Seizure (2006) 15, 235—241

www.elsevier.com/locate/yseiz

REVIEW

Cognitive side effects of anti-epileptic drugs

The relevance in childhood epilepsy
Lieven Lagae *

University Hospitals KULeuven, Department Paediatric Neurology, Herestraat 49, 3000 Leuven, Belgium

Received 14 December 2005; accepted 15 February 2006

KEYWORDS Summary In recent years several new anti-epileptic drugs have been introduced,
Cognition; also for the treatment of childhood epilepsy. A major concern is their effect on
Anti-epileptic drugs; learning and cognitive development. Testing the genuine effects on cognition of the
Childhood epilepsy; anti-epileptic drugs is methodologically not easy. At this moment there are very few
Neuropsychology; controlled trials that systematically examine the cognitive side effects of anti-
IQ; epileptic drugs in childhood epilepsy. The available data indicate that the newer
Development anti-epileptic drugs have a safe cognitive profile when prescribed correctly at the
right dose and in monotherapy. Possible negative effects are mainly found for speed of
processing and attention processes. As these processes are important instruments in
every day learning and cognition, it is necessary to test these newer anti-epileptic
drugs in well designed studies and in specific childhood epilepsy syndromes.
# 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Introduction with refractory epilepsy, a normal IQ was found.1

In clinical practice, it is well known that many
children with epilepsy have cognitive problems,
ranging from mild learning and school problems to
mental retardation or even mental decline.
Although these problems are also encountered in
adults with epilepsy, the impact of epilepsy on
developing cognitive processes is likely to be more
prominent. The proportion of children with cogni-
tive problems is higher in refractory epilepsy than
in well controlled epilepsy. This already points to
the possible deleterious effect of the epileptic
process itself on cognitive development. In a recent
paper, it was shown that only in 16% of the children
* Tel.: +32 16343845; fax: +32 16343842.
E-mail address: Lieven.Lagae@uz.kuleuven.ac.be.
This is in contrast with the data of a pivotal and
rather reassuring study by Ellenberg et al. in a group
of normal children with easier to treat epilepsy. At
the age of 7 years, there was no IQ difference
between epileptic children and their siblings, but
only if there was no pre-existing mental retardation
before the start of the epilepsy.2
Several non-independent factors and each to a
variable extent contribute to the possible cogni-
tive problems in epilepsy but are very difficult to
study separately.3 Probably the most important
determinants are the epileptic process itself and
the underlying brain dysfunction/pathology. Symp-
tomatic epilepsy has a worse outcome than idio-
pathic epilepsy.4 The unique contributions of the
epilepsy-related factors, such as the age of onset,5
type of seizures and epilepsy syndrome, frequency

1059-1311/$ — see front matter # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.seizure.2006.02.013
236
of seizures and epileptic abnormalities on the
EEG are more difficult to disentangle.6 It is the
combination of the underlying brain dysfunction
with an epileptic syndrome at a certain age that
explains the cognitive profile. For example, tuber-
ous sclerosis is highly associated with infantile
spasms in infancy and if these seizures are not
well controlled, many of these children become
mentally retarded and autistic.7 Children with TS
but without infantile spasms at the critical age
have a better prognosis, as well as children with
idiopathic infantile spasms. Another nice example
illustrating these complex interactions is shown in
the paper of Helmstaedter et al. They showed
(in adults) that long lasting (and especially left)
temporal lobe epilepsy is clearly associated with
memory decline, and that this decline could
be stopped after resection of the dysfunctional
hippocampal structures, but only if there was
complete seizure control after the resection.8
Another factor to consider is the psychosocial
environment and educational/school system. It
should be realized that even in 2006, in some
countries, epilepsy is a reason not to send the
children to school, of course increasing the risk for
cognitive problems.
This short review deals with the effects of the
newer anti-epileptic drugs on cognitive function-
ing. It is actually surprising that only recently this
problem has been fully recognized and perhaps
already over-emphasized. A major historical step
in this respect was the setting-the-scene papers
of phenobarbital and its effect on IQ in febrile
seizures.9,10 Long term use of phenobarbital as
preventive medication for febrile seizures was
shown to decrease the IQ-levels, even after dis-
continuation of the drug. This paper was also influ-
ential because it introduced the measurement of
IQ as a major determinant in cognitive studies.
Although IQ remains an interesting and global mea-
sure, it does not allow precise studies of specific
cognitive processes; it only gives a rough estimate
of academic potential.
With the introduction of several new anti-epilep-
tic drugs, with more or less similar efficacy, the
side effect profile and especially the cognitive
and behavioural safety are becoming discriminating
factors when prescribing these drugs. Unfortu-
nately, cognitive safety is not yet a major issue in
the classic randomized controlled trials. In addition,
and this will also be illustrated in this review, it is
very difficult to design a powerful study that unam-
biguously will show the negative or positive cogni-
tive effects of anti-epileptic drugs. Here again, the
non-independency of AEDs, epilepsy syndrome and
brain dysfunction are at play.
L. Lagae
Methodological issues
Already in 1995, Vermeulen and Aldenkamp system-
atically reviewed the potential methodological
problems when studying cognitive processes in epi-
leptic patients. These principles are still valid and
can now be focused more on childhood epilepsy.11
If one wants to study the cognitive effects of an
anti-epileptic drug, it seems logical that this would
be done first in normal non-epileptic subjects. How-
ever, only short term exposure is feasible in non-
epileptics and this will therefore not reflect the
cognitive side effects after prolonged administra-
tion of the drug. Long term and preferentially
monotherapy trials are ideal. More importantly, a
drug should theoretically be tested in well defined
epilepsy syndromes with ‘as homogeneous as possi-
ble’ patient populations. An anti-epileptic drug
theoretically can induce different cognitive effects
in different epilepsy syndromes. For instance, it is
known that frontal epilepsy in a child is more prone
to attention problems12; if this epilepsy would
be treated with a drug with known effects on atten-
tion processes, the attention problems in this child
could become worse, and will indeed over-empha-
size the negative attention side effects of the drug.
In addition, children of different ages are suscep-
tible to different effects of the anti-epileptic drugs.
A similar dysfunction of the attention system at the
age of 4 years can cause other problems in a child of
8 years, even if both children are known with the
same epilepsy syndrome.
Another major pitfall is the seizure frequency.
Studying cognitive effects of an AED after a convul-
sive seizure will certainly influence the cognitive
profile.13 It has been shown that several days after
a seizure, subjects were still not at their cognitive
baseline. Seizure-free patients are therefore the best
candidates for cognitive studies. Along the same line,
and this has received considerable attention in the
last few years, is the effect of ‘subclinical’ epileptic
EEG discharges, which can cause substantial perfor-
mance differences during cognitive testing.14,15 One
can therefore argue that optimal cognitive testing
should always be performed under EEG guidance.16
An underestimated problem is drug dosages and
more specifically drug blood levels. Clinicians do
realize that for optimal seizure control, a drug
blood level is often a bad guide, especially since
we do not understand the exact relationship
between blood and brain levels of the drug. How-
ever, for cognitive issues, drug dosages are perhaps
much more important.17,18
In a way, it seems that two study designs are
optimal, but both are difficult to perform at large
scale:
Cognitive side effects of anti-epileptic drugs 237

- Long term monotherapy in seizure-free patients Table 2 Leuven cognitive battery

with well defined epilepsy: comparison between
Intelligence WPPSI-R, WISC-R
pre-treatment and treatment period. In some
Attention and TEA-Ch, Tower
(benign) epilepsies, double blind cross-over with executive functions
placebo is possible.
- Monotherapy withdrawal study in seizure-free Memory
Verbal AVLT; numbers, stories,
patients.19
word pairs (CMS)
Non-verbal Pictures, dot location,
family scenes, faces (CMS);
Cognitive testing complex figure (ROCF DSS)
Language Boston Naming Test, Token
Several neuropsychological ‘batteries’ can be used
Test, Word Fluency
to study cognitive functions and the influence of
Visual/spatial Developmental Test of Visual
anti-epileptic drugs. Because testing is time con- Motor Integration (VMI)
suming and not every cognitive process can be Motor Purdue Pegboard Test
tested in detail, it is very important to select the
Checklists Child behaviour checklist
most appropriate tests and this should be a hypoth-
(parents), youth self report
esis-driven process. Most batteries therefore are a
(YSR), everyday memory
compromise. However, one should be aware of some questionnaire
basic principles in neuropsychology. One can of
AVLT: Auditory Verbal Learning Test; CMS: Children’s Memory
course define the most important cognitive pro- Scale; ROCF DSS: Rey Osterrieth Complex Figure Developmen-
cesses (Table 1, left column), but here also these tal Scoring System.
categories are not independent. Actually, one can
make a distinction between basic cognitive ‘instru-
ments’ (attention processes, working memory, cog- when you compare their results with age-matched
nitive speed, etc.) and more specific processes controls. To overcome this problem, one can com-
(visuospatial abilities, language, etc.) (Table 1, pare the test results of the patient with the ‘mental
right column). The underlying idea is that one needs age’ instead of the ‘chronological age’. Mental age
the ‘instruments’ to perform normally on the more can be deduced from the non-verbal or verbal IQ.
specific tasks. Therefore, it seems logical that a For instance, a 10-year-old child with a non-verbal
cognitive test battery should at least contain testing IQ of 75 approximately performs at a mental age of
of processing speed and attention. Another metho- 7.5 years and his test results in the specialized
dological remark has to do with the scoring of the neuropsychological batteries should therefore be
tests. Normally, scores are compared with age- compared with 7.5 years controls.20,21 This metho-
appropriate norms and expressed as a z-score or dology allows finding of specific neuropsychological
percentile. However, in mentally retarded children, dysfunctions in one or more domains even in globally
it will be difficult to find specific neuropsychological retarded patients.
dysfunctions: they will perform badly on most tests In Table 2, an example is given of a rather exten-
sive neuropsychological battery that is now being
Table 1 Neuropsychological processes used in our centre for different cognitive studies.
To gain time, we ask the ‘Centre of Student Gui-
 Sensory processing/

}
dance (CLB)’ which is present in every school to
perception
perform an age appropriate IQ test; the more spe-
 Attention/concentration
Cognitive instruments cific tests are done in our centre.
 Speed of processing
 Working memory
 Psychomotor speed Working mechanism of the anti-epileptic
drugs and cognitive profile
 Visuospatial abilities

}
 Problem-solving
 Non-verbal memory
 Verbal memory
 Motor control/
performance
 Verbal reasoning
 Imagery
 General intelligence IQ
In a recent paper by Sankar and Holmes, animal
studies are reviewed that addressed the cognitive
Specific processes side effects of anti-epileptic drugs.22 Theoretically,
knowing the exact working mechanism and the site
of action of anti-epileptic drugs, it should indeed be
possible to predict the type of cognitive side effects
Academic potential of an anti-epileptic drug. Two problems however
arise. First of all, we do not understand the exact
238
working mechanism of all anti-epileptic drugs. It is
not because we know that a drug is working on a
sodium channel, that we automatically understand
why this drug is working in a particular epilepsy
syndrome. Regional and temporal differences of
the expression of this sodium channel in specific
excitatory and inhibitory neurons, for instance, are
a possible reason for the discrepancies we see in
clinical practice. Second, testing cognitive pro-
cesses in rodents, although valuable, remains at a
more rudimentary level with difficult extrapolations
to human cognitive processing.
Nevertheless, some interesting general conclu-
sions can be drawn from this sort of studies. It
appears that sodium channel acting drugs are asso-
ciated with the least amount of cognitive side
effects, while the risk is greatest in drugs with
gabergic action. Gabergic drugs especially influence
vigilance and attentional processes. Anti-glutama-
tergic drugs are more associated with effects on
learning and memory, especially those drugs that
work on the NMDA receptor. Recently, a totally new
type of working mechanism was found in levetira-
cetam. This drug binds to a synaptic vesicle SV2A
and influences the release of several neurotransmit-
tors.23 At this moment, we do not know which
cognitive processes are possibly influenced by this
‘synaptic modulator’, but it underlines the com-
plexity and the inherent risk for too fast and too
simple conclusions in this field.
Comparing older and newer anti-epileptic
drugs
Several excellent reviews are available that
describe the cognitive side effects of the older
and newer anti-epileptic drugs.3,18,24—27. Although
several methodological problems were not dealt
with in the studies on the older anti-epileptic drugs,
some robust findings were reproduced in most stu-
dies, so that some general conclusions are valid.
Also, they provide the background against which the
effects of the newer anti-epileptic drugs should be
compared.
It is clear that all the older drugs can induce
psychomotor slowing, a basic cognitive instrument
(see Table 1), and this to a variable extent.
This was, for instance, nicely illustrated in the
Holmfrid withdrawal study.19 Psychomotor slowing
is generally measured in reaction time studies and
anti-epileptic drugs typically induce a 100—200 ms
increase of reaction time. Although most authors
stress that these effects are minimal, this
reaction time increase can be very critical in some
natural situations and especially during learning
situations.
L. Lagae
Typically, phenobarbital, phenytoin, carbamaze-
pine and valproate are considered as ‘older’ anti-
epileptic drugs. As already mentioned in the Intro-
duction, long term use of phenobarbital in children
is associated with a decrease in IQ.9,10,28 Although
the decrease is usually lower than 10 IQ points,
for some children ‘on the edge’, this decrease
might be substantial. Subsequent use of phenobar-
bital has therefore dramatically decreased in
recent years, no studies have examined the neu-
ropsychological nature of this IQ decrease. In adults
too, phenobarbital has been shown to induce
more cognitive side effects than carbamazepine
and phenytoin.29,30
In general, phenobarbital is worse than valproic
acid and carbamazepine.31,32 However, it should
also be mentioned that in an open label study in
children with well controlled seizures, no IQ differ-
ences were found between the phenobarbital, car-
bamazepine and valproate group.33 In another
study comparing phenytoin, carbamazepine and
valproate in childhood epilepsy, it was shown that
only minimal changes were seen in the phenytoin
group. In this study, carbamazepine treated
children performed worse than valproate treated
children, especially on memory tasks.34 Although
the methodology was certainly not always compar-
able, different studies have shown that carbama-
zepine was better than or equal to phenobarbital
and phenytoin. Comparison of phenobarbital
and phenytoin with valproate yielded variable
results.33—35
Actually, for all these older drugs some adverse
cognitive side effects have been described in child-
hood epilepsy and phenobarbital seems to be the
worst drug in this respect.
In the following paragraphs, the most commonly
used newer anti-epileptic drugs are discussed in
more detail: topiramate, lamotrigine, oxcarbaze-
pine and levetiracetam.
Topiramate
Topiramate is an effective broad spectrum anti-
epileptic drug that is being used frequently in sev-
eral childhood epilepsy syndromes, including some
of the more catastrophic epilepsies, such as the
Lennox Gastaut syndrome. Studies in healthy adult
volunteers have shown that topiramate induces
general mental slowing, psychomotor speed reduc-
tion and concentration problems, illustrating a gen-
eral effect on the cognitive instruments.36 These
effects were also dosage dependent.37 It should be
noted that dosage for topiramate in the first regis-
tration studies was substantially higher than that
Cognitive side effects of anti-epileptic drugs
obtained nowadays in clinical practice. This might
have over-emphasized these negative cognitive
side effects. A postmarketing study confirmed that
cognitive complaints (especially psychomotor slow-
ing) were the primary reason for discontinuation of
the drug but also that, overall, most patients con-
tinued the medication because of its efficacy. In this
study, no specific dosage escalation or final dosage
was associated with a greater risk for cognitive side
effects.38
In epilepsy patients, topiramate also had an
effect on memory and on word fluency, verbal
processing and verbal IQ.39,40 Especially, this latter
effect is unique and still mis-understood. Verbal
memory, verbal fluency and verbal learning were
all shown to be influenced by topiramate. This side
effect is not seen with other anti-epileptic drugs
and could not be predicted directly from animal
studies. In one study, it was estimated that up to
one third of the patients showed word finding
problems.41 At this point, there is no satisfactory
explanation for this effect. As verbal functions
involve the fastest circuits in the brain, one could
hypothesize that topiramate preferentially affects
these circuits.
In children, no systematic studies on cognition
and topiramate have been performed yet. Moreland
et al. showed that about 20% of epileptic children
displayed decreased cognition, however without
any further explanation.42
Lamotrigine
Also, for this anti-epileptic drug, no systematic
studies on cognition in children are available.
As this drug is a rather specific sodium channel
blocker, animal studies predict few cognitive side
effects.22 Indeed, in adult volunteers, no differ-
ences with placebo were found and Aldenkamp
et al.43 and Meador et al.44 even showed positive
effects on some cognitive functions. This was con-
firmed in adult epilepsy patients.36,45—47 For
instance, Smith et al. showed that add-on lamotri-
gine was not associated with adverse cognitive
effects in 81 patients with refractory epilepsy.45
In some studies it was shown that lamotrogine
was able to improve cognitive functioning in refrac-
tory epilepsy in children, sometimes irrespective of
seizure control. This was also shown in mentally
retarded children and adults, although effects
were not always measured quantitatively.48—52
However, one should be careful with this sort of
findings and not be tempted to call this a genuine
psychotropic drug too early. An obvious explanation
could be that this drug decreases the amount of
239
background EEG epileptic activity and therefore
improves basic cognitive possibilities. Overall,
there are no studies in adults that show a negative
cognitive effect of lamotrigine. Therefore, the
conclusion of a recent review by Aldenkamp and
Baker was that lamotrigine was a safe drug at the
cognitive level.53
Oxcarbazepine
Oxcarbazepine is also a sodium channel blocker but
has a narrower spectrum than lamotrigine. It is
especially suited for partial epilepsy syndromes
and is related to carbamazepine but tolerability
and side effect profile are said to be better than
carbamazepine. Again, it is surprising that no spe-
cific cognitive studies in children have been pub-
lished. Curran and Java already in 1993 showed that
oxcarbazepine induced a positive effect on atten-
tion and motor speed in healthy volunteers.54 In
adult epilepsy patients, the drug did not show any
specific cognitive side effects.55—57 Sabers et al.
showed a positive effect on learning and psychomo-
tor speed. In children, the study of Serdaroglu
et al.58 showed that only ‘drowsiness’ was reported
as a possible ‘cognitive’ side effect. Overall, and as
expected, oxcarbazepine seems to be similar in its
cognitive safety as lamotrigine.
Levetiracetam
Levetiracetam is the newest anti-epileptic drug in
most countries and is already widely used in child-
hood epilepsy. It has a broad spectrum profile and is
unique in its working mechanism: levetiracetam
binds to a pre-synaptical SV2A protein and modu-
lates neurotransmitter release.23 Few studies on the
cognitive side effects are available yet. Cramer
et al.59 showed in a large study in adults with
epilepsy that levetiracetam did not differ from
other AEDs in the reported frequency of anxiety,
emotional lability and nervousness. However, no
specific cognitive processes were measured. The
study of Neyens et al.60 showed a positive effect in
cognitive tests in levetiracetam responders and no
difference from placebo in non-responders. Here
again, it is difficult to disentangle seizure reduction
effects on cognition from drug dependent effects.
In this small study, levetiracetam treatment
induced improvement in reaction time, tapping
rate of the non-dominant hand and memory for
simultaneously presented words. In children, acute
psychosis has been described in one,61 but not in
other publications on childhood epilepsy.62
240
Conclusion
It should be clear from this overview that we need
well designed studies in childhood epilepsy that
address the potential cognitive side effects of
anti-epileptic drugs in children. We should be care-
ful to extrapolate the existing data in adults to
children. Minor cognitive side effects in adults
could cause significant learning and cognitive
effects in children. In addition, the existing studies
in adults still suffer from different methodological
flaws, and definite conclusions are therefore diffi-
cult to draw. In general however, the available
data indicate that the newer anti-epileptic drugs
are safer at the cognitive level than the older ones,
and this could become a discriminating factor in
prescription habits.
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