Special Article

Determining the Effects of Antiepileptic Drugs

on Cognitive Function in Pediatric Patients
With Epilepsy
Blaise F. D. Bourgeois, MD

ABSTRACT

The majority of children with epilepsy are of normal intelligence; however, a significant subset suffers from temporary or
permanent cognitive impairment. Factors that affect cognitive function are myriad and include the neuropathology under-
lying the epilepsy, seizures, epileptiform activity, psychosocial problems, and antiepileptic drug side effects. Although
cognitive impairment is often wrongly attributed to the effects of antiepileptic drugs, antiepileptic drugs do impair cogni-
tion in some children. Clinicians should be aware of the differential cognitive effects of antiepileptic drugs and should
monitor cognitive function closely when adding or changing therapy. Based on published data from prospective, chronic
dosing studies, phenobarbital and topiramate have the highest potential for causing cognitive dysfunction. ( J Child Neurol
2004;19(Suppl 1):S15-S24).

The majority of pediatric patients with uncomplicated
epilepsy do not suffer from any permanent or progressive
cognitive deficits as a result of their disorder. This general
lack of deficit has been established by several prospective,
longitudinal studies of IQ in children with epilepsy How-
ever, in certain individuals, or subgroups of patients, cog-
nitive impairment or cognitive decline has been well
documented. Predictors of cognitive decline include over-
medication, poor seizure control, and young age at onset of
epilepsy. Epilepsy origin is also predictive. As a group,
children with symptomatic epilepsy are at a greater risk for
cognitive impairment than are those with idiopathic epilepsy. 1
The specific factors contributing to cognitive impair-
ment in an individual epileptic child can be difficult or
impossible to ascertain. However, several critical factors
Received Feb 25, 2004. Received revised May 28, 2004. Accepted for pub-
lication June 1, 2004.
From the Department of Neurology, Harvard Medical School, and the Division
of Epilepsy and Clinical Neurophysiology, Children’s Hospital Boston,
Boston, MA.
Address correspondence to Dr Blaise F. D. Bourgeois, Department of
Neurology, Harvard Medical School, Division of Epilepsy and Clinical
Neurophysiology, Children’s Hospital Boston. 300 Longwood Avenue, HU
II, Boston, MA 02115. Tel: 617-355-2413; fax: 617-730-0463; e-mail: blaise.bour-
geois@childrens.harvard.edu.
play a role. For many children, the most significant cause
of cognitive impairment is the underlying brain pathology
giving rise to the epileptic disorder (for a review, see Dod-
son5). Other key factors influencing cognitive function
include seizures or epileptiform activity,’ psychosocial dif-
ficulties, and antiepileptic drugs.8 All of these factors are
interrelated, and their contribution to cognitive deficits is
complex (Figure 1). Parents, and even clinicians, tend to
blame cognitive problems on antiepileptic drugs because
they are more tangible and identifiable than other factors;
however, antiepileptic drug effects should not be overrated.
Psychosocial problems are common in children with
epilepsy9 but can be overlooked as a source of cognitive
impairment. The stigma of epilepsy and the fear of having
seizures in public can lead to low self-esteem, social isola-
tion, and depression, all potentially negatively impacting on
cognitive function. Similarly, subclinical epileptiform activ-
ity is another important contributor to cognitive dysfunc-
tion7that can go unrecognized, especially in children whose
seizures are infrequent.
Although antiepileptic drugs are rarely the sole source
of cognitive deficit, they do have the potential to affect cog-
nition significantly in any given patient. Moreover, patients
who are overmedicated are at a substantially increased risk:
toxic antiepileptic drug levels and multiple- antiepileptic
drug regimens have a probable link with cognitive impair-
ment.’’° Because the cognitive effects of antiepileptic

S15
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S16
drugs can potentially be modified by discontinuing the
drug, decreasing the dose, or switching to another med-
ication, it is of critical importance to identify cognitive
deficits potentiated by antiepileptic drug therapy. Identi-
fying and minimizing the cognitive effects of antiepileptic
drugs are even more important in children because their
developing nervous systems can be more vulnerable to the
long-term consequences of antiepileptic drug-induced
cognitive impairment. 11
Researchers have attempted to identify and quantify the
cognitive effects of antiepileptic drugs, but with limited
success. Although hundreds of studies have been performed,
the methodologic flaws, differences in study design, and con-
tradictory results have allowed no clear picture to emerge
(see Table 1 for methodologic issues). 8,12 Furthermore, many
studies have been carried out in adult populations, obscur-
ing the relevance of their findings to the treatment of pedi-
atric populations. Nevertheless, this review summarizes
the current literature, draws general conclusions where
possible, and provides recommendations on methods for
assessing antiepileptic drug-associated cognitive impairment
in children with epilepsy. The studies included in this review
were identified in previous literature searches performed
during the past 20 years. 1.8.13.1-4 Additional studies were iden-
tified via a recent MEDLINE search encompassing the past
3 years. Only prospective studies designed to evaluate cog-
nitive effects after more than 1 week of antiepileptic drug
therapy are included. Although, as mentioned above, many
of these studies suffered from methodologic flaws and
designs differed greatly, studies were not excluded on these
bases. For this reason, results within and across trials should
be interpreted with caution.
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Figure 1. Interrelationship of key factors
affecting cognitive function. AED =
antiepileptic drug.
COGNITIVE EFFECTS OF THE OLDER
ANTIEPILEPTIC DRUGS
Phenobarbital
Phenobarbital was first marketed in the United States in 1912,
making it the oldest of the &dquo;older&dquo; antiepileptic drugs.&dquo; Of
the older antiepileptic drugs, it is also the most likely to affect
cognitive function. Three studies of phenobarbital as
monotherapy in pediatric patients found significant effects
on memory, attention, or IQ when phenobarbital was com-
pared with double-blind placebo,16 when scores were cor-
related to phenobarbital blood levels, 17 and when
phenobarbital treatment was compared with no treatment
after phenobarbital withdrawal in seizure-free patients. 18 A
study in seizure-free adults found cognitive deficits (versus
controls) on 2 of 10 cognitive tasks performed during phe-
nobarbital monotherapy, but no deficits were detected 1 year
after phenobarbital withdrawal. 19 Conversely, two small
open-label studies found no change or only transient changes
in cognitive function in children treated with phenobarbi-
talmonotherapy.20,21
Studies comparing phenobarbital with other older
antiepileptic drugs have generally found worse cognitive per-
formance for patients treated with phenobarbital or no sig-
nificant differences. In two monotherapy studies comparing
phenobarbital with valproic acid, children treated with val-
proic acid performed better on some cognitive tests. In one
of these studies, which was double-blinded, significant dif-
ferences in test scores favoring valproic acid were found for
4 of 35 measures .22 In another open-label study, phenobar-
bital and valproic acid were not compared directly; however,
comparisons between each drug and a control group

Table 1. Methodologic Issues
AED =
antiepileptic drug.
(healthy, age-matched subjects) detected significantly lower
IQ scoresfor the phenobarbital group, but no differences
were found for the valproic acid group.13 A third study com-
pared open-label phenobarbital, valproic acid, and carba-
mazepine monotherapy in seizure-free children with epilepsy.
No differences in IQ scores were detected among the three
antiepileptic drugs at any time point; however, P300 laten-
cies of auditory evoked potentials were prolonged at base-
line, compared with those following antiepileptic drug
withdrawal, in the phenobarbital-treated group only.2~
Two studies compared phenobarbital and carba-
mazepine monotherapy in patients with epilepsy and found
few differences. In a small, open-label study in adults,
patients treated with carbamazepine performed better on
1 of 10 cognitive tasks compared with a similar cohort who
were treated with phenobarbital. Nine months after drug
withdrawal, there were no differences in scores for any of
the tasks.2~ In a small, single-blinded study in children, a bat-
tery of cognitive and behavioral tests were performed in
patients with newly diagnosed partial seizures. No differ-
ences were detected at baseline or over the 12-month fol-
low-up period in the phenobarbital-treated group versus
the carbamazepine-treated group.26 A third study compared
phenobarbital with carbamazepine but also included a
phenytoin treatment arm. In this small, double-blind,
crossover study in adults with complex partial epilepsy,
there were no differences detected between phenobarbital,
carbamazepine, or phenytoin monotherapy for eight of nine
cognitive measures, including P300 latency. The only dif-
ference among the three drugs was a significantly poorer
score on the digit symbol task (a coding task) for the phe-
nobarbital group.21 Any of these three studies might have had
inadequate power to detect differences because of small sam-
ple sizes.
Phenytoin
Phenytoin first entered the market in 1938 and is still widely
prescribed for epilepsy today. 15 The cognitive effects of
phenytoin as determined in chronic dosing studies have
been variable. Comparisons between phenytoin-treated
subjects and nontreated controls have generally found some
cognitive impairment in the phenytoin-treated groups;
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S17
in Studies of Cognitive Effects of Antiepileptic Drugs
however, comparisons between phenytoin and other
antiepileptic drugs have found few significant differences.
In two studies of long-term phenytoin monotherapy,
adult patients performed significantly worse than healthy
controls on approximately 20% of the cognitive measures
from a battery of tests. However, 1 year after phenytoin
withdrawal, there were no differences between patients
and control subjects.19,28 Conversely, in another study, chil-
dren with well-controlled seizures on phenytoin showed
no differences in cognitive performance when comparisons
were made between a trough drug-level condition and a peak
drug-level condition. Notably, the mean level at peak was
at the low end of the accepted therapeutic range, and the
trough level was well below it.~9
Three double-blind studies examined the effects of
phenytoin in healthy adult volunteers. A crossover study
found significant deficits in measures of memory, concen-
tration, and motor and mental speed after phenytoin treat-
ment compared with placebo. 30 Similarly, two studies that
compared phenytoin treatment with a baseline, nondrug con-
dition found significant impairments in cognitive function
after phenytoin treatment. These studies also included a car-
bamazepine treatment arm. Few significant differences
between phenytoin and carbamazepine were detected. One
study found no significant differences31; the other found
impairment in the carbamazepine group (versus phenytoin)
on an interference task and impairment in the phenytoin
group (versus carbamazepine) on a simple motor task after
controlling for antiepileptic drug blood levels. 32
Two open-label studies in children with epilepsy exam-
ined the effects of phenytoin, carbamazepine, and valproic
acid monotherapy on cognitive function. One study mea-
sured cognitive performance multiple times (1, 6, and 12
months from treatment initiation) using a battery of cogni-
tive tests during the first year of treatment in newly diag-
nosed patients. Few differences were found among the
three treatments, and only in one test (processing speed
task), at one time point (1 month), did phenytoin-treated
patients perform more poorly than another group (valproic
acid group). Carbamazepine-treated patients also performed
worse than valproic acid-treated patients for this same
task and time point but also performed worse than the
S18
valproic acid group on a conglomerate of memory tasks at
both 6 and 12 months. Carbamazepine serum levels corre-
lated negatively with performance on memory tasks, but
there was no correlation between serum levels and perfor-
mance in the phenytoin group.33 In the second study, patients
treated with phenytoin performed significantly worse than
those treated with carbamazepine on 1 of 12 cognitive tasks
at baseline and also when retested after antiepileptic drug
withdrawal 6 to 7 months later. Legitimate comparisons
could not be made with the valproic acid group because of
differences in seizure type.34
Carbamazepine
Carbamazepine was approved by the US Food and Drug
Administration (FDA) for use in epilepsy in 1974. Prior to
this approval, it was already in use for treatment of trigem-
inal neuralgia.&dquo; The reported cognitive effects of carba-
mazepine, like phenytoin, have varied according to the
comparison group studied. Comparisons with a nontreat-
ment condition or nontreated control group have gener-
ally found some negative effects of carbamazepine on
cognition. However, when carbamazepine was compared
with other antiepileptic drugs, it tended to perform similarly
to or better than the other antiepileptic drugs.
Four studies compared carbamazepine treatment with
a nontreatment condition. Two crossover studies in healthy
adults found significant cognitive impairment after a month’s
treatment with carbamazepine compared with a nondrug
baseline.31,32 Two studies evaluated the effects of carba-
mazepine in children with epilepsy by comparing cognitive
scores during carbamazepine monotherapy with scores from
nonepileptic control subjects or from a pretreatment or post-
withdrawal phase. 35,36 In both studies, performance was
impaired on a small percentage of tasks from a large battery
during carbmazepine treatment. In one of the studies, a val-
proic acid treatment arm was also included, and although the
two drugs were not compared directly, the number of tests
with significantly decreased scores (versus controls) was
similar in the valproic acid and carbamazepine groups .35 Two
additional studies did not find significant changes during
carbamazepine monotherapy compared with a nontreatment
baseline or controls.19,37 One of these studies also compared
carbamazepine with valproic acid and ethosuximide and
found no differences among the three antiepileptic drugs
after 6 months of treatment .37 Another study in children com-
pared cognitive performance at peak versus trough drug lev-
els of carbamazepine. More significant improvements than
deficits occurred during the peak drug-level condition.’
Numerous studies with a wide variety of study designs
have directly compared carbamazepine with other older
antiepileptic drugs, but these have already been described
in the sections above. In summary, the effect of carba-
mazepine on cognitive function was similar to or better
than phenobarbital in four trials, 217 similar to or better
than phenytoin in five trials ’27,31-34 and similar to valproic acid
in two triaIS24,37 but worse than valproic acid in one trial .33
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Valproic Acid
Valproic acid was approved in the United States in 1978, mak-
ing it the last of the older antiepileptic drugs to come to mar-
ket. 15 Although valproic acid is generally considered to have
a lesser effect on cognitive function than the antiepileptic
drugs that had preceded it, this observation has not been con-
sistently borne out in formal studies. In direct comparison
studies, valproic acid has typically performed as well as or
occasionally better than some antiepileptic drugs, but like
the earlier antiepileptic drugs, it has frequently displayed neg-
ative effects on cognition when compared with placebo, low
doses of valproic acid, or no drug treatment.
Two studies in adult patients on long-term valproic
acid monotherapy found significant cognitive impairment
in seizure-free patients compared with healthy control sub-
jects. In one of these studies, valproic acid-treated patients
performed significantly more poorly than controls on 4 of
10 cognitive measures. Notably, in this same study, patients
treated with other antiepileptic drugs (phenobarbital, car-
bamazepine, and phenytoin) compared more favorably with
controls than did the valproic acid-treated group.19 In the
other study, 3 of 13 measures were negatively affected, one
of which was a global score based on the other 12 measures.39
One year after withdrawal of valproic acid, no differences
were detected between the valproic acid group and control
group in either study. In a double-blind crossover study
performed in healthy adult volunteers, significant decre-
ments were detected in scores for 2 of 17 tasks after 2
weeks of valproic acid treatment compared with placebo.41
Two studies evaluated the differential cognitive effects
of low versus high valproic acid blood levels. In one study,
adult patients were tested after at least 3 months on a low
and high dose of valproic acid. On about one third of the
, tasks in the cognitive battery, patients performed signifi-
cantly worse in the high-dose (mean serum valproic acid
488 ¡.LmollL) than in the low-dose (mean serum valproic acid
184 ¡.LmollL) condition.40 A study in children with epilepsy
compared the effects of low- versus high-dose and peak ver-
sus trough valproic acid levels on cognition. Scores were
worse in the high-dose group for the majority of tasks com-
pared with the low-dose group but reached statistical sig-
nificance for only 4 of 26 tasks. In the within-patients
comparison of peak and trough effects, fewer differences
were apparent. Performance was significantly worse on only
one task during the peak compared with the trough blood-
level condition. 41
Two studies evaluated cognitive performance in newly
diagnosed children receiving valproic acid monotherapy. In
one study, 4 scores (of about 30 measured over the 12-
month period) were significantly worse than those of con-
trols at some point during valproic acid treatment The
other study found no worsening in a composite cognitive
score after 6 and 12 months of valproic acid treatment com-
pared with baseline .37 Both of these studies included a car-
bamazepine treatment group and found similar results in the
carbamazepine group and in the valproic acid group.

Four studies already described above compared the
cognitive effects of valproic acid directly with those of
other antiepileptic drugs. Valproic acid performed as well
or better than carbamazepine in three studies 21.-*11,-17 similarly
to phenytoin in one study,33 and better than phenobarbital
in two studies.22,2-4 The designs and methodologies of these
studies varied considerably.
COGNITIVE EFFECTS OF THE NEWER
ANTIEPILEPTIC DRUGS
After the arrival of valproic acid in 1978, 15 years passed
before another new antiepileptic drug became available in
the United States. In 1993, both felbamate and gabapentin
were approved Because of serious safety issues, includ-
ing aplastic anemia and hepatotoxicity,42 felbamate ther-
apy is recommended only for epilepsy cases that are
refractory to other antiepileptic drugs, and it has not been
systematically studied to determine its cognitive effects.
Gabapentin
Gabapentin is generally considered to be one of the better-
tolerated antiepileptic drugs, but it is also somewhat less
effective for seizure control.43 Its cognitive effects have been
examined in several studies; however, no study has evalu-
ated it in children, and only one study has included patients
with epilepsy. Based on these few studies, gabapentin com-
pares favorably with placebo, carbamazepine, and topiramate.
In the study of adult patients with partial epilepsy, dou-
ble-blind placebo or gabapentin therapy was added to a
stable baseline of one or two other antiepileptic drugs.
Patients were treated for 3 months at increasing dose lev-
els (up to 2400 mg/day) and then crossed over to the alter-
nate therapy after a washout period. No significant
differences were detected between gabapentin and placebo
for any tests in the cognitive battery at any time point (after
1, 2, or 3 months of treatment). 44
Three studies have compared gabapentin with carba-
mazepine in healthy adult volunteers. Two of these were dou-
ble-blind crossover studies with 5-week treatment periods:
one was performed in young and middle-aged adult volun-
teers4’ and the other in elderly volunteers.46 Both found sig-
nificant differences in favor of gabapentin in a subset of the
cognitive variables examined. The third study was a double-
blind, parallel-group design with 12-week treatment periods.
This study found equivalency between gabapentin- and car-
bamazepine-treated subjects on individual cognitive mea-
sures, but the gabapentin group performed significantly
better than the carbamazepine group on a global score sum-
marized over seven variables.’ In all three of these studies,
however, both the gabapentin and carbamazepine groups
performed more poorly on a subset of cognitive measures
when compared with a nondrug baseline.
Only one study compared gabapentin with any of the
newer antiepileptic drugs. This was a small, single-blind,
parallel-group study comparing gabapentin, topiramate,
and lamotrigine in healthy volunteers over a 4-week treat-
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S19
ment period (ii 5 or 6 per treatment group). After 4 weeks,
=
both the gabapentin and lamotrigine groups performed sig-
nificantly better than the topiramate group in one
(gabapentin) or two (lamotrigine) of the four cognitive vari-
ables measured. There were differences from a nondrug
baseline for the topiramate group but not the gabapentin and
lamotrigine groups.-48
Lamotrigine
In 1994, lamotrigine was added to the expanding array of
marketed antiepileptic drugs in the United States. 1-5 Similar
to gabapentin, only a limited number of published studies
have systematically examined the cognitive effects of lam-
otrigine. No studies have included children, and only a cou-
ple of studies evaluated patient populations. Within this
limited database, lamotrigine has not been shown to nega-
tively affect cognitive function in patients compared with
a prelamotrigine baseline and had fewer negative effects in
healthy volunteers than did topiramate or carbamazepine.
Two studies in adult patients found no cognitive changes
from baseline when lamotrigine was added to existing
antiepileptic drug therapy. One of these was a small open-
label study that included patients on two to four concomi-
tant antiepileptic drugs at baseline. After 3 months of
lamotrigine as add-on therapy, no decrease in cognitive
abilities was detected in a battery of 12 cognitive tasks.4° In
another study, lamotrigine was added to carbamazepine
monotherapy. No significant changes from baseline were
detected after 5 months of add-on lamotrigine therapy. 50
In studies comparing lamotrigine with other antiepilep-
tic drugs in healthy adult volunteers, lamotrigine had less
effect on cognitive function than either carbamazepine or
topiramate and was similar to gabapentin. A double-blind
crossover study found significantly better scores for the lam-
otrigine group on 7 of 20 cognitive tasks compared with the
carbamazepine group after 10 weeks on the drug. The car-
bamazepine group showed significant worsening from base-
line on 12 of 20 tasks; the lamotrigine group worsened on
none and improved on 1 of 20.:)1 In a study described above,
lamotrigine-treated subjects performed significantly better
than topiramate-treated subjects and similarly to gabapentin-
treated subjects after 4 weeks. Only the lamotrigine and
gabapentin groups did not worsen compared with base-
line.-48 A third study in healthy volunteers compared lamot-
rigine with valproic acid and found superiority for
lamotrigine in 2 of 16 cognitive measures 52 ; however, because
a noncomparable, subtherapeutic dose of lamotrigine was
used, these results are clinically irrelevant.
Topiramate
Topiramate received FDA approval in 1996.15 Although top-
iramate has proven to be one of the more efficacious
antiepileptic drugs,-51 it may also have a more negative
impact on cognition. Several studies (described below)
have systematically examined its cognitive effects and
reported significant negative findings. Furthermore, the
incidence of subjective reports of cognitive side effects has
S20
been high.&dquo; Slower titration of topiramate (25 mg/week) can
minimize cognitive side effects. 55
Two studies measured performance on a battery of
tests during topiramate therapy (in addition to other
antiepileptic drugs) and after topiramate withdrawal in
adult patients. One study found significant improvement after
topiramate withdrawal on 5 of 6 variables, 56 whereas the
other study detected improvement in 13 of 41 variables.&dquo; In
both studies, changes to concomitant antiepileptic drugs
were also made in some subsets of the patients, but this was
not accounted for in the analyses. Another study in adult
patients reversed this paradigm and evaluated cognitive
performance before and after topiramate was added to
baseline antiepileptic drug therapy. Three of eight cognitive
variables worsened after approximately 6 months of topi-
ramate treatment. 57 A fourth study in adult patients measured
weekly cognitive performance on two measures of attention,
whereas topiramate dose (as an add-on to one to two base-
line antiepileptic drugs) was adjusted as clinically indicated
over 12 weeks. The specifics of the tasks were varied each
week to reduce practice effects. In four of nine patients, the
topiramate dose was significantly negatively correlated
with performance on one variables. 58
Two studies compared topiramate with valproic acid as
add-on therapy to carbamazepine in adult patients. One
study was double-blinded and included a placebo group. In
this study, after 8 weeks of titration and 12 weeks on sta-
ble maintenance therapy (maximum dose 400 mg/day top-
iramate, 2250 mg/day valproic acid), the topiramate group
had significantly worse scores on 2 of 24 variables compared
with valproic acid and on 4 of 24 variables compared with
placebo.’9 In the second study, with a slower titration phase,
topiramate-treated patients performed more poorly than
valproic acid-treated patients on 1 of 10 variables after 12
weeks of maintenance therapy (target dose 200-400 mg/day
topiramate, 1800 mg/day valproic acid). 55
The only study comparing topiramate with other sec-
ond-generation antiepileptic drugs was already described
above. In this study of healthy adults, the topiramate group
performed significantly worse than the gabapentin group on
one of four measures and worse than lamotrigine on two of
four measures after a 4-week titration to 5.7 mg/kg topira-
mate, 7.1 mg/kg lamotrigine, or 35 mg/kg gabapentin. 48
Tiagabine
Tiagabine was granted US marketing approval in 1997.1’
Four studies evaluated its cognitive effects in adult patients
and found no negative effects compared with placebo or
older antiepileptic drugs (phenytoin or carbamazepine).
Two double-blind, parallel-group studies compared 12
weeks of tiagabine maintenance therapy with placebo as an
add-on medication to other antiepileptic drugs. In both
studies, cognitive scores were not different between those
patients on tiagabine versus those on placebo. In one study,
changes from baseline showed no significant differences in
any of 20 cognitive measures. 60 In the other, the placebo
group had a significantly better score on only 1 of 19 variables
Downloaded from jcn.sagepub.com at WAYNE STATE UNIVERSITY on April 13, 2015
(P < .05), which would be expected by chance. Reductions
in seizure frequency in the tiagabine group were not con-
sidered in the placebo versus tiagabine comparisons A third
double-blind study compared add-on tiagabine therapy with
placebo using a crossover design. After 7 weeks of therapy,
no differences were detected for any variables in a battery
of 20 tasks.&dquo;
Only one study compared tiagabine with other
antiepileptic drugs. In this study, patients on either carba-
mazepine or phenytoin at baseline had tiagabine, carba-
mazepine, or phenytoin added to the regimen so that all
patients were receiving two different antiepileptic drugs
for a 16-week treatment period. For patients on a carba-
mazepine baseline, comparisons of phenytoin versus
tiagabine as add-on therapy detected no differences between
these antiepileptic drugs (phenytoin =
tiagabine). For
patients on a phenytoin baseline, the tiagabine add-on group
performed better on 2 of 19 variables compared with the car-
bamazepine add-on group. 63
Levetiracetam
Levetiracetam was approved in late 1J9J15 but was not mar-
keted in the United States until 2000.~4 Levetiracetam is a
pyrrolidine derivative, and initial speculation about the drug
included a theory that it could enhance cognition, as has been
shown with some of the other pyrrolidine derivatives. 65
Unfortunately, this theory has not yet been well tested. The
only published data on levetiracetam meeting the require-
ments of this review are either subjective or from evaluations
in adult volunteers after only 8 days of treatment.
The subjective data were collected as part of a large clin-
ical trial that included a quality of life assessment (QOLIE-
31). In this double-blind study, adult patients had either
levetiracetam or placebo added to a stable antiepileptic
drug regimen for up to 18 weeks. Patient-reported cognitive
function was unchanged in the levetiracetam groups (1000
or 3000 mg/day) but worsened in the placebo group, and a
significant difference among the three treatment groups
was detected. The positive cognitive effects of seizure reduc-
tion were not accounted for in this analysis; however, a
further analysis based on seizure response found improve-
ments in cognitive scores for the levetiracetam responders,
no change for levetiracetam nonresponders, and similar
declines in scores in placebo-treated patients regardless of
response. 66
Additionally, levetiracetam (1500 mg/day), oxcar-
bazepine (1200 mg/day), and carbamazepine (800 mg/day)
were compared with placebo and baseline in healthy adult
volunteers in a small crossover study (0. Mecarelli, MD,
unpublished data, 2004). After 8 days of treatment, the car-
bamazepine group, but not the oxcarbazepine and leve-
tiracetam groups, performed significantly worse compared
with baseline on a reaction time task. The P100 latency
from color visual evoked potentials was significantly
increased in the carbamazepine and oxcarbazepine groups
(versus placebo and/or baseline). This slowing occurred
for all five stimulation patterns tested in the carbamazepine
 S21

Table 2. Overview of Cognitive Effects of Antiepileptic Drugs

AED =
antiepileptic drug; CBZ carbamazepine; ESM ethosuximide; GBP gabapentin; LEV levetiracetam; LTG lamotrigine; OXC oxcarbazepine; PB phenobarbital;
= = = = = = =

PHT =
phenytoin; TGB= tiagabine; TPM topiramate; VPA valproic acid; ZNS zonisamide; I = generally negative effects on cognition vs comparison group; T generally
= = = =

positive effects on cognition vs comparison group; - generally equal effects on cognition vs comparison group.
=

*Depending on the study, the antiepileptic drug might have been compared with placebo, a lower dose of the same antiepileptic drug, a nondrug baseline, or a nontreated
control group.
’Includes both double-blind and open-label studies of greater than 1 week’s duration.
Study subjects varied by study and included adult and pediatric subjects, normal volunteers, and epilepsy patients. Some studies were counted twice because they included
comparisons with placebo or no drug as well as comparisons with other antiepileptic drugs.

group and for two patterns in the oxcarbazepine group. Zonisamide

Levetiracetam did not significantly affect P100 latencies. All
three antiepileptic drug groups improved on an attention task
compared with placebo.
Oxcarbazepine
Oxcarbazepine was approved by the FDA in 2000.i~ Only a
few studies, none in children, have examined its cognitive
effects. Two studies evaluated oxcarbazepine in adult
patients. In one of these, newly diagnosed patients received
In 2000, zonisamide became the last of the antiepileptic
drugs to come to market in the United States. 15 Only one cog-
nitive study has been performed with zonisamide. This
small, open-label, pilot study in patients with refractory
partial seizures measured a battery of tasks at baseline and
after 3 and 6 months of zonisamide as add-on treatment. After
3 months, scores significantly worsened on about one third
of the tasks, and a significant negative correlation between
a memory quotient and plasma levels of zonisamide was

oxcarbazepine or other antiepileptic drugs as monotherapy
for 4 months. Compared with baseline, oxcarbazepine-
treated patients improved in 1 of 20 cognitive tasks and
worsened in none. Patients treated with carbamazepine,
valproic acid, phenobarbital, or phenytoin monotherapy
had similar results. The analysis did not adjust for improve-
ments in seizure frequency.67 The other study was a double-
blind comparison of oxcarbazepine with phenytoin
monotherapy in newly diagnosed patients. No differences
between oxcarbazepine and phenytoin were detected in
any of the seven cognitive variables measured at any of the
time points (baseline or after 6 or 12 months of treatment).68
A study in healthy adult volunteers examined the effects
of 2 weeks of treatment with oxcarbazepine compared with
placebo in a double-blind, crossover fashion. Multiple mea-
sures were taken over multiple time points with few sig-
nificant differences detected (two measures were better
on oxcarbazepine, one was worse compared with placebo).69
Another crossover study in healthy adults, already described
above, found worsening in P100 latencies, but improve-
ment in an attention task, in oxcarbazepine-treated patients
compared with placebo.
detected. By 6 months, scores had improved somewhat,
and differences from baseline were no longer statistically
significant.7°
CONCLUSIONS
Although many studies have attempted to measure and
compare the cognitive effects of antiepileptic drugs, the
flaws in methodology and differences across studies have
muddied the interpretation of their findings. In general, it
appears that when mean data are compared across groups,
the older antiepileptic drugs tend to perform more poorly
compared with placebo or a nondrug condition (Table 2).
When comparing older antiepileptic drugs among them-
selves, however, few differences emerge. Only phenobarbital
showed some consistency toward an inferior performance
compared with other antiepileptic drugs of its generation.
Data on the newer antiepileptic drugs are sparse com-
pared with those on the older ones. No studies that met the
requirements of this review were performed in children, and
only a few well-designed studies included patients with
epilepsy. Generalizing across the newer antiepileptic drugs,

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S22
Table 3. Neuropsychologic Battery for Assessing
Adapted from Bourgeois.8
TOVA Test of Variables of Attention; WAIS
= Wechsler Adult Intelligence Scale; WISC
= =
Wide Range Assessment of Memory and Learning.
*Most helpful.
it appears that they performed more favorably compared
with placebo or no drug than have the older antiepileptic
drugs and also performed as well or better than the older
antiepileptic drugs in the few studies that made direct com-
parisons (see Table 2). Topiramate is the exception among
the newer antiepileptic drugs, however. Most studies of
topiramate have detected significant negative changes in cog-
nition regardless of the comparator group. Data are mini-
mal for zonisamide and levetiracetam, making it difficult to
assess these two antiepileptic drugs at the current time. Sim-
ilarly, comparisons between the newer antiepileptic drugs
are also lacking. Based on a small handful of studies,
gabapentin and lamotrigine have performed similarly to
one another and better than topiramate.
In summary, a variety of factors can affect cognition in
a certain subset of children with epilepsy. Much skill is
required on the part of the clinician to elucidate these fac-
tors and mitigate those that can be influenced. The cogni-
tive impact of an antiepileptic drug is one of those factors
that potentially can be alleviated and is therefore important
to address. Clinicians should consider evaluating cognitive
function prior to adding or switching an antiepileptic drug,
and this evaluation should include neuropsychologic screen-
ing (Table 3). As evidenced by the studies reviewed here,
changes can be subtle and require thorough investigation.
Antiepileptic drugs known to have more severe cognitive
effects should be avoided in patients who might be more vul-
nerable. However, it is important to keep in mind that chil-
dren react differently to an antiepileptic drug based on their
own particular neuropathology. Findings from studies,
although helpful, usually provide perspective on the &dquo;aver-
age&dquo; patient only. Individualization of antiepileptic drug
therapy is essential. If one antiepileptic drug impairs cog-
nition, trying another antiepileptic drug with a differing
pharmacologic profile might lead to success. Most of all, it
is critical to guard against ovemedication. Slow= titration to
the lowest effective dose and avoidance of polytherapy
when possible are the keys.
Acknowledgment
I wish to thank Amy Nlorgan. PhD, for her help with Table 3.
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Effects of Antiepileptic Drugs on Cognitive Function in Children
Wechsler Intelligence Scale for Children; WMS =
Wechsler Memory Scale; WRAML =
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