Author: Section Editor: Deputy Editor

3/30/2021 Seizures and epilepsy in children: Initial treatment and monitoring - UpToDate
Author: Angus Wilfong, MD

Section Editor: Douglas R Nordli, Jr, MD
Deputy Editor: John F Dashe, MD, PhD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2021. | This topic last updated: Nov 18, 2020.
INTRODUCTION
Children with epilepsy, particularly infants, differ from adults not only in the clinical
manifestations of their seizures, but also in the presence of unique electroencephalogram
(EEG) patterns, etiologies, and response to antiseizure drugs. The immature brain,
particularly in the neonate and young infant, differs from the adult brain in the basic
mechanisms of epileptogenesis and propagation of seizures. It is more prone to seizures,
but seizures are more apt to disappear as the child grows.
This topic presents an overview of the initial treatment of seizures and epileptic syndromes
in children. Other aspects of seizures and epilepsy in children are presented separately:
Seizures and epilepsy in children: Classification, etiology, and clinical features

Seizures and epilepsy in children: Clinical and laboratory diagnosis
Epilepsy syndromes in children
Benign focal epilepsies of childhood
Seizures and epilepsy in children: Refractory seizures
Epilepsy in children: Comorbidities, complications, and outcomes
Neonatal seizures and epilepsy are reviewed elsewhere. (See "Overview of neonatal
epilepsy syndromes" and "Clinical features, evaluation, and diagnosis of neonatal seizures"
and "Treatment of neonatal seizures" and "Etiology and prognosis of neonatal seizures".)
WHEN TO START ANTISEIZURE DRUG THERAPY
A child's first seizure may be caused by an acute illness, such as a metabolic derangement
or infectious disorder, and be nonrecurrent, or may represent the beginning of epilepsy. A
decision must be made about initiating chronic antiseizure drug treatment if a potentially
reversible acute cause is not found during the evaluation. (See "Seizures and epilepsy in
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children: Clinical and laboratory diagnosis" and "Seizures and epilepsy in children: Clinical
and laboratory diagnosis", section on 'Setting in which episodes occur'.)
Unprovoked seizure — The term "unprovoked seizure" refers to a seizure of unknown

etiology as well as one that occurs in relation to a preexisting brain lesion or progressive
nervous system disorder (often referred to as a remote symptomatic seizure). Unprovoked
seizures are distinct from seizures due to an acute condition such as a toxic or metabolic
disturbance, fever, head trauma, or acute stroke (ie, acute symptomatic seizures). (See
"Seizures and epilepsy in children: Classification, etiology, and clinical features", section on
'Definitions'.)
The approach to starting antiseizure drug therapy for a first-ever versus a second
unprovoked seizure is reviewed in the sections that follow.
First unprovoked seizure
● In most cases, we refrain from starting antiseizure drug therapy for a child with a first
unprovoked seizure. This approach is consistent with the current practice of most
neurologists. Similarly, a consensus statement from the International League Against
Epilepsy (ILAE) states that in an otherwise well infant, a policy of "wait and see" with
close follow-up monitoring is reasonable after a first afebrile seizure [1]. Even if the
child has a static encephalopathy, treatment can be withheld until a recurrence pattern
is established.
● Antiseizure drug treatment may be warranted after a first unprovoked seizure for
select children with specific epilepsy syndromes [2]. As an example, treatment with a
broad spectrum antiseizure drug would be indicated for a teenager with a first-time
generalized tonic-clonic seizure whose EEG showed 4 to 6 Hz generalized spike and
slow wave activity, confirming the diagnosis of juvenile myoclonic epilepsy (JME). In
addition, the risk of seizure recurrence is higher in children with a potential remote
symptomatic etiology, particularly if the seizure was focal and the
electroencephalogram (EEG) or brain magnetic resonance imaging (MRI) is abnormal;
in such cases, the benefits of immediate antiseizure drug therapy may outweigh the
risks.
In all cases, the decision should be individualized, weighing the risks of recurrent seizure
against the potential risks and benefits of antiseizure drug therapy and incorporating
patient values and preferences. Treatment is reasonable when the benefits of reducing the
risk of a second seizure are greater than the risks of pharmacologic adverse effects [3].
Factors influencing the decision — The main factors to consider in deciding

whether or not to treat a child with a first-time unprovoked seizure include:

• The risk for recurrent seizures, which varies based on clinical factors. (See 'Risk of
seizure recurrence' below.)
• The relative risk reduction that can be expected from immediate antiseizure drug
therapy. Limited data in children suggest that early versus delayed antiseizure
drug therapy reduces the short-term risk of a recurrent seizure but does not
appear to affect the long-term prognosis of epilepsy. Specifically, starting
antiseizure drug treatment after a first unprovoked seizure does not confer
additional benefit for long-term seizure control compared with starting after a
second seizure [3]. (See 'Effects of early versus deferred therapy' below.)
• The risks of not treating, which include another seizure with its attendant risk of
injury and psychologic stigma (including restrictions on driving and work
environment in teenagers and young adults) and, infrequently, status epilepticus.
• The risks of chronic antiseizure drug therapy, which includes possible effects on
school performance and behavior, allergic reactions, and systemic toxicity. The
financial burden of chronic antiseizure drugs, office visits, and laboratory tests
should also be considered.
Risk of seizure recurrence — The child who is neurologically normal, has no history

of a prior neurologic illness, and has an unprovoked seizure with no evident acute cause
has an approximately 25 percent risk of having another seizure in the next year and a 45
percent risk over the next three years [4-6].
Clinical factors associated with an increased risk of recurrent seizures include:
● Prior neurologic insult (ie, remote symptomatic seizure)

● Significant brain MRI findings
● Abnormal EEG
The magnitude of risk associated with each one of these factors varies, and the additive
effects of multiple risk factors have not been clearly established. In a large prospective
study of 283 children with a first-time unprovoked seizure, neurologically normal children
with no history of prior neurologic illness had a 24 percent risk of having a seizure in the
next year [4,5]. The one-year recurrence risk increased to 37 percent in children with a prior
neurologic insult (remote symptomatic), such as cerebral palsy, and increased to 70 percent
in patients who had two seizures separated by at least 24 hours. Most but not all of the
children in this study were not treated with an antiseizure drug.
In the same study, the one-year recurrence risk was 41 percent if the EEG was abnormal
(epileptiform activity, focal or generalized slowing) compared with 15 percent in children
with a normal EEG [4].
In another study, significant MRI findings, present in 16 percent of children, were

associated with a twofold higher incidence of recurrent seizure by 27 months (80 versus 44
percent) and were more predictive of short-term seizure recurrence than EEG findings [7].
Status epilepticus as the presenting seizure may be another risk factor for recurrent
seizures, although the available data are less consistent [4,8].
Effects of early versus deferred therapy — In adults, immediate antiseizure drug

therapy after a first-time unprovoked seizure reduces the risk of recurrence by
approximately 35 percent at one to two years postseizure [9]; more limited data in children
suggest that the short-term benefits of antiseizure drug therapy are similar to those in
adults.
Withholding treatment until after the second seizure does not alter the long-term
prognosis of epilepsy, however. A study that randomly assigned 419 patients with a first
tonic-clonic seizure to immediate antiseizure drug therapy or treatment only after a second
seizure found that immediate treatment reduced the short-term relapse rate [10]. However,
at one and two years, the number of patients who remained seizure free in the early-
treatment and delayed-treatment groups were similar (83 to 87 percent at one year, 60 to
68 percent at two years). A similar study of 1443 patients (38 percent were ≤19 years old)
found that immediate antiseizure drug treatment reduced the short-term (one- to two-year)
risk of seizure relapse, but had no effect on the long-term risk of relapse [11]. The benefit of
immediate treatment was lost by four years after a first seizure and by six years after
multiple seizures.
The long-term risk of mortality after a single seizure appears to be quite low, and there is
no evidence that treatment after an initial seizure has any impact on mortality. In a cohort
study of 407 children with a first unprovoked seizure, four had a seizure-related death over
a 14-year observation period [5]. Each of these had multiple seizures that were not fully
controlled with antiseizure drug treatment; none died prior to initiation of antiseizure drug
therapy, and two had been treated after the first seizure that was status epilepticus.
Second unprovoked seizure — We start antiseizure drug therapy for most children who
present with a second unprovoked seizure, since seizure recurrence indicates that the
patient has a substantially increased risk for additional seizures (ie, epilepsy) [12].
There are some exceptions, however. Many parents elect no antiseizure drugs if the
seizures are infrequent and/or mild. The definitions of "infrequent" and "mild" may vary
from parent to parent. By contrast, children with absence seizures, atonic seizures or drop
attacks, and infantile spasms are virtually always treated, since they usually present to the
clinician with an already established pattern of frequent seizures.

Acute symptomatic seizure — An acute symptomatic seizure (also referred to as a

provoked seizure or reactive seizure) is a seizure that occurs in close temporal association
with an acute systemic illness or brain insult. Children who have a seizure in the setting of
an acute illness (eg, acute infection, acute head injury) have a low risk of seizure recurrence
compared with other children with a first seizure [13]. When a seizure is associated with a
specific underlying acute etiology, seizure recurrence is likely only if the underlying etiology
recurs. Examples include seizures associated with febrile illnesses, metabolic
derangements (eg, hyponatremia), and concussion.
Management of acute symptomatic seizures should be focused on correction of the acute

provoking illness or anomaly and preventing its recurrence. Children with an acute
symptomatic seizure may not require antiseizure drug therapy. Exceptions include
hospitalized children who are recovering from an acute illness that triggered seizures (eg,
correctable conditions such as severe electrolyte disturbances with dehydration, diabetes
insipidus, syndrome of inappropriate secretion of antidiuretic hormone secretion [SIADH]);
they may be loaded and maintained on an antiseizure drug for several days to a week or
two, but antiseizure therapy is usually stopped before hospital discharge. Children with
acute seizures due to meningitis or encephalitis are more likely to stay on antiseizure drug
therapy for a little longer after hospital discharge. Children with acute posttraumatic
seizures after a concussion often do not require any antiseizure therapy. Children with
severe traumatic brain injury requiring intensive care will usually receive maintenance
antiseizure drug coverage regardless of whether they have had seizures.
Febrile seizure — Children presenting with a first-time febrile seizure have an

approximately 30 to 35 percent chance of having another febrile seizure during early
childhood. Although antiseizure drugs have been shown to lower the risk of recurrent
febrile seizures, given the benign nature of febrile seizures, the risks of side effects from
antiseizure drugs generally outweigh the benefits for most patients. This is discussed in
more detail separately. (See "Treatment and prognosis of febrile seizures", section on 'Role
of preventive therapy'.)
SELECTION OF AN ANTISEIZURE DRUG
There is an ever-growing list of antiseizure drugs and nonpharmacologic therapies

available to manage childhood epilepsy [14]. Traditionally, the medications have been
separated into "older" and "newer" groups based upon their historic regulatory approval
and availability. Typically, when a medication is first approved for epilepsy, it receives an
"on-label indication" for add-on (adjunctive) therapy for partial-onset seizures in adults.
Then, as experience grows and other studies are done, the use of the drug may expand to
other seizure types and younger age groups.

Seizure-related considerations — The antiseizure drug chosen for initial therapy should

be one that is effective for a particular seizure type or syndrome [15,16]. The initial work-up
should include an attempt to determine the specific type of seizure the child experienced
and, if possible, the epilepsy syndrome. The optimal choice of antiseizure drug depends on
the type of seizure and the epilepsy syndrome. (See "Seizures and epilepsy in children:
Classification, etiology, and clinical features" and "Epilepsy syndromes in children".)
For some epilepsy syndromes, available data support choosing certain antiseizure drugs
over others as first-line therapy. Examples include:
● Corticotropin (ACTH) for infantile spasms (see "Management and prognosis of infantile
spasms", section on 'Hormonal therapy')
● Ethosuximide or valproate for childhood absence epilepsy (see "Childhood absence
epilepsy", section on 'Treatment')
● Valproate for juvenile myoclonic epilepsy (see "Juvenile myoclonic epilepsy", section on
'Valproate')
For other types of epilepsy, such as focal epilepsy due to a remote symptomatic cause or
mesial temporal sclerosis, there are no clear differences in efficacy among various
antiseizure drugs, and clinicians generally choose first-line therapy based on other drug-
related factors such as side effects, cost, and dosing intervals. Levetiracetam, which has
broad-spectrum activity and has minimal drug interactions, has become a common choice
for first-line treatment of early-life epilepsy, although other drugs are equally reasonable
and the choice should be individualized [17]. (See 'Drug-related considerations' below.)
In some cases, particularly for generalized epilepsy syndromes, seizures may be

aggravated by the administration of a narrow-spectrum antiseizure drug, when a broad-
spectrum antiseizure drug is more appropriate ( table 1). As examples, carbamazepine
and phenytoin have been reported to worsen absence and myoclonic seizures in
individuals with idiopathic generalized epilepsy [18-21]. (See "Epilepsy syndromes in
children" and "Childhood absence epilepsy", section on 'Drugs to avoid' and "Juvenile
myoclonic epilepsy", section on 'Antiseizure drugs to avoid'.)
Drug-related considerations — Drug-related factors include dose formulation, dose

frequency, the relative risk of certain side effects, and the potential for drug-drug
interactions. Single-drug therapy is the goal of epilepsy treatment. Monotherapy is
associated with better compliance, fewer adverse effects, less potential for teratogenicity,
and lower cost than is polytherapy. Drug interactions are avoided and pharmacokinetics are
simplified.
In the absence of clear differences in efficacy among various antiseizure drugs, clinicians
must choose first-line therapy primarily based on pharmacokinetics, adverse effects, and

consideration of drug-drug interactions. Cost effectiveness is also desirable; as an example,

the World Health Organization recommends phenobarbital as the treatment of choice for
partial and tonic-clonic seizures in countries with restricted resources [22]. The
pharmacology and specific indications for individual antiseizure drugs are discussed
separately. (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse
effects".)
Pharmacokinetics and formulation
● Half-life – A long serum half-life allows for relatively smooth serum levels with less
frequent daily dosing that can enhance medical compliance ( table 2A-B). Examples
of drugs that require only once- or twice-daily dosing include antiseizure drugs that
come in a sustained-release form (eg, phenytoin, carbamazepine, valproic acid,
levetiracetam, lamotrigine) or have particularly long half-lives (ethosuximide,
phenytoin, phenobarbital, zonisamide). These antiseizure drugs allow for "make-up
dosing." As an example, if a child on ethosuximide misses the once-a-day dose, it can
be taken the next day with the regularly scheduled dose.
● Elimination kinetics – Elimination kinetics also should be considered when choosing

an antiseizure drug. With linear or first-order kinetics, a constant fractional amount of
the drug is eliminated over time, independent of the concentration of the drug in the
serum. With nonlinear, dose-dependent, saturable, or concentration-dependent
kinetics, as the level of the drug increases, clearance declines as the elimination
mechanisms become saturated. Linear kinetics is more desirable.
Valproate, carbamazepine, and phenytoin have nonlinear kinetics. Phenytoin is

particularly troublesome, with linear kinetics at low serum levels, and nonlinear kinetics
as the serum level approaches the low- to mid-therapeutic range. Thus, a small
increase in dose may lead to a large and potentially toxic increase in the serum level. At
high serum levels, phenytoin's half-life is significantly longer. At these higher levels, it
may take only a minimal increase in the daily dose to attain the target level; in some
cases, this increase is made every other day.
● Formulations – In infants and younger children, oral suspensions, chewable tablets,

and sprinkle formulations may be useful.
Adverse effects — The adverse effects of antiseizure drugs make a significant

contribution to reduced quality of life in patients with epilepsy. While many antiseizure
drug adverse effects seem to be common to this entire class of medicines (eg, drowsiness,
dizziness, diplopia, and imbalance), others are more specific to an individual drug. These
should be considered in selecting an antiseizure drug, since certain adverse effects are
either more likely or more problematic in certain patients.

● Common neurotoxic and systemic side effects are summarized in the table ( table 3).
● Less common, often idiosyncratic, but potentially serious adverse events are
summarized separately ( table 4).
The adverse effects of individual drugs are discussed in detail separately. (See "Antiseizure
drugs: Mechanism of action, pharmacology, and adverse effects".)
Teratogenicity — There is an increased risk of major and minor congenital

malformations in fetuses exposed to antiseizure drugs. These risks are best characterized
for valproate, phenobarbital, phenytoin, and topiramate, but other antiseizure drugs may
also be implicated, particularly in the context of antiseizure drug polytherapy. In addition,
some antiseizure drugs have been associated with long-term neurocognitive effects and an
increased risk for autism spectrum disorders. These and other risks are discussed in detail
separately. (See "Risks associated with epilepsy during pregnancy and postpartum period",
section on 'Effect of AEDs on the fetus and neonate'.)
Growing awareness of the fetal risks of in utero exposure to valproate in particular,

together with recognition that valproate is one of the most effective drugs for certain types
of epilepsy that commonly affect adolescent girls (eg, juvenile myoclonic epilepsy), have led
a joint task force of the Commission on European Affairs of the International League
Against Epilepsy (ILAE) and the European Academy of Neurology to issue a special report to
provide guidance on the use of valproate in girls and women of childbearing potential [23].
Key aspects of the task force recommendations include the following:
● As in other patient populations, treatment choices in girls with epilepsy should be that
of a shared decision between clinician and patients, based on a careful risk-benefit
assessment of reasonable treatment options for the patient's seizure or epilepsy type.
● Given the risks associated with valproate exposure in utero, valproate should be
avoided whenever possible as initial treatment of epilepsy in girls and women of
childbearing potential.
● Valproate should generally be avoided for treatment of focal epilepsies, since multiple
alternative, equally effective drugs are available that may have lower teratogenic risks.
● For cases in which valproate is considered the most effective option (eg, some genetic
generalized epilepsies), valproate can still be considered as a first-line treatment
option. In such cases, patients and caregivers should be informed of the risks
associated with valproate use during pregnancy (see "Risks associated with epilepsy
during pregnancy and postpartum period", section on 'Valproate') as well as the
relative risks and benefits of alternative treatment options. Options for effective
contraception in the setting of antiseizure drug therapy should also be reviewed. (See
'Additional considerations in adolescent girls' below.)
● When valproate is used in girls and women of childbearing potential, it should be

prescribed at the lowest effective dose and, when possible, at doses not exceeding 500
to 600 mg/day.
Additional considerations relevant to antiseizure drug therapy in women with epilepsy who
are planning pregnancy or who become pregnant are reviewed separately. (See
"Management of epilepsy during preconception, pregnancy, and the postpartum period",
section on 'Preconception management'.)
Drug-drug interactions — Many commonly used drugs can alter the metabolism of

antiseizure drugs and vice versa ( table 5A-C). Strong hepatic enzyme inducers (eg,
phenytoin, phenobarbital, primidone, carbamazepine, oxcarbazepine, felbamate) will lower
the levels of drugs metabolized in the liver, and liver enzyme inhibitors (eg, valproate) will
slow the metabolism of the same drugs. Cimetidine, propoxyphene, erythromycin,
fluoxetine, and clarithromycin are examples of enzyme inhibitors used in children that may
elevate the serum levels of some antiseizure drugs.
Many of the newer antiseizure drugs are nonenzyme-inducing drugs and therefore have
less potential for drug-drug interactions. Nonenzyme-inducing antiseizure drugs such as
levetiracetam are a common choice as first-line therapy when the avoidance of drug-drug
interactions is critical, such as in children with tumor-associated epilepsy who are being
treated with chemotherapy.
Specific interactions of antiseizure drugs with other medications may be determined using
the Lexicomp drug interactions tool.
INITIATION OF ANTISEIZURE DRUG THERAPY
Baseline laboratory evaluation — Routine laboratory tests are not necessary for many
antiseizure drugs; exceptions include cannabidiol, carbamazepine, felbamate, valproate,
and others as listed in the tables ( table 2A-B). (See "Antiseizure drugs: Mechanism of
action, pharmacology, and adverse effects".)
Before initiating valproate in children under the age of three years, or in children who
might have a neurometabolic disorder, we suggest obtaining serum ammonia, pyruvate,
lactate, and carnitine levels and serum amino acid and urine organic acid analyses.
Valproate should be avoided if there is clinical suspicion that the child's illness is
progressive when no etiology has been determined. (See "Valproic acid poisoning", section
on 'Hepatotoxicity'.)
Role of pretreatment HLA testing — Screening for the human leucocyte antigen (HLA)-
B*1502 allele is recommended prior to starting carbamazepine or oxcarbazepine in
patients with Asian ancestry.
The risk of carbamazepine-induced hypersensitivity reactions, including Stevens-Johnson

syndrome (SJS) and toxic epidermal necrolysis (TEN), is increased in patients with HLA-
B*1502 allele, which occurs almost exclusively in individuals with Asian ancestry. An
increased risk of SJS or TEN in patients with the HLA-B*1502 allele has also been described
for oxcarbazepine and phenytoin, although the magnitude of the risk appears to be lower
than with carbamazepine. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis:
Pathogenesis, clinical manifestations, and diagnosis", section on 'HLA types' and
"Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects", section on
'Carbamazepine' and "Antiseizure drugs: Mechanism of action, pharmacology, and adverse
effects", section on 'Oxcarbazepine' and "Antiseizure drugs: Mechanism of action,
pharmacology, and adverse effects", section on 'Phenytoin and fosphenytoin'.)
Carbamazepine, oxcarbazepine, and phenytoin should be avoided in patients known to

carry the HLA-B*1502 allele unless the estimated benefits clearly outweigh the risks.
Drug administration and dosing — The kinetics of an antiseizure drug determine the

initial dose and the interval between dose increments during titration. Suggested dosing
regimens, target serum levels, and laboratory testing for many commonly used antiseizure
medications are listed in the table ( table 2A-B).
Titration and maintenance dosing should be individualized:
● Most antiseizure drugs should be started at approximately 10 to 25 percent of the

planned maintenance dose. Antiseizure drugs with a long half-life can be started at
close to the maintenance dose. In general, the dose should be increased at intervals
not exceeding five half-lives to allow the serum level to plateau between each dose
increment. If seizures are frequent, the titration may be accelerated to achieve a
therapeutic benefit, but this may come at the cost of increased side effects.
● The antiseizure drug dose should be increased until seizures stop, unremitting adverse
effects occur, or serum levels reach a high or supratherapeutic range without a
significant impact upon seizure frequency. The recommended upper therapeutic serum
levels of most of the antiseizure drugs can be exceeded if side effects are absent. This
should be done with particular caution with phenytoin because of its nonlinear
pharmacokinetics and with valproate because of dose-related thrombocytopenia (
table 2A-B).
● If adverse effects appear with upward titration but are tolerable, the dose should
remain stable for several weeks to determine if the symptoms remit. Dose increases
can continue at a slower rate if side effects remit and seizures continue.
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● Some patients may require greater-than-standard doses of an antiseizure drug to

reach therapeutic levels. Low levels at high doses often are caused by poor compliance
but also may be secondary to hypermetabolism of the antiseizure drug (ie, higher-
than-normal clearance because of increased hepatic metabolism). If levels are not
increasing as anticipated and noncompliance is unlikely, the child should be given a
loading dose under medical observation and levels should be measured over the next
12 to 24 hours. A genetically regulated hypermetabolism probably exists if levels
remain low, and higher daily doses are indicated.
● Occasionally, children manifest slow drug clearance, often caused by inherited

variations in the degradation enzymes. These individuals require lower maintenance
doses.
● Ideally, daily antiseizure drug doses should be given at intervals shorter than the half-
life in order to avoid wide excursions in serum levels. The longer the half-life, the less
frequent the dosing. Compliance is improved when medications are taken on schedule
and prompted by an association with a routine daily activity, such as mealtime or
brushing teeth. A variation of an hour or so in scheduled dosing is usually not
significant. Children should not be awakened at night to take antiseizure drugs.
● As a child grows, the antiseizure drug dose may need to be increased to keep up with
his or her body mass. However, the clearance of some antiseizure drugs decreases and
approaches adult rates in adolescence. Serum levels may remain stable as the
declining per kilogram dose is balanced by the declining clearance.
Additional considerations in adolescent girls — As noted above, the potential

teratogenicity of various antiseizure drugs should be discussed and weighed when
choosing a specific antiseizure drug in girls, since in many cases initial therapy will be
continued long term, into the childbearing years. (See 'Teratogenicity' above and "Risks
associated with epilepsy during pregnancy and postpartum period", section on 'Effect of
AEDs on the fetus and neonate'.)
The importance of an effective method of contraception should also be reviewed with girls
who are sexually active or may become sexually active while taking antiseizure drugs.
Certain antiseizure drugs have the potential to lower the efficacy of hormonal
contraception through hepatic enzyme induction ( table 6). Conversely, hormonal
contraception can lower serum levels of some antiseizure drugs (eg, lamotrigine) [24]. The
World Health Organization (WHO) suggests that individuals taking enzyme-inducing
antiseizure drugs or lamotrigine use a method of contraception other than hormonal pill,
patch, or ring contraceptives [25]. Long-acting reversible contraceptive methods are an
effective alternative in this setting. (See "Management of epilepsy during preconception,

pregnancy, and the postpartum period", section on 'Birth control' and "Contraception:
Counseling and selection".)
Folate supplementation is advised in adolescent girls on antiseizure drugs and those with
folate deficiency.
FOLLOW-UP AND MONITORING
Utility of serum drug levels — Serum antiseizure drug levels are informative for certain
antiseizure drugs but not others. Antiseizure drugs for which serum drug levels can be
useful are noted in the tables ( table 2A-B). The availability of a serum drug level testing
for an antiseizure drug does not always mean that levels are useful clinically. As an
example, serum drug levels for levetiracetam can be ordered but have not been shown to
correlate with clinical efficacy or tolerability [26].
Even for antiseizure drugs where serum levels are useful, serum levels should not be used
in isolation to guide to therapy. The therapeutic range is different for each patient. Many
patients will achieve seizure control at levels below the recommended range; others require
higher levels. There is no reason to increase the dose if seizures stop when the serum level
is "low" or "subtherapeutic." If the level reaches the "therapeutic range," yet seizures
continue, the level should be increased as long as there are no adverse effects.
It is helpful to obtain a baseline antiseizure drug level once seizure control has been
attained, which can be compared with a level obtained when seizures recur to determine
whether the breakthrough is caused by a low serum level. Serum levels may be low from
poor compliance, interaction with another medication, decreased absorption (eg, during a
diarrheal illness or gastritis with vomiting), or change in medication preparation (eg, brand
name to generic drug formulation). If a child is placed on another long-term medication,
measuring the antiseizure drug level after the dose of the new drug has been stabilized
may be necessary.
Monitoring for specific drugs — Routine laboratory screening of hematologic and hepatic

function is generally not necessary for asymptomatic children receiving antiseizure drugs (
table 2A-B) [27,28]. However, certain antiseizure drugs require monitoring based on
specific dose-related or idiosyncratic adverse effects, as listed below.
Children on long-term antiseizure drugs, especially enzyme-inducing drugs such as

phenytoin, carbamazepine, and phenobarbital, have an increased prevalence of
hyperlipidemia, low folate, low vitamin B12, and hyperhomocysteinemia [29,30]. Screening
for hyperlipidemia and folate deficiency should be considered in older children on enzyme-
inducing antiseizure drugs.

● Valproate – Although routine monitoring of hepatic function has not been shown to
permit early identification of serious toxicity or improve outcome for patients taking
valproate (valproic acid), many clinicians choose to obtain LFTs once or twice a year in
patients who are clinically asymptomatic. The US Food and Drug Administration (FDA)
recommends checking LFTs prior to initiating treatment and at frequent intervals
thereafter, especially during the first six months. Hepatic enzyme elevations that are
less than three times normal in an asymptomatic child are unlikely to be significant.
Higher levels should be repeated in a few weeks and the medications stopped if levels
are increasing rapidly or if the child becomes symptomatic.
Valproate is associated with a relatively high incidence of minor and usually

insignificant elevations of one or more liver enzymes and serum ammonia. In a study
of 206 adults and children taking anticonvulsants including phenytoin, carbamazepine,
valproic acid, and phenobarbital, the serum gamma glutamyl transpeptidase (GGT) was
elevated in 75 percent and alanine aminotransferase (ALT) in 25 percent [31]. Other
researchers have confirmed these results [32]. Elevations in aspartate transaminase
(AST) are recorded less commonly and may be a more specific marker of liver
dysfunction.
Increases in plasma ammonia are common and may occur in the absence of abnormal
liver function tests. Risk factors for hyperammonemia in children taking valproate
include young age, increased valproate dose, low serum carnitine, and concomitant
use of phenytoin, phenobarbital, carbamazepine, or a carbonic anhydrase inhibitor (eg,
acetazolamide, topiramate, or zonisamide). (See "Valproic acid poisoning", section on
'Hyperammonemia'.)
Most cases of fatal hepatotoxicity with valproate have been in children younger than
three years and usually occurred in the first six months of therapy [33]. These children
often develop encephalopathies and are on polytherapy because of the severe nature
of their seizures. It seems likely that many of these patients have an underlying
metabolic disorder causing the seizures (eg, urea cycle defects, organic acidurias,
mitochondrial cytopathies, storage diseases, or other progressive syndromes of
unknown etiology such as Alpers syndrome), which are exacerbated by exposure to
valproic acid. Also, in some cases, the liver enzymes remain normal despite advanced
hepatic failure with nausea, vomiting, worsening of seizures, and encephalopathy.
● Carbamazepine – In practice, we typically obtain a CBC after the first month of

carbamazepine therapy. If the white blood count (WBC) is significantly decreased, it is
repeated every three to four weeks until the counts stabilize. If the absolute neutrophil
count (ANC) falls below 800 to 1000, the medication should be stopped.

Leukopenia is not uncommon with carbamazepine, often appearing in the first two to
three months of therapy [34]. Severe aplastic anemia or agranulocytosis is reported but
rare, occurring in 2 per 575,000 exposures. These severe blood dyscrasias are more
common in adults. A drop of the white count into the 3000 to 4000 range characterizes
the more common benign leukopenia, which will usually gradually return toward
normal or may remain at a mildly low level for the duration carbamazepine therapy.
● Oxcarbazepine – Hyponatremia has been reported with the use of oxcarbazepine, but
this is very rare in children. The two predominant risk factors appear to be concomitant
use of other "sodium-depleting" medications (eg, tricyclic antidepressants, thiazide
diuretics, atypical antipsychotics) and excessive free water consumption. The effect is
dose related and usually occurs within the first three months of therapy or following
the addition of another sodium-depleting medication. It is not usually necessary to
reduce or stop oxcarbazepine due to hyponatremia; the serum sodium level usually
gradually returns to normal or remains at a mildly reduced level and is nearly always
asymptomatic. For sodium levels less than 120 mEq/L or symptoms of hyponatremia, a
dose reduction of oxcarbazepine or mild fluid restriction is usually successful. (See
"Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects", section
on 'Hyponatremia'.)
● Topiramate and zonisamide – Due to the risk of metabolic acidosis and

nephrolithiasis, serum bicarbonate should be measured at baseline and monitored
periodically thereafter in children treated with topiramate or zonisamide. Dose
reduction or drug discontinuation should be considered in patients with persistent or
severe metabolic acidosis. If the drug is continued, alkali therapy may be warranted as
in type 2 (proximal) renal tubular acidosis. (See "Treatment of distal (type 1) and
proximal (type 2) renal tubular acidosis".)
Topiramate and zonisamide are partial carbonic anhydrase inhibitors and may cause a
mild to moderate chronic metabolic acidosis or nephrolithiasis in a minority of children
[35-41]. As an example, a 2014 systematic review found that metabolic acidosis was
present in 29 percent of patients on topiramate and in 7 percent of patients on
zonisamide [41]. The risk and severity of acidosis are increased if there are other
predispositions to metabolic acidosis, such as renal disease or concurrent use of a
ketogenic diet [35,36]. (See "Ketogenic dietary therapies for the treatment of epilepsy"
and "Seizures and epilepsy in children: Refractory seizures", section on 'The ketogenic
diet'.)
Potential complications of chronic metabolic acidosis in children include impaired

growth, rickets, or osteomalacia [42,43].

● Vigabatrin – Vigabatrin is associated with risks of permanent retinal dysfunction and

concentric visual field constriction that have been noted as early as nine months after
initiation of treatment [44]. The frequency of deficits increases with treatment duration
and cumulative dose. Baseline and serial ophthalmologic evaluations are required in
children treated with vigabatrin. In the United States, prescribers, patients, and
pharmacies must participate in the Risk Evaluation and Mitigation Strategies (REMS)
program. (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse
effects", section on 'Vigabatrin' and "Management and prognosis of infantile spasms",
section on 'Vigabatrin'.)
Monitoring for adverse events — The clinician should be vigilant and have a high index of
suspicion for adverse events in any child receiving chronic antiseizure drugs. A seemingly
benign illness that lasts for more than a few days should prompt a complete blood count
(CBC) and/or liver function studies. Vomiting (the most common early symptom of
hepatotoxicity or pancreatitis), prolonged unexplained fever, easy bruising, extreme fatigue
or lethargy, flu-like symptoms, unexplained worsening of seizures, change in mental status,
and abdominal pain should lead to further investigations [45].
However, with the exception of felbamate, which is associated with a relatively high risk of
aplastic anemia and requires close laboratory monitoring ( table 2A-B), the risk of serious
adverse effects with most of the antiseizure drugs is low. In most instances, serious adverse
events occur in the first few months after the antiseizure drug is initiated.
Note that many idiosyncratic reactions related to antiseizure drugs, including Stevens-
Johnson syndrome, toxic epidermal necrolysis, serum sickness reactions, and pancreatitis,
are not predicted by presymptomatic blood test abnormalities; an exception is
carbamazepine-induced hypersensitivity reactions related to certain human leucocyte
antigen [HLA] types). (See 'Role of pretreatment HLA testing' above.)
A family history can be helpful in making decisions about laboratory testing. Adverse
reactions to medications, particularly those that are hematologic or cutaneous, or a strong
family history of autoimmune disorders, should heighten the concern for idiosyncratic
reactions and hematologic complications. A family as well as personal history of renal
stones should be sought when topiramate or zonisamide is considered [37,38]. (See
"Nephrolithiasis in renal tubular acidosis".)
Bone health — Screening for vitamin D deficiency and supplementation with calcium and
vitamin D are low-risk interventions that are suggested for children and adults on long-
term antiseizure drug therapy. (See "Antiseizure medications and bone disease" and
"Ketogenic dietary therapies for the treatment of epilepsy", section on 'Adverse effects' and
"Epilepsy in children: Comorbidities, complications, and outcomes", section on 'Bone
health'.)
Psychiatric and behavioral health screening — Increased suicidality has been linked to

several antiseizure drugs. Patients taking antiseizure drugs should be monitored for
emergence or worsening of suicidal ideation or depression. The International League
Against Epilepsy (ILAE) endorses routine screening of cognition, mood, and behavior in
new-onset epilepsy [46].
Routine screening can take the form of self-report questionnaires, computerized

assessment batteries, and/or clinical questioning of mood, psychologic adjustment, and
subjective cognitive complaints (eg, attention, memory, or word-finding difficulties). Formal
neuropsychologic assessment may be considered when a focal cognitive deficit is
suspected or apparent or when there is a question of neurodevelopmental delay,
behavioral or learning difficulties, or cognitive decline. Serial neuropsychologic
assessments can also be useful for evaluating the effects of the disorder and its treatment.
(See "Epilepsy in children: Comorbidities, complications, and outcomes", section on
'Psychiatric and behavioral health'.)
ADHERENCE TO ANTISEIZURE DRUGS
Nonadherence — Rates of nonadherence to prescribed antiseizure drug therapy are

difficult to measure but are probably higher than is generally appreciated and can
contribute to inadequate seizure control. One prospective observational study in 124
children (2 to 12 years old) with newly diagnosed epilepsy found that 58 percent
demonstrated nonadherence during the first six months of treatment [47]. A pattern of
nonadherence was often established within the first month. In a follow-up study of the
same cohort, nonadherence during the first six months was associated with worse seizure
control at four years [48].
The complexity of drug regimens and the occurrence of side effects are believed to
contribute to nonadherence. Low socioeconomic status has also been identified as a risk
factor [47].
Improving adherence — We advise measures to promote general medication adherence,

such as daily pill boxes and automated pill dispensers to organize and keep track of
medication dosing, and smartphone apps for patients and caregivers that send reminders
when it is time to take medications and notifications if a dose has been missed.
Small studies have explored ways to improve upon adherence in patients with epilepsy. A
systematic review of randomized trials testing the effectiveness of adherence interventions
in adults (five trials) and children (one trial) with epilepsy found that behavioral
interventions (eg, use of intensive reminders) were associated with somewhat better
results than education and counseling [49].

REFRACTORY SEIZURES
Most children with epilepsy achieve reasonably good seizure control with antiseizure drug
therapy, but some are refractory despite numerous medications. Medical treatment failure
is often apparent early in the course of treatment. In these cases, referral to a
comprehensive epilepsy center is appropriate to explore additional therapeutic options,
including epilepsy surgery, vagus nerve stimulation, and the ketogenic diet. (See "Seizures
and epilepsy in children: Refractory seizures".)
DURATION OF ANTISEIZURE DRUG THERAPY
When to consider withdrawal — Withdrawal of antiseizure drug therapy should be

considered in most children who are seizure-free for two years or longer, regardless of the
etiology of the seizures. Children with neurologic deficits may also be considered for
antiseizure drug withdrawal if they have been seizure-free for an extended period of time,
even though the presence of a motor or cognitive deficit is a risk factor for recurrence. (See
'Risk of seizure relapse after withdrawal' below.)
Method of withdrawal — Antiseizure drugs should be tapered rather than halted abruptly.

There are limited data to guide an antiseizure drug tapering schedule [50]. Rapid changes
(over days to a few weeks) in drug treatment increase the risk of seizures. Slower rates of
antiseizure drug taper, over several weeks to a few months, are generally recommended. In
particular, benzodiazepines and barbiturates are associated with withdrawal seizures and
should be discontinued very gradually.
Risk of seizure relapse after withdrawal — For patients who have been seizure free for a
two-year period, the likelihood of seizure recurrence after stopping antiseizure drugs is
approximately 30 to 40 percent [51,52].
● Length of seizure-free period – A meta-analysis of five studies found that earlier

discontinuation (before two years) of antiseizure drug therapy was associated with a
higher risk for seizure relapse (risk ratio [RR] 1.34), particularly in children with focal
epilepsy or an abnormal electroencephalogram (EEG) [53]. Longer seizure-free periods
were associated with only a slightly lower incidence of recurrence, and therefore longer
observation periods (ie, >2 to 3 years) are not warranted.
● Other risk factors – The following factors indicate an increased likelihood of recurrent
seizures with discontinuation of antiseizure drugs:
• Presence of a motor or cognitive deficit.

• Abnormal EEG at the time of discontinuation in children with epilepsy of unknown

cause [54]. The predictive value of EEG in children with remote symptomatic
epilepsy is not as clear.
• Certain acquired or genetic epilepsies [52,54]. Note that some genetic epilepsies
nearly always remit (eg, childhood absence) but others rarely do (eg, juvenile
myoclonic epilepsy [JME]).
• Structural abnormality on brain magnetic resonance imaging (MRI).
• Short treatment period (6 to 12 months) prior to discontinuation [55,56].
Factors that may be predictive of good outcome include [54-57]:
• Younger age
• Having only absences as a seizure type
In one study of 65 children with cerebral palsy and epilepsy, antiseizure drug treatment
was stopped after at least two seizure-free years; seizure relapse occurred in 42
percent [58]. Children with hemiplegia had a higher relapse rate (62 percent) than did
those with a paraplegia (14 percent). This probably relates to the fact that the major
pathology with paraplegia is in the subcortical white matter with minimal involvement
of the more epileptogenic cortical neurons. In this study, the EEG at the time of
discontinuation was not of value in predicting recurrence.
● Risk of intractable seizures – The risk of recurrent intractable seizures after

discontinuing antiseizure drugs in seizure-free children is very low. In a cohort study of
260 children who became seizure free and stopped antiseizure drugs and were
followed for four to five years, three children (1 percent) developed recurrent seizures
that could not be controlled again with medication [59]. It is not clear that these
recurrent seizures could have been prevented had antiseizure drugs not been
discontinued.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Seizures and
epilepsy in children".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces
are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Epilepsy in children (The Basics)")
● Beyond the Basics topic (see "Patient education: Treatment of seizures in children
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● In most cases, we refrain from starting antiseizure drug therapy for a child with a first
unprovoked seizure, which is a seizure of unknown etiology as well as one that occurs
in relation to a preexisting brain lesion or progressive nervous system disorder.
However, antiseizure drug treatment may be warranted after a first unprovoked
seizure for select children with specific epilepsy syndromes or those with a high risk of
seizure recurrence, including those with a potential remote symptomatic etiology,
particularly if the seizure was focal and the electroencephalogram (EEG) or brain
magnetic resonance imaging (MRI) is abnormal. (See 'First unprovoked seizure' above.)
● We start antiseizure drug therapy for most children who present with a second
unprovoked seizure, since seizure recurrence indicates that the patient has a
substantially increased risk for additional seizures (ie, epilepsy). (See 'Second
unprovoked seizure' above.)
● Antiseizure drug therapy is generally not warranted for children who have a seizure in
the setting of an acute illness or brain insult (eg, acute infection, acute head injury)
since they have a low risk of seizure recurrence (See 'Acute symptomatic seizure'
above.)
● Given the benign nature of febrile seizures, the risks of side effects from antiseizure
drugs generally outweigh the benefits for most patients. This is discussed in more
detail separately. (See "Treatment and prognosis of febrile seizures", section on 'Role of
preventive therapy'.)

● The antiseizure drug chosen for initial therapy should be one that is effective for a
particular seizure type or syndrome and that is safe and well tolerated. Other
considerations include dose formulation, dose frequency, the relative risk of certain
adverse effects, and the potential for drug-drug interactions. Suggested dosing
regimens, target serum levels, and laboratory testing for many commonly used
antiseizure medications are listed in the table ( table 2A-B). (See 'Initiation of
antiseizure drug therapy' above.)
● Serum antiseizure drug levels are informative for certain antiseizure drugs but not
others, and some antiseizure drugs (eg, valproate, carbamazepine, oxcarbazepine,
topiramate, zonisamide, and vigabatrin) require monitoring based on specific dose-
related or idiosyncratic adverse effects, as noted in the table ( table 2A-B). (See
'Follow-up and monitoring' above.)
● Vigilance for adverse events is warranted for any child receiving chronic antiseizure
drugs. A seemingly benign illness that lasts for more than a few days should prompt a
complete blood count (CBC) and/or liver function studies. Vomiting (the most common
early symptom of hepatotoxicity or pancreatitis), prolonged unexplained fever, easy
bruising, extreme fatigue or lethargy, flu-like symptoms, unexplained worsening of
seizures, change in mental status, and abdominal pain should lead to further
investigations. (See 'Monitoring for adverse events' above.)
● Increased suicidality has been linked to several antiseizure drugs. Patients taking
antiseizure drugs should be monitored for emergence or worsening of suicidal
ideation or depression. (See 'Psychiatric and behavioral health screening' above.)
● Most children with epilepsy achieve reasonably good seizure control with antiseizure
drug monotherapy or polytherapy, but some are refractory despite numerous
medications. Medical treatment failure is often apparent early in the course of
treatment. In these cases, referral to a comprehensive epilepsy center is appropriate to
explore additional therapeutic options, including epilepsy surgery, vagus nerve
stimulation, and the ketogenic diet. (See "Seizures and epilepsy in children: Refractory
seizures".)
● Withdrawal of antiseizure drug therapy should be considered in most children after

two years without seizures, regardless of the etiology of the seizures. The likelihood of
recurrence after a two-year period without seizures is approximately 30 to 40 percent.
Antiseizure drugs should be tapered rather than halted abruptly. (See 'Duration of
antiseizure drug therapy' above.)
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3/30/2021 Seizures and epilepsy in children: Initial treatment and monitoring - UpToDate

Author: Angus Wilfong, MD

Seizures and epilepsy in children: Classification, etiology, and clinical features

WHEN TO START ANTISEIZURE DRUG THERAPY

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Unprovoked seizure — The term "unprovoked seizure" refers to a seizure of unknown

First unprovoked seizure

Factors influencing the decision — The main factors to consider in deciding

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Risk of seizure recurrence — The child who is neurologically normal, has no history

Clinical factors associated with an increased risk of recurrent seizures include:

● Prior neurologic insult (ie, remote symptomatic seizure)

In another study, significant MRI findings, present in 16 percent of children, were

Effects of early versus deferred therapy — In adults, immediate antiseizure drug

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Acute symptomatic seizure — An acute symptomatic seizure (also referred to as a

Management of acute symptomatic seizures should be focused on correction of the acute

Febrile seizure — Children presenting with a first-time febrile seizure have an

SELECTION OF AN ANTISEIZURE DRUG

There is an ever-growing list of antiseizure drugs and nonpharmacologic therapies

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Seizure-related considerations — The antiseizure drug chosen for initial therapy should

In some cases, particularly for generalized epilepsy syndromes, seizures may be

Drug-related considerations — Drug-related factors include dose formulation, dose

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consideration of drug-drug interactions. Cost effectiveness is also desirable; as an example,

Pharmacokinetics and formulation

● Elimination kinetics – Elimination kinetics also should be considered when choosing

Valproate, carbamazepine, and phenytoin have nonlinear kinetics. Phenytoin is

● Formulations – In infants and younger children, oral suspensions, chewable tablets,

Adverse effects — The adverse effects of antiseizure drugs make a significant

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Teratogenicity — There is an increased risk of major and minor congenital

Growing awareness of the fetal risks of in utero exposure to valproate in particular,

● When valproate is used in girls and women of childbearing potential, it should be

Drug-drug interactions — Many commonly used drugs can alter the metabolism of

INITIATION OF ANTISEIZURE DRUG THERAPY

patients with Asian ancestry.

The risk of carbamazepine-induced hypersensitivity reactions, including Stevens-Johnson

Carbamazepine, oxcarbazepine, and phenytoin should be avoided in patients known to

Drug administration and dosing — The kinetics of an antiseizure drug determine the

Titration and maintenance dosing should be individualized:

● Most antiseizure drugs should be started at approximately 10 to 25 percent of the

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● Some patients may require greater-than-standard doses of an antiseizure drug to

● Occasionally, children manifest slow drug clearance, often caused by inherited

Additional considerations in adolescent girls — As noted above, the potential

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FOLLOW-UP AND MONITORING

Monitoring for specific drugs — Routine laboratory screening of hematologic and hepatic

Children on long-term antiseizure drugs, especially enzyme-inducing drugs such as

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Valproate is associated with a relatively high incidence of minor and usually

● Carbamazepine – In practice, we typically obtain a CBC after the first month of

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● Topiramate and zonisamide – Due to the risk of metabolic acidosis and

Potential complications of chronic metabolic acidosis in children include impaired