence is
available from case series: in one prospective series
of adult patients with SE, levetiracetam appeared to
be most efficacious in focal SE but was ineffective in
all cases of secondarily generalized SE, 61 although
the number of patients in each group was small. In a
retrospective comparison of levetiracetam, phenytoin, and VPA in adult patients, levetiracetam
appeared to be less effective than VPA (and not
statistically different from phenytoin). 50 Published
evidence specifically regarding the use of levetiracetam in pediatric SE is even more limited, with small
numbers of patients with SE reported as part of
larger series of children with seizures. 62,63 At
present, there are insufficient data to recommend
the routine use of levetiracetam as an acute
second-line therapy in pediatric SE, although this
is certainly an area for further study.
Second-line therapy should be administered in a
timely fashion in patients failing benzodiazepines. A
goal for anticonvulsant therapy in SE through the
first dose of fosphenytoin (or other second-line IV
anticonvulsant) should be approximately 20 minutes. A sample protocol used in our institution for
the acute treatment of SE is illustrated in Figure.
Refractory Status Epilepticus
Children that continue to experience continuous
seizure activity despite therapeutic doses of 2 AEDs
(benzodiazepine plus second-line therapy) meet the
criteria for refractory SE (RSE); there is no minimum
duration of seizure required for this diagnosis.
Mortality and neurologic morbidity are higher for
children experiencing RSE as compared with children who respond to first- or second-line therapy. In a
44
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meta-analysis of pediatric refractory generalized
convulsive SE, overall mortality was 16%. Although
reporting of neurologic sequelae of SE varied between
the studies selected for meta-analysis, a new neurologic morbidity was present after RSE in 57% of the 61
patients where data were available. 64 In another
series of children with RSE, 7 of 22 died as a result of
the RSE, and no previously healthy child returned to
their neurologic baseline. 65
After failure of a second-line agent, complete
suppression of seizure activity with a continuous
infusion of an anticonvulsant is recommended. In
some clinical situations, providers may elect to trial a
bolus dose of another anticonvulsant (phenobarbital or
VPA) prior to use of a continuous infusion. A
neurologist should be consulted if available, and
intensive care unit (ICU) admission should be strongly
considered. Respiratory suppression may need to be
tolerated to achieve seizure control; intubation may be
required to secure the airway. Hypotension is a
potential adverse effect of continuous infusion of
anesthetics and should be avoided, particularly because cerebral autoregulation may be impaired by the
continuous seizure activity. Video-electroencephalogram (EEG) monitoring should be considered for all
patients in RSE, both to guide management and to
monitor for subclinical seizures. Up to one third of
these patients experience electrographic seizures after
the convulsive SE is controlled. 66 These seizures may
only be detectable with EEG.
Midazolam or pentobarbital are commonly used as
continuous infusions for the treatment of RSE. In a
retrospective study of 358 children, midazolam
infusion resulted in eventual seizure control in
64.5%. 67 Adverse effects included primarily respiratory suppression; no causal relationship between midazolam and cardiovascular depression was observed.
In one meta-analysis, midazolam was associated with a
more rapid return to consciousness and lower intubation rates than barbiturates or inhalational anesthetics. 68 Midazolam infusion is started at a rate of
50 to 100 ug/kg/h and titrated upward to a range of 600
to 1200 ug/kg/h. At our institution, we increase by
increments of 50 to 100 ug/kg/h every 15 to 20
minutes. As discussed previously, continuous EEG
monitoring should be obtained while using continuous
infusions of anticonvulsants. In one adult study of
midazolam use in RSE, breakthrough seizures were
present in 56% of patients, and these were subtle or
entirely subclinical in 89%. 69
Similarly, pentobarbital can be administered as a
continuous infusion for the control of RSE. 70,71
Pentobarbital infusion can be initiated with a loading
dose of 5 to 8 mg/kg, followed by a continuous infusion
at a rate of 0.5 to 1 mg/kg/h. This infusion may be
increased as needed to 3 to 5 mg/kg/h. Pentobarbital is
associated with a significant degree of CNS and
respiratory suppression. Hypotension is more common than that seen with infusions of midazolam, 68 and
patients on pentobarbital infusion require cardiac and
respiratory monitoring in an ICU. The long-half life of
pentobarbital can limit the ability of providers to
obtain a neurologic examination, even after the
infusion has been discontinued.
Nonconvulsive Status Epilepticus
Nonconvulsive SE in pediatric patients encompasses a broad range of conditions, with varying
clinical presentations, prognosis, and management.
Common subtypes that may present to emergency
providers include absence SE, complex partial SE
(focal seizures with alteration of consciousness),
and NCSE in children in coma, which may be seen
in critically ill children and may follow CSE. 72
Absence SE occurs almost exclusively in children
with idiopathic primary generalized epilepsy and
may present with confusion and drowsiness. Children may be alert enough to automatically perform
some routine activities. Automatisms and jerking
movements of the face and limbs may be present.
Complex partial SE may present in a similar fashion,
with confusion and potentially a lack of focal
features; these children may cycle between unresponsive and partially responsive phases. 72 Both of
these conditions require EEG for definitive diagnosis and should be considered in the differential
diagnosis of children presenting with an unexplained encephalopathy, particularly in children
with a known diagnosis of absence or focal epilepsy.
The potential for NCSE in coma has been increasingly recognized in recent years for both children and
adults. In a study of 236 comatose children and adults,
NCSE was identified in 8%. 73 Nonconvulsive SE may
represent the primary cause of an encephalopathy, or
may be secondary to an underlying CNS lesion leading
to both seizures and unresponsiveness. The potential
for NCSE is of particular concern in encephalopathic
critically ill children. In a series of 178 unresponsive
children in ICU monitored with EEG, NCSE was
identified in 33%. 74 In another study, EEG monitoring
was obtained on all encephalopathic patients admitted
to a pediatric ICU, and NCSE was identified in 18%. 75
Nonconvulsive SE may often follow CSE, even if the
clinical seizures have responded to AED therapy. In a
study of adults and children with CSE, 48% of patients
demonstrated persistent electrographic seizures after
treatment of SE, whereas 14% met the criteria for
NCSE. 76 In a retrospective series of 19 children with
NCSE who were comatose or stuporous at the time
STATUS EPILEPTICUS IN THE PEDIATRIC EMERGENCY DEPARTMENT / KURZ AND GOLDSTEIN • VOL. 16, NO. 1 45
of diagnosis, 5 initially presented with CSE, whereas
the remainder had no seizures prior to diagnosis of
NCSE. 77 Children being treated for RSE or children
who do not have improvement of their mental status
after treatment of CSE should have continuous
EEG monitoring to assess for NCSE. Similarly, EEG
should be considered in the evaluation of unresponsive children without a clear etiology, particularly in the setting of critical illness.
SUMMARY
Status epilepticus is a common neurologic emergency that frequently presents to pediatric emergency providers. Although criteria for the definition
of SE vary, there is agreement that treatment should
begin early in the course of continuous seizures.
Delay in treatment increases the risk of prolonged
seizure, medication unresponsiveness, and potential neuronal injury. Treatment protocols may differ
across institutions, but should share common
principles of rapid treatment with appropriate
doses of AEDs. Initial therapy with a benzodiazepine, followed by a second-line agent (typically
fosphenytoin), should be achieved within the first
20 minutes of SE. The initial diagnostic workup
should occur concurrently and should be focused on
identifying acute symptomatic causes of SE that are
either reversible or impact acute management.
Assessment of glucose and electrolytes should be
obtained, an LP obtained in febrile patients, and
neuroimaging performed in all cases where the
underlying etiology is not immediately apparent.
Patients failing appropriate doses of 2 AEDs have
RSE; further treatment can include additional IV
AEDs and continuous infusions of midazolam or
pentobarbital. Patients with RSE will often require
admission to a pediatric ICU for ongoing treatment.
A high index of suspicion should be maintained
regarding NCSE, particularly in patients that do not
have an improvement in mental status after
treatment of CSE.
Acknowledgments
This work was supported by The Ruth D. & Ken M.
Davee Pediatric Neurocritical Care Program.
Conflict of interest: The authors have no conflicts
of interest to disclose.
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