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Seizures and epilepsy in children: Initial treatment and monitoring

Author
Angus Wilfong, MD
Section Editor
Douglas R Nordli, Jr, MD
Deputy Editor
April F Eichler, MD, MPH
Disclosures: Angus Wilfong, MD Grant/Research/Clinical Trial Support: Novartis [epilepsy (Everolimus)]; UCB [epilepsy (Bivaracetam)]; Pfizer [epilepsy
(Pregabalin)]; Upsher-Smith [epilepsy (intranasal Midazolam)]; G-W Pharma [epilepsy (cannabidiol)]; Lundbeck [epilepsy (clobazam)]; Acorda
[epilepsy].Douglas R Nordli, Jr, MD Grant/Research/Clinical Trial Support: NIH [febrile status, SUDEP]. Consultant/Advisory Boards: Eisai [AED
(zonisamide, perampanel)]. April F Eichler, MD, MPH Equity Ownership/Stock Options: Johnson & Johnson [Dementia (galantamine), Epilepsy
(topiramate)].
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level
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and must conform to UpToDate standards of evidence.
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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2016. | This topic last updated: Jan 18, 2016.
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 treatment of seizures and epileptic syndromes in children. Treatment of neonatal
seizures and the treatment of specific epilepsy syndromes are presented separately. (See "Seizures and epilepsy in children:
Classification, etiology, and clinical features" and "Clinical and laboratory diagnosis of seizures in infants and
children" and "Epilepsy syndromes in children" and "Benign focal epilepsies of childhood" and "Treatment 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 "Clinical and laboratory diagnosis of seizures in infants and children" and "Clinical and laboratory
diagnosis of seizures in infants and children", section on 'Setting in which episodes occur'.)
First-time unprovoked seizure The decision whether to treat a child with an antiseizure drug after an initial unprovoked
seizure is an individualized one, weighing the risks of recurrent seizure against the potential risks and benefits of antiseizure
drug therapy and incorporating patient values and preferences.
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 'Acute symptomatic seizure' below.)
The main factors to consider in making a decision of whether or not to treat a chid 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. (See 'Effects of early versus deferred therapy' below.)
The risks of not treating, which include another seizure with its attendant risk of injury and psychological stigma
(including restrictions on driving and work environment in teenagers and young adults) and, infrequently, status
epilepticus.
The risks of chronic antiseizure drugs, which include 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.

A practice parameter for the treatment of a child with a first unprovoked seizure published by the Quality Standards
Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society provides
the following recommendations [1]:
Treatment with antiseizure drugs is not indicated for the prevention of the development of epilepsy.
Treatment with antiseizure drugs may be considered when the benefits of reducing the risk of a second seizure are
greater than the risks of pharmacologic and psychosocial side effects.
This is consistent with the current practice of most neurologists to refrain from treating a child with a first unprovoked seizure.
A consensus statement from the International League Against Epilepsy (ILAE) similarly 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 [2]. Even if the child has a
static encephalopathy, treatment can be withheld until a recurrence pattern is established. The risk of seizure recurrence is
higher in children with a potential remote symptomatic etiology, particularly if the seizure was focal and the EEG abnormal; in
such cases, the benefits of immediate antiseizure drug therapy may outweigh the risks.
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 a 24 percent risk of having another seizure in the next year and a
45 percent risk over the next 14 years [3,4].
Clinical factors associated with an increased risk of recurrent seizures include:
Prior neurologic insult (ie, remote symptomatic seizure)
Significant magnetic resonance imaging (MRI) findings
Abnormal electroencephalogram (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. Several studies illustrate the risk spectrum:
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 [3,4]. 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 [3].
In another study, significant magnetic resonance imaging (MRI) findings, present in 16 percent of children, were more
predictive of short-term seizure recurrence than EEG findings [5].
Status epilepticus as the presenting seizure may be another risk factor for recurrent seizures, although the available data are
less consistent [3,6].
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 post-seizure [7]; 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, as
demonstrated by the following studies:
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 [8]. 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 [9].
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 [4]. 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 Most children who present with a second unprovoked seizure are started on antiseizure
drug therapy, since seizure recurrence indicates that the patient has a substantially increased risk for additional seizures (ie,
epilepsy).
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. In 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 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 [10]. 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 such as hyponatremia, and
concussion. Management of these seizures should be focused on correction of the acute provoking illness or anomaly and
preventing its recurrence.
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'.)
Neonatal seizure Neonatal seizures may be the first, and sometimes the only, clinical sign of a central nervous system
disorder in the newborn infant. Seizures may indicate the presence of a potential treatable etiology and should prompt an
immediate evaluation to determine the cause and institute etiologic-specific therapy. (See "Clinical features, evaluation, and
diagnosis of neonatal seizures", section on 'Etiologic evaluation'.)
The decision whether or not to institute antiseizure drug therapy depends on multiple factors, including seizure duration and
severity as well as seizure etiology. The management of neonatal seizures is discussed in more detail separately.
(See "Treatment of neonatal seizures".)
SELECTION OF AN ANTISEIZURE DRUG 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.
There is an ever-growing list of antiseizure drugs and nonpharmacologic therapies available to manage childhood epilepsy.
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 highly effective for a
particular seizure type or syndrome [11,12]. 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 others, 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 chose first-line therapy based on other drugrelated factors such as side effects, cost, and dosing intervals. (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 andphenytoin have been reported to worsen absence and myoclonic seizures in individuals with

idiopathic generalized epilepsy [13-16]. (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 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 [17]. The pharmacology and specific indications for individual antiseizure drugs are discussed separately.
(See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects".)
Pharmacokinetics and formultation 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 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 halflife 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.
In infants and younger children, oral suspensions, chewable tablets, and sprinkle formulations may be useful.
Side effects The adverse effects of antiseizure drugs make a significant contribution to reduced quality of life in patients
with epilepsy. While many antiseizure drug side effects (eg, drowsiness, dizziness, diplopia, and imbalance) seem to be
common to this entire class of medicines, others are more specific to an individual drug. These should be considered in
selecting an antiseizure drug, since certain side 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 phenobarbital, phenytoin, valproate, 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 and pregnancy", section on 'Effect of
antiseizure drugs on the fetus'.)
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
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 [18]. 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 patients
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 and
pregnancy", 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 and pregnancy", 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 non-enzyme inducing drugs and therefore have less potential for drug-drug
interactions. Non-enzyme 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 drug interactions tool (LexiInteract online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the
individual drug information topics in the section on Drug interactions.
INITIATION OF ANTISEIZURE DRUG THERAPY
Baseline laboratory evaluation Most clinicians obtain screening laboratory tests before initiating antiseizure drug
therapy with a complete blood count (CBC) and platelet count, liver and renal function tests, glucose, electrolytes, total
protein, albumin, and globulin.
In children under the age of three or those who might have a neurometabolic disorder, one should also consider obtaining
serum ammonia, pyruvate, lactate, and carnitine levels and serum amino acid and urine organic acid analyses before
initiating valproic acid.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 The risk of carbamazepine-induced hypersensitivity reactions, including StevensJohnson syndrome and toxic epidermal necrolysis, is increased in patients with the HLA-B*1502 allele, which occurs almost
exclusively in individuals with Asian ancestry. A similar association has been identified for the HLA-A*3101 allele, which is
prevalent in a broader range of ethnicities, although data are more limited. Screening for HLA-B-*1502 is recommended in
patients with Asian ancestry prior to starting carbamazepine. Similar associations have been described for phenytoin,
although the magnitude of the risk is less clear than with carbamazepine. (See "Antiseizure drugs: Mechanism of action,
pharmacology, and adverse effects", section on 'Role of HLA testing' and "Antiseizure drugs: Mechanism of action,
pharmacology, and adverse effects", section on 'Phenytoin'.)
Due to the chemical similarity between carbamazepine and oxcarbazepine, available clinical information, and preclinical data
showing a direct interaction between oxcarbazepine and HLA-B*1502 protein, the FDA revised the oxcarbazepine label in
2014 to suggest testing for the HLA-B*1502 allele in genetically at-risk populations (ie, those with Asian ancestry) before
initiating treatment with oxcarbazepine [19]. Oxcarbazepine, carbamazepine, and phenytoin should be avoided in patients
carrying the HLA-B*1502 allele unless the estimated benefits clearly outweigh the risks. (See "Antiseizure drugs: Mechanism
of action, pharmacology, and adverse effects", section on 'Oxcarbazepine'.)
Drug administration and dosing The kinetics of an antiseizure drug determine the initial dose and the interval between
dose increments during titration (table 2A and table 2B). Most antiseizure drugs should be started at about 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 side 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.
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 A number of issues are important to consider in preadolescent and
adolescent girls when initiating antiseizure drug therapy. As discussed 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 and pregnancy", section on 'Effect of antiseizure drugs on the fetus'.)
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) [20]. 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 [21]. Long-acting reversible contraceptive methods are an effective alternative in this setting.
(See "Overview of contraception".)
FOLLOW UP AND MONITORING
Serum drug levels Serum antiseizure drug levels are available and informative for certain antiseizure drugs but not
others. 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 [22]. Antiseizure drugs for which serum drug levels can be useful are noted in the tables (table
2A-B).
Even for these antiseizure drugs, 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 have a baseline antiseizure drug level once seizure control has been attained, which can be compared with
levels obtained when seizures recur to ascertain whether the breakthrough is caused by low serum levels 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.

Other laboratory monitoring Although routine laboratory screening of hematologic and hepatic function is commonly
done in children receiving antiseizure drugs, evidence is convincing that this routine laboratory testing is not cost effective or
necessary [23,24].
With the exception of felbamate, which is associated with a relatively high risk of aplastic anemia and requires close
laboratory monitoring, the risk of serious side effects with most of the antiseizure drugs is extremely small and, in most
instances, appears in the first few months after the antiseizure drug is initiated. 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 (with the exception of carbamazepine-induced
hypersensitivity reactions related to certain HLA types). (See 'Role of pretreatment HLA testing' above.)
Once a child has been on a stable antiseizure drug regimen for several months, there is little indication for routine monitoring
of laboratory studies (table 2A-B). The clinician should be clinically vigilant and have a low 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 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 [25].
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 hematological complications. A family as well as personal history of renal stones should be
sought when topiramate or zonisamide is considered [26,27]. (See "Nephrolithiasis in renal tubular acidosis".)
Specific drugs Certain antiseizure drugs require monitoring based on specific dose-related or idiosyncratic adverse
effects.
Valproic acid 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 [28]. Other researchers have
confirmed these results [29]. 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 [30]. 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 Alper's 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.
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.
Carbamazepine Leukopenia is not uncommon with carbamazepine, often appearing in the first two to three months
of therapy [31]. 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.
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 ANC falls below 800 to
1000, the medication should be stopped.
Topiramate and zonisamide These antiseizure drugs are partial carbonic anhydrase inhibitors and may cause a mild
to moderate chronic metabolic acidosis in up to two-thirds of children and can also cause nephrolithiasis [26,27,32,33].
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 [32,33] (see "The ketogenic diet" and "Seizures and epilepsy in children:
Refractory seizures and prognosis", section on 'The ketogenic diet'). Potential complications of chronic metabolic
acidosis in children include impaired growth, rickets, or osteomalacia [34,35].
For these reasons, the 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".)
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 doserelated 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'.)
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 [36]. The frequency of deficits increases with
treatment duration and cumulative dose. Baseline and serial ophthalmologic evaluations are required in children treated
with vigabatrin, which can only be prescribed through the Support, Help, and Resources for Epilepsy (SHARE)
program. (See "Management and prognosis of infantile spasms", section on 'Side effects and monitoring'.)
Bone health Both epilepsy and antiseizure drugs are associated with adverse effects on bone health. Children with
epilepsy who are treated with antiseizure drugs are at increased risk for reduced bone density, impaired bone growth, and
vitamin D deficiency [37]. Both enzyme-inducing and non-enzyme inducing antiseizure drugs as well as the ketogenic diet
have been implicated in risk of bone disease.
Although few studies have rigorously evaluated strategies for prevention and treatment of bone disease in patients with
epilepsy, screening for vitamin D deficiency and supplementation with calcium and vitamin D are low-risk interventions that
are suggested in children and adults on long-term antiseizure drug therapy. (See "Antiepileptic drugs and bone
disease" and "The ketogenic diet", section on 'Adverse effects'.)
Psychiatric and behavioral health screening Children with epilepsy are at increased risk for psychiatric, cognitive, and
behavioral health problems related to the disease itself, the underlying etiology of seizures in some cases, and the side
effects of therapy. Depression, suicidality, and attention deficit hyperactivity disorder are particularly important to address at
follow up visits.
The International League Against Epilepsy (ILAE) endorses routine screening of cognition, mood, and behavior in new-onset
epilepsy [38]. Routine screening can take the form of self-report questionnaires, computerized assessment
batteries, and/or clinical questioning of mood, psychological adjustment, and subjective cognitive complaints (eg, attention,
memory, or word-finding difficulties). Formal neuropsychological 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 neuropsychological assessments can also be useful for evaluating the effects of the disorder and
its treatment.
Depression and suicidality Increased suicidality has been linked to several antiseizure drugs in randomized placebocontrolled studies of patients with epilepsy over five years of age, according to a January 2008 FDA report [39]. The elevated
risk (0.43 versus 0.22 percent) was observed as early as one week after starting medication and continued though the 24
weeks of study observation. The effect was consistent in the 11 antiseizure drugs studied, and the FDA considers this risk
likely to be shared by all antiseizure drugs.
Patients taking antiseizure drugs should be regularly monitored for emergence or worsening of suicidal ideation or
depression. An approach to the assessment of suicidality in children is discussed separately. (See "Suicidal behavior in
children and adolescents: Evaluation and management", section on 'Identification of suicide risk'.)
Attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is one of the most common
psychiatric comorbidities in children with epilepsy, with a reported prevalence ranging from 12 percent in a general
population-based survey to as high as 60 percent in patients with severe epilepsy treated at tertiary care epilepsy clinics [4042]. Children with ADHD and epilepsy are more likely than those without epilepsy to manifest the predominantly inattentive

subtype of ADHD, rather than the hyperactive-impulsive subtype [41,43]. (See "Attention deficit hyperactivity disorder in
children and adolescents: Clinical features and evaluation", section on 'ADHD'.)
Recognition of ADHD in children with epilepsy is important because effective treatments exist, and ADHD has been
associated with decreased health-related quality of life in children with epilepsy [41]. Stimulants have not been well studied in
patients with epilepsy because of concern that they may lower the seizure threshold, and patients with epilepsy were
excluded from clinical trials establishing the safety and efficacy of stimulant medications. Although one dose-escalation study
of sustained-release methylphenidate in children with epilepsy found a slight increase in seizure frequency at high doses
[44], other data, primarily in the form of retrospective case series and small prospective studies, suggest that low to medium
doses of methylphenidate are safe and effective, even in children with active seizures [45-52].
In our experience, ADHD is very prevalent in children with epilepsy. We recommend that all children with epilepsy undergo
standardized psychoeducational testing through their school or in our clinic. Once a diagnosis of ADHD is made, behavioral
therapies are offered as first-line intervention. If academic problems persist, then therapy with stimulant medication is offered
to all but the most unstable patients. Caregivers and classroom teachers are advised to monitor the childs seizure burden
carefully when the stimulant medication is first introduced. In our experience, it is rare to see a significant deterioration in
seizure control.
The treatment of children and adolescents with ADHD is discussed in detail separately. (See "Attention deficit hyperactivity
disorder in children and adolescents: Overview of treatment and prognosis".)
Adherence to antiseizure drugs 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 [53]. 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 [54].
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 [53].
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 (5 trials) and children (1 trial) with epilepsy found that
behavioral interventions (eg, use of intensive reminders) were associated with somewhat better results than education and
counselling [55].
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 addition
therapeutic options, including epilepsy surgery, vagus nerve stimulation, and the ketogenic diet. (See "Seizures and epilepsy
in children: Refractory seizures and prognosis".)
STOPPING ANTISEIZURE DRUG THERAPY 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 twoyear period without seizures is approximately 30 to 40 percent [56,57].
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 (RR = 1.34), particularly in children with focal epilepsy or an abnormal EEG
[58]. Longer seizure-free periods are associated with only a slightly lower incidence of recurrence, and therefore longer
observation periods (ie, >23 years) are not warranted.
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.
The following factors indicate an increased likelihood of recurrent seizures with discontinuation of antiseizure drugs:
Presence of a motor or cognitive deficit.
Abnormal electroencephalogram (EEG) at the time of discontinuation in children with epilepsy of unknown cause [60].
The predictive value of EEG in children with remote symptomatic epilepsy is not as clear.
Symptomatic epilepsy [57,60].

Short treatment period (6 to 12 months) prior to discontinuation [61,62].


Other factors that may be predictive of good outcome are a younger age and having only absences as a seizure type [6063].
Even though the presence of a motor or cognitive deficit is a risk factor for recurrence, children with neurologic deficits
should also be considered for antiseizure drug withdrawal if they have been seizure-free for an extended period of time. In
one study, seizure relapse occurred in 41.5 percent of 65 children with cerebral palsy and seizures after at least two seizurefree years [64]. Children with hemiplegia had a much higher relapse rate (61.5 percent) than did those with a paraplegia
(14.3 percent). This probably relates to the fact that with paraplegia, the major pathology 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.
Antiseizure drugs should be tapered rather than halted abruptly. There are limited data to guide an antiseizure drug tapering
schedule [65]. 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.
DRIVING AND OTHER RESTRICTIONS States vary widely in driver licensing requirements for patients with epilepsy as
well as the responsibilities of physicians to notify state authorities [66]. This topic is discussed in more detail elsewhere.
(See "Driving restrictions for patients with seizures and epilepsy".)
In school-aged children with epilepsy, questions may arise about participation in sports and other activities, and clinicians
may be asked to provide medical clearance before a child can participate in certain sports. These decisions should be
individualized, weighing not only the potential risks of participation but also the benefits of physical exercise and social
engagement [67]. Factors to consider include the type of sport, the probability of a seizure occurring during the activity and
related implications, the amount of supervision available during the activity, the patients seizure type and severity, the
consistency of any prodromal symptoms, relevant seizure precipitants, a history of seizure-related accidents or injuries,
recent seizure control, degree of adherence to therapy, and the willingness of the patient and parents to take on risk. The
International League Against Epilepsy has published a consensus-based guideline on this topic, which divides sports into
three risk categories and proposes a decision-making framework for each risk category [67].
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 5 th 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 10 th 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 information: Epilepsy in children (The Basics)")
Beyond the Basics topics (see "Patient information: Treatment of seizures in children (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
The decision whether to treat a child after an initial unprovoked seizure is an individualized one that depends on
multiple factors, including the estimated risk for seizure recurrence, the risk of side effects from antiseizure drug
therapy, and patient values and preferences. (See 'When to start antiseizure drug therapy' above.)
The child who is neurologically normal, has no history of neurologic illness, and no evident acute cause for the
seizure has an approximately 25 percent risk of a recurrent seizure in the next year, and a nearly 50 percent risk
of seizure over the next 10 to 15 years.
Clinical factors associated with an increased risk for recurrent seizure after a first-time unprovoked seizure
include prior neurologic insult, significant MRI findings, and an abnormal electroencephalogram (EEG). (See 'Risk
of seizure recurrence' above.)
Children who have a seizure in the setting of an acute illness have a low risk of seizure recurrence compared to
other children with a first seizure. (See 'Acute symptomatic seizure' above.)

Treatment with an antiseizure drug reduces the risk of recurrent seizures, however, withholding treatment until
after the second seizure does not alter the long-term prognosis of epilepsy. (See 'Effects of early versus deferred
therapy' above.)
Most neurologists refrain from starting antiseizure drug therapy in a child with a first unprovoked seizure, estimating
that the risks of side effects outweigh the modest benefit of antiseizure drug therapy in preventing a recurrent seizure.
Even if the child has a static encephalopathy, treatment can be withheld until a recurrence pattern is established. The
risk of seizure recurrence is higher in children with a potential remote symptomatic etiology, particularly if the seizure
was focal and the EEG abnormal; in such cases, the benefits of immediate antiseizure drug therapy may outweigh the
risks. (See 'First-time unprovoked seizure' above.)
We recommend initiating antiseizure drug therapy in children with recurrent, unprovoked seizures (Grade 1A).
Occasionally, antiseizure drug therapy is deferred in this setting if seizures are brief, nondisruptive, and infrequent.
(See 'Second unprovoked seizure'above.)
The antiseizure drug chosen for initial therapy should be one that is highly effective for a particular seizure type or
syndrome and that is safe and well tolerated. Other considerations include dose formulation, does frequency, the
relative risk of certain side effects, the potential for drug-drug interactions. (See 'Initiation of antiseizure drug
therapy' above.)
Routine laboratory screening of hematologic and hepatic function is commonly done in children receiving antiseizure
drugs, but the value of this practice and a recommended frequency is not defined. (See 'Follow up and
monitoring' above.)
Most clinicians obtain screening laboratory tests before initiating antiseizure drug therapy with a CBC and platelet
count, liver and renal function tests, glucose, electrolytes, total protein, albumin, and globulin. (See 'Baseline
laboratory evaluation' above.)
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, with the exception of hypersensitivity reactions related to carbamazepine (and
possibly phenytoin and oxcarbazepine) in patients with certain human leucocyte antigen (HLA) types. (See 'Role
of pretreatment HLA testing' above.)
In children under the age of three or those who might have a neurometabolic disorder, one should consider
obtaining serum ammonia, pyruvate, lactate, and carnitine levels and serum amino acid and urine organic acid
analyses before initiating valproic acid. Valproate should be avoided if there is clinical suspicion that the child's
illness is progressive when no etiology has been determined. (See 'Specific drugs' above.)
Once a child has been on a stable antiseizure drug regimen for several months, there is little indication for
routine monitoring of laboratory studies. The clinician should be clinically vigilant and have a low 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 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 'Other laboratory monitoring' 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 addition
therapeutic options, including epilepsy surgery, vagus nerve stimulation, and the ketogenic diet. (See "Seizures and
epilepsy in children: Refractory seizures and prognosis".)
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 'Stopping
antiseizure drug therapy' above.)
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