INVITED REVIEW
Status Epilepticus in Children
Vincent Zimmern* and Christian Korff†
Child Neurology Division, Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, U.S.A.; and †Pediatric Neurology Unit, Department of the
*
Woman, Child and Adolescent, University Hospitals, Geneva, Switzerland.
Summary: For various reasons, status epilepticus in children
is different than in adults. Pediatric specificities include
status epilepticus epidemiology, underlying etiologies,
pathophysiological mechanisms, and treatment
options. Relevant data from the literature are presented
for each of them, and questions remaining open for
T here are no significant differences between the definition of
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status epilepticus (SE) in adults and that in children. The
International League Against Epilepsy (ILAE) has a new
definition of SE, given as “a condition resulting either from the
failure of the mechanisms responsible for seizure termination or
from the initiation of mechanisms, which lead to abnormally,
prolonged seizures (after time point t1) and which can have long-
term consequences (after time point t2), including neuronal
death, neuronal injury, and alteration of neural networks.”1 Exact
times for t1 and t2 are defined for tonic–clonic SE, focal SE with
impaired consciousness, and absence SE, but there are limited
data for these time points in pediatric SE, including neonatal SE.2
The same definitions that hold for adults regarding refractory
(RSE) and super-refractory (SRSE) apply to pediatric SE.
EPIDEMIOLOGY/BURDEN
Estimates vary as to the prevalence and mortality of
pediatric SE.3–7 A 2018 review of the global literature suggests
that SE affects about 3 to 42 per 100,000 children per year, with
an overall mortality of about 3%.8 Estimates of incidence and
mortality for pediatric RSE and SRSE remain limited. Current
estimates suggest that RSE accounts for 10% to 40% of pediatric
SE cases, whereas SRSE accounts for 7% to 12.8%.9,10 Mortality
estimates range from 16% to 43.5%11–13 for RSE, while a recent
study from Germany suggests a pediatric SRSE mortality rate of
11.7%.10 As for the mortality risk by age group, it is now well-
established that younger children have higher rates of morbidity
and mortality in SE than older children, irrespective of the
etiology.14,15 However, it should be added that in older children,
etiology is an important predictor of survival.16 Etiology, but not
duration, is also a predictor of recurrence risk of seizures and SE,
with metabolic and structural causes having the highest risk.5
Recurrence of SE occurs in about 20% of cases in a 4-year period
after initial presentation, with most recurrences occurring 2 years
after the first event. Recent analyses suggest a 16% recurrence
The authors have no funding or conflicts of interest to disclose.
Address correspondence and reprint requests to Christian Korff, MD, Pediatric
Neurology Unit, Department of the woman, Child and Adolescent, University
Hospitals, CH-1211 Geneva 14, Switzerland; e-mail: christian.korff@hcuge.ch.
Copyright Ó 2020 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/20/3705-0429
DOI 10.1097/WNP.0000000000000657
clinicalneurophys.com Journal of Clinical Neurophysiology Volume 37, Number 5, September 2020
Copyright © by the American Clinical Neurophysiology Society. Unauthorized reproduction of this article is prohibited.
future studies on status epilepticus in childhood are
listed.
Key Words: Status epilepticus, Children, Current situation, Open
questions.
(J Clin Neurophysiol 2020;37: 429–433)
rate within the first year (95% confidence interval: 10%–24%)
after a first-ever convulsive SE, regardless of whether the episode
of SE was related to prolonged febrile seizures or not.17 Risk of
epilepsy after SE is estimated at 13% to 74%.5
ETIOLOGY
Several studies suggest that infections and fever underlie most
pediatric SE cases.18 Specifically, 32% to 52% of cases of pediatric
SE involved febrile seizures while 9% to 17% involved either an
acute metabolic derangement or central nervous system infec-
tion.6,19,20 The age of the patient also plays a role in how likely an
etiology is to be found. In a large study of children presenting in
convulsive SE,6 the younger the child (especially if younger than
one year), the more likely an acute etiology was to be found.
Although febrile processes are associated with the onset of SE in
the pediatric population, it remains unclear why some febrile
processes lead to SE while others do not. Genetic factors have been
suspected,21 but no genetic variants predisposing to SE have been
discovered. In a twin study of SE, a higher rate of concordance was
found in monozygotic twins compared with dizygotic twins,21 but
at this time, there is not enough evidence to support routine genetic
testing of pediatric SE patients.22 Other risk factors for febrile
pediatric SE under study include infection with human herpesvirus
6 (HHV6) and herpesvirus 7 (HHV7).23,24
PATHOPHYSIOLOGY
The pathophysiology of SE is covered in detail elsewhere in
this review. Here, we mention certain pathophysiologic aspects
that are unique to pediatric SE.
Critical periods of brain development, which are related to
rapid growth in neuronal populations, seem to play an important
role in the outcomes of SE and in the possibility of recovery.25
Normal development of brain regions is dependent on proper
synaptogenesis and synaptic dynamics. Animal models suggest
that interruption of synaptic activation or improper activation
through seizures during said critical period may result in poor
recovery.25 For example, rat pups that have seizures during P9 to
P18 have reduced myelin accumulation that is permanent26 and
also have permanent modification of their hippocampal place
429
 V. Zimmern and C. Korff
cells.27 Another way in which developmental stages affect the
origins and outcomes of SE is by way of the metabolic rate of the
brain. Neonates and infants have slow metabolic rates and minimal
excitatory circuits, but by childhood, the metabolic rate is higher
than it is in adults with more excitatory circuits, leading to greater
vulnerability but improved potential for recovery.25,28
Developmental age also affects pharmacoresistance. In adults,
self-sustaining seizures arise from changes in neurotransmitter
density. Gamma-aminobutyric acid (GABAA) receptors become
increasingly internalized during SE, whereas glutamate (primarily
N-Methyl-D-Aspartate) receptors become increasingly expressed at
the synapse.29 The loss of GABAA receptors and increase in
synaptic glutamate receptors then lead to decreased inhibition and
increased excitation, which may explain why the pharmacoresist-
ance of seizures to benzodiazepines increases with seizure pro-
longation.30–32 Still, there is no clear evidence of a similar transition
in the neonatal and infant brain.25 Moreover, the immature brain
tends to underexpress GABAA receptors and overexpress glutamate
receptors at baseline25 compared with the adult brain. Activation of
these same postsynaptic GABAA receptors in young animals can
lead to depolarization (i.e., excitation) instead of the inhibition seen
in adult animals.33–35 Understanding whether the neurotransmitter
transition seen in adults exists in neonates and infants may lead to
greater insights into the appropriate pharmacotherapy for self-
sustaining seizures in those age groups.
Seizure circuits also seem to be age-dependent. In electro-
graphic seizure models, the tendency for a focal seizure to
generalize and become self-sustaining is readily noted in adult
animals, but the same electrographic activity remains confined in
young animals.25,36,37 Why seizures in neonates and infants tend
not to generalize and self-sustain compared with those in adults is
an ongoing area of investigation.
The long-term effects of SE on the developing brain continue
to be studied. Repeated neuronal firing, with or without systemic
changes, can lead to cell death and lasting effects on behavior,
learning, and memory.25,38 Since most neurons are postmitotic,
recovery from seizure-related damage that is endured early in life is
limited. Even without cell death, research in infant rats suggests that
a single episode of SE results in reduced brain weight, delayed
behavioral milestones, and reduced seizure threshold (Table 1).25,39
The pharmacotherapy deployed to stop seizures may be
contributing to the neuronal damage.25 Several animal studies
suggest that N-Methyl-D-Aspartate antagonists, GABA agonists,
and anesthetics give rise to apoptosis of various neuronal
populations, with the highest vulnerability being in rodents whose
ages correspond to human neonates and infants.40–43 Although
there is no conclusive evidence of such damage from antiseizure
drugs in human neonates, there is concern that the first-line agents
for neonatal seizures may worsen seizure-related brain injury
through a “developmental drug-induced apoptosis.”25
Neuroinflammation, mediated by cytokine (e.g., IL-1beta, TNF-
alpha, and IL-6) and COX-2 expression, is induced in both febrile
and afebrile SE.44–48 Moreover, neuroinflammation is believed to
modulate SE through a lowered seizure threshold, altered neuro-
transmitter release and uptake, and changes in transcriptional activity
of genes that regulate synaptic plasticity.44 The neuroinflammation of
SE is made worse by oxidative stressdthe excessive production of
reactive oxygen and nitrogen species (ROS and RNS).44 Oxidative
430 Journal of Clinical Neurophysiology Volume 37, Number 5, September 2020
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Status Epilepticus in Children
TABLE 1. Summary of Specific Findings in Various Fields of
Pediatric Status Epilepticus
Area Summary
Epidemiology Status epilepticus affects 3–42 per 100,000 children
per year, with a mortality rate of 3%.
Younger children have higher rates of mortality
compared with older children.
Etiology Etiology is a predictor of both survival and
recurrence risk.
Infections and febrile illness remain leading
etiologies. Genetic causes are suspected.
Pathophysiology Critical periods of brain development seem to play
an important role in the outcomes of SE as well as in
the possibility of recovery.
The immature brain tends to underexpress GABAA
receptors and overexpress glutamate receptors at
baseline compared with the adult brain.
Activation of postsynaptic GABAA receptors in
young animals can lead to cell depolarization (i.e.,
excitation).
Treatment Rectal diazepam is traditionally considered the
treatment of choice for SE treatment in young
children without intravenous access
Intramuscular midazolam and intravenous lorazepam
are considered equally effective benzodiazepines for
the initial management of SE in children.
Phenytoin and levetiracetam are equally effective
second-line agents. There is no consensus on third-
line agents.
Antiseizure medications for neonatal seizures may
induce neuronal damage through “drug-induced
apoptosis.”
Future research Research should focus, among others, on identifying
clinical and genetic risk factors, improving animal
models, achieving a consensus on second and third-
line agents, and establishing the role of
immunotherapy and anti-inflammatories in the
management of SE.
GABA, gamma-aminobutyric acid; SE, status epilepticus.
stress furthers the process of neuroinflammation during SE,49
a finding reinforced by the discovery of markers of oxidative stress
in the central nervous system of children with SE.50 With regard to
the role of neuroinflammation and ROS in pediatric SE, animal
models suggest that the neuroinflammatory response resolves more
rapidly in the immature animal than in the adult, whereas glial
activation and the production of cytokines follow an age-dependent
pattern.44 These findings suggest a role for anti-inflammatory and
antioxidant medications in the treatment of pediatric SE.
DIAGNOSTIC STRATEGIES
While there is evidence to support lumbar puncture and
blood cultures in children with SE and co-occurring infection,
there is insufficient evidence to suggest these same measures for
patients presenting in SE without clinical indications of ongoing
infection. For SE and RSE, finger-stick blood glucose levels,
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 Status Epilepticus in Children
regular vital sign checks, brain imaging (except for patients with
a known epilepsy diagnosis), serum electrolytes including
calcium and magnesium, and continuous EEG monitoring are
always recommended.11 There are currently no specific recom-
mendations regarding toxicologic or metabolic testing in similar
situations.22
TREATMENT
First-Line Treatment for SE
First-line management of pediatric SE consists of benzodiaz-
epine administration, usually midazolam, lorazepam, or diazepam,
for up to two doses. Rectal diazepam has been traditionally
considered as the best option for young children without
intravenous access. A recent meta-analysis pooled the outcomes
of 16 randomized clinical trials, 6 of which were double-blinded,
each comparing midazolam, lorazepam, or diazepam with each
other or with other nonbenzodiazepine agents in pediatric patients
with SE,51 looking at both seizure cessation and respiratory
depression as primary and secondary outcomes, respectively. All
in all, this study concluded that intramuscular (IM) midazolam and
IV lorazepam were equally effective in treating pediatric SE, and
both were superior to IV or IM diazepam.
Rectal preparations of benzodiazepines in emergency depart-
ments have also been compared with other preparations. In
a systematic review, times to drug administration and seizure
cessation in emergency departments were shown to be shorter with
non-IM midazolam compared with IV or rectal diazepam, but IV
and rectal diazepam were just as safe and effective as non-IM
midazolam.52 In a recent randomized clinical trial published after the
publication of this systematic review, IM midazolam was shown to
be as effective as rectal diazepam, and time to drug administration
was significantly shorter with IM midazolam.53 Since delays to
a first-dose antiseizure drug are associated with prolongation of SE
in some patients,54 further studies on non-IM and rectal preparations
that are easier to administer than IV medications will prove helpful.
Neonatal seizures have been traditionally been managed
with phenobarbital as first-line agent, followed by fospheny-
toin.55,56 In the only randomized trial of first-line agents for
neonatal seizures, phenobarbital was not found to be more
effective than fosphenytoin, and neither agent was entirely
effective in resolving the seizures.57
Second-Line Treatment for SE
Phenytoin is largely considered the main medication for
second-line management after failure of benzodiazepines. Two
randomized control trialsdthe Concept trial and the Eclipse trial,
both published in 2019dexamined the role of levetiracetam as an
equally efficacious and safe substitute for phenytoin, given its
lower side-effect profile.58,59 Both studies showed that levetirace-
tam is nonsuperior to phenytoin, but it was noted that given the
comparative ease of administration and low side-effect profile,
levetiracetam could be considered an appropriate alternative to
phenytoin. The results of a third study called ESETT, also looking
at the role of levetiracetam as a substitute for phenytoin, are
pending.60
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V. Zimmern and C. Korff
Third-Line Treatment for SE including RSE and SRSE
Many medications and interventions have been attempted as
third-line agents for SE and RSE. Few randomized controlled
trials exist to give practitioners guidance on how to proceed.
Case reports and small studies support the use of continuous
infusions of benzodiazepines,61 barbiturates,62,63 propofol,62
ketamine,64–66 isoflurane,67–71 immunotherapy,72,73 corticoste-
roids,74 neurosteroids,75,76 lidocaine,77 hypothermia,78–80 elec-
troconvulsive therapy,81–83 vagal nerve stimulation,84,85
magnesium,86–88 and ketogenic diet.89–93
FUTURE RESEARCH DIRECTIONS
Much remains to be learned about SE in children. Signif-
icant research questions that are and should continue to be
investigated include the following:
1. What are the clinical and genetic risk factors for the
development of RSE and SRSE?
2. What are the short-term and long-term sequelae of the
various treatments available for SE, RSE, and SRSE18?
3. How does the functional anatomy of SE evolve over time
from the neonatal to the pediatric stages? What are the roles
of the various neurotransmitters and ion channels in the
evolution of the functional anatomy?
4. Can we produce animal models that more accurately
reproduce the human pathophysiology of SE, including
animal models of specific genetic or acquired epilepsy
syndromes94?
5. What age- and sex-specific biomarkers exist or can be
developed for the evaluation of epileptogenesis and treat-
ment response in pediatric SE94 ?
6. What are the optimal first-, second-, and third-line agents for
SE, RSE, and SRSE?
7. Should different agents be given as first, second, third lines if
the cause of SE is a known genetic or acquired syndrome18?
8. What is the ideal timing of these various medications?
9. What is the role of early polytherapy or combination of
medications95?
10. What is the role of immunotherapy, anti-inflammatory
medications, and antioxidants in the treatment of SE44?
The answer to many of these questions will come through
large, multicenter, pediatric-specific randomized clinical trials.
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