Current Treatment Options in Neurology (2011) 13:560–573

DOI 10.1007/s11940-011-0148-3

Pediatric Neurology (Harvey S. Singer, Section Editor)

Treatment of Pediatric Status

Epilepticus
Tobias Loddenkemper, MD1,*
Howard P. Goodkin, MD, PhD2
Address
*,1Harvard Medical School, Division of Epilepsy and Clinical Neurophysiology,
Fegan 9, Children’s Hospital Boston, 300 Longwood Ave., Boston, MA 02115, USA
Email: tobias.loddenkemper@childrens.harvard.edu
2
Departments of Neurology and Pediatrics, University of Virginia Health Sys-
tems, PO Box 800394, Charlottesville, VA 22908, USA
Email: hpg9v@virginia.edu

Published online: 29 September 2011

* Springer Science+Business Media, LLC 2011

Opinion statement
Status epilepticus is characterized by a prolonged, self-sustaining seizure or re-
peated seizures without return to baseline. The clinical manifestations of status
epilepticus in children and adults range from overt generalized convulsions to
more subtle behavioral manifestations, including unresponsiveness in the setting
of the intensive care unit. Status epilepticus is the most common neurologic
emergency of childhood. A large proportion of these episodes are the result of
a prolonged febrile seizure or an acute symptomatic etiology. Fortunately, status
epilepticus occurs without consequence for many children, but for others, it is
correlated with long-term neurologic dysfunction or death. Treatment of status
epilepticus should commence promptly upon its recognition, using predefined
treatment protocols. The goal of treatment is the rapid termination of the seizure,
to minimize the acute and chronic effects of this emergency and to allow for the
prompt assessment and management of the underlying precipitant. Currently, the
drug class of first choice in the in-hospital and out-of-hospital treatment of status epilep-
ticus is the benzodiazepines, which may need to be quickly followed by a next-line agent,
as the efficacy of the benzodiazepines is negatively correlated with seizure duration. Tra-
ditionally, these next-line agents have included phenobarbital and phenytoin, but emerg-
ing evidence supports the use of intravenous formulations of other antiepileptic drugs. If
the first two agents fail, high-dose intravenous midazolam or anesthetic therapy should be
rapidly initiated. This paper reviews the current treatment options and strategies for pedi-
atric patients with status epilepticus.

Introduction
Status epilepticus (SE) presents as a prolonged, self-
sustaining seizure or as recurrent seizures without re-
turn to baseline. The behavioral characteristics of SE
range from overt primary or secondarily generalized
convulsions to the nonconvulsive forms characterized
by periods of altered mental status that varies from
prolonged confusion (absence SE, complex partial
SE) to unresponsiveness.
 Pediatric Status Epilepticus Loddenkemper and Goodkin 561

Independent of its behavioral characteristics, SE
represents a dynamic, evolving syndrome. The initial
or “impending” stage is characterized by repeated iso-
lated seizures. These seizures begin to lengthen and
then merge, resulting in “established” SE [1]. If the sei-
zure persists, the established phase evolves to a later stage
during which the clinical manifestations may be subtle,
electromechanical dissociation ensues, and the EEG is
characterized by periodic epileptiform discharges. Early
in SE, homeostatic mechanisms are capable of compen-
sating for metabolic demands, but as the seizure persists,
these mechanisms fail, producing a situation in which
the CNS is susceptible to injury.
SE represents the most common neurologic emergen-
cy of childhood. In a prospective, population-based
study performed in Richmond, Virginia, the incidence
of SE was estimated at approximately 50 episodes of
SE per year per 100,000 population [2, Class III]. In that
study, the highest incidence of SE occurred in children,
primarily before 1 year of age, and in adults older than
60 years of age. In the recent prospective, community-
based North London Status Epilepticus in Childhood
Surveillance Study (NLSTEPSS), the incidence of SE dur-
ing childhood was 17 to 23 episodes of SE per year per
100,000 population; again, the highest incidence was
in children less than 1 year of age [3, Class III]. Many
of these children had no prior history of seizures or neu-
rologic disorder [4••, Class IV].
SE in children may have both acute and remote
causes. In the NLSTEPSS study, prolonged febrile seiz-
ures and acute etiologies (e.g., trauma, CNS infection,
stroke, metabolic abnormalities) accounted for 50%
of the episodes of SE.
Death and neurologic morbidity are severe conse-
quences of SE. Recent case fatality rates for children
have ranged from 3% [3] to 9.3% [5•, Class IV], with
the higher value reported in a study restricted to chil-
dren with SE treated within the setting of an intensive
care unit (ICU). Outcome is most highly predicted by
etiology and age. Factors that have also intermittently
been linked to outcome include duration [6, Class IV]
and response to treatment.

Treatment

& Diagnosis of convulsive SE typically is not difficult, but pseudostatus

epilepticus should be considered, although it is rare in children. Non-
convulsive forms of SE (NCSE), especially in the ICU setting, require
EEG for diagnosis and management. In a recent study of 100 critically ill
children with an acute encephalopathy in an ICU setting, electrographic
seizures were recorded in 46 patients and SE was diagnosed in 19 [7••,
Class IV]. In the child who has undergone apparently successful treat-
ment for convulsive SE but continues to have encephalopathy, contin-
uous EEG may be required to ensure the absence of NCSE.
& The first step in SE treatment, as in other emergency situations, is to
secure the airway, provide breathing support, and ensure circulation.
In parallel, a glucose check should be performed. The additional
diagnostic evaluation of a child with SE is reviewed in the American
Academy of Neurology’s practice parameter [8, Class IV].
& Current treatment protocols for convulsive SE in children and adults
are based on a stepwise progression of medications that begins with
the rapid application of a benzodiazepine, followed by a loading
dose of an intravenous agent such as phenytoin (Fig. 1). It should be
noted that these protocols are based on limited controlled trials
performed predominantly in adults. The most beneficial treatment
algorithm for both children and adults is not known.
562 Pediatric Neurology (Harvey S. Singer, Section Editor)

Figure 1. A potential approach to convulsive status epilepticus in children. The first step should always be to take care of airway,
breathing, and circulation (ABCs). The first-line antiepileptic drug (AED) is usually a benzodiazepine (lorazepam), followed by a
loading dose of phenytoin, and then another intravenous (IV) epilepsy medication, most frequently phenobarbital, levetiracetam, or
valproic acid. Additional (and overlapping) systemic management should consider potential correction of hypoxia, hemodynamics,
hyperthermia, hypoglycemia, and hyponatremia. Diagnostic laboratory tests, EKG, and imaging may be obtained simultaneously. If
status epilepticus becomes refractory (at the latest, after failure of the second medication), continuous EEG monitoring should be
initiated. If treatment with two or three AEDs fails, burst suppression with midazolam or pentobarbital may be initiated. In children
less than 2 years of age, a pyridoxine trial should be considered. PE phenytoin equivalents; PR per rectum.

& The first-line and second-line treatment of complex partial and ab-
sence SE is similar to the treatment of convulsive SE. It is unusual for
these forms of SE to require coma induction and the therapies for
refractory SE that are described below. These forms of SE can typi-
cally be approached with small, repeated doses of intravenous lora-
zepam or midazolam and the start of a long-term antiepileptic agent.
& The need for rapid treatment of NCSE encountered in the ICU setting
is debated, as the long-term effects of these nonconvulsive seizures
are largely unknown and may depend on the underlying cause. Al-
though studies suggest that NCSE is associated with mortality and
neurologic morbidity [9, Class IV], it is not known whether treating it
alters outcome.
& In the absence of a rigid national standard for the treatment of SE
[10, Class IV], SE treatment is guided by clinical guidelines and
practice parameters [8]. As these parameters represent suggestions
and recommendations, it is suspected that treatment protocols vary
between medical centers. Nevertheless, an overriding principle that
should guide all protocols is that rapid treatment of SE is mandatory
both in and out of the hospital, as seizure duration is negatively
correlated with the probability of a seizure self-terminating [11, Class
IV] and with treatment efficacy [12, Class I; 13, 14, Class III]. Rec-
ognition of the essential need for rapid treatment of SE is reflected in
current operational definitions of SE, which have defined SE as sei-
zure durations as short as 5 min [15, Class IV]. Furthermore, rapid
effective treatment not only minimizes the potential untoward effects
 Pediatric Status Epilepticus Loddenkemper and Goodkin 563

of the seizure but also allows for the prompt assessment and man-
agement of the underlying precipitant.
& SE is increasingly being treated in the out-of-hospital setting.
Current options for out-of-hospital treatment include buccal
midazolam [16, Class I], intranasal midazolam [17•, Class III],
intramuscular midazolam, and rectal diazepam [17•, Class IV]. A
study that compared the pre-hospital treatment of SE in adults
using diazepam (5 mg) or lorazepam (2 mg) versus placebo
demonstrated that these out-of-hospital treatments were safe in
that patient population [18, Class I].
& In a case of the child who is known to be predisposed to SE, the
family or long-term care facility should be provided with a set of
guidelines for acute, out-of-hospital seizure management as well as
back-up plans for activating emergency medical services. For all
children with convulsive SE, every minute of delay between SE onset
and emergency room arrival is associated with a 5% cumulative in-
crease in the risk that the episode will last longer than 60 min [13],
illustrating the importance of having a treatment plan that includes
out-of-hospital treatment.

Pharmacologic treatment
& For all medications listed below, a known hypersensitivity to that
medication is a contraindication.

First-Line treatment: The 1,4-benzodiazepines

& The 1,4-benzodiazepines are positive allosteric modulators of the
GABAA receptors. These receptors are heteropentameric, ligand-gated
chloride channels that mediate both synaptic and tonic inhibition.
The receptor’s benzodiazepine sensitivity is dependent on the pres-
ence of an α subunit in the receptor assembly. The binding of the
benzodiazepine to the receptor appears to increase the apparent as-
sociation of GABA to the receptor, with the net result of an increase
in GABA-mediated inhibition.
& Factors making the 1,4-benzodiazepines the drug class of first choice
in the treatment of SE include their effectiveness against a number of
seizure types, their rapid onset of action upon entering the brain, and
their relative safety [19, Class IV].
& Based on both adult data [18, 20, Class III] and pediatric data
[21, Class IV], adequate first-line treatment with a benzodiaze-
pine is crucial for seizure termination. In children, underdosing
of benzodiazepines in the emergency room was correlated with
ICU admission [21].
& The success of benzodiazepine therapy is inversely related to seizure
duration. This decrease in efficacy in established and late SE is po-
tentially the result of a rapid modification in the postsynaptic GABAA
564 Pediatric Neurology (Harvey S. Singer, Section Editor)

receptor population that is due, in part, to activity-dependent, subunit-

specific trafficking of the receptors [22, Class IV].
& Meta-analyses comparing the efficacy of benzodiazepines in the
acute management of convulsive SE in children have concluded that
intravenous lorazepam was at least as effective as intravenous diaz-
epam and was associated with fewer adverse effects [23, Class IV].
Midazolam, by any route, was superior in efficacy to diazepam given
by any route [24, Class IV].
& Ease of administration and degree of patient satisfaction favor non-
rectal routes (buccal or intranasal application). With buccal or in-
tranasal application, there are some concerns, however, regarding
possible aspiration or lack of effectiveness in patients with nasal
congestion.
& As a class, the major adverse effects of the 1,4-benzodiazepines in-
clude sedation, respiratory depression, cardiac dysrhythmia, and
ataxia. Paradoxic excitation can be observed. Treatment with more
than two doses of benzodiazepines was associated with respiratory
depression, defined as a fall in oxygen saturation below 92% [13].
The absence of respiratory monitoring is a relative contraindication
to the repetitive use of benzodiazepines.
& The use of the benzodiazepines in combination with other CNS
depressants can synergistically increase the risk of CNS depression.
& Benzodiazepine dosing in neonates may differ from provided dose
ranges. Benzodiazepines have been associated with myoclonic jerks
in neonates and very-low-birth-weight infants [25, Class IV]. There-
fore, the drug of first choice for neonates diagnosed with seizures
traditionally has been phenobarbital.
Lorazepam
Standard dosage Lorazepam may be given at a dose of 0.05 to 0.1 mg/kg (maximum, 4 mg/
dose) intravenously over 2 to 5 min. The dose may be repeated if needed,
with monitoring for respiratory depression. A buccal formulation is available
in Canada and Europe (up to 2 mg per dose).
Diazepam
Standard dosage Diazepam may be given at a dose of 0.2 to 0.5 mg/kg intravenously over 2 to
5 min. The rectal dose is based on age and weight. Typical doses range from
0.5 to 0.75 mg/kg. Doses may be repeated if needed, with monitoring for
respiratory depression.
Midazolam
Standard dosage Intravenous midazolam is typically reserved for the treatment of pro-
longed, refractory SE (see below). Buccal [16] or intranasal midazolam
doses range from 0.2 to 0.5 mg/kg, up to 10 mg per dose. Currently, no
buccal midazolam has been approved by the US Food and Drug Ad-
ministration (FDA). Buccal or intranasal application of the intravenous
midazolam solution may be an option. One randomized trial found no
difference in efficacy between intranasal midazolam and rectal diazepam
 Pediatric Status Epilepticus Loddenkemper and Goodkin 565

as a rescue medication for terminating seizures at home in children with

epilepsy [17•].

Second-Line treatment
& The second-line medications are all available in intravenous formu-
lations. Phenytoin and its prodrug, fosphenytoin, are traditionally
the drugs of first choice among this group, but no comparative
treatment trials have compared these agents.
Phenytoin and fosphenytoin
Phenytoin limits the repetitive firing of action potential through stabi-
lization of the inactive form of neuronal voltage-dependent sodium
channels.
Fosphenytoin is the water-soluble disodium phosphate ester of phe-
nytoin. It is rapidly and entirely converted to free phenytoin by serum
and tissue alkaline phosphatases. It is increasingly used instead of in-
travenous phenytoin in treating SE, as it does not result in tissue injury
upon extravasation and has a lower risk of cardiac arrhythmia. Fosphe-
nytoin is dosed in phenytoin equivalents (PE).
In a study comparing 90 children treated with lorazepam and 88
treated with a diazepam-phenytoin combination, no difference in SE
termination was found [26•, Class III].
Standard dosage Phenytoin may be given at a dose of 20 mg/kg at a rate of 1 mg/kg per
minute (maximum 50 mg/minute). Fosphenytoin may be given at a dose of
20 mg PE/kg intravenously at a rate of 3 mg PE/kg per minute (maximum
150 mg PE/minute). Cardiovascular monitoring is recommended during
intravenous application. Because fosphenytoin must be converted to phe-
nytoin, the time to optimal CNS phenytoin concentration is roughly similar
despite the faster infusion rate of fosphenytoin.
Major adverse effects The main adverse effects associated with these medications are bradyar-
rhythmia, hypotension, and local tissue necrosis (with phenytoin). There are
rare reports of “purple glove syndrome” in children [27, Class IV].
Main drug interactions Phenytoin is highly protein-bound and a strong P450 enzyme–inducing
agent.
Special points When intravenous access is not available, fosphenytoin may be given intra-
muscularly. In infants, it can be difficult to maintain therapeutic levels of
phenytoin and fosphenytoin.
Cost Fosphenytoin is relatively more expensive than phenytoin.
Phenobarbital
Phenobarbital is a long-acting barbiturate that not only enhances GABA-
mediated inhibition but also may antagonize AMPA receptors and inhibit
neurotransmitter release.
Standard dosage Phenobarbital may be given at a dose of 20 mg/kg as single or divided ap-
plication (2 mg/kg per minute in children G40 kg up to 100 mg/minute in
children 940 kg). This dose will achieve a plasma level of about 20 mg/L
(86.2 μmol/L). A dose of 5 to 20 mg/kg may be repeated every 15 to 20 min
as needed, with cardiorespiratory monitoring. Repetitive intravenous phe-
566 Pediatric Neurology (Harvey S. Singer, Section Editor)

nobarbital doses have been used for coma induction and treatment of per-
sistent refractory SE. Oral loading doses of up 80 mg/kg (reaching plasma
level concentrations of 283 μmol/L) have also been described [28, Class IV].
Major adverse effects Intravenous loading of phenobarbital is associated with CNS and respiratory
depression as well as hypotension. Respiratory and cardiac monitoring is
recommended. High levels of phenobarbital can suppress brainstem reflexes.
Contraindications Phenobarbital can exacerbate porphyria.
Main drug interactions Phenobarbital is a potent enzyme inducer.
Valproic acid
Several mechanisms of action have been reported, including increasing
GABA synthesis, inhibiting GABA transaminase, stabilizing voltage-gated
sodium channels, and inhibiting T-type calcium channels.
Standard dosage The ideal loading dose of this medication has not been established. Previous
pediatric studies have used doses of 20 to 40 mg/kg. Although the manu-
facturer recommends slow rates of infusion (G20 mg/min), an open-label,
randomized controlled study comparing valproic acid and diazepam dem-
onstrated the efficacy and safety of an initial valproic acid loading dose of
30 mg/kg infused over 1 to 5 min [29, Class III]. Intravenous valproic acid
stopped clinical SE and NCSE in 32 (78%) of 41 children in one series [30,
Class IV]. SE remained refractory in 9 patients (22%). Treatment success
differed based on the type of SE, varying from 0% (0/2) in epilepsia partialis
continua to 90% (9/10) in generalized tonic-clonic SE.
Major adverse effects The black box warnings for valproic acid include serious or fatal hepatic
failure and pancreatitis. The risk factors for hepatoxicity include underlying
metabolic disorders in children less than 2 years of age, mitochondrial dis-
orders, and polytherapy. In addition to these idiosyncratic reactions, a dose-
related increase in serum transaminases, Stevens-Johnson syndrome, and
thrombocytopenia may occur.
Contraindications Valproic acid is contraindicated in those with active hepatitis, pancreatitis, or
known or suspected mitochondrial disease.
Main drug interactions Valproic acid is an enzyme inhibitor and will compete with other protein-
bound drugs.
Special points Children may develop an encephalopathy following the administration of
valproic acid. Although an elevated ammonia level may be present, its absence
does not exclude valproic acid as the cause. Carnitine supplementation has been
recommended, specifically for critically ill and developmentally delayed chil-
dren treated with valproic acid.
Levetiracetam
It is proposed that levetiracetam inhibits neurotransmitter release via its
binding of the vesicular protein Synaptic Vesicle Protein 2A (SV2A). The
absence of drug-drug interactions, renal clearance, low risk of sedation,
and the absence of cardiac side effects makes it an ideal drug to consider
for the treatment of SE.
Standard dosage The ideal loading dose has not been established, but 20 to 40 mg/kg intra-
venously has been safely administered in the past. Doses of 30 mg/kg were
well tolerated in children and appeared most effective in single seizure events
[31, Class IV]. The dose may need to be adjusted for children with renal
dysfunction.
 Pediatric Status Epilepticus Loddenkemper and Goodkin 567

Major adverse effects With the exception of agitation, this medication is well tolerated. Overdosing
has occasionally resulted in respiratory depression and coma [32].
Main drug interactions None.
Lacosamide
Lacosamide was recently approved by the FDA for the adjunct treatment
of partial seizures in patients older than 17 years of age. Its proposed
mechanism of action is the enhancement of the slow inactivation of
voltage-dependent sodium channels.
Standard dosage The ideal loading dose has not been established. The successful treatment of
refractory SE in an 8-year-old boy using 25 mg twice daily has been described
[33, Class IV]. We have used lacosamide in children (age 8 years or older)
with refractory epilepsy, using median starting doses of 1.3 mg/kg per day
and maintenance doses of 4.7 mg/kg per day [34, Class IV].
Major adverse effects Lacosamide can prolong the PR interval. Therefore, it should be used with
caution in patients with known cardiac conduction problems.
Main drug interactions None known.

Intravenous treatment of refractory SE and special episodes of SE

& SE is considered refractory when seizures persist despite adequate
treatment with two different medications, independent of its dura-
tion. A recent review of 542 children found that convulsive SE was
terminated after first-line treatment in 42% and after second-line
treatment in 35%. [4••]. These results are similar to those in the
NLSTEPSS study, in which 18% of children required anesthesia for
seizure termination [13].
& Special circumstances involving SE include SE in postoperative
patients or patients with head trauma, metabolic disorders prone to
increase intracranial pressure, CNS infection, or organ dysfunction
[35, Class IV]. In these circumstances, early seizure control is re-
quired, and failure of a benzodiazepine may need to be followed
immediately by anesthetic control of the seizure.
& Treatment of these children requires a team approach within an ICU
setting. Continuous bedside EEG monitoring is essential to assist in
medication titration.
& The aim of treating persistent refractory SE is to usually achieve a
burst suppression EEG pattern for at least 24 to 48 h to stop seizures
and to prevent seizure recurrence during weaning from coma-in-
ducing medication. However, no completed randomized controlled
trials are available to support the current practice of duration and
depth of coma or to define the superiority of one medication over
another [36, Class IV].
& The diagnosis of pyridoxine-dependent seizures should be consid-
ered in a patient with refractory SE for which no other cause has been
determined. Following the administration of pyridoxine under EEG,
568 Pediatric Neurology (Harvey S. Singer, Section Editor)

clinical seizures may stop within minutes to hours and improvement

of the EEG may be noted. The standard recommended dose is
100 mg given intravenously. If the child fails to respond, a second
dose up to 500 mg can be considered. Given the possible untoward
effects of apnea, bradycardia, and hypotension, respiratory moni-
toring is required when this vitamin is administered. Intravenous
overdose (usually 10 g or higher) or long-term use is associated with
an irreversible sensory neuropathy.
& In a follow-up study 2 years after refractory SE, all patients continued to
have intractable epilepsy and severe learning disabilities [37, Class IV].
Midazolam
Standard dosage Midazolam can be given as a loading dose of 0.1–0.3 mg/kg followed by a
continuous infusion starting at 1 μg/kg per minute. The infusion can be ti-
trated upwards every 5 min as needed to terminate the seizure or achieve
burst suppression. The reported range has been 1 to 18 μg/kg per minute
with a mean of 2.3 μg/kg per minute Among 358 children who received
intravenous midazolam therapy for SE [38, Class IV], seizure suppression
was obtained in 231 (64.5%). The effectiveness of midazolam was lower
when midazolam was initiated more than 3 h after seizure onset. None of
the 10 deaths that occurred during the treatment period were associated with
midazolam therapy.
Pentobarbital
Standard dosage Pentobarbital can be given as a loading dose of 3 to 15 mg/kg followed by a
typical maintenance dose of 1 to 5 mg/kg per hour. Among 23 pediatric
patients treated with pentobarbital [39, Class IV], 12 were controlled, 6 were
unresponsive, and 5 relapsed after discontinuation or during tapering. The
mortality rate among the relapsing and nonresponding groups combined
was 90.9%. No deaths occurred among the responders.
Major adverse effects Intravenous loading is associated with CNS and respiratory depression as
well as hypotension. Respiratory and cardiac monitoring is recommended.
High levels of pentobarbital can suppress brainstem reflexes.
Contraindications Pentobarbital can exacerbate porphyria.
Main drug interactions Pentobarbital is a potent enzyme inducer. In addition, concurrent use with
valproic acid may lead to hyperammonemia.
Propofol
Propofol is a short-acting, intravenous sedative hypnotic that enhances
GABA-mediated inhibition through direct activation of GABAA receptors.
It is also reported to inhibit NMDA receptors and reduce the concen-
tration of extracellular glutamate.
Standard dosage Intravenous loading doses of up to 2 mg/kg have been described. In older
adolescents, this dose may be followed by maintenance doses of 2 to 5 mg/kg
per hour. The short half life of 1 to 2 h permits rapid titration and withdrawal.
Doses of 5 mg/kg per hour over prolonged periods should be avoided because
of propofol infusion syndrome (PrIS).
Major adverse effects Propofol leads to sedation and potentially respiratory depression. PrIS
may lead to cardiovascular compromise due to lactate acidosis, hyper-
 Pediatric Status Epilepticus Loddenkemper and Goodkin 569

triglyceridemia, and rhabdomyolysis [40, Class IV]. In a retrospective

review, PrIS was found in 10% of patients treated with high-dose pro-
pofol and in none of the 10 patients treated for refractory SE without
propofol [40]. Frequent lactate checks may facilitate earlier recognition
of PrIS. Partial exchange transfusion may prevent death in children with
PrIS [41, Class IV].
Contraindications Because of the possible induction of PrIS, prolonged used is relatively con-
traindicated in infants and young children and in those with mitochondrial
disorders, metabolic acidosis, or hypertriglyceridemia.
Main drug interactions None.
Ketamine
Ketamine is an NMDA receptor antagonist.
Standard dosage A loading dose of 0.5 to 2 mg/kg followed by continuous intravenous in-
fusion of 5 to 20 μg/kg per minute has been used in adults [42, Class IV]. The
oral application of the parenteral ketamine solution (50 mg/mL) in
pediatric patients with NCSE at a dosage of 1.5 mg/kg per day in two
divided doses has been reported to terminate NCSE within 24 to 48 h
[43, Class IV].
Major adverse effects Ketamine can lead to hypertension, tachycardia, and respiratory depression.
Contraindications Ketamine is relatively contraindicated in patients who may be harmed
by an elevation in blood pressure (such as those with increased intra-
cranial pressure).
Main drug interactions Ketamine is both an enzyme inhibitor and inducer (CYP2C9).
Lidocaine
Lidocaine is another intravenous agent that has been used in treating
refractory SE.

Additional treatment options for refractory SE

Inhalational anesthetics
& If intravenous agents are ineffective or cause unacceptable adverse
effects, or if intravenous access cannot be maintained, the inhala-
tional anesthetic isoflurane can be considered.

Oral antiepileptic medications

Topiramate
Multiple mechanisms of action have been proposed, including enhanced
GABA-mediated inhibition, inhibition of sodium currents, enhanced
potassium channel conduction, inhibition of L-type calcium channels,
decrease of glutamatergic transmission, and inhibition of carbonic
anhydrase.
Standard dosage The ideal dose of this medication has not been established. Loading
doses of 5 to 10 mg/kg per day via a nasogastric route were reported in
14 selected children with refractory SE the median time to seizure ces-
570 Pediatric Neurology (Harvey S. Singer, Section Editor)

sation in 12 of the 14 patients was 5.5 h (range 2–48), and 2 patients

did not respond [44, Class IV].
Major adverse effects Topiramate is associated with metabolic acidosis, sedation, oligohidrosis,
acute myopia, and secondary angle closure glaucoma.
Main drug interactions Topiramate may enhance the risk of encephalopathy induced by valproic acid and
may increase phenytoin levels when phenytoin metabolism is near saturation.
Special points An intravenous solution is in preparation.
Other oral antiepileptic medications
Oxcarbazepine, carbamazepine, rufinamide, felbamate, pregabalin [45,
Class IV], and others may also be added by nasogastric tube.

Surgical procedures

Resective epilepsy surgery

Standard procedure Surgery aims to remove the epileptogenic zone, resulting in seizure freedom or a
reduction that allows tapering of antiepileptic medications [46, Class IV]. The
resection is based on location of the epileptogenic zone, as determined by EEG
seizure onset and possibly structural lesions, avoiding suspected eloquent areas.
Following the surgery, the patient should be monitored for neurologic deficits
resulting from the resection of eloquent cortex and for postsurgical complica-
tions such as hemorrhage or infection.
Special points The seizure onset zone may be difficult to recognize on EEG after several
days or weeks of SE.
Vagus nerve stimulation
Standard procedure Left vagus nerve stimulation at settings ranging from 1 to 1.75 mA (pulse
width 500 μs, signal frequency 30 Hz, on time 30 s, off time 5 min) was
reported to slowly abort SE [47, Class IV].
Complications Rare complications of vagus nerve stimulation include asystole and bradycardia.
Immunomodulatory approaches
Standard procedure Immunomodulation may be attempted in several forms: corticosteroids,
adrenocorticotropic hormone (ACTH) therapy, intravenous immunoglobulin
(IVIG), and plasmapheresis.
Complications Infection. Renal complications and aseptic meningitis may be seen with
IVIG, and aseptic meningitis and hypertension with ACTH.
Contraindications These therapies are relatively contraindicated in children with congenital
immune defects or those at risk from immunosuppression.
Special points The therapeutic effect may in part be related to the etiology of SE, such as
NMDA receptor encephalitis or Hashimoto encephalitis.
Ketogenic diet
Standard procedure The ketogenic diet can be administered via gastrostomy tube or modified
parenteral nutrition.
 Pediatric Status Epilepticus Loddenkemper and Goodkin 571

Complications Hypoglycemia, electrolyte imbalance, dehydration, hepatitis, pancreatitis,

metabolic acidosis.
Contraindications Selected metabolic disorders. Although the ketogenic diet may be
beneficial for patients with pyruvate dehydrogenase deficiency and
glucose transporter 1 deficiency syndrome, it is contraindicated in py-
ruvate carboxylase deficiency, disorders of fatty acid oxidation and
metabolism, or porphyria, as well as in some other metabolic
disorders.
Hypothermia
Standard procedure Moderate hypothermia (31–35°C) achieved via an endovascular cooling
system has been described, in conjunction with barbiturate or benzodiaze-
pine coma [48, Class IV]. Older data indicate effectiveness of deeper hypo-
thermia in SE.
Complications Hypothermia may influence medication clearance by decreasing P450 en-
zyme activity.
Contraindications No absolute contraindications.
Electroconvulsive therapy
Standard procedure Electroconvulsive therapy (ECT) has been reported to successfully terminate
SE in children and adults [49, 50, Class IV].
Complications Postictal agitation and cardiovascular compromise. ECT may initially exac-
erbate the SE.
Contraindications Preexisting cardiovascular conditions are a relative contraindication to ECT.

Emerging treatments
& Future treatment options may include adjunct application of mag-
nesium, deep brain stimulation or closed loop stimulation, trans-
cranial magnetic stimulation, and Doppler ultrasound, as well as
targeted drug delivery systems or chronotherapy.

Disclosure
Dr. Loddenkemper serves on the Laboratory Accreditation Board for Long-Term (Epilepsy and ICU) Mon-
itoring (ABRET); performs video-EEG long-term monitoring, EEGs, and other electrophysiological studies
at Children’s Hospital Boston and bills for these procedures; is funded by an Early Career Physician-Sci-
entist Award by the Milken Family Foundation and American Epilepsy Society, by the Epilepsy Founda-
tion of America, by the Center for Integration of Medicine and Innovative Technology, by the NIH, by
the Translational Research Program at Children’s Hospital Boston, by the Program for Patient Safety
and Quality at Children’s Hospital Boston, and by a Career Development Fellowship Award from Harvard
Medical School and Children’s Hospital Boston; and received investigator-initiated research support from
Eisai Inc within the past year.
Dr. Goodkin has served as a consultant to Avanir Pharmaceuticals within the past year. He receives research
support from the National Institutes of Health.
572 Pediatric Neurology (Harvey S. Singer, Section Editor)
References and Recommended Reading
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
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