224 Antiepileptic Drug Management
in Children
Mathilde Chipaux . Olivier Dulac . Catherine Chiron . Rima Nabbout
Introduction
Antiepileptic drugs (AEDs) are the major therapeutic inter-
vention in epilepsy care. The initial aim of therapy is freedom
from seizures without significant adverse reaction. This has
now been broadened to include optimal quality of life with
regard to physical, educational, social, and psychological func-
tioning. The choice of AED primarily depends on syndrome
type, whereas length of treatment is mainly determined by
etiology. Adequate dose of AED is personal and targeted by
the decrease or the absence of seizures. Approximately 60% of
newly diagnosed patients become seizure-free on a single AED
(monotherapy) (Kramer 1997). It is estimated that about 40%
of patients require a combination of drugs and, in spite of
polytherapy, 30% of them are not satisfactorily controlled. In
addition, another 25% suffer from significant adverse effects.
In patients with drug resistance, and in selected cases of focal
epilepsies, neurosurgical options can be proposed. For other
syndromes, non-pharmaceutical therapies such as ketogenic
diet, palliative surgery (i.e., callosotomy), or vagal nerve stim-
ulation could be useful.
AEDs Particularities in Pediatrics
Initiation of Treatment in Infantile
Epilepsies
Once epilepsy is diagnosed, the most appropriate AED is
selected if treatment is indicated. Before choosing a drug, the
syndrome should be identified because drug choice depends
on the syndromic form and inappropriate medication may
worsen the outcome. For example, in symptomatic partial
epilepsies, vigabatrin is usually preferred before 1 year of age,
then carbamazepine can be given (to minimize the risk of
spasms before 6 months). Valproate is often the first choice
in generalized epilepsies, including severe myoclonic epilep-
sy in infancy. If there is any suspicion of an inherited error of
metabolism, some of which represent a contraindication to
the use of valproate, clobazam could be considered.
Brain Immaturity: Seizure Consequences
and Adverse Effects of AEDs in Brain
Development
The fact that neonates and toddlers have a high incidence of
seizures is supported by seizure models in developing
C.P. Panayiotopoulos (ed.), Atlas of Epilepsies, DOI 10.1007/978-1-84882-128-6_224,
# Springer-Verlag London Limited 2010
animals, which show that the immature brain has an
increased susceptibility to seizures compared to adult brains.
Recurrent seizures in immature rats result in long-term
cognitive impairment regarding learning, memory, and be-
havior. These changes are paralleled by modifications in
brain connectivity, dendritic morphology, receptors, ion
channels, and neurogenesis. The interaction between electri-
cal discharges during seizures and the resulting modifica-
tions of neuronal circuits in maturation may be a major
determinant of brain function and maturation.
Parallel to the consequences of seizures, long-term effects
of AEDs are not clearly delineated, particularly in children.
Some AEDs may have a significant and immediate effect on
cognitive function and behavior, particularly barbiturates,
benzodiazepines, vigabatrin, and topiramate. These symp-
toms are more common in children (Glauser 2004). Pheno-
barbital may cause depression. Topiramate, levetiracetam,
and vigabatrin may produce irritability and aggressive be-
havior, particularly in children with cognitive impairment.
Age-Dependent Pharmacokinetics and
Pharmacodynamics
The pharmacokinetics of AEDs vary according to matura-
tional stage and show a great intra- and interindividual
variability. Specific pharmacokinetic features include slower
gastrointestinal absorption rate, higher volumes of distribu-
tion, higher apparent clearance value, and shorter half-life
than in adults (Siddiqui et al. 2003). As a result, dose may
need to be increased in infants and the intervals between
doses needs to be shortened. Valproic acid and phenobarbi-
tal exhibit relatively favorable pharmacokinetics in infants,
whereas carbamazepine daily dosages need to be increased
up to twofold compared to older children and adults.
Tolerability profiles may differ in children. The risk of
hepatic failure with valproate increases below 2 years. This
may be explained by undiagnosed inherited metabolic dis-
ease decompensated by valproate, including Alpers disease.
Benzodiazepines induce in children a paradoxal hyperexcita-
tion, with sleep disorders rather than somnolence.
Palatability
Available formulations are often unsatisfactory for the use in
young children. Before 6 years, they cannot swallow solid
 1506

Table 224-1. Summary of indications, posology, adverse events, potential worsening, and blood monitoring of main antiepileptic drugs (AEDs)
Potential
worsening in
224
epilepsy (Perruca
Product Indications Posology Adverse effects et al. 1998) Blood level monitoring
Benzodiazepine Generalized and partial 0.1 mg/kg/j Neurological: severe sedation, Potential Not needed
clonazepam epilepsies, myoclonic epilepsies Status epilepticus: 0.05 mg/ fatigue, drowsiness, behavioral aggravation of
kg then 0.1 mg/kg every 6 h. and cognitive impairment, tonic seizures
Withdrawal: 50% decrease restlessness, aggressiveness,
every 6 h up to 0.1 mg/kg/d hypersalivation. and
then give the drug orally to coordination disturbances.
continue the withdrawal Tolerance and withdrawal
syndrome
Benzodiazepine Generalized epilepsies, partial Twice daily Not needed
clobazam epilepsies, myoclonic epilepsies, Child: 0.5 mg/kg/d
epilepsy with CSWS Neonate: up to 1 mg/kg/d
>12 years: 530 mg/d
Carbamazepine Partial epilepsy Three times daily for oral Idiosyncratic rash, sedation, Potential In infants (private
Antiepileptic Drug Management in Children

Ethosuximide Absence epilepsy, myoclonic
epilepsies, epilepsy with CSWS
Felbamate (Pellock Secondarily generalized
1999) epilepsies: LennoxGastaut
syndrome, cortico-resistant
infantile spasms
formulation, twice for solid
form
Child: Up to 1520 mg/kg/d
with weekly step of 10 mg/kg/
week
Neonate: 30 mg/kg/d
>12 years: 1015 mg/kg/d
If one intake is forgotten,
increase the next one
up to 50%
Once or twice daily
Step every week
<12 years: 2030 mg/kg/d
>12 years: 20 mg/kg/d
Twice or three times daily
414 years: start with
7.510 mg/kg/d then increase
10 mg/kg/3 days up to
45 mg/kg/d
>14 years: start with
6001200 mg/d then increase
headache, ataxia, nystagmus,
diplopia, tremor, impotence,
hyponatremia, cardiac
arrhythmia
Life threatening: Hepatic and
hematological failure
Idiosyncratic rash, anorexia,
gastrointestinal, weight loss,
drowsiness, photophobia,
headache
Life threatening: Renal, hepatic,
and hematological failure
Skin rash, fever, edema, nausea,
anorexia, loss of weight, fatigue,
insomnia
Life threatening: Medullar
aplasia (risk is about 1/4000 a
5000) and hepatic failure (risk is
about 1/18500 to 25000)
aggravation of pharmacokinetics) Suspicion of
myoclonia, severe intoxication if side effects are
myoclonic epilepsy present
in infancy, Doose
syndrome
Targeted plasmatic level:
4080 mg/l
Toxicity >100 mg/l Decrease the
dose by 50% if valproate
comedication
Cytochrome P450 inducer: if
comedication, decrease
valproate, carbamazepine,
vigabatrin or phenytoin to
7080% of their efficient dose
Monitor blood count and
hepatic enzymes level every
 6001200 mg/week up to
3600 mg/d
Gabapentin (Lee Partial epilepsies Twice daily
et al. 1996; Increase every 3 days
Appleton et al. >4 years: 2050 mg/kg/d
1999a) >12 years: 300 mg x 2/d the
first day, then 300 mg x 3/d
the second day up to 1200
mg/d
Rufinamide LennoxGastaut syndrome Twice daily
<30 kg without valproate:
initially 200 mg/d, increased
in 200 mg/day increments
every 2 days up to 1000 mg/
day
<30 kg with valproate:
200 mg/day, increased every
2 days to 400 mg/d
>30 kg: initially 400 mg/day,
increased by 400 mg/day
increments every 2 days up to
1800 mg/d for 3050 kg,
2400 mg/d for >5070 kg and
3200 mg/d for >70 kg
Lamotrigine Idiopathic generalized Twice daily
(Matsuo et al. 1993; epilepsies, absence epilepsies, 212 years: 25 mg/kg/d if
Motte et al. 1997; Doose syndrome, secondarily comedication with valproate
Beran et al. 1998; generalized epilepsies: Lennox and 1015 mg/kg/d in
Guerini et al. 1998; Gastaut syndrome, cortico- monotherapy (or with an
Duchowny et al. resistant infantile spasms, partial enzymatic inducer
1999) epilepsies comedication):
If LTG + VPA: 0.2 mg/kg/d
during 15 days then
0.5 mg/kg/d during 15 days
then 1 mg/kg/d during
15 days then 2 mg/kg/day.
Maximum dose 5 mg/kg/d
If LTG + CBZ (partial
Weight gain, peripheral edema,
fatigue, behavioral changes,
nausea, dizziness, ataxia,
nystagmus, headaches,
agitation. Their frequency seem
not to be dose-related
Behavioral impairment is more
frequent in pediatrics:
hyperactivity, agitation,
irritability
Nausea, vomiting, pneumonia,
nasopharyngitis sinusitis, rhinitis,
anorexia, epistaxis, abdominal
pain, constipation, dyspepsia,
diarrhea, rash, acne Neurological:
anxiety, insomnia, abnormal
coordination, nystagmus,
psychomotor hyperactivity,
tremor, diplopia, blurred vision,
vertigo, somnolence, ataxia,
headache, dizziness
Rash reversible if withdrawal, if
not, Lyell syndrome may occur.
Vomiting, nausea Neurological:
Headache dizziness in case of
rapid titration of the treatment
tics, insomnia, diplopia, ataxia,
asthenia
15 days
Immediate withdrawal in case of
neutropenia <1500/mm3 or
thrombocytopenia <150000/
mm3 or hepatitis
Potential
aggravation of
myoclonia
Concentrations may be
decreased by coadministration
with carbamazepine,
phenobarbital, phenytoin,
vigabatrin, or primidone.
Rufinamide may decrease
phenytoin clearance and
increase phenytoin steady state
plasma concentrations
phenytoin dose reduction
should be considered
Potential In case of rash, lamotrigine
aggravation of should be immediately stopped
severe myoclonic and a medical exam is needed to
epilepsy in infancy evaluate the gravity of the
To slow stepwise impairment. The probability
beginning of the decreases if the titration is
Antiepileptic Drug Management in Children
treatment in case of stepwise, at about 6% and 25%
acute worsening of in case of comedication with
the epilepsy valproate. The risk increases in
children, compared to adults,
estimated respectively at 1 and
0.3%.
224
1507
 1508
Table 224-1. (Continued)
Potential
worsening in
epilepsy (Perruca
Product Indications Posology Adverse effects et al. 1998) Blood level monitoring
224

epilepsies): carbamazepine
In the other cases: 2 mg/kg/d
during 15 days then 5 mg/kg/
d during 15 days then
1 mg/kg/d during 15 days
then 10 mg/kg/day.
Maximum dose 15 mg/kg/d
>12 years: If LTG + VPA: 25
mg every other day during 15
days then 25 mg/d every 15
days then 100200 mg/d
If monotherapy: 50 mg/d
during days then 100 mg/d
during 15 days then
200500 mg/d
Antiepileptic Drug Management in Children

Levetiracetam Generalized epilepsies, Doose Twice daily
(Aeby et al. 2005; syndrome, partial epilepsies <12 years: start with
Glauser et al. 2006) 510 mg/kg/d then increase
10 mg/kg/every week up to
50 mg/kg/day
>12 years: 500 mg
2/day
during 715 days then
1 g
2 /day during 715 jours
then 1.5 g
2/ if needed
Oxcarbazepine Partial epilepsies Twice daily
(Nielsen et al. 1988; <6 years: 2030 mg/kg/d
Glauser et al. 2000) with weekly of 10 mg/kg/
week
>6 years: 1015 mg/kg/d
Phenobarbital Generalized epilepsies except Once a day
absence epilepsy, partial Child: 35 mg/kg/d
epilepsies Adult: 23 mg/kg/d
Irritability, behavior changes, No drug interaction
asthenia, dizziness
Headache, dizziness, weakness, Potential Immediate withdrawal in case of
nausea, somnolence, ataxia, aggravation of rash
diplopia, nausea, idiosyncratic myoclonia, severe
rash, dry mouth myoclonic epilepsy
Hyponatremia risk is higher with in infancy, Doose
oxcarbazepine than syndrome
carbamazepine, disappears after
withdrawal or reducing
posology
Life threatening: hepatic and
hematological failure
Idiosyncratic rash, severe Potential In case of prolonged use, add
drowsiness, sedation, insomnia, aggravation of vitamin D and calcium
impairment of cognition and

Phenytoin (Richard Generalized and partial
et al. 1993) epilepsies
Stiripentol (Perez Severe myoclonic epilepsy in
et al. 1999; Chiron infancy (comedication with
et al. 2000; Chiron clobazam)
et al. 2006)
Partial epilepsies (comedication
with carbamazepine)
Sulthiame Absence epilepsy, myoclonic
epilepsies, epilepsy with CSWS
Tiagabine Partial epilepsies
Twice daily
Child: 38 mg/kg/d
Adult: 26 mg/kg/d
Twice daily
Child: 50 mg/kg/d
Twice to four times daily, with
a great quantity of liquid
increase weekly
<2 years: 125 mg/d
26 years: 125250 mg/d
610 years: 250500 mg/d
1014 years: 250750 mg/d
Adult: 7501000 mg/d
Twice daily
>12 years: 0.51 mg/kg/d
Adult: 7.515 mg/d then 5
15 mg/every week up to 15
30 mg/d (3050 mg/d in case
concentration, hyperkinesia and
agitation, Shoulder-hand
syndrome
Life-threatening: hepatic and
hematological failure
Idiosyncratic rash, ataxia,
drowsiness, lethargy, sedation,
encephalitis, gingival
hyperplasia, hirsutism,
dysmorphism, nausea, diplopia,
vomiting, osteomalacia
Life-threatening: hepatic and
hematological failure
Fatigue, insomnia, ataxia,
oculomotor effects, hypotonia
and digestive effects (anorexia,
nausea), moderate neutropenia
At long term, anorexia and
weight loss Reduce dose of
every comedication using
cytochrome P450 metabolism
(see above)
Nausea, anorexia, loss of weight,
metabolic acidosis, dyspnea,
tachypnea, headache, visual
impairment, hypotonia, ataxia,
acute psychotic disorder,
hepatitis
Stupor or spike-wave stupor,
weakness, vertigo, fatigue,
irritability, ideomotor slowness,
dysarthria, abdominal pain. Most
of them are transient and occur
severe myoclonic
epilepsy in infancy
Potential Difficulty to stabilize plasmatic
aggravation of level Monitor plasma level every
myoclonia, severe 2 weeks until stabilization
myoclonic epilepsy Plasma level target: s 515 mg/l
in infancy, Doose Toxicity >20 mg/l
syndrome, and
tonic seizures
Decrease clobazam to 0.5 mg/
kg/d and valproate to 1015 mg/
kg/d
Decrease carbamazepine to 50%
of efficient dose
Maintain EpoxyCBZ/CBZ <0.1
CBZ around 1015 mg/l
CBZ EpoxyCBZ between 0.6
and 3
If EpoxyCBZ/CBZ >0.1: increase
STP STP inhibit cytochrome P450
decrease EpoxyCBZ (responsible
for adverse effects) and increase
CBZ Targeted plasmatic level:
1015 mg/l
phenytoin and lamotrigine
plasma level if comedication
adverse effects if comedication
with Primidone
Antiepileptic Drug Management in Children
Potential If enzymatic inducer
aggravation of comedication (carbamazepine,
myoclonia phenytoin, phenobarbital),
increase dose of tiagabine
224
1509

Table 224-1. (Continued)
Product Indications Posology
of enzymatic inducer
comedication
Topiramate Symptomatic partial and Administer 2 daily doses
(Tassinari et al. generalized epilepsies, Dravet >4 years: 15 mg/kg/jd. Start
1996; Shorvon syndrome, Doose syndrome with 0.51 mg/kg/d and
1996; Eltermann increase of 0.51 mg/kg every
et al. 1999; Sachdeo 2 weeks
et al. 1999; Kroll- <4 years without MA:
Seger et al. 2006) 1 mg/kg/d for 2 days then
increase of 1 mg/kg/2 days up
to 10 mg/kg/d
Infantile spasms: 3 mg/kg/d
during 3 days then 6 mg/kg/d
during 3 days then 9 mg/kg/d
Adult: 200600 mg/d
Valproate Absence epilepsy, generalized Three times daily if liquid
and partial epilepsies, myoclonic formulation, once or twice
epilepsies daily if other forms
Child: 2030 mg/kg/d with
step increase of 10 mg/kg/
every week Neonate: 3040
mg/kg/d Adult: 2030 mg/
kg/d
Vigabatrin (Chiron Infantile spasms, partial Twice daily
et al. 1991; Lortie epilepsies Child: 4080 mg/kg/d
et al. 1997; Eke et al. Infant with spasms:
1997; Appleton 100150 mg/kg/d
et al. 1999b; Wild Adult: 2 g/day up to 4 g/d
et al. 2007)
CSWS, Continuous SpikesWaves in Sleep; MA, marketing authorization
Adverse effects
during the beginning of the
treatment
Language dysfunction,
somnolence, anorexia, weight
loss, diplopia, nystagmus,
fatigue, nervousness, difficulties
of concentration and attention,
memory loss, psychomotor
slowing, paresthesia, depression,
headaches, ataxia.
Metabolic acidosis, renal calculi,
acute angle closure glaucoma.
Renal calculi are reported if
ketogenic diet
Nausea, vomiting ! reduce
dose or change for solid forms
Dyspepsia, weight gain, hair loss,
headaches
Tremor ! reduce dose
In women: ovarian cysts,
amenorrhea, teratogenesis
(spina bifida) and
neurodevelopmental effects
Toxic hepatitis
Excitability, fatigue, weight gain
Hypotonia in neonate Visual field
defects (visual ability remains
normal), linked to the cumulative
dose and the duration of
treatment Excitability, motor
instability nausea, vomiting !
reduce dose or use solid forms
Myoclonus
1510
Potential
worsening in
224
epilepsy (Perruca
et al. 1998) Blood level monitoring
If comedication with phenytoin,
increase phenytoin plasmatic
level
If carbamazepine comedication,
decrease topiramate
Plasmatic levels are not directly
related to the efficacy and blood
level monitoring is unnecessary,
except to confirm that the
treatment is currently given to
the child.
Antiepileptic Drug Management in Children
Theoretically, no Hepatic enzyme monitoring in
risk of aggravation the first month of treatment and
in any epileptic if hepatitis symptoms
syndrome (some Drug interactions
cases report in Avoid in case of mitochondrial
idiopathic partial impairment (mainly Alpers
epilepsies) syndrome), Beta oxidation or
urea defects Targeted plasmatic
level: 40100 mg/l
Toxicity >120 mg/l
Potential Ophthalmologic exam before
aggravation of the beginning of vigabatrin
myoclonia, severe therapy if the child is cooperant
myoclonic epilepsy and the monitoring every
in infancy, Doose 6 months during vigabatrin
syndrome therapy
In case of previous visual
impairment, vigabatrin should
be avoided if possible
 Antiepileptic Drug Management in Children 224 1511

Table 224-2. EMEA current licensed indications for antiepileptic drugs (AEDs)
AED EMEA Current licensed indications
Carbamazepine Sole or adjunctive therapy for partial-onset seizures with or without secondary generalization and generalized
tonicclonic seizures in patients 1 year of age.
Clobazam Adjunctive therapy of epilepsy in patients >3 years of age.
Clonazepam All clinical forms of epileptic disease and seizures in infants, children, and adults, especially absence seizures,
including: atypical absence; primary or secondarily generalized tonicclonic, tonic, or clonic seizures; partial-
onset seizures; various forms of myoclonic seizures, myoclonus, and associated abnormal movements.
Ethosuximide Monotherapy in absence seizures. When generalized tonicclonic seizures and other forms of epilepsy coexist
with absence seizures, ethosuximide may be administered in combination with other AEDs.
Felbamate Combination therapy in refractory LennoxGastaut syndrome >4 years.
Gabapentin (1) Adjunctive therapy of partial-onset seizures with and without secondarily generalized tonicclonic seizures in
patients 6 years of age. (2) Monotherapy in the treatment of partial-onset seizures with and without secondary
generalization in adults and adolescents 12 years of age.
Lamotrigine (1) Monotherapy in adults and children 12 years of age for partial-onset seizures with or without secondarily
generalization, secondarily and primarily generalized tonicclonic seizures. (2) Adjunctive therapy in adults and
children 2 years of age for partial-onset seizures with or without secondarily generalization, secondarily and
primarily generalized tonicclonic seizures. (3) The treatment of seizures associated with LennoxGastaut
syndrome.
Levetiracetam (1) Monotherapy for partial-onset seizures with or without secondarily generalization for patients aged 16 years
and older with newly diagnosed epilepsy. (2) Adjunctive therapy for partial-onset seizures with or without
secondarily generalization in patients 4 years of age. (3) Adjunctive therapy in the treatment of myoclonic
seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy. (4) Adjunctive therapy
for primary generalized tonicclonic seizures in patients 12 years of age with idiopathic generalized epilepsy.
(5) Levetiracetam concentrate is an alternative for patients when oral administration is temporarily not feasible.
Oxcarbazepine Monotherapy or adjunctive therapy for partial-onset seizures with or without secondarily generalized tonic
clonic seizures in patients 6 years of age.
Phenobarbital All forms of epilepsy except absence seizures in patients of any age, including neonates.
Phenytoin Sole or adjunctive therapy for patients of any age with tonicclonic seizures, partial-onset seizures or a
combination of these, and the prevention and treatment of seizures occurring during or following neurosurgery
and/or severe head injury.
Primidone Management of grand mal and psychomotor (temporal lobe) epilepsy. It is also of value in the management of
partial or Jacksonian seizures, myoclonic jerks, and akinetic attacks.
Pregabalin Not authorized in children. Adjunctive therapy in adults with partial-onset seizures with or without secondary
generalization.
Rufinamide Adjunctive treatment of seizures associated with LennoxGastaut syndrome in patients 4 years of age.
Sulthiame Licensed in a small number of European countries for the treatment of benign partial epilepsy (Rolandic
epilepsy), as a second-line drug.
Stiripentol In conjunction with clobazam and valproate, as adjunctive therapy of refractory generalized tonicclonic
seizures in patients with severe myoclonic epilepsy in infancy (SMEI or Dravets syndrome) whose seizures are
not adequately controlled with clobazam and valproate.
Tiagabine Adjunctive therapy for partial-onset seizures in patients 12 years of age.
Topiramate (1) Monotherapy in patients 6 years of age with newly diagnosed epilepsy who have generalized tonicclonic
seizures or partial-onset seizures with or without secondarily generalized seizures. (2) Adjunctive therapy in
patients 2 years of age who are inadequately controlled on conventional first-line AEDs for partial-onset
seizures with or without secondarily generalized seizures; seizures associated with LennoxGastaut syndrome
and primary generalized tonicclonic seizures. The efficacy and safety of conversion from adjunctive therapy to
TPM monotherapy has not been demonstrated.
Valproate Monotherapy and adjunctive therapy for any form of epilepsy in patients at any age.
Vigabatrin (1) Monotherapy in the treatment of infantile spasms. (2) Adjunctive therapy for partial-onset seizures with or
without secondarily generalized seizures in patients at any age.
Zonisamide Not authorized in children; adjunctive therapy for partial-onset seizures with or without secondary
generalization in patients 18 years of age.
1512 224 Antiepileptic Drug Management in Children
forms (tablets and capsules) and some AEDs are not yet
developed in a child-friendly formulation. Recently, an in-
novative formulation of valproate as controlled-release for-
mulation (microspheres), suitable for low daily dosages, was
developed with a possible better palatability.
AEDs Modalities in Pediatrics
> Table 224-1 summarizes the main indications of AEDs
with posology, adverse effects, potential worsening, and the
need for blood levels monitoring. These data are based on
literature review and on our group experience. In > Table
224-2, European Medecines Agency (EMEA) current
licensed indications are reported.
Recommendations for the Development
of New AEDs in Pediatrics
The guidelines are currently under revision for the develop-
ment of new AEDs in children, in Europe. The proposals the
authors made (Chiron et al. 2008) are noticed in italics in the
following:
Clinical Situations where Extrapolation
from Adult to Children can be Made
Extrapolation is impossible before 2 years because epilepsy
syndromes are different, even in partial epilepsy (where
infantile spasms could appear), cognitive impact is a key
point outcome, pharmacokinetics are unpredictable, and
tolerability might be different (hepatitis, metabolic acidosis).
Extrapolating from adult epilepsies to childhood-specific
syndromes is not possible as these syndromes do not exist
in adulthood (infantile spasms) or present different seizure
types and sometimes different response to AEDs (Dravet
syndromes). Extrapolating from adults to children may be
possible in focal epilepsies after 23 years of age, regarding
efficacy of a new AED, because the epilepsy is similar. However,
tolerability must be explored in children-dedicated studies
and age-specific pharmacokinetics data are required until
1217 years; a population approach should be encouraged
when possible.
Global Strategy in the Pediatric
Development Plan of New AEDs
Development of new AEDs in children faces difficulties
recruiting in clinical trials and lack of financial interest of
pharmaceutical companies (Chiron et al. 2008). Since
January 2007, a new regulation in Europe requires that
every new AED with a potential use in children should be
studied in a pediatric population. Recently introduced AEDs
have been developed in order to improve the benefit risk/
balance of standard therapy. Traditionally, new AEDs have
all been first evaluated in add on studies. Differences exist in
efficacy and tolerability profile depending of seizure type,
age, and epilepsy syndrome. Epilepsy syndromes may exhibit
several types of seizures (interictal paroxysmal activity that
may contribute to impact cognition). While controlling the
most invalidating seizure type, a new drug may worsen
another seizure type (or trigger major interictal paroxysms).
Therefore, inclusion criteria should be syndrome-based and
efficacy evaluation seizure (and EEG) based, focusing on the
major seizure type but also taking into account the other types
of seizures (and interictal EEG). To summarize, it is impor-
tant to explore the efficacy in all epileptic syndromes/seizure
types as early as possible in the development of the medicinal
product allows, in parallel to the development in partial
epilepsy (Trevathan 2003). The global strategy should avoid
any a priori before any clinical investigation has given
some insight.
References
Aeby A, Poznanski N, Verheulpen D, Wetzburger C, Van BP (2005)
Levetiracetam efficacy in epileptic syndromes with continuous
spikes and waves during slow sleep: experience in 12 cases. Epilepsia
46(12):19371942
Appleton R, Fichtner K, LaMoraux L (1999a) Gabapentin as add-on therapy
in children with refractory partial seizures: a 12-week, multicentre,
double-blind, placebo-controlled study. Epilepsia 40(8):11471154
Appleton R, Peters ACB et al. (1999b) Randomised, placebo-controlled
study of vigabatrin as first-line treatment of infantile spasms. Epilepsia
40(11):16271633
Beran RG, Berkovic SF, Dunagan FM (1998) Double-blind, placebo-con-
trolled, crossover study of lamotrigine in treatment-resistant general-
ised epilepsy. Epilepsia 39(12):13291333
Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N, Mumford J (1991)
Therapeutic trial of vigabatrin in refractory infantile spasms. J Child
Neurol (Suppl 2):S52S59
Chiron C, Dulac O, Pons G (2008) Antiepileptic drug development in
children: considerations for a revisited strategy. Drugs 68(1):1725
Chiron C, Marchand MC, Tran A, Rey E, dAthis P, Vincent J et al. (2000)
Stiripentol in severe myoclonic epilepsy in infancy: a randomised pla-
cebo-controlled syndrome-dedicated trial. STICLO study group. Lancet
356(9242):16381642
Chiron C, Tonnelier S, Rey E, Brunet ML, Tran A, dAthis P et al. (2006)
Stiripentol in childhood partial epilepsy: randomized placebo-con-
trolled trial with enrichment and withdrawal design. J Child Neurol
21(6):496502
Duchowny M, Pellock JM, Graf WD, Billard C, Gilman J, Casale E et al.
(1999) A placebo-controlled trial of lamotrigine add-on therapy for
partial seizures in children. Lamictal Pediatric Partial Seizure Study
Group. Neurology 53(8):17241731
Eke T, Talbot JF, Lawden MC (1997) Severe persistent visual field constric-
tion associated with vigabatrin. BMJ 314(7075):180181
Elterman RD, Glauser TA, Wyllie E, Reife R, Wu SC, Pledger GA (1999)
Double-blind, randomized trial of topiramate as adjunctive therapy for
partial-onset seizures in children. Topiramate YP Study Group. Neurol-
ogy 52(7):13381344
Glauser TA (2004) Behavioral and psychiatric adverse events associated with
antiepileptic drugs commonly used in pediatric patients. J Child Neurol
19(Suppl 1):S25S38 Review
Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ,
Lu Z (2006) Double-blind placebo-controlled trial of adjunctive leve-
tiracetam in pediatric partial seizures. Neurology 66(11):16541660
Glauser TA, Nigro M, Sachdeo R, Pasteris LA, Weinstein S, Abou-Khalil B
et al. (2000) Adjunctive therapy with oxcarbazepine in children with

partial seizures. The Oxcarbazepine Pediatric Study Group. Neurology
54(12):22372244
Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O (1998)
Lamotrigine and seizure aggravation in severe myoclonic epilepsy.
Epilepsia 39(5):508512
Kramer G (1997) The limitations of AED monotherapy. Epilepsia
38(suppl 5):S9S13
Kroll-Seger J, Portilla P, Dulac O, Chiron C (2006) Topiramate in the
treatment of highly refractory patients with dravet syndrome. Neuro-
pediatrics 37(6):325329
Lee DO, Steingard RJ et al. (1996) Behavioral side effects of gabapentin in
children. Epilepsia 37:8790
Lortie A, Chiron C, Dumas C, Mumford JP, Dulac O (1997) Optimizing the
indication of vigabatrin in children with refractory epilepsy. J Child
Neurol 12(4):253259
Matsuo F, Bergen D, Faught E et al. (1993) Placebo-controlled study of the
efficacy and safety of lamotrigine in patients with partial seizures.
Neurology 43:22842291
Motte J, Trevathan E, Arvidsson JF, Barrera MN, Mullens EL, Manasco P
(1997) Lamotrigine for generalized seizures associated with the Lennox-
Gastaut syndrome. Lamictal Lennox-Gastaut Study Group. N Engl
J Med 337(25):18071812
Nielsen OA, Johannessen AC et al. (1988) Oxcarbazepine-induced hypona-
tremia, a cross-sectional study. Epilepsy Res 2:269271
Pellock JM (1999) Felbamate. Epilepsia 40(suppl 5):S57S62
Antiepileptic Drug Management in Children 224 1513
Perez J, Chiron C et al. (1999) Stiripentol: efficacy and tolerability in
children with epilepsy. Epilepsia 40(11):16181626
Perruca E, Gram L et al. (1998) Antiepileptic drugs as a cause of worsening
seizures. Epilepsia 39:517
Richard MO, Chiron C, dAthis P, Rey E, Aubourg P, Dulac O et al. (1993)
Phenytoin monitoring in status epilepticus in infants and children.
Epilepsia 34(1):144150
Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger GA (1999)
cDouble-blind, randomized trial of topiramate in Lennox-Gastaut
syndrome. Topiramate YL Study Group. Neurology 52(9):18821887
Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB et al.
(2003) Association of multidrug resistance in epilepsy with a poly-
morphism in the drug-transporter gene ABCB1. N Engl J Med
348(15):14421448
Shorvon SD (1996) Safety of topiramate: adverse events and relation-ships
to dosing. Epilepsia 37(suppl 2):S18S22
Tassinari CA, Michelucci R, Chauvel P et al. (1996) Double-blind, placebo-
controlled trial of topiramate (600 mg daily) for the treatment of
refractory partial epilepsy. Epilepsia 37(8):763768
Trevathan E (2003) Antiepileptic drug development for therapeutic
orphans. Epilepsia 44(Suppl 7):1925
Wild JM, Ahn HS, Baulac M, Bursztyn J, Chiron C, Gandolfo E et al.
(2007) Vigabatrin and epilepsy: lessons learned. Epilepsia 48(7):
13181327