Antiepileptic Drug Treatment of Epilepsy in Children

Antiepileptic Drug REVIEW ARTICLE

Treatment of Epilepsy C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
in Children
By Ahsan N. V. Moosa, MD
ABSTRACT
PURPOSE OF REVIEW: The treatment of epilepsy in children is highly
individualized at each and every major step in the management. This review
examines various factors that modify the treatment from the point of
initiation of therapy to the decision to stop an antiepileptic drug (AED).
RECENT FINDINGS:AED therapy leads to seizure freedom in about 70% of all

children with epilepsy. AED initiation could be delayed until a second
seizure in most children and may be avoided altogether in many children
with self-limited childhood focal epilepsies. Three key factors influence
the choice of AED: seizure type(s), efficacy of the drug for the seizure type,
and the side effect profile of the drug(s). For epileptic spasms, steroids
and vigabatrin are the most effective treatment options. For absence
seizures, ethosuximide and valproic acid are superior to lamotrigine.
For focal seizures, many newer AEDs have favorable side effect profiles
with efficacy comparable to older-generation drugs. For generalized
epilepsies, valproic acid remains the most effective drug for a broad range
of seizure types. Genetic and metabolic etiologies may guide unique
treatment choices in some children. After 2 years or more of seizure
freedom, if the recurrence risk after AED withdrawal is acceptable, slow
weaning of AEDs should be done over the span of 6 weeks or longer.
After discontinuation, about 70% of patients remain seizure free, and of
those with recurrence, the majority achieve seizure control with restarting CITE AS:
an AED. When treatment with two or more AEDs fails, other treatment CONTINUUM (MINNEAP MINN)
opportunities for drug-resistant epilepsy, including epilepsy surgery, 2019;25(2, EPILEPSY):381–407.
vagal nerve stimulation, and dietary therapies should be considered.

Address correspondence to
Dr Ahsan N. V. Moosa, Epilepsy
SUMMARY: Carefully selected medical therapy guided by seizure type and Center, Cleveland Clinic, 9500
AED characteristics is effective in more than two-thirds of children Euclid Ave, Desk S-51, Cleveland,
OH 44195, naduvia@ccf.org.
with epilepsy.
RELATIONSHIP DISCLOSURE:
Dr Moosa reports no disclosure.
INTRODUCTION UNLABELED USE OF
M
PRODUCTS/INVESTIGATIONAL
ore than two-thirds of children with newly diagnosed USE DISCLOSURE:
epilepsy respond to antiepileptic drug (AED) treatment and Dr Moosa reports no disclosure.
enter long-term remission.1,2 Lack of response to the initial
two appropriately selected AEDs predicts poor response © 2019 American Academy
to other drugs.3 Hence, choosing the initial AED is of of Neurology.
CONTINUUMJOURNAL.COM 381
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

ANTIEPILEPTIC DRUG TREATMENT OF EPILEPSY IN CHILDREN
paramount importance. Seizure type and epilepsy phenotype are the

primary drivers of antiepileptic therapy selection. In adults, the dichotomous
classification of seizures into focal and generalized is valuable in guiding
AED choices. However, in young children, the expression of epilepsy has
certain age-dependent characteristics with unique seizure types and syndromes,
requiring therapies seldom used in adults. Additionally, the seizure burden
can be very high in many children with refractory epilepsies such as
Lennox-Gastaut syndrome in which multiple seizures per day are common.
Treatment of such children often requires polytherapy that may cause
cognitive, sedative, and behavioral side effects that adversely affect quality
of life even more than seizures. A carefully selected treatment regimen
implemented systematically may assist in minimizing seizures and, more
importantly, minimizing adverse effects of medication, improving the overall
quality of life. On the other end of the spectrum, certain childhood epilepsies
have a benign long-term prognosis and may not need long-term AEDs.
This article will address common scenarios in pediatric epilepsy practice,
including when to start an AED, which factors determine the AED selection, and
when to consider stopping AED therapy.
INITIATING ANTIEPILEPTIC DRUG THERAPY

The decision to initiate an AED primarily depends on the risk of seizure
recurrence. A recurrence risk of 60% or more is often considered the cutoff
for initiating an AED. A clinical diagnosis of epilepsy is met when a child has two
or more unprovoked seizures or if the predicted risk of recurrence of seizure is
60% or more after the first seizure.4 Factors linked to increased recurrence after a
first seizure include the presence of an abnormal neurologic examination,
abnormal brain MRI, abnormal EEG, and a history of nocturnal seizures.5 The
presence of any one of these factors elevates the risk of seizure recurrence by
twofold in many adult patients. Abnormal EEG and seizures related to remote
brain injury predict increased risk for recurrence in children.6,7
Naturally, the question about AED initiation arises after the first seizure.5
Early initiation of AED treatment after the first seizure has been shown to
delay the second seizure, although the long-term prognosis is unchanged
irrespective of whether treatment is started early or delayed until a second
seizure. Delaying a second seizure by immediately starting AEDs may be
clinically meaningful for many adults who wish to regain and retain their
ability to drive as soon as possible; this consideration is clearly not relevant for
young children.
Three key factors alter the approach to the initiation of treatment for epilepsy
in children.
Benign Natural History of Some Epilepsies in Children

In selected children with self-limited childhood focal epilepsies (with
centrotemporal or occipital spikes), long-term daily AED treatment may not be
needed because children invariably outgrow their tendency to have seizures.6
Because seizures are frequently focal and nocturnal, many families are
comfortable not initiating a daily AED, even after several recurrent seizures.
Daytime seizures, longer seizures, generalized tonic-clonic seizures, and
sometimes caregiver preferences may necessitate the need for initiation
of treatment.
382 APRIL 2019

Cognitive-Behavioral Side Effects of Antiepileptic Drugs KEY POINTS
AEDs may have a potentially negative impact on cognition and behavior in
● A clinical diagnosis of
children. The effect on an individual child is largely unpredictable, and data from epilepsy is met when a child
newer AEDs in children are lacking. Cognitive adverse effects are of utmost has two or more unprovoked
importance to parents and influence the decision to initiate medication. seizures or if the predicted
risk of recurrence of seizure
is 60% or more after the
Young Children Do Not Drive
first seizure.
Because of the absence of driving expectations in young children, daily AEDs are
rarely, if ever, started after the first seizure.7 In clinical settings with a very ● In selected children with
high risk of seizure recurrence, such as in tuberous sclerosis, malformation of self-limited childhood
cortical development, and acute encephalitis, early initiation of an AED after the focal epilepsies (with
centrotemporal or occipital
first seizure may be considered. In most other situations, AED initiation could spikes), long-term daily
be delayed until the occurrence of a second seizure. antiepileptic drug treatment
Initiation of treatment before the onset of epilepsy has been debated in may not be needed because
selected diseases known to have high risk of developing epilepsy. For example, children invariably outgrow
their tendency to have
children with tuberous sclerosis are at high risk of developing infantile spasms in seizures.
the first year of life, and this is linked to poor cognitive outcome. If a child is
diagnosed with tuberous sclerosis early in life before the occurrence of seizures, ● The single most important
initiation of treatment before the onset of seizures has been proposed by some determinant of treatment
choice is the type of seizure
experts. European experts have proposed serial EEGs in infancy and early
that is being targeted.
treatment (with vigabatrin) when epileptiform abnormalities emerge on EEG.8
There is limited evidence to support this approach, especially because of the
neurotoxic risks related to vigabatrin therapy. However, if the EEG shows
features to suggest early hypsarrhythmia, then one could consider therapy even
if overt spasms have not occurred.
SELECTING AN ANTIEPILEPTIC DRUG

More than 25 different antiepileptic medications are available for clinical use. In
the past 2 decades, several newer medications have become available, which, in
general, have fewer side effects and minimal drug interactions.9 Selection of the
first AED requires a careful consideration of several factors, with a focus on
efficacy and tolerability. Factors guiding the choice of an AED include the
epilepsy syndrome, patient characteristics, AED pharmacology, and
socioeconomic/cultural factors, as shown in TABLE 5-1.10
Epilepsy Syndrome Diagnosis

The single most important determinant of treatment choice is the patient’s
epilepsy syndrome diagnosis, especially the range of seizure types being targeted.
Most seizure types are recognizable with careful history taking supported by
other data from the neurologic examination, EEG, and neuroimaging. The
dichotomous classification of seizures into focal and generalized seizure types is
still helpful in guiding the treatment choice. Some patients may have seizures
with both focal and generalized features, and in others, a clear distinction
between focal and generalized seizures may not be possible in the early stages
with only a few seizures to analyze. Two seizure types—epileptic spasms and
absence seizures—typically seen in children have unique treatment options,
discussed later in this review. Both are easily recognizable by history and
interictal EEG; when in doubt, a brief video-EEG monitoring session to confirm
the seizure type may be rewarding, as illustrated in CASE 5-1. Children with
epileptic spasms and absences typically have frequent seizures, which enables

capturing on video-EEG with shorter periods of monitoring. Myoclonic and tonic

seizures are other seizure types that need careful AED selection to ensure efficacy
and avoid exacerbation or worsening of seizure frequency or severity.
Antiepileptic Drug Pharmacology

Some AEDs are considered broad spectrum because they are effective against a
wide range of seizure types. Some drugs are known to be ineffective for certain
seizure types and, in rare instances, may worsen specific seizure types. The side
TABLE 5-1 Factors Determining the Selection of Antiepileptic Drugsa
Epilepsy Characteristics
◆ Seizure type
◆ Epilepsy syndrome
◆ Seizure frequency
◆ Disease
Patient Characteristics
◆ Age
◆ Sex
◆ Pregnancy
◆ Comorbidity
◆ Previous medications
◆ Other concurrent medications
◆ Allergies
◆ Ethnicity/genomics
Antiepileptic Drug Characteristics
◆ Efficacy spectrum
◆ Side effects
◆ Antiepileptic drug interactions
◆ Rapid/slow titration
◆ Half-life and dosing frequency requirements (eg, once a day versus 2 times daily)
◆ Forms (pill/liquid)
◆ Interaction with oral contraceptives
◆ Teratogenic risk
Others
◆ Cost
◆ Insurance
◆ Availability
◆ Personal choice
a
Reprinted with permission from Cross JH, et al, Front Neurol.10 © 2017 Cross, Auvin, Falip, Striano and
Arzimanoglou.
384 APRIL 2019

effect profile of the drugs is the next major determinant. Drugs with a low risk of KEY POINTS
drowsiness and cognitive dulling are preferred. Mechanism of action is
● Drugs with low risk of
particularly important when selecting drugs for polytherapy because drugs with drowsiness and cognitive
a similar mechanism of action may cause synergistic adverse effects. Other dulling are preferred.
factors that influence AED choice include the half-life of the drug (determining
the number of doses per day), ability to titrate rapidly (the need for slower ● A higher risk of
Stevens-Johnson syndrome
titration with lamotrigine precludes its use in children with frequent seizures and
in patients of Asian ancestry
in the intensive care unit setting), interaction with other AEDs and with oral with the HLA-B*1502 allele
contraceptives, and availability in IV and oral liquid formulations. The and a risk of liver failure with
cross-allergenic potential between drugs also may need to be considered in valproic acid in patients with
patients with prior allergies. a POLG1 mutation are two
noteworthy situations in
which pharmacogenomics
Patient Characteristics factors influence
Patient variables unrelated to epilepsy phenotype shape the choice of therapy, as antiepileptic drug selection.
shown in TABLE 5-2. Age and sex have major influences on the choice of AED. In
newborns, phenobarbital has long been used as the first-line agent. Special
challenges related to epilepsy in women of childbearing potential are addressed
elsewhere; refer to the article “Treatment of Women With Epilepsy” by Mona
Sazgar, MD, FAES, in this issue of Continuum.11 Comorbidities such as liver
disease, renal dysfunction, behavioral problems, obesity, and comedications (eg,
warfarin) may influence AED choice. A higher risk of Stevens-Johnson
syndrome in patients of Asian ancestry with HLA-B*1502 allele and a risk of liver
failure with valproic acid in patients with a POLG1 mutation are two noteworthy
situations in which pharmacogenomic factors influence AED selection.12
SOCIOECONOMIC AND PERSONAL PREFERENCES. Although every effort should

be made to prescribe the most effective medication with the fewest side effects,
other personal and socioeconomic factors should also be taken into account. The
cost of the medication, insurance coverage, and the copay costs may influence
drug selection for many families. Risk aversion to side effects of medications
varies among individuals. Although some families of children with epileptic
spasms may object to injectable steroids, others may view the risk of irreversible
peripheral visual field loss with vigabatrin as unacceptable. Availability of the
medication also may be a limiting factor.
EVIDENCE-BASED CHOICE OF ANTIEPILEPTIC DRUGS IN FOCAL AND

GENERALIZED EPILEPSIES
Until the mid-1990s, only a handful of AEDs was available for routine use. Since
then, about 20 newer medications have become available for clinical use. Newer
drugs are initially tested in adults (typically for focal epilepsies) and are typically
approved for clinical use if they show more than a 50% reduction in seizures at 12
to 16 weeks of therapy. Randomized placebo-controlled trials are critical to
establishing the efficacy of a new AED because of the natural fluctuations in
seizure frequency. A review by the International League Against Epilepsy on
evidence for initial monotherapy provided a summary of the level of evidence in
specific epilepsy syndromes, as shown in TABLE 5-3.13 This review also highlights
flaws in many trials and reiterates that some AEDs not listed in the table may be
useful based on clinical experience, case series, or by expert consensus. Although
placebo-controlled trials are crucial for testing new medications, practicing
clinicians often look for information that compares the efficacy of a new drug to

old established drugs to identify opportunities to improve seizure control.

Well-conducted randomized controlled trials providing such information in
children are lacking for several AEDs.
Head-to-head comparison studies between newer and older AEDs are not
undertaken frequently. Findings from SANAD (Standard and New Antiepileptic
Drugs) trials (A and B) established good efficacy of lamotrigine for focal epilepsy
compared with carbamazepine; valproic acid, an older AED, remains the most
effective drug for generalized seizures.14,15 Network meta-analysis of several
CASE 5-1 A 4-year-old boy was referred for management of refractory epilepsy
that started at 18 months of age. His seizures were described as episodes
of confused behavior and walking aimlessly with intermittent, sudden
simultaneous movements of “arms up and head down” occurring every
few seconds to a minute, about 10 to 15 times in a cluster. He had four to
five such clusters a day. His language abilities regressed after the onset of
seizures. He had persistent seizures despite treatment trials with
levetiracetam, valproic acid, topiramate, zonisamide, clobazam,
felbamate, ethosuximide, and ketogenic diet. His prior evaluation at age
2 years had shown a normal brain MRI and multifocal and generalized
epileptiform discharges on EEG. Epilepsy gene panel and CSF analysis for
metabolic disorders were negative.
Video-EEG evaluation at 4 years of age showed features consistent
with hypsarrhythmia, as shown in FIGURE 5-1. The seizures were confirmed
to be epileptic spasms with diffuse ictal patterns. Brain MRI showed
features of subtle cortical dysplasia centered on the right middle frontal
gyrus. This subtle lesion that had not been evident at a younger age likely
became apparent later as myelination was more complete by age 4 years,
providing better gray-white contrast. The child was started on oral
prednisolone for the treatment of epileptic spasms. His seizures
completely stopped within 1 week. Follow-up EEG showed resolution of
hypsarhythmia but showed focal right frontal sharp waves. The child
continued to be seizure free at the 2-year follow-up and showed steady
progress in development and learning.
COMMENT This case highlights the importance of choosing the appropriate treatment
based on the seizure type, which was steroids for epileptic spasms in this
4-year-old child, whose combined features of epileptic spasms and
developmental regression are diagnostic of West syndrome. West
syndrome is commonly associated with an underlying malformation of
cortical development, as seen in this patient. Epileptic spasms may start or
persist in older children. Even in patients with focal malformations,
appropriate medical therapy (steroids or vigabatrin or both) may lead to
remission of epileptic encephalopathy. This child is at risk of focal seizures
in later life, but the resolution of epileptic encephalopathy was critical
for improving the developmental outcome. If the treatment with steroids
had failed, one would consider vigabatrin before considering surgical
treatment.
386 APRIL 2019

trials of various AEDs may provide additional information about comparative
efficacy. Network meta-analysis allows researchers to “combine direct evidence
and indirect evidence across the network of drugs”16 from many trials. In a recent
network meta-analysis, 10 AEDs (carbamazepine, lamotrigine, levetiracetam,
oxcarbazepine, valproic acid, zonisamide, topiramate, phenytoin, phenobarbital,
and gabapentin) commonly used as monotherapy in epilepsies (both partial
and generalized epilepsies) were studied.16 Seventy-seven trials were included
in this analysis, of which individual participant data were available for 69% of
FIGURE 5-1
EEG and MRI findings of the patient in CASE 5-1. A, Interictal EEG shows features of
hypsarrhythmia. B, Ictal EEG shows burst of diffuse slowing (black arrow) concurrent with
spasms followed by attenuation of background activity. C, Axial T2-weighted brain MRI
shows signal abnormalities (white arrows) in the right middle frontal gyrus consistent with
cortical dysplasia.

study patients (n = 12,391) from 36 trials. The trials included both children and
adults with focal seizures and generalized tonic-clonic seizures. Patients with
only absence seizures were excluded. The included trials had at least one pairwise
comparison with two other AEDs in the network. The primary outcome used was
the time to withdrawal of allocated treatment (retention time), which reflects
both effectiveness and tolerability, relevant to clinical decision making. The time
to a second seizure and 6-month and 12-month remission rates were also analyzed.
The results of this network meta-analysis showed that, for focal seizures,
lamotrigine and levetiracetam were significantly better than carbamazepine,
which was better than phenytoin and phenobarbital. For generalized seizures,
TABLE 5-2 Patient Characteristics to Consider in Antiepileptic Drug Selection
Patient Factors Antiepileptic Drug Choice Modifiers Comments

Young women on oral Many enzyme inducers decrease estrogen Intrauterine devices preferred; lamotrigine and
contraceptives levels: eg, phenobarbital, phenytoin, estrogen have a two-way interaction, decreasing
carbamazepine, felbamate, perampanel, the levels of each other
oxcarbazepine, topiramate, and lamotrigine
Pregnant/planning to Valproic acid carries a high (20% to 25%) risk of Risk of neural tube defects with many AEDs is
become pregnant cognitive and behavioral problems reduced by periconceptual folic acid
Obesity Topiramate, zonisamide, and felbamate may Weight gain: valproic acid, carbamazepine,
cause weight loss vigabatrin, and gabapentin
Weight neutral: lamotrigine, phenytoin, and
levetiracetam
Comorbid migraines Topiramate and valproic acid may be effective Targeting seizure type with the right AED should
for migraines supersede the urge to “dual” treatment
Comorbid depression Valproic acid, lamotrigine, and carbamazepine Some AEDs may worsen depression. The US Food
are mood stabilizers and Drug Administration (FDA) includes a warning
for all AEDs about increased suicidal risk based on
an analysis of 11 AEDs in 2008 that found a nearly
twofold increased risk for suicidal behavior or
ideation in patients treated with AEDs compared
to placebo.
Comedication with Enzyme inducers (phenobarbital, phenytoin, In general, many newer AEDs with some
warfarin carbamazepine, perampanel) may reduce exceptions are safe to use with warfarin
effectiveness
Behavioral problems/ Many AEDs are reported to cause psychosis, eg, Neuropsychiatric side effects may occur with any
psychosis levetiracetam, phenobarbital, topiramate, AED; large individual variability in susceptibility
perampanel, vigabatrin, and zonisamide
Kidney stones Topiramate, zonisamide, and ketogenic diet Potassium citrate supplementation is effective in
carry a minor risk of kidney stones preventing renal stones while on ketogenic diet
Liver disease Avoid hepatotoxic drugs: pharmacokinetic Frequent serum level monitoring may be needed
principles guide dosing to titrate; check free levels when appropriate
Renal disease Avoid nephrotoxic drugs: pharmacokinetic Caution about various dialysis types and their effect
principles guide dosing on AED removal; follow serum drug levels closely
AED = antiepileptic drug.
388 APRIL 2019

Level of Evidence for Efficacy of Antiepileptic Drugs for Each Seizure Type TABLE 5-3
and Childhood Epilepsy Syndromea
Seizure Type or Epilepsy Class I Class II Class III Level of Evidence for Efficacy for Effectiveness
Syndrome Studiesb Studiesb Studiesb (Drug Names in Alphabetical Order)c
Children with partial onset 1 0 19 Level A: Oxcarbazepine

seizures
Level B: None
Level C: Carbamazepine, phenobarbital,
phenytoin, topiramate, valproic acid, and
vigabatrin
Level D: Clobazam, clonazepam, lamotrigine, and
zonisamide
Self-limited epilepsy with 0 0 3 Level A: None

centrotemporal spikes
Level B: None
Level C: Carbamazepine and valproic acid
Level D: Gabapentin, levetiracetam,
oxcarbazepine, and sulthiame
Children with absence 1 0 7 Level A: Ethosuximide and valproic acid

seizures
Level B: None
Level C: Lamotrigine
Level D: None
Children with generalized 0 0 14 Level A: None

tonic-clonic seizures
Level B: None
Level C: Carbamazepine, phenobarbital,
phenytoin, topiramate, and valproic acid
Level D: Oxcarbazepine
Juvenile myoclonic epilepsy 0 0 1 Level A: None

Level B: None
Level C: None
Level D: Topiramate and valproic acid
a
Modified with permission from Glauser T, et al, Epilepsia.13 © 2013 John Wiley and Sons.
b
Classification of evidence of antiepileptic drug efficacy13 includes the following classes. Class I evidence: A prospective randomized controlled
trial or meta-analysis of randomized controlled trials in a representative population that meets all the following six criteria: treatment duration
of >48 weeks, double blind, efficacy as primary outcome, not forced to exit study by predetermined number of emergent seizures, demonstrated
superiority or with effectiveness lower limit (95% confidence interval) above a 20% lower boundary relative to the adequate comparator’s
points estimate of efficacy using a preprotocol study population for noninferiority trials, and appropriate statistical analysis. Class II evidence:
A double blind randomized controlled trial or meta-analysis meeting Class I except for treatment duration between >24 weeks and <48 weeks OR
effectiveness lower limit is between 21% and 30% lower boundary relative to the adequate comparator’s points estimate of efficacy. Class III
evidence: A randomized controlled trial or meta-analysis not meeting the criteria for Class I or Class II category: examples include an open-label
study, a study with forced exit criterion, and noninferiority studies lacking adequate comparator. Class IV evidence: Evidence from
nonrandomized, prospective, controlled, or uncontrolled studies, case series, or expert reports.
c
Level A: Established efficacy of antiepileptic drug as initial monotherapy (>Class I studies OR meta-analysis meeting Class I criteria OR >2
Class II studies). Level B: Probably effective antiepileptic drug as initial monotherapy (one Class II study OR meta-analysis meeting Class II criteria).
Level C: Possibly effective antiepileptic drug as initial monotherapy (>2 Class III double-blind or open-label studies). Level D: Potentially
effective antiepileptic drug as initial monotherapy (one Class III double-blind or open-label study OR >1 Class IV clinical studies OR data from
expert committee reports).

valproic acid was superior to phenobarbital, topiramate, and carbamazepine.

Phenytoin and phenobarbital were shown to delay seizure recurrence, suggesting
early seizure control, but this may occur at the expense of adverse side effects as
evident from lower retention rate compared with newer AEDs.16 Another similar
network meta-analysis of only pediatric patients, from 42 studies (n = 5652) with
22 different AEDs, yielded somewhat similar findings.17 Carbamazepine and
lamotrigine were superior in new-onset focal epilepsies, and levetiracetam and
perampanel may have some advantage in refractory focal epilepsies.
Most studies on newer AEDs are conducted in adults, and the approval for
pediatric patients required additional studies. Collaborative efforts between the
Pediatric Epilepsy Academic Consortium for Extrapolation (PEACE) and the US
Food and Drug Administration (FDA) have paved the way for early approval
of newer AEDs in children.18 Drugs approved for focal seizures in adults
(monotherapy or adjunct therapy) may be approved for children older than
4 years with focal seizures without the need for additional efficacy studies in
children because of similarities in disease profile. Age-targeted pharmacokinetic
TABLE 5-4 Response to Treatment With Steroids and/or Vigabatrin in Children With
Infantile Spasms
Study Outcome Measurea Steroidsb Vigabatrin

First Monotherapy
UKISS (only patients Spasm cessation on days 13 and 14 72% (40/55) 54% (28/52)
without tuberous
sclerosis)23 Sustained spasm control with no relapse until 12–14 months 40% (22/55) 37% (19/52)
of age
PERC24 Cessation of spasms in 2 weeks of therapy, with resolution 49% (74/151) 36% (17/47)
of hypsarrhythmia sustained at 3 months
Second Monotherapyc
UKISS25 Any period of 48-hour freedom from spasms after day 14 74% (14/19) 75% (9/12)
of therapy
PERC study26 Cessation of spasms in 2 weeks of therapy, with resolution of 56% (10/18) 55% (17/31)
hypsarrhythmia sustained at 3 months
Steroids Plus
Study Outcome Measurea Steroids Onlyb Vigabatrin
Combined Therapy Versus Steroids Only
ICISS21 No witnessed spasms between days 14 and 42 57% (108/191) 72% (133/186)
Electroclinical responders (no spasms and EEG resolution of 55% (104/189) 66% (123/186)
hypsarrhythmia)
EEG = electroencephalogram; ICISS = International Collaborative Infantile Spasms Study; PERC = Pediatric Epilepsy Research Consortium;
UKISS = United Kingdom Infantile Spasms Study.
a
Differences in outcome measures may account for response rates; outcome measures reported by PERC and ICISS are more akin to clinical
practice.
b
Steroids group included children with either oral prednisolone or IM adrenocorticotropic hormone.
c
Second monotherapy refers to use of the medication in patients for whom the other drug failed. For example, children on second monotherapy
with steroids for whom vigabatrin had failed.
390 APRIL 2019

studies to determine dosages to achieve levels comparable to adults still need to KEY POINTS
be conducted to achieve the indications. Using this approach, newer AEDs, such
● The results of a network
as eslicarbazepine, brivaracetam, and lacosamide, are now approved for use in meta-analysis showed
children aged 4 years and older with partial onset seizures. that, for focal seizures,
lamotrigine and
TREATMENT APPROACHES IN SELECTED PEDIATRIC levetiracetam were
significantly better than
EPILEPSY PHENOTYPES
carbamazepine, which
In this section, treatment approaches to four epilepsy phenotypes with unique was better than phenytoin
electroclinical characteristics, frequently seen in pediatric epilepsy practice, and phenobarbital.
are discussed.
● The results of a network
meta-analysis showed that,
Epileptic Spasms (West Syndrome) for generalized seizures,
Epileptic spasms typically occur in infants (hence, these were previously called valproic acid was superior to
infantile spasms) but may occur in older children with early or extensive brain phenobarbital, topiramate,
injury. Typical epileptic spasms are characterized by sudden, brief stiffening of and carbamazepine.
the whole body, predominantly the axial muscles, that occur in clusters lasting ● The American Academy
several seconds to minutes. Because epileptic spasms occur in the setting of an of Neurology quality
epileptic encephalopathy, early diagnosis and aggressive treatment are critical to committee recommends
optimize both seizure and cognitive outcomes. Delay in treatment initiation with initiation of therapy within
7 days of the onset of
epileptic spasms has been shown to negatively affect developmental outcome.19
epileptic spasms to improve
The American Academy of Neurology (AAN) quality committee recommends developmental outcome.
initiation of therapy within 7 days of the onset of spasms to improve
developmental outcome.20 Recent data suggest that spasm control is also better ● Steroids (oral prednisone
with early treatment initiation.21 For these reasons, at our and many other or IM adrenocorticotropic
hormone) and vigabatrin are
centers, children with new-onset epileptic spasms are emergently admitted to the mainstays of therapy for
initiate workup and treatment. epileptic spasms.
Steroids (oral prednisone or IM adrenocorticotropic hormone [ACTH]) and
vigabatrin are the mainstays of therapy for epileptic spasms. Vigabatrin has ● Reversible hyperintense
signal abnormalities in white
superior efficacy in epileptic spasms caused by tuberous sclerosis complex. With matter, basal ganglia,
all other etiologies, steroids are preferred. In the United States, most clinicians thalamus, and brainstem
prefer IM ACTH over oral steroids, unless parental choices steer toward oral have been reported in as
steroids. There is insufficient evidence to suggest that oral steroids are equivalent many as 30% of infants
treated with vigabatrin.
to ACTH.21,22 Children for whom one form of treatment fails frequently respond
to other treatment. TABLE 5-4 shows the response rate of steroids and vigabatrin
in various settings: as initial monotherapy, second monotherapy (after failure of
one of the two therapies), and combination therapy.21,23–26 The steroids of choice
(prednisolone versus synthetic ACTH versus natural ACTH), dosage regimen
(low-dose or high-dose ACTH), and duration of treatment vary among centers.
A suggested treatment schedule proposed by the Pediatric Epilepsy Research
Consortium is shown in TABLE 5-5.24
Steroid treatment carries the risk of hypertension, hyperglycemia, weight
gain, and reversible hypertrophic cardiomyopathy; these risks are higher with
high-dose ACTH therapy. Vigabatrin carries the risk of retinal toxicity leading
to irreversible peripheral field constriction. The exact clinical impact of such
effects in this group of children with spasms is unknown because many may not
be able to undergo a visual field examination. Periodic eye examinations may
help in recognizing signs of retinal toxicity. Reversible hyperintense signal
abnormalities in white matter, basal ganglia, thalamus, and brainstem have been
reported in as many as 30% of infants treated with vigabatrin.27 Doses of
vigabatrin higher than 150 mg/kg should be avoided, particularly in young

infants. Every attempt should be made to minimize the duration of vigabatrin

exposure to 1 year or less even in good responders.
In previously healthy children with new-onset epileptic spasms and no
apparent etiology, most clinicians prefer to use ACTH because some children will
develop sustained remission after the initial course of steroid therapy.28 A
positive response to treatment is defined as control of spasms and resolution of
hypsarrhythmia on EEG performed 2 weeks after initiation of steroids.22,24 If
children do not achieve seizure freedom or if hypsarrhythmia persists, vigabatrin
therapy should be considered. Concurrent therapy with another AED, such
as topiramate or zonisamide, is frequently used along with steroids, especially
in cases with a known etiology (such as malformations or ischemic brain
injury), but the usefulness of this practice is not proven. The simultaneous
administration of steroids and vigabatrin improves treatment response
compared with steroids alone (TABLE 5-4). However, with such a strategy,
some children may be exposed to the long-term risks of vigabatrin unnecessarily.
TABLE 5-5 Treatment Guidelines for Infantile Spasms Recommended by the Pediatric
Epilepsy Research Consortiuma
Days Dose
Adrenocorticotropic Hormoneb
1–14 75 U/m2 IM 2 times daily
15–17 30 U/m2 IM in the morningc
18–20 15 U/m2 IM in the morning
21–23 10 U/m2 IM in the morning
24–29 10 U/m2 IM every other morning (3 doses)
Prednisolone
1–14 10 mg orally 4 times dailyc,d
15–19 10 mg orally 3 times daily
20–24 10 mg orally 2 times daily
25–29 10 mg/d orally
Vigabatrine
1–3 50 mg/kg/d, divided 2 times daily
4–6 100 mg/kg/d, divided 2 times daily
>7 150 mg/kg/d, divided 2 times dailyc
IM = intramuscular.
a
Modified with permission from Knupp KG, et al, Ann Neurol.24 © 2016 John Wiley and Sons.
b
Check blood pressure 2 times a day for 2 days, then weekly; check urine for glucose at 48 hours and then
weekly.
c
If there is no clinical response by day 14, consider an alternative treatment.
d
If there is no clinical response after day 7, the dose can be increased to 20 mg 3 times a day. If done so, for
days 15–19, it would be 10 mg 4 times a day and proceed per table from day 20.
e
Side effects (eg, sedation, hypotonia) may necessitate slower titration.
392 APRIL 2019

Children in whom therapy with steroids and vigabatrin fails should be
evaluated for epilepsy surgery. Often in this setting, surgery is guided by the
lesion detected on brain MRI, sometimes supported by electroclinical features
suggesting concordant focality, and brain fludeoxyglucose positron emission
tomography (FDG-PET) findings. Nearly 80% achieve an Engel class I outcome
in lesional surgical series of epileptic spasms in infants with lesional MRI.29
Lesions are often obvious, but smaller and subtle lesions may not be apparent
until follow-up imaging is performed. Ketogenic diet is an option for medically
refractory cases in whom surgery is not an option. Anecdotal reports of
successful seizure control have been reported with other medications, including
clonazepam, clobazam, topiramate, zonisamide, and valproate, but these should
not be accepted as initial therapy.28
Genetic causes are increasingly diagnosed with wider availability of
panel-based gene testing for early childhood epilepsies. Treatable metabolic
causes, such as pyridoxine-dependent seizures, should be considered early, when
the etiology is not obvious. Empiric challenge with pyridoxine may be considered
when awaiting results of genetic/metabolic testing.30
Absence Seizures
Absence seizures are characterized by sudden, brief periods of unawareness and
unresponsiveness variably accompanied by subtle head nods, eye flutter, and
other facial movements. They often occur several times per day. EEG during the
episodes show 3-Hz generalized spike-and-wave complexes in classical cases.
Typical absence seizures occur in the setting of childhood absence epilepsy and
juvenile absence epilepsy syndromes in which the absence seizures are the
primary seizure type. Other seizure types, such as generalized tonic-clonic
seizures and myoclonic jerks, may coexist in other syndromes, and this may
influence the choice of therapy. Atypical absences may occur in children with
epileptic encephalopathies, such as Lennox-Gastaut syndrome and Doose
syndrome. Typical absence seizures compared with atypical absences respond
better to medical therapy.
TABLE 5-6 shows the response rate of ethosuximide, valproic acid, and
lamotrigine, the three most effective AEDs for absence seizures, from two major
Response to Treatment in Children With Absence Seizures TABLE 5-6
Initial Monotherapy (Blinded Study)28,30 Ethosuximide (n = 154) Valproic Acid (n = 146) Lamotrigine (n = 146)
“Freedom from failure” a

16–20 weeks 53% 58% 29%
12 months 45% 44% 21%

b 29
Second Monotherapy (Open Label) Ethosuximide (n = 75) Valproic Acid (n = 78) Lamotrigine (n = 55)
“Freedom from failure”a 16–20 weeks 63% 65% 45%
12 months 57% 49% 36%
a
Failure was defined as persistent absence seizures or occurrence of new generalized tonic-clonic seizures or other seizure types or intolerable
side effects (as defined in the study protocol) at or before the specified end point (eg, 16 weeks or 12 months).
b
Second monotherapy refers to use of the medication in patients for whom one of the other two drugs failed. For example, ethosuximide was
prescribed as a second monotherapy for children after failure of valproic acid or lamotrigine as initial therapy.

KEY POINTS studies.31,32 Both valproate and ethosuximide produce comparable rates of
seizure control, but ethosuximide has a favorable side effect profile, particularly
● Both valproate and
ethosuximide produce
in the behavioral domain. For these reasons, in children with only absence
comparable rates of seizure seizures, ethosuximide is the drug of choice.31,33 Open-label studies on children
control for absence for whom one of the three AEDs failed showed that the success rate with an
seizures, but ethosuximide alternative medication remains as high as with initial therapy, as shown in
has a favorable side effect
TABLE 5-6. In children with a partial response to either medication,
32
profile, particularly in the
behavioral domain. combination therapy with valproate and ethosuximide may be successful.
Lamotrigine, although having a favorable side effect profile, is inferior to
● The focus of management ethosuxmide and valproic acid in seizure control. Other medications reported to
in Lennox-Gastaut have anecdotal success include clonazepam and zonisamide. Ketogenic diet is a
syndrome should be on the
overall quality of life and not promising option for refractory absences. Rare reports of response to amantadine
seizure count per se. exist, and it can be tried in refractory cases.34 In patients with other coexisting
generalized seizure types, valproate and lamotrigine may be better suited; if
● Valproic acid is absence seizures remain poorly controlled in such cases, coadministration of
frequently used as a
first-line medication for
ethosuximide may be needed.
children with Lennox-
Gastaut syndrome because Lennox-Gastaut Syndrome
of its broad spectrum of Lennox-Gastaut syndrome is an electroclinical syndrome characterized by
action against various
drug-resistant epileptic encephalopathy manifesting with multiple seizure types:
seizure types.
motor (tonic, atonic, tonic-clonic, and tonic-atonic) and nonmotor (atypical
absences and nonconvulsive status epilepticus). Generalized slow-spike-wave
complexes at 1.5 Hz to 2.5 Hz are a characteristic EEG finding. Lennox-Gastaut
syndrome constitutes 1% to 4% of all childhood epilepsies and is typically
refractory to medications with only less than 10% achieving seizure freedom.10
Most children with Lennox-Gastaut syndrome develop seizures before 5 years of
age and almost all before 8 years of age. One-third of children with epileptic
spasms (West syndrome phenotype) may evolve to Lennox-Gastaut syndrome.
The etiology is heterogeneous, and structural brain lesions and genetic causes
predominate; about 30% do not have a known etiology. Cognitive delays may
precede or follow the onset of epilepsy, depending on the etiology.
Management of Lennox-Gastaut syndrome is particularly challenging because
of the low likelihood of seizure freedom with available treatment options.
Seizures are frequent, occurring daily in many patients. Prioritizing the goals
and setting expectations early during the course will assist caregivers. “Drop
attacks” (most frequently due to tonic-atonic seizures) causing injuries are a
major factor affecting the quality of life of patients and caregivers. Preventing
injuries with use of a helmet and changes in the living environment with
occupational therapy guidance should be emphasized. Patients almost always
need polytherapy, and many may experience adverse effects of polytherapy,
affecting their quality of life. The focus should be on the overall quality of life
and not seizure count per se. Many caregivers prefer rare or even regular
breakthrough seizures over cognitive and sedating drug side effects.
A suggested treatment algorithm for newly diagnosed Lennox-Gastaut
syndrome, proposed by experts, shown in FIGURE 5-2 illustrates various
therapeutic options.10 Valproic acid is frequently used as a first-line medication
because of its broad spectrum of action against various seizure types. TABLE 5-7
shows the efficacy of various AEDs that have been tested in patients with
Lennox-Gastaut syndrome in double-blind placebo-controlled trials.10,35–40 In all
these trials, patients were on other AED(s), and the study drug was used as
394 APRIL 2019

FIGURE 5-2
A suggested treatment algorithm for a newly diagnosed patient with Lennox-Gastaut
syndrome.
AED = antiepileptic drug.
a
Use for intermittent, short-term treatment of crisis episodes.
b
In combination with valproate or clobazam.
Reprinted with permission from Cross JH, et al, Front Neurol.10 © 2017 Cross, Auvin, Falip, Striano
and Arzimanoglou.
adjunct therapy. A Cochrane review concluded that no drug is superior to

another.41 Overall, lamotrigine, rufinamide, felbamate, clobazam, topiramate,
and cannabidiol offer a greater than 50% reduction in the overall seizure burden
in 26% to 65% of patients. High-dose clobazam has been particularly effective in
reducing drop seizures.39 Long-term follow-up of patients on clobazam suggests
that the effect in responders is sustained in about 85% of patients at 1 and 3 years
of treatment. Of note, despite its popular use in Lennox-Gastaut syndrome, no
controlled trials have been done with valproic acid. An addition to the

armamentarium for treatment of Lennox-Gastaut syndrome occurred in June

2018, with the FDA approval of cannabidiol oral solution for the treatment of
seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in
patients 2 years of age and older.42
Nonpharmacologic treatments include ketogenic diet, vagal nerve stimulation
(VNS), corpus callosotomy, and resective surgery.10 Multiple open-label
(retrospective and prospective) studies have reported more than 50% reduction
in seizures in 40% to 51% of patients treated with ketogenic diet. A dedicated
ketogenic diet team is necessary to implement the diet in this challenging
population. A treatment trial of 3 months on the diet is generally warranted to
TABLE 5-7 Seizure Reduction Rates of Selected Antiepileptic Drugs in Lennox-Gastaut

Syndrome
Reduction in Drop Reduction in Generalized

Reductionb in Overall Seizures Seizures Compared Tonic-Clonic Seizures
Antiepileptic Druga Compared With Placebo With Placebo Compared With Placebo
Felbamate Felbamate 26% reduction versus 5% increase 44% decrease 40% reduction versus 12%
Study Group, 199335 versus 7% decrease increase
Lamotrigine 32% reduction versus 9% increase 34% reduction 36% reduction versus 10%
Motte et al, 199736 versus 9% reduction increase
33% versus 16% had >50% reduction 37% versus 22% had 43% versus 20% had
>50% reduction >50% reduction
Topiramate 20.6% reduction versus 8.8% reduction 15% reduction Not analyzed separately
Sachdeo et al, 199937 versus 5% increase
33% versus 8% for >50% reduction of drop
and tonic-clonic seizures
Rufinamide 33% reduction versus 12% decrease 42.5% reduction 46% reduction versus 18%
Glauser et al, 200838 versus 1.4% increase decrease
Clobazamc High-dose clobazam 65% reduction High-dose Not analyzed separately

Ng et al, 201139 versus 9% reduction clobazam: 68%
reduction versus
12% reduction
78% had >50%

reduction versus
32% with placebo
Cannabidiol 41% reduction versus 14% reduction 44% reduction Not analyzed separately
Thiele et al, 201840 versus 22%
reduction
44% had >50%

reduction versus
20% with placebo
a
All medications were used as adjunctive therapy. Results are not comparable across studies because several differences exist between the
studies, including the seizure types, etiology, and other medications. Valproic acid, the most frequently used medication in Lennox-Gastaut
syndrome, has not been tested against a placebo.
b
Posttreatment reduction of seizures reported at about 12 to 14 weeks of therapy.
c
The clobazam trial included three different dose regimens (0.25 mg/kg/d: low dose; 0.5 mg/kg/d: medium dose; and 1 mg/kg/d: high dose).
There was a linear trend toward increasing dose and increased efficacy in seizure control (not shown in the table). However, higher doses of
clobazam were associated with higher dropout rates, the majority of which were related to adverse effects.
396 APRIL 2019

determine if the diet if efficacious. Corpus callosotomy may be useful in KEY POINT
preventing injurious falls due to tonic-atonic seizures. The seizure reduction with
● Two commonly used
VNS in Lennox-Gastaut syndrome is comparable to its response in other epilepsy treatment options for
types. A pooled analysis of four studies reported a responder (50% or more electrical status epilepticus
seizure reduction) rate of 55% with VNS in Lennox-Gastaut syndrome. VNS is in slow-wave sleep include
less effective for atonic seizures and may be more effective for myoclonic high-dose nightly
benzodiazepines and
jerks.10,41 All patients with structural abnormalities on brain MRI should be
steroids.
carefully evaluated for resective epilepsy surgery. Electroclinical features are
frequently unhelpful for localization of epilepsy with a Lennox-Gastaut
syndrome phenotype.43 Additional testing, such as positron emission
tomography (PET), ictal single-photon emission computed tomography
(SPECT), and magnetoencephalography (MEG), may also be of only minimal
value. Experience of the center is of paramount importance in selecting surgical
candidates, both for including and excluding surgical options.
Electrical Status Epilepticus in Slow-Wave Sleep

Electrical status epilepticus in slow-wave sleep (ESES), also referred as continuous
spikes in slow-wave sleep (CSWS), is a unique epileptic encephalopathy seen in
children, often between the ages of 4 and 8 years, characterized by variable
regression of language or cognitive function with other neurobehavioral
problems secondary to near-continuous epileptiform discharges in slow-wave
sleep. ESES involving the posterior language cortices manifesting with auditory
agnosia and language regression is referred to as Landau-Kleffner syndrome. As
with many other epileptic encephalopathies, the etiology is heterogeneous,
ranging from structural to genetic causes. ESES may also occur in the setting of
self-limited childhood focal epilepsy. For research criteria, ESES is diagnosed
when 85% or more of slow-wave sleep is occupied by spike-and-slow waves. In
patients with clinical dysfunction attributable to ESES, clinicians may start
treatment even with a lower spike burden.44 The treatment decision is not always
straightforward because some children with self-limited childhood focal epilepsy
may have ESES based on EEG criteria without the accompanying cognitive
dysfunction, and such children are best monitored clinically for regression.
Conversely, in children with major chronic cognitive dysfunction at baseline, the
impact of the spike-wave burden on cognition may be unclear.
Treatment of ESES poses several challenges with fewer effective treatment
options.45,46 Evidence-based recommendations for the treatment of ESES are
lacking because of a lack of well-conducted prospective studies in this
heterogeneous epilepsy syndrome with various etiologies. Two commonly
used treatment options for ESES include steroids and high-dose nightly
benzodiazepines. Conventional AEDs may also reduce the spike burden,
and frequently used medications for this purpose include valproic acid,
ethosuximide, levetiracetam, clobazam, and sulthiame.47 Sulthiame is not
available in the United States but is used in European countries. Most clinicians
avoid using drugs such as carbamazepine, oxcarbazepine, phenytoin, and
phenobarbital because they have been reported to worsen ESES.47
From a pooled analysis of 112 studies with a total of 575 patients undergoing
910 treatments for ESES, the EEG and cognitive improvement rates of 282
consecutive patients with 585 treatment responses are shown in TABLE 5-8.46
Among medical therapies, steroids had the highest chance for success. Two
factors are evaluated to monitor response to treatment: spike burden in sleep on

EEG and improvement in cognitive, language, or behavioral symptoms. Children

who were developmentally and cognitively normal before the onset of the ESES
respond favorably to treatment and have a better prognosis. A longer duration of
ESES before treatment also influences the outcome negatively. It is not
uncommon to see improvement in EEG without notable improvement in clinical
symptoms because there may be a lag between EEG resolution and clinical
improvement. A lack of clinical improvement despite sustained resolution of
ESES on EEG may indicate that the behavioral and cognitive problems in such a
patient may be secondary to the underlying etiology per se and not linked to its
EEG expression. In patients who achieve remission, close clinical monitoring and
periodic assessment of EEG in sleep would be needed to monitor the response.
For medically refractory ESES secondary to focal epileptogenic lesions,
epilepsy surgery is often an effective option.46 Frequently, lesions that cause the
ESES phenotype are large with involvement of the thalamus, thereby suggesting
a role for the thalamus in the genesis of ESES syndrome. Children with structural
lesions that are not surgically amenable tend to have the worst outcome. The role
of multiple subpial transection of the posterior perisylvian language/auditory
cortices for the treatment of Landau-Kleffner syndrome remains controversial.48
DISEASE-MODIFYING OR DISEASE-SPECIFIC TREATMENT

In most instances, the treatment of epilepsy has been essentially symptomatic
with an aim to reduce the recurrence of seizures with conventional AEDs. The
natural history of the underlying etiology most often determines if long-term
remission occurs. In few selected etiologies, there may be opportunities for
disease-modifying treatment, such as in autoimmune epilepsies and
genetic/metabolic disorders. The field of autoimmune epilepsy is still in an
evolving phase, and the treatment opportunities will become clearer over the
next decade. In children, metabolic and genetic causes may offer unique
TABLE 5-8 Response Rate of Commonly Used Treatments for Electrical Status
Epilepticus in Slow-Wave Sleep/Continuous Spikes in Slow-Wave Sleep
From a Pooled Analysis of 575 Casesa
Electroencephalogram
Improvement, Clinical Improvement, Any Improvement, Odds Ratio of
Treatment % (95% CI) % (95% CI) % (95% CI) Favorable Response
Conventional antiepileptic 33 (28–38) 32 (26–37) 34 (29–39) Reference (for other

drugs (n = 310) odds ratios below)
Steroids (n = 100) 68 (58–77) 70 (60–79) 75 (67–83) 4.4 (2.9–6.7)
Benzodiazepines (n = 171) 46 (37–56) 45 (35–54) 59 (50–68) 2.2 (1.5–3.2)
Surgery (n = 30) 74 (58–91) 83 (70–97) 93b 9.8 (4.1–23.1)
Others (n = 38) 26 (8–44) 71 (53–89) 58 (42–74) 1.2 (0.9–1.6)
CI = confidence interval.
a
Modified with permission from Van Den Munckhof B, et al, Epilepsia.46 © 2013 John Wiley and Sons.
b
No 95% confidence interval is available because of the small sample size and large proportion of patients who showed improvement.
398 APRIL 2019

therapeutic options targeted to specific diseases or disease pathogenesis, as
shown in TABLE 5-9.49,50
Therapeutic options in specific genetic/metabolic diseases may occur
in several forms. In some instances, supplementation with deficient
cofactors/nutrients leads to better seizure control. Examples include pyridoxine
for pyridoxine-dependent seizures; ketogenic diet in glucose transporter
deficiency, providing alternative fuel when glucose transport to the brain is
defective; and biotin supplementation in biotinidase deficiency. Some of these
syndromes may present as a commonly seen epilepsy syndrome, such as absence
epilepsy, as illustrated in CASE 5-2.49,51
Specific AEDs are known to worsen the epilepsy in certain diseases. Examples
include phenytoin, carbamazepine, and lamotrigine in Dravet syndrome due to
SCNA1 mutation.49,50 Specific AEDs may be selectively more effective in certain
channelopathies. Examples include phenytoin and other sodium channel
Selected List of Genetic Diagnosis Modifying Treatment of Epilepsies TABLE 5-9
Genetic Disease Preferred Treatment Comments
SLC2A1 (glucose Ketogenic diet Glucose transport across the blood-brain barrier defective;
transporter 1 defect) providing ketones and fatty acids as alternative fuel by
ketogenic diet
ALDH7A1 Pyridoxine ± folinic acid Pyridoxine-dependent epilepsy
PNPO Pyridoxal 50 -phosphate Pyridoxal phosphate deficiency
SCN8A Phenytoin, carbamazepine, and Sodium channel blockers useful with “gain of function”
oxcarbazepine mutations; supratherapeutic levels of phenytoin may be
needed
SCN2A Phenytoin, carbamazepine, and Likely useful in case of “gain of function” mutations;
lamotrigine supratherapeutic levels of phenytoin may be needed
KCNQ2 Phenytoin and carbamazepine Retigabine offered some promise but was pulled from
market because of long-term retinal and skin adverse
effects
TSC1 and TSC2 (tuberous Vigabatrin and rapamycin Vigabatrin is effective for epileptic spasms; rapamycin
sclerosis types 1 and 2) inhibits hyperactive mammalian target of rapamycin
pathway and reduces tumor size and seizures
GRIN2A Memantine (N-methyl-D-aspartate Few case reports; likely only in selected mutation
[NMDA]) receptor antagonist)
KCNT1 Quinidine Initial case report reported benefit; not shown to be useful
in a controlled trial
SCN1A Valproic acid, clobazam, Avoid sodium channel blockers such as phenytoin,
topiramate, and stiripentol carbamazepine, and lamotrigine; case series of benefits
with fenfluramine
POLG1 No preferred antiepileptic drug High risk of hepatic failure with valproic acid
treatment

CASE 5-2 A 4-year-old girl was evaluated for management of refractory absence
seizures. Staring spells were noted since the age of 9 months but were
not diagnosed as seizures until about 3 years of age. Brief episodes of
behavioral arrest with unresponsiveness lasting 5 to 10 seconds were
noted several times per day at the time of diagnosis. EEG showed 3 Hz
spike-wave complexes consistent with the diagnosis of absence
epilepsy, as shown in FIGURE 5-3. Seizures decreased but persisted
despite adequate trials of ethosuximide and valproic acid, initially as
monotherapy and later in combination. She had mild gross and fine
motor delays and needed physical and occupational therapy. No major
cognitive difficulties were reported.
A genetic evaluation at age 4 years revealed a heterozygous mutation
c.227G>A (p.Gly76Asp) in the SLC2A1 gene. SCL2A1 gene mutation causes
glucose transporter type 1 (GLUT1) deficiency syndrome, which may
manifest with early-onset absence seizures. The child was started on the
ketogenic diet with a dramatic decrease in seizures.
FIGURE 5-3
EEG of the patient in CASE 5-2 shows generalized 3-Hz spike-wave complexes.
COMMENT This case highlights the importance of identifying the etiology of epilepsy,
which may have unique treatment implications: in this case, ketogenic diet
for GLUT1 deficiency in this child. The SLC2A mutation, more popularly
described as GLUT1 disease, causes defective transport of glucose across
the blood-brain barrier. Low glucose in the central nervous system is
known to cause cognitive delays, seizures, ataxia, paroxysmal dyskinesias,
and eye movement abnormalities. In a series of 34 children with early-onset
(before the age of 4 years) absence epilepsy, four children (12%) had
pathogenic mutations in the SLC2A mutation; these findings were
replicated in another cohort of 55 patients.50 Genetic testing for GLUT1
deficiency should be considered in early-onset absences as well as in
refractory absences in older children as well.
400 APRIL 2019

blockers in channelopathies such as SCN8A, SCN2A, and KCNQ2 mutations. In KEY POINTS
particular, higher doses of phenytoin are effective in SCN8A epilepsy.49,50,52
● Examples of antiepileptic
Unconventional medications targeted toward dysfunctional receptors and or drugs known to worsen
channels and pathways is another approach. Examples include the use of epilepsy in certain diseases
quinidine in KCNT1 mutation, memantine in GRIN2A mutation, and everolimus include phenytoin,
in mammalian target of rapamycin (mTOR) signaling. The response in this group carbamazepine, and
lamotrigine in Dravet
is variable and may be affected by the specific type(s) of mutations. Missense
syndrome due to SCNA1
mutations in different locations in the same gene may have varied effects, with mutation.
one being responsive to a specific medication, whereas another may not be
responsive.50 Clinical evidence has suggested specific medications to be ● A pooled analysis of five
particularly more effective in some disease phenotypes, although the exact trials in children provided
evidence to support a
mechanisms are poorly understood, for example, the use of vigabatrin in minimum 2-year
epileptic spasms secondary to tuberous sclerosis. seizure-free period before
Experience with many of the above-described therapies is limited to relatively considering the need for
few patients. A few hypothetical precision medicine options based on the continued treatment.
pathophysiology of the genetic effects have been proposed. With a better
understanding of the pathogenesis and cellular electrophysiology of genetic
epilepsies, more treatment options are likely to emerge.
DISCONTINUATION OF ANTIEPILEPTIC DRUGS

Once a remission is achieved for a sustained period, the question of duration of
therapy arises, and every attempt should be made to minimize the duration of
AED exposure in children. A pooled analysis of five trials in children provided
evidence to support a minimum 2-year seizure-free period before considering the
need for continued treatment.53 At the time of weaning of AEDs, the concerns of
clinicians, patients, and families center on the risk of recurrence after stopping
AEDs, the risk of evolving intractable seizures after weaning, and the potential
risks of serious harm from recurrent seizures, including status epilepticus,
sudden unexpected death in epilepsy (SUDEP), and injuries or accidents.53
The risk of recurrence should be reassessed periodically, primarily determined
by epilepsy syndrome/etiology and EEG findings. In practice, one may categorize
children whose epilepsy is in remission into three groups, based on their risk
of recurrence, that influence the duration of AED therapy.54,55
In the first group, the natural history of epilepsy is predictably benign, and
chances for remission are very high. Examples include self-limited childhood
focal epilepsies with centrotemporal spikes and Panayiotopoulos syndrome, in
which the majority of children outgrow their tendency to have seizures by
puberty. These constitute 15% to 20% of all children with epilepsies. In this
category, one would consider weaning of AEDs after 2 years of seizure freedom
or even earlier in some cases. Some children with these syndromes may have
persistent interictal abnormalities but may have outgrown the tendency to have
clinical seizures. If seizures were to recur, their long-term outlook is not altered.
A second group consists of children with very high risk of seizure recurrence,
with very low chances for sustained remission. Examples include epileptic
encephalopathies secondary to genetic disorders and epilepsy secondary to major
bilateral malformations. Achieving seizure freedom in such patients is often
difficult. When children are seizure free for a longer period, families and
clinicians may attempt to reduce polypharmacy. EEG in most cases continues
to show epileptiform abnormalities. This group constitutes about 10% to 15%
of all children with epilepsy.

The majority of children with epilepsy belong in the “uncertain” group for
whom the long-term chances for seizure remission without AEDs are not very
predictable. Long-term remission rates may vary between etiologies, ranging
from 70% in childhood absence epilepsy to 15% with juvenile myoclonic epilepsy
(in adulthood).54–56 Many symptomatic focal epilepsies and those in which the
etiology is unknown also belong to this category. The presence of structural
abnormalities does not always indicate the need for long-term therapy. For
example, a child with seizures secondary to stroke may be able to come off
the AED after a period of remission. In a population-based cohort of children
with epilepsy (the study excluded self-limited childhood focal epilepsy with
centrotemporal spikes, previously referred to as benign rolandic epilepsy) 70%
CASE 5-3 A 6-year-old boy with global delay and left hemiparesis was evaluated
for medically intractable epilepsy. His seizure symptomatology
suggested generalized tonic and atypical absence seizures. Between the
ages of 1 and 5 years, he had two phases of seizure freedom for 2 years on
medications. Subsequently, he had subtle seizures with momentary
leaning to one side and eye flutter, along with subtle changes in
awareness and behavior, several times per hour during wakefulness. He
was listless and lethargic for most of the day. Treatment failed with four
antiepileptic drugs (AEDs) (valproate, lamotrigine, levetiracetam, and
clobazam) and a trial of oral prednisolone. A video-EEG study showed
abundant diffuse slow-spike-wave complexes, higher over the right
hemisphere, as shown in FIGURE 5-4. Runs of slow-spike-wave complexes
occupied 60% to 70% of the awake period and 80% to 90% of the
sleep period. Subtle eye flutter, head bobbing, and alterations of
responsiveness occurred several times concurrent with runs of spike-
wave complexes. Focal abnormalities in the right frontocentral region
were also noted. Brain MRI showed extensive right hemispheric dysplasia
(FIGURE 5-4C).
A right disconnective hemispherectomy was performed. The boy
became seizure free after surgery; a mild worsening of left hemiparesis
recovered to the preoperative baseline. Postoperative EEGs showed the
expected findings after the hemispherectomy. At 6 weeks postsurgery,
one of the three AEDs was weaned and stopped. A second AED was
weaned off after 6 months of freedom from seizures. On follow-up, he
became more attentive, interactive, and verbal, partly attributed to
reduction of AEDs. He is maintained on one medication with a plan to
wean after seizure freedom for 1 year after surgery.
COMMENT This case highlights the role of epilepsy surgery in patients with medically
refractory lesional epilepsies. Surgery could have been considered earlier
in this child, but he had periods of “remission” on medical therapy. Such
malformations carry very low chances for sustained long-term seizure
freedom. This case also illustrates that, after successful epilepsy surgery,
AED weaning could be considered early in patients on polytherapy.
402 APRIL 2019

of children who had achieved sustained seizure freedom remained seizure free
after discontinuation of AEDs, and 30% had one or more recurrences.55 The
authors of this study estimated that stopping the AEDs increases the risk of
recurrence twofold, suggesting that continued treatment does not guarantee
against recurrence. Risk factors for increased recurrence include epileptiform
abnormalities on EEG, epilepsy onset before 2 years of age and after 10 years
of age, intellectual disability (IQ <70), history of status epilepticus, and higher
seizure burden before and during treatment.53 The risk of recurrence is high
in the initial 1 to 2 years after discontinuation. In one series, 97% of children who
had recurrence after AED withdrawal achieved remission with reinitiation
of AEDs.55
FIGURE 5-4
EEG and MRI findings of the patient in CASE 5-3. A, Interictal EEG shows generalized
slow-spike-wave complexes (2 Hz) and right frontal sharp waves. B, Ictal EEG shows
bisynchronous spike-wave complexes, higher on the right side, concurrent with clinical
seizures. C, Axial fluid-attenuated inversion recovery (FLAIR) brain MRI shows extensive
right hemispheric dysplasia with volume loss.

There are no systematic data available about the risk of SUDEP and other
injuries related to seizures in patients after AED discontinuation; the risk is
estimated to be very low. Driving needs; ease with which initial control was
achieved; the severity of seizures; and psychological, economic, and cultural
factors further shape the decision making. Some risk-averse patients and families
may choose to continue medications and not “rock the boat” despite a low
predicted risk, whereas another family may decide to wean and stop medications
even with a higher risk. Once the patient and family elect to wean, most clinicians
wean the AED over 6 weeks to 3 months and one drug at a time for patients
receiving polytherapy. A comparison of slow weaning over 9 months versus
relatively faster weaning over 6 weeks showed no significant difference in
seizure recurrence risk.57
In summary, in most children with epilepsy, if the child is seizure free on
medication(s) for 2 years, then AED tapering should be strongly considered
unless the recurrence risk is estimated to be very high. For patients who become
seizure free after epilepsy surgery, withdrawal could be considered at 1 year of
seizure freedom. In patients who are on multiple AEDs, tapering of some AEDs
may be appropriate even as early as a few weeks after a potentially successful
surgery, as shown in CASE 5-3.
RESCUE MEDICATIONS FOR HOME USE TO PREVENT STATUS

EPILEPTICUS
Prescribing non-IV rescue medications for outside hospital use to prevent status
epilepticus should be considered in children at risk of prolonged seizures or acute
repetitive seizures. Rectal diazepam is the only FDA-approved medication for
“bouts of increased seizure activity” and is the most commonly used rescue
medication in the United States.58 The approval for rectal diazepam by the FDA
was based on two randomized trials that showed a decrease in seizures in
children with acute repetitive seizures.59,60 Multiple trials have shown
midazolam is effective for prolonged seizures and acute repetitive seizures
when administered through IM, intranasal, or buccal routes.61–63 In a network
meta-analysis of efficacy of non-IV medication for acute convulsive seizures, IM
and intranasal midazolam had superior efficacy over rectal diazepam. Rectal
diazepam is available as prepackaged syringes in specific dosages. Off-label use of
intranasal midazolam is common in practice. The IV midazolam formulation is
readily available, and this may be used with an appropriate delivery device, such
as an atomizer or syringe, based on the route of administration. Oral clonazepam,
either as liquid or dissolvable wafer, is frequently prescribed, but the evidence to
support its use is limited. Somnolence is a common adverse effect with all rescue
medications, but respiratory depression is rare.59–63 The choice of rescue
medication is guided by the age of the patient, ease of administration, and
personal preferences. For older children and teenagers, families prefer to use
intranasal midazolam over rectal diazepam.
CONCLUSION
An individualized approach tailored to each patient and the family’s goals and
expectations is critical to the successful management of epilepsy in children. For
patients with new-onset epilepsies, specific evidence-based recommendations
404 APRIL 2019

are available for choosing medications primarily based on specific characteristics KEY POINTS
of epilepsy. These decisions are further shaped by patient characteristics, AED
● The majority of children
side effects, and cultural and socioeconomic factors. AED tapering should be with epilepsy belong in the
considered after 2 years or more of seizure freedom. In children with medically “uncertain” group for whom
refractory epilepsy, nonpharmacologic therapies, including epilepsy surgery and the long-term chances for
ketogenic diet, should be considered. Precision medicine opportunities based seizure remission without
antiepileptic drugs are not
on specific genetic diagnosis are emerging and may lead to more treatment
very predictable.
opportunities in many genetic epilepsies in the future. In all children with
epilepsy, general precautions to avoid injuries during seizures should always be ● Pooled analyses of
emphasized, and rescue medications, such as rectal diazepam or intranasal studies in children who had
midazolam, to avoid a prolonged seizure should be considered. achieved sustained seizure
freedom show that 70%
remained seizure free
after discontinuation of
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Antiepileptic Drug Treatment of Epilepsy in Children

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Antiepileptic Drug Treatment of Epilepsy in Children

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Antiepileptic Drug REVIEW ARTICLE

RECENT FINDINGS:AED therapy leads to seizure freedom in about 70% of all

vagal nerve stimulation, and dietary therapies should be considered.

INTRODUCTION UNLABELED USE OF

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paramount importance. Seizure type and epilepsy phenotype are the

INITIATING ANTIEPILEPTIC DRUG THERAPY

Benign Natural History of Some Epilepsies in Children

382 APRIL 2019

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SELECTING AN ANTIEPILEPTIC DRUG

Epilepsy Syndrome Diagnosis

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capturing on video-EEG with shorter periods of monitoring. Myoclonic and tonic

Antiepileptic Drug Pharmacology

TABLE 5-1 Factors Determining the Selection of Antiepileptic Drugsa

384 APRIL 2019

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SOCIOECONOMIC AND PERSONAL PREFERENCES. Although every effort should

EVIDENCE-BASED CHOICE OF ANTIEPILEPTIC DRUGS IN FOCAL AND

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old established drugs to identify opportunities to improve seizure control.

386 APRIL 2019

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TABLE 5-2 Patient Characteristics to Consider in Antiepileptic Drug Selection

Patient Factors Antiepileptic Drug Choice Modifiers Comments

AED = antiepileptic drug.

388 APRIL 2019

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Children with partial onset 1 0 19 Level A: Oxcarbazepine

Self-limited epilepsy with 0 0 3 Level A: None

Children with absence 1 0 7 Level A: Ethosuximide and valproic acid

Children with generalized 0 0 14 Level A: None

Juvenile myoclonic epilepsy 0 0 1 Level A: None

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valproic acid was superior to phenobarbital, topiramate, and carbamazepine.

Study Outcome Measurea Steroidsb Vigabatrin

Combined Therapy Versus Steroids Only

390 APRIL 2019

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infants. Every attempt should be made to minimize the duration of vigabatrin

1–14 75 U/m2 IM 2 times daily

15–17 30 U/m2 IM in the morningc

18–20 15 U/m2 IM in the morning

21–23 10 U/m2 IM in the morning

24–29 10 U/m2 IM every other morning (3 doses)

1–14 10 mg orally 4 times dailyc,d

15–19 10 mg orally 3 times daily

20–24 10 mg orally 2 times daily

25–29 10 mg/d orally

1–3 50 mg/kg/d, divided 2 times daily

4–6 100 mg/kg/d, divided 2 times daily

>7 150 mg/kg/d, divided 2 times dailyc

392 APRIL 2019

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Response to Treatment in Children With Absence Seizures TABLE 5-6

“Freedom from failure” a

12 months 45% 44% 21%

“Freedom from failure”a 16–20 weeks 63% 65% 45%

12 months 57% 49% 36%

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394 APRIL 2019