Original Article

Status Epilepticus and Acute

Serial Seizures in Children
Wendy G. Mitchell, MD

ABSTRACT

Status epilepticus is defined as a seizure that persists for a sufficient length of time or is repeated frequently enough to
produce a fixed and enduring epileptic condition of 30 minutes or longer. Status epilepticus is a life-threatening condition
that often occurs in children. The degree of mortality and neurologic morbidity, as well as the risk for recurrence, is highly
dependent on the etiology and duration of the seizures. Although much has been written about pediatric status epilepti-
cus, many issues remain unresolved. A better understanding of the different types of seizures and their etiologies may help
in the prevention and treatment of status epilepticus. The vast extent of status epilepticus in both children and adults man-
dates that new options for prevention and treatment be given a close scrutiny and high priority. This article will review
the most current information on convulsive and nonconvulsive status epilepticus, including the potential for neurologic
damage, changes in magnetic resonance imaging after status epilepticus, risk for recurrence, and current treatment options
available for treating status epilepticus in children. (J Child Neurol 2002;17:S36–S43).

INTRODUCTION come. Recent literature has helped to clarify some of the

The purposes of this article are to review the literature
regarding status epilepticus in children including morbid-
ity, mortality, sequelae, treatment, and prevention. Specifi-
cally reviewed are the influences of age, etiology, type of
status epilepticus, and precipitants on outcome; neu-
roimaging changes after status epilepticus; and the conse-
quences of nonconvulsive status epilepticus, both idiopathic
and in the setting of severe acute brain insult. Treatment
options for serial and clustered seizures, uncomplicated
status epilepticus, refractory status epilepticus, and non-
convulsive status epilepticus will be reviewed.
MORTALITY AND MORBIDITY
OF STATUS EPILEPTICUS
Status epilepticus has been the subject of numerous stud-
ies, with highly variable distributions of etiology and out-
Received Sept 7, 2001. Received revised Dec 12, 2001. Accepted for publi-
cation Dec 12, 2001.
This study was supported by a grant from Elan Biopharmaceuticals.
Address correspondence to Dr Wendy G. Mitchell, Neurology Division, Children’s
Hospital Los Angeles, 4650 Sunset Blvd, Neurology, Box 82, Los Angeles, CA
90027. Tel: 323-669-2498; fax: 323-667-2019; e-mail: wmitchell@chla.usc.edu.
interactions of etiology, pattern of seizures, and outcome.
Mortality and Morbidity of Status Epilepticus by Etiology
In both adults and children, the etiology of status epilepti-
cus is the primary determinant of both mortality and new
neurologic deficits.1 The causes and origins of status epilep-
ticus can be broken into four general categories:
1. Acute symptomatic. The greatest mortality and highest
rates of new neurologic deficits occur in patients whose
status epilepticus is caused by an acute neurologic con-
dition, such as encephalitis, meningitis, head trauma, or
stroke.2,3
2. Known epilepsy. Mortality and rates of new neurologic
deficits are very low in circumstances when the patient
has a known, preexisting epilepsy, regardless of the eti-
ology of status epilepticus (medication noncompliance,
intractable epilepsy, etc).
3. Febrile status epilepticus. In population-based studies,
morbidity and mortality are negligible in febrile status
epilepticus,4 except when there is an accompanying cen-
tral nervous system illness such as meningitis or
encephalitis.
4. First seizure in idiopathic epilepsy. Mortality and mor-
bidity are low.

S36
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Mortality and Morbidity of Status Epilepticus
in Neonates and Young Infants
The mortality and neurologic morbidity of neonatal status
epilepticus or serial seizures are high, generally reflecting
the underlying etiologies. In some series, more than 30% of
infants have substantial neurologic handicaps and/or ongo-
ing epilepsy. It is not clear if this is because neonatal seizures
affect brain development or if the seizures are a symptom
of underlying brain insult or dysfunction.5 Many episodes of
neonatal status epilepticus can be presumed to be acute
symptomatic, reflecting underlying acute or subacute brain
insults. Variable reports of the outcome of neonatal seizures
are highly dependent on the mix of etiologies in the subject
pools. Persistent electrographic seizures after cessation of
clinical status epilepticus are common in babies under
2 months of age and are generally considered ominous,
indicating substantial underlying brain insult or metabolic
abnormality.
Benign forms of neonatal status epilepticus exist in
the settings of benign familial neonatal convulsions or sta-
tus epilepticus caused by hypocalcemia, vitamin B6 depen-
dency, and other treatable inborn errors.6 Outcome in
neonatal status epilepticus caused by these benign condi-
tions is presumably substantially better than in infants with
acute brain insults.
Both status epilepticus and refractory status epilepti-
cus have a higher incidence in infants (less than 1 year) than
later in childhood or in adolescence.7
Potential for Subtle Neurologic
Damage from Status Epilepticus
In animals, persistent nonconvulsive status epilepticus can
be demonstrated to cause permanent changes in brain struc-
ture and function, using various models of status epilepti-
cus. Lithium-pilocarpine–induced nonconvulsive status
epilepticus in adult rats produces lasting morphologic dam-
age, even though behavior returns to baseline with cessa-
tion of the electrographic seizure discharges.8 In humans,
neuron-specific enolase has been used as a marker of neu-
ronal damage. Neuron-specific enolase is markedly ele-
vated by obviously damaging events such as cardiac arrest,
perinatal hypoxic-ischemic encephalopathy, or severe head
trauma.9,10 Elevations of neuron-specific enolase in blood and
cerebrospinal fluid after episodes of status epilepticus have
been used as a marker of neuronal damage, with the impli-
cation that the status epilepticus caused the damage.11
DeGiorgio et al studied a group of adults with various
causes of status epilepticus.12 They found that neuron-
specific enolase was most significantly elevated by sub-
clinical electrographic status epilepticus, probably reflecting
the underlying brain injury that precipitated subclinical sta-
tus epilepticus. However, milder elevations were also appar-
ent after complex partial or generalized convulsive status
epilepticus, as well as in a single subject with absence sta-
tus epilepticus. Findings of elevations of neuron-specific eno-
lase have led to the suggestion that status epilepticus may
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Status Epilepticus and Acute Serial Seizures / Mitchell S37
be causing permanent changes in the human brain, even in
the absence of obvious acute neurologic sequelae.
Mortality and Morbidity of Status
Epilepticus by Duration of Seizures
Prolonged seizures lasting 10 to 29 minutes are not cur-
rently considered status epilepticus. There have been pro-
posals that the definition of status epilepticus be revised to
include continuous convulsive seizures lasting longer than
10 minutes.13,14 The basis for this is the observation that
nearly all convulsive seizures terminate in less than 3 min-
utes and that seizures lasting for more than 10 minutes
have a much greater chance of continuing into frank status
epilepticus. There are arguments both supporting and reject-
ing this redefinition, and there is no consensus at this time.
Mortality and Morbidity of Refractory Status Epilepticus
Refractory status epilepticus is defined as ongoing inter-
mittent or continuous status epilepticus after administration
of adequate dosages of two standard anticonvulsant drugs
(ie, benzodiazepine plus phenytoin, phenobarbital plus
phenytoin, etc). Continuous status epilepticus has a higher
mortality and morbidity rate than intermittent status epilep-
ticus.15 Nearly all series show morbidity and mortality of
refractory status epilepticus to be high, with a large pro-
portion of pediatric survivors showing new neurologic
deficits.16,17 A similar pattern is seen in adults.18 However,
the etiology of refractory status epilepticus may be a major
determinant of outcome. Many episodes of refractory sta-
tus epilepticus are caused by acute neurologic insults and
infections, such as encephalitis. Seizures and status epilep-
ticus are symptoms of the underlying condition, not deter-
minants of outcome in and of themselves.
CHANGES IN MAGNETIC RESONANCE
IMAGING AFTER STATUS EPILEPTICUS
Recent studies have shown that magnetic resonance imag-
ing (MRI) done shortly after bouts of febrile status epilep-
ticus may reveal abnormalities in mesial temporal lobes. It
has been suggested that these lesions are “precursors” of
mesial temporal sclerosis. Isolated reports document pro-
gression of such lesions on rare occasions to an MRI appear-
ance of mesial temporal sclerosis.19 There has been one
report of a group of children with prolonged, focal status
epilepticus who demonstrated progressive mesial temporal
lesions on MRI; however, several had predisposing factors
including focal cyst in the choroid fissure, suggesting that
a structural abnormality was the basis of the prolonged
febrile seizure.20 Some of the lesions resolved on serial MRI
without volume loss in the temporal lobe.21 Other acute
reversible lesions have been demonstrated on single pho-
ton emission computed tomography (SPECT) scanning.22 In
one small study of adults serially scanned with volumetric
MRI, none showed progressive volume loss of the hip-
pocampus after status epilepticus.23
S38 Journal of Child Neurology / Volume 17, Supplement 1, January 2002
Population-based studies of children with status epilep-
ticus do not demonstrate MRI changes after status epilep-
ticus. Conversely, they demonstrate mesial temporal
sclerosis in some children shortly after onset of unpro-
voked seizures without prior history of status epilepticus or
prolonged febrile seizures.
RECURRENCE RISK OF STATUS EPILEPTICUS
Parallel to risk of mortality and morbidity, risk of recurrence
of status epilepticus is dependent on age and etiology.
Status Epilepticus as the First Presentation of Seizures
The risk of recurrent status epilepticus is dependent on its
etiology in a child whose first episode of seizures presents
as status epilepticus. When status epilepticus is the first pre-
sentation of seizures attributable to remote symptomatic
causes, recurrence risk is much higher than if the underly-
ing seizure disorder is idiopathic.24–27
Neither the risk of seizure recurrence nor the risk of
recurrent status epilepticus is different in idiopathic status
epilepticus compared with other first unprovoked idio-
pathic seizures. The risk of epilepsy, however, remains sub-
stantially higher in children with remote symptomatic status
epilepticus.24 In contrast, for patients having acute symp-
tomatic status epilepticus, the risk of later seizures is sub-
stantially higher than in those with single acute symptomatic
seizures.28 The risk of recurrent status epilepticus after a first
unprovoked seizure is higher in children with remote symp-
tomatic epilepsy.25
Status Epilepticus Recurrence Risk
in Patients with Established Epilepsy
In children with established epilepsy who have an episode
of status epilepticus, recurrence risk is at least partially
dependent on the underlying etiology of the epilepsy. There
is a substantially higher recurrence risk in children with
remote symptomatic compared with those with idiopathic
epilepsy. Children with epilepsy caused by degenerative
conditions have the highest risk of recurrent status epilep-
ticus. When status epilepticus is provoked by noncompliance
with anticonvulsant drug administration, future episodes may
be largely preventable.
ELECTROGRAPHIC STATUS EPILEPTICUS
Nonconvulsive Status Epilepticus in
the Patient With Altered Mental Status
Occasionally, a patient without a known history of epilepsy
presents with altered mental status and is found to have non-
convulsive status epilepticus on electroencephalogram
(EEG).29 These patients generally respond promptly to a sin-
gle dose of benzodiazepine, and the status epilepticus may
not recur, even without subsequent treatment. A recently
described syndrome of ring chromosome 20 is associated
with repeated episodes of nonconvulsive status epilepti-
cus.30 Nonconvulsive status epilepticus may also be an eti-
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ology of coma in an acutely ill patient whose seizures are
detected only through EEG monitoring.31
Children with severe mixed generalized epilepsy (such
as Lennox-Gastaut syndrome) may present with decline in
performance or confusion, with EEG showing continuous
spike-wave discharges. It is not certain that this represents
a true instance of nonconvulsive status epilepticus, and the
spike-wave discharges may be interictal and nearly contin-
uous for weeks or months at a time. Treatment in this cir-
cumstance is much less successful, with only transient
benefits noted with acute use of benzodiazepines. Some
reports indicate that intravenous benzodiazepines may have
either no response or may even paradoxically worsen a
patient with Lennox-Gastaut syndrome and nonconvulsive
status epilepticus.32,33 Benzodiazepines have occasionally
been reported to precipitate tonic seizures in patients with
Lennox-Gastaut syndrome treated for nonconvulsive status
epilepticus.34–38 However, one study suggests that continu-
ous electrographic epileptiform discharges (without clini-
cal symptoms) may be harmful even in this instance, as
evidenced by elevations in neuron-specific enolase.39 Ele-
vations of neuron-specific enolase in patients with pro-
longed nonconvulsive status epilepticus suggest that
nonconvulsive status epilepticus may be harmful, despite
the absence of systemic perturbations associated with con-
vulsive status epilepticus, such as in patients with complex
partial status epilepticus.40
Electrographic Seizures in Patients Whose
Clinical Status Epilepticus Has Abated
Immediately after stopping clinical status epilepticus, EEG
may continue to show electrographic seizures.41 Despite
this, some patients recover consciousness after the usual
postictal period without recurrent seizures. When the level
of consciousness remains depressed in a patient after
apparently successful treatment of status epilepticus, EEG
is indicated to rule out continued nonconvulsive status
epilepticus.
It is uncertain whether further doses of antiepileptic
drugs are helpful for the patient whose EEG shows elec-
trographic seizures immediately after clinical cessation of
status epilepticus. If nonconvulsive status epilepticus or
intermittent electrographic seizures persist with altered
mental status, treatment should be the same as for refrac-
tory status epilepticus.
EEG Monitoring in Treatment of Status Epilepticus
Although immediate EEG after cessation of uncomplicated
status epilepticus is not generally indicated, it should be
strongly considered in a patient whose mental status fails
to improve after the immediate postictal period to rule out
nonconvulsive status epilepticus.
Continuous EEG monitoring may also help determine
that abnormal movements and mental status changes after
status epilepticus are not attributable to seizures (postur-
ing, myoclonus, etc.) and presumably would not be helped
by further administration of anticonvulsants.42

Critically ill, postoperative, or head injury patients who
require therapeutic paralysis for management or who have
a high likelihood of seizures because of underlying condi-
tions should be considered candidates for intermittent or
continuous EEG monitoring to detect clinically inapparent
seizures. Nonconvulsive status epilepticus after acute head
injury carries an ominous prognosis. In one study of 94
adult patients with moderate to severe head injuries mon-
itored with continuous EEG, 6 subjects had electrographic
and/or clinical status epilepticus, all of whom died, compared
to 18 of 73 (24%) in the nonseizure group.43 It is not clear in
this setting whether the significantly worse prognosis of
patients with electrographic status epilepticus reflects the
severity of the underlying trauma or the continuing damage
caused by status epilepticus.
Similarly, continuous EEG monitoring should be
strongly considered for neonates who have had significant
acute neurologic insults (ie, hypoxic-ischemic encephalopa-
thy, intracranial bleeding, or stroke) and whose general
condition requires therapeutic paralysis (ie, for severe res-
piratory distress, meconium aspiration, extracorporeal
membrane oxygenation, etc.) because of the high frequency
of seizures in this population.44
TREATMENT OF SERIAL SEIZURES
OR PROLONGED SEIZURES
Does Treatment of Prolonged or Clustered
Seizures Prevent Status Epilepticus?
There is minimal evidence to support or refute the con-
tention that immediate treatment of a prolonged seizure or
clustered seizures prevents progression to status epilepti-
cus. In one study, adults with intractable temporal lobe
epilepsy whose seizures clustered were more likely to have
status epilepticus than those with isolated seizures, but
this was a highly select group.45 It is still unclear what per-
centage of seizure clusters goes on to clinical status epilep-
ticus if not acutely treated. In the pivotal trials of rectal
diazepam gel (Diastat®), the rate of progression to frank sta-
tus epilepticus in children or adults with seizure clusters was
low, regardless of whether they received active treatment
or placebo. However, subjects who were known to habitu-
ally progress from clustered seizures to status epilepticus
were specifically excluded from the studies.46,47 Neverthe-
less, it is generally accepted that clusters of seizures or
prolonged episodes should be halted and that such treatment
may, in some instances, prevent progression to status epilep-
ticus.
Treatment Options: Acute Seizure
Clusters and Prolonged Seizures
Various types of benzodiazepine delivered via diverse routes
have been reported to be efficacious in treating serial or pro-
longed seizures:
• Rectal diazepam gel. Diastat is the only approved rectal
diazepam formulation in North America, although other
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Status Epilepticus and Acute Serial Seizures / Mitchell S39
formulations are available in Europe and Asia.46–49 It has
been the subject of two double-blind controlled studies
and several subsequent open-label studies, which docu-
mented safety and efficacy for terminating seizure clus-
ters. There is long experience with use of various forms
of rectal diazepam in Europe, both for status epilepticus
and for seizure clusters.50,51 The North American expe-
rience with rectal diazepam solution in children is more
limited but is also positive.52–55 Anticonvulsant levels
(200 ng/mL) are attained with rectal diazepam gel within
5 minutes in a child. Adult absorption of the rectal gel
attains anticonvulsant levels somewhat later (15 minutes).56
• Nasal midazolam. Midazolam can be quickly and effec-
tively administered intranasally in the emergency depart-
ment or by paramedics in the field using the parenteral
solution instilled intranasally. Although not an approved
use or route, it offers a reasonable alternative to intra-
venous medication if placement of an intravenous line is
problematic in a child with seizures. Nasal midazolam is
rapidly absorbed, attaining anticonvulsant levels in min-
utes.57 Some children might find the nasal route more
acceptable than the rectal if they are interictal and awake
and alert when it is administered.58 One study demon-
strated that peak midazolam levels were attained about
12 minutes after nasal administration, with a similar half-
life for both nasal and intravenous administration and
approximately 55% bioavailability.59
• Buccal midazolam. Several studies have shown rapid
mucosal absorption of midazolam, with peak levels
attained in approximately 20 minutes in adults.60 Bad
taste is a problem for children who are awake when it is
administered. In one small study, children with pro-
longed seizures of greater than 5 minutes in duration, but
not status epilepticus, were randomized to receive either
buccal midazolam or rectal diazepam. The results in
terms of time to cessation of the seizure were similar.61
• Intramuscular midazolam. Midazolam is water soluble
and, unlike diazepam, rapidly absorbed from an intra-
muscular site. Case reports62 and one small, randomized
study compared intramuscular midazolam to intravenous
diazepam in children presenting to an emergency room
in status epilepticus. Because of substantially faster
administration, time to cessation of seizures was shorter
with intramuscular midazolam.63
• Oral diazepam. One study demonstrated the ability to
prevent febrile seizures with oral diazepam given for
febrile illness. It is not generally indicated for serial
seizures because of slow onset.64
• Oral or buccal lorazepam. These options are occasion-
ally useful for seizure clusters and breakthrough seizures65
but not for status epilepticus or prolonged seizures.
Pharmacokinetic concerns related to the use of ben-
zodiazepines for acute seizures include the relative absorp-
tion rate of rectal lorazepam versus diazepam, which makes
rectal lorazepam a substantially less effective choice.
S40 Journal of Child Neurology / Volume 17, Supplement 1, January 2002
Notably, tolerance may develop rapidly to repeated use of
any form of benzodiazepine, by any route.
TREATMENT OF UNCOMPLICATED
STATUS EPILEPTICUS IN CHILDREN
Treating children based on clinical data from adult studies
is never optimal; however, large, randomized, double-blind
studies in children with status epilepticus do not exist. Gov-
ernment regulations require signed consent forms before a
patient may participate in a clinical trial. Yet because sta-
tus epilepticus requires immediate treatment, taking time
to have a consent form signed by a parent is unrealistic in
such an emergency. The option of preconsent has been
viewed as unlikely to succeed, given the unpredictability of
who will experience an episode of status epilepticus. For
adults, research studies of care in emergencies for which con-
sent is unobtainable have been performed with waiver of
consent. However, US Food and Drug Administration reg-
ulations make it challenging to receive approval for a blinded
study of status epilepticus in children that implements
waiver of consent. Physicians caring for children have lit-
tle choice but to make clinical decisions based on adult tri-
als and nonblinded pediatric case series.
Randomized, double-blinded studies in adults (Veterans
Affairs)66 and nonrandomized studies in children67 support
the use of lorazepam68 and phenobarbital as monotherapy.
Alternatively, diazepam followed by phenytoin or fos-
phenytoin is effective.
Various anecdotal reports and small randomized stud-
ies of nasal midazolam versus intravenous diazepam in chil-
dren presenting with febrile status epilepticus documented
that seizures stopped more quickly with nasal midazolam
because of shorter duration until administration.69,70
Additional options, reported anecdotally, include other
intravenous benzodiazepines, midazolam bolus and/or con-
tinuous drip,71–74 and midazolam by other routes.75 Intra-
venous valproic acid has been reported to be effective in
status epilepticus,76,77 but there is a risk of hypotension.
Propofol78,79 has been reportedly used effectively for acute
status epilepticus. Rectal paraldehyde has long been reported
to be effective but is rarely currently used (Table 1).80
Table 1. Treatment of Pediatric Status Epilepticus
Treatment supported by randomized, double-blinded studies in
adults and nonrandomized studies in children
Lorazepam68
Phenobarbital
Diazepam followed by phenytoin
Fosphenytoin
Treatment supported by anecdotal reports
Intravenous benzodiazepines: midazolam bolus, continuous
drip71–74
Nasal midazolam75
Intramuscular midazolam75
Intravenous valproic acid76,77
Intravenous propofol78,79
Rectal paraldehyde80
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TREATMENT OF REFRACTORY
STATUS EPILEPTICUS IN CHILDREN
If appropriate dosages of two standard anticonvulsant drugs
(ie, diazepam and phenytoin, lorazepam and phenobarbital,
or phenobarbital and phenytoin) fail to stop clinical and elec-
trographic seizures, status epilepticus is considered refrac-
tory. There are no randomized, blinded studies in either
adults or children. Table 2 shows the treatments generally
accepted as useful, with published case series or case
reports.17,75,78,79,81–88
There are relative advantages and disadvantages to
each of the listed treatments that must be balanced against
the gravity of the clinical situation. In nearly all circum-
stances of refractory status epilepticus, treatment in an
intensive care setting is mandatory. Intubation and respi-
ratory support are very frequently necessary. Pentobarbital
commonly causes hypotension, necessitating the use of
pressors for support.82,89 Benzodiazepines by continuous
drip, such as diazepam81 or midazolam,75,82–84 are reported
to cause less hypotension than pentobarbital.82,89 Intermit-
tent intravenous phenobarbital boluses may be somewhat
easier to manage and may cause less hypotension. However,
the availability of parenteral phenobarbital is currently
severely limited in North America because of production
problems (as of the summer of 2001).
With continuous administration of benzodiazepines or
barbiturates, tolerance develops rapidly and dosage must
be escalated frequently.82,89 When dosage is extremely high,
significant quantities of propylene glycol are administered
along with the medication. With very prolonged use of mida-
zolam, pharmacokinetics may be altered with a sustained
half-life.90
Propofol has been reported to cause hyperlipidemia and
may cause severe systemic acidosis.78,79,85 “Propofol syn-
drome” (lactic acidosis and systemic collapse with sus-
tained use of propofol) has been reported when propofol is
used in pediatric intensive care for sedation and has been,
at times, fatal.91,92 Currently, a “dear doctor” letter from the
manufacturer, endorsed by the US Food and Drug Admin-
istration, cautions against the use of propofol for sedation
in the pediatric intensive care unit because of an excess in
mortality in a controlled study comparing 1% and 2% propo-
fol preparations with other forms of sedation. There is no
specific mention of use of propofol for status epilepticus as
the condition has not been subjected to formal studies.
Table 2. Treatment of Refractory Pediatric Status Epilepticus
Treatment generally accepted as useful
High-dose intravenous phenobarbital17
Continuous intravenous pentobarbital drip
Continuous intravenous benzodiazepine drip (diazepam81 or
midazolam)75,82–84
Continuous intravenous propofol drip78,79,85
Intravenous valproic acid86
Continuous intravenous lidocaine87
Ketamine88
Inhalant anesthetics

When no reasonable alternative exists, however, propofol
may be considered with extremely vigilant monitoring and
appropriate consent.
WHERE DO WE GO FROM HERE?
There is much that is still unknown about status epilepticus.
Areas for future research and trials span a broad area and
include the following:
• Determining whether interruption of “prolonged” seizures
(5–25 minutes) prevents status epilepticus
• Conducting a randomized treatment trial of status epilep-
ticus in children comparable to the Veterans Affairs trial
• Carrying out controlled trials, or at least more system-
atic comparisons of results, of treatment for refractory
status epilepticus
• Evaluating the outcome of nonconvulsive status epilep-
ticus in children, comparing the various treatment options
The vast extent of status epilepticus in both children and
adults mandates that new options for prevention and treat-
ment be given a close scrutiny and high priority.
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