CNS Drugs 1996 May; 5 (5): 358-368

1172-7047/96/0005-0358/$05.50/0

ADVERSE EFFECTS

Adls International Limited. All rights reserved.

Cognitive Adverse Effects of

Antiepileptic Drugs
Incidence, Mechanisms and Therapeutic Implications
Reetta Kiilviiiinen, 1 Marja A.ikiii 1 and Paavo J. Riekkinen Sr 2
1 Department of Neurology, University Hospital of Kuopio, Kuopio, Finland
2 A.l. Virtanen Institute, University of Kuopio, Kuopio, Finland

Contents
Summary
.................................... .
1. Cognition and Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Antiepiieptic Drugs and Cognitive Function: Overview and Mechanisms
3. Effect of Standard Antiepileptic Drugs on Cognitive Function .
3. 1 Early Studies . . . . . . . . . . . . . . . . . . . . . . . . .
3.2 Recent Studies and Re-evaluations . . . . . . . . . . .
4. Effect of Newer Antiepileptic Drugs on Cognitive Function
4. 1 Felbamate . .
4.2 Gabapentin . .
4.3 Lamotrigine . .
4.4 Oxcarbazepine
4.5 Remacemide
4.6 Tiagabine .
4. 7 Topiramate
4.8 Vigabatrin .
4.9 Zonisamide
5. Therapeutic Implications and Conclusions

Summary

358
359
359
359
359
360
362
362
362
363
363
363
364
364
364
365
365

Several early studies suggested that differences exist between antiepileptic

drugs (AEDs) in terms of their propensity to cause adverse effects on cognitive
functions, favouring carbamazepine over phenobarbital (phenobarbitone), phenytoin
and valproic acid (sodium valproate). The combined results of recent studies in
patients and healthy volunteers reveal that at therapeutic serum concentrations
phenobarbital, phenytoin, carbamazepine, oxcarbazepine and valproic acid produce nearly comparable adverse effects on higher cognitive functions.
The newer AEDs (with the exception of zonisamide and topiramate) appear
to induced fewer cognitive adverse effects than the older agents. Furthermore,
there is limited evidence that gabapentin, lamotrigine and vigabatrin may have
beneficial effects on cognitive function. Some of the newer AEDs may also have
neuroprotective effects that can prevent seizure-induced neuronal damage, and
so reduce cognitive dysfunction. This is an important clinical consideration, as
even modest differences between older and newer AEDs are relevant for patients.

359

Cognitive Adverse Effects of Antiepileptic Drugs

1. Cognition and Epilepsy

Cognition is defined as the ability of a person to
use information about and from the environment in
an adaptive manner.1 11The evaluation of cognitive
functions plays an important role in assessing epileptic seizure disorders, because in these conditions,
by definition, the brain is dysfunctional.l 21Both epileptic seizures and the interictal epileptiform discharges may potentially cause structural brain damage and cognitive disturbancesPI Significant numbers
of patients with epilepsy have been shown to have
interictal impairment of specific cognitive functions,
such as memory, attention and speed of mental processing, compared with healthy controls.1 471However, there are various pathological, physiological
and pharmacological features that may cause this
cognitive disturbance rather than the epileptic process per se.l 8 1Thus, in the interpretation of studies
on cognition in epilepsy several confounding factors must be taken into account, including:
the aetiology and duration of epilepsy
seizure frequency and type
subclinical seizures
postictal state
antiepileptic drugs (AEDs)
various environmental, social and psychodynamic
factors.

2. Antiepileptic Drugs and Cognitive

Function: Overview and Mechanisms
The general opinion in the literature is that standard AEDs impair cognitive functions in epileptic
patients, as well as in healthy individuals. This occurs very diffusely through effects on memory, sustained attention and mental and motor speed.l 9- 14 1
However, there is also evidence that, even with a
moderate reduction in the dose or the number of
AEDs administered, cognitive abilities improve in
a circumscribed manner for those functions that are
represented by the areas having the most significant
pathological substrate.l 15 16 1These findings suggest
the possibility of selective effects of AEDs on cognitive functions.
On the other hand, the use of AEDs in a patient
with epilepsy may (and in an ideal case, it should)
Adis International Limited. All rights reserved.

also exert a beneficial effect on cognition by controlling seizures and subclinical epileptiform discharges. In addition, an ideal AED should prevent
further epileptogenesis and progression of neuronal damage and, hence, cognitive dysfunction.
The mechanisms by which AEDs produce interictal cognitive impairments are presumed to reflect
their direct actions in the brain. However, AEDs
also have numerous systemic effects, such as endocrine and metabolic effects, that can indirectly influence cerebral function.1 8 1
When AEDs are used in the usual therapeutic
range, the immediate cognitive adverse effects may
be subtle.l 91However, this does not diminish their
importance. Moreover, both animal and human
studies indicate that a variety of AEDs may adversely affect the developing CNS.I 1718 1As it is now
recognised that long-lasting structural and functional plasticity in response to neural activity also
occurs in adults,l31 the long term, irreversible effects of AEDs may not be limited to the developing
brain.

3. Effect of Standard Antiepileptic

Drugs on Cognitive Function
3. 1 Early Studies

It was only after the early 1970s that emphasis

was placed on the cognitive adverse effects associated with the use of AEDs.1 191 Polytherapy with
standard AEDs was shown to increase the risk of
these adverse effects.l 2021 1In general, more severe
cognitive adverse effects were shown to be associated with higher blood concentrations of standard
AEDs.l22-241
By the early 1980s, several investigators had
started to emphasise the importance of cognitive
adverse effects in determining drug choice. One of
the most important studies leading to this change
in attitudes was that by Dodrill and Troupin.1 25 1
They found that phenytoin and carbamazepine did
not differ in efficacy, but significant differences in
favour of carbamazepine were observed on 4 cognitive measures and I personality measure from a
total of 35 neuropsychological tests. The authors
CNS Drugs 1996 May; 5 (5)

360

concluded that while the majority of tests failed to

identify differences between the 2 drugs on neuropsychological functions, carbamazepine treatment
was associated with fewer errors on mental tasks
that required attention and problem solving and an
improvement in emotional status. These properties
supported the use of carbamazepine as the AED of
choice in several seizure disorders.
These results were supported by a large series
of studies carried out at the national hospitals in the
UK:!1 4,24,26,27J the effects of phenytoin, carbamazepine, valproic acid (sodium valproate), clonazepam
and clobazam were evaluated in volunteers using a
neuropsychological test battery. Some significant
deficits of performance were recorded for all drugs,
but impairments were most marked following the
use of phenytoin and clonazepam. Administration
of phenytoin in the therapeutic range resulted in
impairments on measures of memory and mental
and motor speed. Clonazepam impaired mental
speed, central cognitive processing ability, memory
and perceptuomotor performance.
Andrewes et al.l 28 l compared cognitive performance in new referrals with epilepsy (who were well
controlled on either phenytoin or carbamazepine
monotherapy) and an untreated control group. In
this study, 32 statistical comparisons were performed, 3 of them favouring carbamazepine and 1
favouring phenytoin. In the first large Veterans Administration Cooperative Study,!7l which enrolled
622 recently diagnosed patients, it was only after
the total behavioural toxicity battery was calculated that the cognitive adverse effects of carbamazepine were observed to be less than those of
phenytoin, phenobarbital (phenobarbitone) and
primidone.
3.2 Recent Studies and Re-evaluations

On the basis of the studies cited in section

3.1,!7,14,251 in the early and mid 1980s the use of
carbamazepine was favoured, especially over phenytoin. In late 1980s and early 1990s, however, it was
noted that many of the earlier studies suffered from
methodological problems. !9-11 1 More adequate designs and reanalyses of the early studies have
Adis International Limited. All rights reserved.

Kiilviiiinen et al.

shown that the differential cognitive effects of

AEDs are subtle.
In the first Veterans Administration Cooperative
Study (see section 3.1 ),171 examination of the raw
data (the means and standard deviations) for the
neuropsychological tests of each AED group revealed no significant trend among carbamazepine,
phenytoin, phenobarbital and primidone during the
follow-up.l 2930 1 However, in this study none of the
drug-treated groups showed improvement in scores
related to practice effects, whereas practice effects
could be seen in several tests in the matched control
group. The lack of a practice effect may be the first
indicator of an effect of AEDs on cognition. In
these studies, the serum concentrations of AEDs
remained in the therapeutic range. These results
suggest that all 4 AEDs studied have some adverse
effect on cognition even at therapeutic concentrations,l7l and it was later emphasised that even
carbamazepine seems to prevent normal practice
effects) 13 1
Psychomotor performance was compared in
healthy individuals, untreated patients with epilepsy and patients receiving long term AED therapy)5l Drug-treated patients performed worse than
either untreated patients or controls on choice reaction time, card sorting, a short term memory task
and finger tapping. Patients receiving carbamazepine, phenytoin or valproic acid monotherapy performed similarly to each other and to those patients
receiving polytherapy.
Duncan et aU 31 1 evaluated possible differential
effects of the removal of phenytoin, carbamazepine
and valproic acid on cognitive function. All 3
AEDs adversely affected simple motor skills to a
similar degree. Performance on 1 measure of attention and concentration improved in patients treated
earlier with phenytoin, and did not alter with the
removal of carbamazepine or valproic acid. This
test was, however, only 1 out of 64 performed.
Gillham et al.l 321 studied cognitive function in
adult epileptic patients established on monotherapy
with carbamazepine, phenytoin or valproic acid. No
individual test discriminated between the drugs. It
was only with composite memory and psychomotor
CNS Drugs 1996 May: 5 (5)

Cognitive Adverse Effects of Antiepileptic Drugs

scores that some differences were seen. The patients receiving phenytoin performed less well on
composite memory score and those receiving
carbamazepine less well on composite psychomotor score than controls or valproic acid recipients.
In 1989, Dodrill and Temkinl 33 1reanalysed their
earlier work of neuropsychological data in 70 adult
patients receiving phenytoin monotherapy.l 221 Initially, significant differences favoured the low serum
concentration group over the high serum concentration group in neuropsychological performance.
However, when a simple measure of motor speed
was covaried out, all statistically significant differences between the groups disappeared. In 1991,
Dodrill and Troupinl 341 reanalysed another of their
earlier worksl 25 1 by eliminating patients with
phenytoin concentrations greater than 30 mg/L (today's standard therapeutic range is 10 to 20 mg/L).
The statistical significance of all neuropsychological differences between carbamazepine and phenytoin disappeared. Dodrill and Wilenskyl 351 reported
detailed neuropsychological evaluations on 198
adults before and after 5 years of stable AED therapy. In this study, there was no evidence for insidious cognitive losses with phenytoin and other
AEDs over time with normal therapeutic serum
concentrations and in the absence of active seizure
disorders.
The second Veterans Administration Cooperative
Studyl361 compared the effects of carbamazepine
and valproic acid in patients with recently diagnosed
partial epilepsy. The impact of carbamazepine and
valproic acid monotherapy on cognitive functioning was similar, and both AEDs produced minimal
negative effects in comparison with pretreatment
baseline performance.
In contrast, Forsythe et aJ.l 371 found some tendency for harmful effects of carbamazepine on
memory tasks and on tasks with a strong visuomotor
component when they investigated children with
new-onset seizures. The patients were randomly
assigned to carbamazepine, phenytoin or valproic
acid. Whereas valproic acid was significantly better than carbamazepine, phenytoin was not significantly different from the other 2 AEDs.
Adis lnternafional Limited. All rights reserved.

361

The cognitive effects of phenytoin have been

evaluated when the drug is used as prophylaxis
against post-traumatic epilepsy. The study was a
randomised, placebo-controlled design and included
244 patients.l 38 1 On the basis of the results of this
study, it was concluded that phenytoin has cognitive adverse effects compared with no-drug conditions. The investigators argued that the use of phenytoin for seizure prophylaxis should be seriously
questioned after the first week since it does not
prevent the development of post-traumatic epilepsy
and has adverse effects.
The cognitive effects of phenytoin and carbamazepine have also been evaluated when used as
prophylactic AED therapy after brain injury in a
double-blind, placebo-controlled study of 82 patients.l391 The results of the study indicated that
both drugs had some negative effects on cognitive
functions, especially those with significant motor
and response speed components. In this study,
carbamazepine appeared to have a slightly greater
negative effect on higher-level skills in the braininjured population, as judged by its effect on verbal
fluency, verbal and visual memory, and more complex attentional tests.
Meador et al.l 40-43 1have performed randomised,
double-blind crossover studies using an extensive
neuropsychological battery both in patients and in
healthy volunteers. At first, they compared the effects of carbamazepine, phenobarbital and phenytoin for 3 months each in 15 patients with partial
complex epilepsy.l 401The patients had comparable
neuropsychological performance on each AED
studied. Carbamazepine and phenytoin were compared in a study of healthy adults with 1-month
follow-up.l 41 1 When blood AED concentrations
were employed as covariates, there were only 2 significant differences between the drugs, one favouring carbamazepine and the other favouring phenytoin. On the other hand, several tests showed mild
deterioration comparing either drug with nondrug
conditions, although not in the memory tasks. The
next study used a different, perhaps more demanding, verbal memory task and the performance was
CNS Drugs 1996 May; 5 (5)

Kiilviiiinen eta/.

362

impaired by both AEDs, but still the effect of the 2

AEDs did not differ.1 42 1
In the most recent of their studies, Meador et
aJ.1 43 1compared phenobarbital, phenytoin and valproic acid in 59 healthy adults. More than one-half
of the variables exhibited AED effects compared
with nondrug baselines, and all 3 AEDs had some
untoward effects. Differential AED effects on cognition were present for approximately one-third of
the variables. Phenobarbital produced the worst
performance, whereas there was no difference between phenytoin and valproic acid.
In summary, earlier studies contrasted the more
detrimental effects of phenytoin, phenobarbital and
clonazepam with the lesser detrimental effects of
carbamazepine and the intermediate effects of
valproic acid.1 14 1Most of the recent well controlled
clinical studies are consistent with the following conclusion: when used at serum concentrations in the
therapeutic range, all standard AEDs cause comparable and rather subtle cognitive adverse effects.1 10 11 1
On the other hand, all standard AEDs have doserelated adverse effects on cognition, but individual
variability in tolerating different doses is great.1 9 1

4. Effect of Newer Antiepileptic Drugs

on Cognitive Function
Standard AEDs are unable to control seizures
in as many as 30 to 50% of patients with epilepsy.144.451 In addition, all standard AEDs are associated with frequent adverse effects, which necessitate withdrawal of the drug in about I 0% of
patients.l 44 .451 Furthermore, most of the standard
AEDs possess only antiseizure effects rather than
antiepileptogenic effects in a kindling model of epilepsy or human post-traumatic epilepsy.1 44 .451Few
of these drugs have neuroprotective effects.l 44 45 1
The clinical need for new AEDs is therefore
clear, and during the past I 0 years more than 20
agents have reached clinical evaluation or have
been marketed.1 44 45 1

4. 1 Felbamate
In addition to antiseizure effects, felbamate has
been shown to have a neuroprotective effect in an Adis International Limited. All rights reserved.

imal models of hypoxic-ischaemic injuries and status epilepticus.1 46 -48 1However, early clinical experience was associated with an unacceptably high
incidence of aplastic anaemia,1 49 1 and immediate
withdrawal of patients from treatment with felbamate was recommended in 1994. Nevertheless,
many patients have benefited significantly from
this drug and continue to receive it despite the currently known risks. All clinical trials were, however, stopped and, therefore, the cognitive effects
of the drug have not been adequately investigated.

4.2 Gabapentin
Gabapentin has several advantages as a new AED.
It has a wide safety margin and it appears to be
unusually well tolerated during long term administration .1 50 1
Early evaluation of the cognitive effects of
gabapentin suggested that it might have limited adverse, and even beneficial, effects on cognition.l 51 1
Dodrill et aJ.l 52 1compared the cognitive effects of
gabapentin with those of carbamazepine and a
combination of gabapentin and carbamazepine in
15 healthy individuals. At the end of each drug
treatment period, patients were tested for neuropsychological and psychosocial effects and effects
on mood. The results of this study suggested that
gabapentin has limited or no adverse effects on
cognitive function and might be associated with
improved performance on measures of memory
and attention.
At present, data concerning the cognitive effects
of gabapentin in patients with epilepsy are limited.
In at least 3 long term studies using gabapentin as
add-on therapy, patients have reported improved
well-being and cognitive functioning.1 53 -55 1 The
potential cognitive effects are currently being evaluated in a double-blind, dose-controlled, multicentre clinical trial evaluating conversion to
gabapentin monotherapy, and in an open-label extension study.l 56 1Preliminary data show that all 12
significant changes reported so far were in the direction of improvement during gabapentin treatment. Further studies comparing gabapentin with
standard AEDs as monotherapy are needed.
CNS Drugs 1996 May; 5 (5)

363

Cognitive Adverse Effects of Antiepileptic Drugs

4.3 Lamotrigine
Lamotrigine reduces glutamate release by acting on sodium channels. It has not been tested extensively in kindling models, but it does not block
or delay the rate of development of frontal cortical
kindling in rats.l 57 1 Lamotrigine protects against
kainate-induced neurotoxicityl 58 1and against focal
cerebral ischaemia.1 59 1
Human volunteer studies suggest that at therapeutic doses Iamotrigine causes less impairment of
psychomotor function than diazepam, carbamazepine and phenytoin.1 6061 1 In healthy young volunteers and elderly individuals with age-associated
memory impairment,I 62 1Jamotrigine caused significant prolongation of auditory event-related potential latency and attenuation of potential amplitude, suggesting an increase in cortical arousal. In
the same study lamotrigine improved simple memory function, probably owing to a practice effect;
however, no effect was seen on mental attention.
However, lamotrigine slowed simple psychomotor
speed (finger tapping).
In a randomised, controlled, double-blind trial
of add-on lamotrigine therapy,l 63 1no difference between placebo and lamotrigine therapy was demonstrated on a small battery of 3 neuropsychological tests measuring concentration, psychomotor
performance and repetitive mental activity. The study
did not include any evaluation of memory functions.
In this study, lamotrigine therapy was also associated with improved scores in quality-of-life measures. A sense of well-being has been reported frequently by patients on lamotrigine.1 64 1
In recent large monotherapy trials, lamotrigine
produced fewer CNS-related adverse effects than
carbamazepine or phenytoin;1 65 66 1 however, no formal neuropsychological evaluation was included.
Further studies comparing Iamotrigine with
standard AEDs in monotherapy should be performed.
4.4 Oxcarbazepine
Oxcarbazepine (I 0, ll-dihydro-1 0-oxo-carbamazepine) is structurally very similar to carbamaze Adls lnternalional Limited. All rights reserved.

pine. The metabolism of oxcarbazepine does not

result in the formation of carbamazepine-1 0, 11-epoxide, which is the active metabolite of carbamazepine that is responsible for a number of adverse
effects. For this reason, oxcarbazepine may be better tolerated than carbamazepine, although the difference is probably modest.l 67 1 Oxcarbazepine
does not prevent the development of kindling.l 68 1
According to data from a healthy volunteer
study, oxcarbazepine might have a slight stimulant
effect on memory and psychomotor activity.l 69 1 In
a !-year follow-up study involving newly diagnosed patients receiving oxcarbazepine or carbamazepine, no deterioration of memory and attention
was observed.l 70 1When carbamazepine, oxcarbazepine and valproic acid were compared in a 4-month
follow-up study in patients with epilepsy, only a
minimal effect on cognition was found.l7 11 In a 1year double-blind, follow-up study in newly diagnosed patients randomised to either oxcarbazepine
or phenytoin monotherapy, the cognitive performance of patients receiving oxcarbazepine was
comparable with that of individuals receiving
phenytoin.1 72 l Moreover, no clear practice effect
was seen in either drug group.
4.5 Remacemide
Remacemide has antagonist activity at the Nmethyl-D-aspartate (NMDA) receptor complex.
Being a low affinity, noncompetitive antagonist,
remacemide causes less behavioural toxicity than
dissociative, anaesthetic-like competitive NMDA
receptor antagonists, such as dizocilpine (MK80 I ).1 731 In animal models, remacemide significantly reduces the volume of ischaemic damagel 741
and attenuates memory impairment after ischaemia.l751
A total of 300 individuals have so far participated in clinical trials of remacemide. Assessments
of cognitive functions have been incorporated into
nearly all studies conducted to date. So far, in
healthy volunteers, short-lived adverse cognitive
changes occur following high single doses of
remacemide, but these changes seem to attenuate
on repeated administration.f7 61
CNS Drugs 1996 May; 5 (5)

Kiilviiiinen eta/.

364

4.6 Tiagabine

Tiagabine is a potent and specific y-aminobutyric acid (GABA) uptake inhibitor that has been
shown to possess potent anticonvulsant activity in
a variety of seizure models. In a perforant pathway
stimulation model of status epilepticus, tiagabine
reduced the severity of seizures.l 77 1 In a manner
possibly associated with the reduction in seizure
number and severity, tiagabine treatment also reduced seizure-induced damage to pyramidal cells
in the hippocampus as well as impairment of the
spatial memory associated with hippocampal damage.J771
The neuropsychological effects of tiagabine in
patients have been evaluated in 3 studies. No cognitive or EEG changes were observed at low daily
doses during a 7-week follow-up.J7 8 1 In a doubleblind, placebo-controlled study comparing the effects of placebo with those of average daily doses
of tiagabine, no adverse effects on cognitive abilities or quality of life were found during a 12-week
follow-up.l 79 1The third study protocol consisted of
a randomised, double-blind, placebo-controlled,
parallel-group add-on regimen and an open-label
extension phase with 18- to 24-month followup.1801 The neuropsychological and EEG evaluation did not indicate any adverse effects of tiagabine during the double-blind phase at low dosages
or long term open phase at higher dosages up to 80
mg/day. The daily dosages in the long term followup of this study were higher than in the previous
reports. According to these studies, tiagabine does
not seem to produce significant cognitive adverse
effects as add-on therapy. Monotherapy trials with
cognitive testings are ongoing.
4. 7 Topiramate

Topiramate is a new AED with an anticonvulsant

profile similar to that of carbamazepine and phenytoin. However, the cognitive and gastrointestinal
adverse effects, as well as teratogenic effects, of the
drug can limit its use.
In a small, open-label follow-up study oftopiramate as add-on therapy, recall and word fluency did
Adls International Umlted. All rights reserved.

not decline during a IS-month follow-up.l 81 1However, the mean score on attention declined slightly
over time. Another study evaluated the effects of
topiramate monotherapy and reported similar results, i.e. some of the cognitive functions measured
seemed to become impaired.i 82 1These studies lacked
controls for practice effects. Therefore, well controlled cognitive function studies with topiramate
are required.
4.8 Vigabatrin

Vigabatrin is a selective, irreversible inhibitor

of GABA transaminase. Inhibition of this enzyme
produces greater available pools of presynaptic
GABA for release in CNS synapses. Vigabatrin has
both antiepileptogenic and antiseizure properties in
the kindling modeJI 83 1and it has also been shown
to protect hippocampal structure and function in
the perforant pathway stimulation model of epilepsy.184l Another study with the perforant pathway
stimulation model compared the effects ofvigabatrin
with those of carbamazepine.l 85 l Both treatments
had similar anticonvulsant efficacy during the
stimulation, but only vigabatrin decreased seizureinduced neuronal damage.
In long term use vigabatrin is relatively free of
adverse effects, except for a few instances of psychosis and depression. Several studies of the cognitive effects of vigabatrin as add-on therapy have
reported no adverse effects on a broad range of cognitive and quality-of-life measures,I86-90J
Vigabatrin has also been compared with carbamazepine as initial monotherapy in a randomised
trial including 100 patients.l 91 92 1 It had no detrimental effects on cognitive functions during a 12month follow-up.l 91 1 Retrieval from both episodic
and semantic memory and flexibility of mental processing improved significantly in successfully
treated vigabatrin patients compared with those receiving carbamazepine (see fig. I). Simple psychomotor speed slowed in carbamazepine-treated patients compared with vigabatrin recipients. To
some extent the improvement seen in the latter performance may depend on a practice effect. However,
the improvement was seen only in vigabatrin paCNS Drugs 1996 May; 5 (5)

365

Cognitive Adverse Effects of Antiepileptic Drugs

t4

t2

Baseline
o Untreated t2 months

.,to
"E
0

!0

Q;

~ 6
::::J

t4

t2

Baseline
o Carbamazepine t2 months

.,to

"E
0

!
0

tients, suggesting that carbamazepine may indeed

prevent practice effects. The study also included an
untreated control group, in which there was an improvement in the scores in retrieval from episodic
memory (see fig. I) and in tasks requiring flexibility of mental processing, but not in retrieval from
semantic memory. Thus, it seems that vigabatrin
may have some advantages regarding cognitive
function in patients with epilepsy beyond a simple
practice effect. The results were similar after a 24month follow-up.1 92 1
Currently, vigabatrin is the most extensively
studied of the newer AEDs with regard to cognitive
effects, and it seems that it has fewer cognitive adverse effects than the standard AED, carbamazepine.
Double-blind comparison of the effects of vigabatrin
and carbamazepine monotherapies are ongoing to
confirm this finding.

Q;

4.9 Zonisamide

~ 6
::::J

t4

t2
U)

"E

Baseline
o Vigabatrin t2 months

to

~ 8

~E

::::J

Fig. 1. The performance of patients on the List Learning Test

across learning trials (1 to 4) and in delayed recall and delayed
recognition. Scores at baseline and t2 months' follow-up are
presented for untreated patients and for those receiving
carbamazepine or vigabatrin (n =t00).91 1 Symbol:* indicates
p::; 0.05 compared with baseline, multivariate analysis of covariance (MANCOVA) for repeated measures, post-hoc analysis,
the drug/control group as the between subjects factor.

Adls lntematlonal Umlted. All rights reserved.

Zonisamide is a sulphonamide derivative with

an anticonvulsant efficacy similar to that of phenytoin and carbamazepine, but with a wider therapeutic index. However, in the kindling model, zonisamide delays the development of generalised
kindled seizures.l 93 1 The disadvantages of zonisamide include a fairly high incidence of drowsiness and cognitive impairment.1 94 1
In a preliminary cognitive study,l 95 l zonisamide
used as add-on therapy appeared to adversely affect specific cognitive function such as acquisition
and consolidation of new information. Previously
learned material, such as vocabulary, and psychomotor performance were not affected. There were
no clinical symptoms or signs of toxicity. However, the findings also suggested the development
of tolerance to the adverse cognitive effects after
24 weeks of therapy. Well controlled studies are
needed to further evaluate the cognitive effects of
zonisamide.

5. Therapeutic Implications and

Conclusions
The therapeutic response to AEDs varies greatly
among individual patients. Similarly, there are
CNS Drugs 1996 May; 5 (5)

Kiilviiiinen eta/.

366

great individual differences among patients with

regard to AED-induced adverse effects, including
cognitive effects. In the clinical setting, the AED
of choice should always be the one that produces
the best seizure control and fewest adverse effects
for the particular patient. Cognitive performance
should become an increasingly important consideration in the decision regarding which AED to prescribe.
The ultimate goal of the modern drug treatment
of epilepsy should not only be the cessation of seizures, but also the prevention of further epileptogenesis and progression of neuronal damage and
cognitive dysfunction. New drug treatments should
protect neurons from excitotoxic cell damage and
harmful neuronal reorganisation that occurs after
brain insult, but not interfere with the normal plasticity and restorative processes. Therefore, whenever AEDs are studied their neuroprotective as well
as cognitive effects must be evaluated. In particular, controlled monitoring of neuropsychological
test performance is an essential supplement to the
collection of subjective reports of CNS-related adverse effects of AEDs.

References
I. Neisser U. Cognition and reality. San Francisco: W.H. Freeman
and Co .. 1980
2. Dodrill CB. Behavioral effects of antiepileptic drugs. In: Smith
D, Treiman D. Trimble M, editors. Neurobehavioral problems
in epilepsy. Advances in neurology. Vol. 55. New York: Raven
Press, 1991:213-24
3. Sutula TP, Cavazos JE, Woodard AR. Long-term structural and
functional alterations induced in the hippocampus by kindling: implications for memory dysfunction and the development of epilepsy. Hippocampus 1994; 4: 254-8
4. Aikia M, Kalviainen R. Riekkinen Sr PJ. Verbal learning and
memory in newly diagnosed partial epilepsy. Epilepsy Res
1995 Oct; 22: 157-64
5. Brodie MJ, McPhail E, Macphee GJA, et al. Psychomotor impairment and anticonvulsant therapy in adult epileptic patients. Eur J Clin Pharmacal 1987; 31: 655-60
6. Kalviainen R, Aikia M, Helkala E-L, et at. Memory and attention in newly diagnosed epileptic seizure disorder. Seizure
1992; I: 255-62
7. Smith DB, Mattson RH, Cramer JA, et al. Results of a nationwide veterans administration cooperative study comparing
the efficacy and toxicity of carbamazepine, phenobarbital,
phenytoin and primidone. Epilepsia 1987; 28: 50-8
8. Engel J, Bandler R, Griffith NC, et al. Neurobiological evidence
for epilepsy-induced interictal disturbances. In: Smith DB,
Treiman OM, Trimble MR, editors. Neurobehavioral problems in epilepsy. New York: Raven Press, 1991:97-111

Adis International Limited. All rights reserved.

9. Devinsky 0. Cognitive and behavioral effects of antiepileptic.

Epilepsia 1995; 36 Suppl. 2: 46-65
I 0. Dodrill CB. Cognitive and psychosocial effects of epilepsy
on adults. In: Wyllie E, editor. The treatment of epilepsy:
principles and practices. Philadelphia: Lea & Febiger,
1993: 1133-40
II. Loring OW, Meador KJ. Cognitive and behavioral effects of
antiepileptic drugs: issues in epilepsy and quality of life. Epilepsy Foundation of America, 1993
12. Meador KJ. Loring OW. Cognitive effects of antiepileptic
drugs. In: Devinsky 0, Theodore WH, editors. Epilepsy and
behavior. New York: Wiley-Liss, 1991: 151-70
13. Smith DB. Cognitive effects of antiepileptic drugs. In: Smith D.
Treiman D, Trimble M, editors. Neurobehavioral problems in
epilepsy. Advances in neurology. Vol 55. New York: Raven
Press, 1991: 197-212
14. Trimble MR. Anticonvulsant drugs and cognitive function: a
review of the literature. Epilepsia 1987; 28: 37-45
15. Durwen HF, Elger CE, Helmstaedter C, et al. Circumscribed
improvement of cognitive performance in TLE patients with
intractable seizures following reduction of anticonvulsant
medication. J Epilepsy 1989; 2: 147-53
16. Durwen HF, Elger CE. Verbal differences in epileptic patients
with left and right temporal lobe foci - a pharmacologically
induced phenomenon? Acta Neural Scand 1993; 87: 1-8
17. Gaily EK, Granstrom ML, Hiilesmaa VK, et al. Head circumference in children of epileptic mothers: contributions of
drug exposure and genetic background. Epilepsy Res 1990;
5:217-22
18. Ransom BR, Elmore JG. Effects of antiepileptic drugs on the
developing central nervous system. In: Smith D, Treiman D,
Trimble M, editors. Neurobehavioral problems in epilepsy.
Advances in neurology. Vol. 55. New York: Raven Press,
1991: 225-37
19. Trimble MR, Reynolds EH. Anticonvulsant drugs and mental
symptoms. PsychoiMed 1976; 6: 169-78
20. Shorvon SO, Reynolds EH. Reduction in polypharmacy for epilepsy. BMJ 1979; 2: 1023-5
21. Thompson P, Trimble MR. Anticonvulsant drugs and cognitive
functions. Epilepsia 1982; 23: 531-44
22. Dodrill CB. Diphenylhydantoin serum levels, toxicity, and
neuropsychological performance in patients with epilepsy.
Epilepsia 1975; 16: 593-600
23. Thompson P, Trimble MR. Comparative effects of anticonvulsant drugs on cognitive functioning. Br J Clin Pract 1982; 18:
154-6
24. Thompson PJ, Trimble MR. Anticonvulsant serum levels: relationship to impairments of cognitive functioning. J Neural
Neurosurg Psychiatr 1983; 46: 227-33
25. Dodrill CB, Troupin AS. Psychotropic effects of carbamazepine
in epilepsy: a double-blind comparison with phenytoin. Neurology 1977; 27: 1023-8
26. Thompson PJ, Huppert FA, Trimble MR. Phenytoin and cognitive functions: effects on normal volunteers and implications
for epilepsy. Br J Clin Psycho! 1981; 20: 155-62
27. Thompson PJ, Trimble MR. Sodium valproate and cognitive
functioning in normal volunteers. Br J Clin Pharmacal 1981;
12: 819-24
28. Andrewes DG, Bullen JG, Tomlinson L, et al. A comparative
study of the cognitive effects of phenytoin and carbamazepine
in new referrals with epilepsy. Epilepsia 1986; 27: 128-34
29. Nichols ME, Meador KJ, Loring OW. Neuropsychological effects of antiepileptic drugs: a current perspective. J Clin Neuropharmacol 1993; 16:471-84

CNS Drugs 1996 May; 5 (5)

367

Cognitive Adverse Effects of Antiepileptic Drugs

30. Smith DB. Anticonvulsants, seizures and performance: the Veteran's Administration experience. In: Trimble MR, Reynolds
EH, editors. Epilepsy, behaviour and cognitive function.
Chichester: John Wiley & Sons Ltd, 1988: 67-78
31. Duncan JS, Shorvon SD, Trimble MR. Effects of removal of
phenytoin, carbamazepine and valproate on cognitive function. Epilepsia 1990; 31: 584-91
32. Gillham RA, Williams N, Wiedmann KD, et al. Cognitive function in adult epileptic patients established on anticonvulsant
monotherapy. Epilepsy Res 1990; 7: 219-25
33. Dodrill CB, Temkin NR. Motor speed is a contaminating factor
in evaluating the cognitive effects of phenytoin. Epilepsia
1989; 30: 453-7
34. Dodrill CB, Troupin AS. Neuropsychological effects of carbamazepine and phenytoin: a reanalysis. Neurology 1991; 41:
141-3
35. Dodrill CB, Wilensky AJ. Neuropsychological abilities before
and after 5 years of stable antiepileptic drug therapy. Epilepsia
1992; 33: 327-34
36. Prevey ML, Delaney RC, Cramer JA, et al. Valproate versus
carbamazepine: comparison of effects on cognitive functioning ]abstract]. Epilepsia 1992; 33 Suppl. 3: 110
37. Forsythe I, Butler R, Berg I, et al. Cognitive impairment in new
cases of epilepsy randomly assigned to carbamazepine,
phenytoin and sodium valproate. Dev Med Child Neurol
1991; 33: 524-34
38. Dikmen SS, Temkin NR, Miller B, et al. Neurobehavioral effects of phenytoin prophylaxis of posttraumatic seizures.
JAMA 1991; 265: 1271-7
39. Smith KR, Goulding PM, Wilderman D, et al. Neurobehavioral
effects of phenytoin and carbamazepine in patients recovering from brain trauma: a comparative study. Arch Neurol
1994; 51: 653-60
40. Meador KJ, Loring DW, Huh K, et al. Comparative cognitive
effects of anticonvulsants. Neurology 1990; 40: 391-4
41. Meador KJ, Loring DW, Allen ME, et al. Comparative cognitive
effects of carbamazepine and phenytoin in healthy adults.
Neurology 1991; 41: 1537-40
42. Meador KJ, Loring DW, Abney OL, et al. Effects of carbamazepine and phenytoin on EEG and memory in healthy adults.
Epilepsia 1993; 34: 153-7
43. Meador KJ, Loring DW, Moore EE, et al. Comparative cognitive effects of phenobarbital, phenytoin, and valproate in
healthy adults. Neurology 1995; 45: 1494-9
44. Kalviainen R, Keranen T, Riekkinen Sr PJ. Place of newer antiepileptic drugs in the treatment of epilepsy. Drugs 1993; 46:
1009-24
45. Kalviainen R, Riekkinen PJ. New antiepileptic drugs. Exp Opin
Invest Drugs 1995; 4: 955-62
46. Chronopoulos A, Stafstrom C, Thurber S, et al. Neuroprotective
effect of felbamate after kainic acid-induced status epilepticus. Epilepsia 1993; 43: 693-6
47. Wallis RA, Panizzon KL, Nolan JP. Glycine-induced CAl excitotoxicity in the rat hippocampal slice. Brain Res 1994; 664:
115-25
48. Wasterlein CG, Adams LM, Hattori H, et al. Felbamate reduces
hypoxic-ischemic brain damage in vivo. Eur J Pharmacol
1992; 212: 275-8
49. Mattson RH. Efficacy and adverse effects of established and
new antiepileptic drugs. Epilepsia 1995; 36 Suppl. 2: 13-26
50. Ramsay RE. Clinical efficacy and safety of gabapentin. Neurology 1994; 44 Suppl. 4: 23-30
51. Saletu B, Grunberger J, Linzmayer L. Evaluation of encephalothrophic and psychotropic properties of gabapentin in

Adis lntematlonal

Llm~ed.

All rights reserved.

52.

53.

54.

55.

56.
57.

58.

59.
60.

61.

62.

63.

64.
65.

66.

67.

68.

69.

70.

71.

72.

man by pharmaco-EEG and psychometry. Int J Clin Pharmacol Ther Toxicol 1986; 24: 362-73
Dodrill CB, Wilensky AJ, Ojemann LM. Neuropsychological,
mood, and psychosocial effects of gabapentin ]abstract].
Epilepsia 1992; 33 Suppl. 3: 117-8
Abou-Khalil B, McLean M, Castro 0, et al. Gabapentin in the
treatment of refractory partial seizures ]abstract]. Epilepsia
1990; 31:644
Handforth A, Treiman DM, Norton LC. Effect of gabapentin on
complex partial seizure frequency ]abstract]. Neurology
1989; 39 Suppl. I: 114
Ojemann LM, Wilensky AJ, Temkin NR, et al. Long-term treatment with gabapentin for partial epilepsy. Epilepsy Res 1992;
13: 159-65
Arnett JL, Dodrill CB. Effects of gabapentin on cognitive functioning and mood ]abstract]. Epilepsia 1995; 36 Suppl. 3: 32
O'Donnell RA, Miller AA. The effect of lamotrigine upon development of cortical kindled seizures in the rat. Neuropharmacology 1991 ; 30: 253-8
McGeer EG, Zhu SG. Lamotrigine protects against kainate but
not ibonate lesions in rat striatum. Neurosci Lett 1990; 4:
348-51
Smith SE, Meldrum BS. Cerebroprotective effect of lamotrigine after focal ischemia in rats. Stroke 1995; 26: 117-22
Cohen AF, Ashby L, Crowley D, et al. Lamotrigine (BW 430C),
potential anticonvulsant: effects on the central nervous system in comparison with phenytoin and diazepam. Br J Clin
Pharmacol 1985; 20: 619-29
Hamilton MJ, Cohen AF, Yuen AWC, et al. Carbamazepine and
lamotrigine in healthy volunteers: relevance to early tolerance
and clinical trial dosage. Epilepsia 1993; 34: 166-73
Mervaala E, Koivisto K, Hanninen T, et al. Electrophysiological and neuropsychological profiles of lamotrigine in young
and age-associated memory impairment subjects [abstract].
Neurology 1995; 46 Suppl. 4: 259
Smith D, Baker G, Davies G, et al. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia 1993; 34:
312-22
Fitton A, Goa KL. Lamotrigine: an update of its pharmacology
and therapeutic use in epilepsy. Drugs 1995; 50: 691-713
Brodie MJ, Richens A, Yuen AWC. Double-blind comparison
of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995; 25: 476-9
Steiner TJ, Silveira C, Yuen AWC. Comparison of lamotrigine
and phenytoin monotherapy in newly diagnosed epilepsy [abstract]. Epilepsia 1994; 35:61
Grant S, Faulds D. Oxcarbazepine: a review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia
and affective disorders. Drugs 1992; 43: 873-88
Silver JM, Shin C, McNamara JO. Antiepileptogenic effects of
conventional anticonvulsants in the kindling model of epilepsy. Ann Neurol 1991; 29: 356-63
Curran HV, Java R. Memory and psychomotor effects of oxcarbazepine in healthy human volunteers. Eur J Clin Pharmacol 1993; 44: 529-33
Laaksonen R, Kaimola K, Grahn-Teravainen E, et al. A controlled trial of the effects of carbamazepine and oxcarbazepine
on memory and attention ]abstract]. 16th International Epilepsy Congress; 1985; Hamburg.
Sabers A. The effect of carbamazepine, sodium-valproate and
oxcarbazepine on neuropsychological functions in patients
with epilepsy ]abstract]. Acta Neurol Scand 1990; 82: 80
Aikia M, Kalviainen R, Sivenius J, et al. Cognitive effects of
oxcarbazepine and phenytoin monotherapy in newly diag-

CNS Drugs 1996 May: 5 (5)

Kiilviiiinen eta!.

368

73.
74.

75.

76.

77.

78.

79.
80.

81.
82.
83.

84.

85.

nosed epilepsy: one year follow-up. Epilepsy Res 1992; II:

199-203
Rogawski MA. The NMDA receptor, NMDA antagonists and
epilepsy therapy: a status report. Drugs 1992; 44: 279-92
Bannan PE, Graham 01, Lees KR, et al. Neuroprotective effect
of remacemide hydrochloride in focal cerebral ischemia in the
cat. Brain Res 1994; 664: 271-5
Ordy JM, Thomas GJ. Remacemide effects on memory and
hippocampal CA I neuronal damage in the rat four-vessel occlusion model of global cerebral ischemia [abstract]. Soc
Neurosci Abstr 1991; 17: 1081
Jamieson V. Preclinical and early clinical experience: remacemide hydrochloride safety - anticonvulsant and neuroprotectant? Satellite symposium in 21st International Epilepsy
Congress; 1995 Sept 4-8; Sydney
Halonen T, Nissinen J, Jansen J, et al. Tiagabine prevents seizures, neuronal damage and memory impairment in experimental status epilepticus. Eur J Pharmacol. In press
Sveinbjornsdottir S, Sander JWAS, Patsalos PN, et al. Neuropsychological effects of tiagabine, a potential new antiepileptic drug. Seizure 1994; 3: 29-35
Dodrill C, Arnett JL, Sommerville K, et al. Tiagabine [abstract].
Epilepsia 1995; 36 Suppl. 3: 31
Kalviainen R, Aikia M, Mervaala E, et al. Long-term cognitive effects of tiagabine [abstract]. Epilepsia 1995; 36
Suppl. 3: 149
Privitera M. Long-term cognitive effects of topiramate [abstract]. Epilepsia 1995; 36 Suppl. 3: 152
Brooks J, Sachdeo R, Lim P. Topiramate: neuropsychometric
assessments [abstract]. Epilepsia 1995; 36 Suppl. 3: 273
Shin C, Rigsbee LC, McNamara JO. Anti-seizure and anti-epileptogenic effect of gamma-vinyl-gamma-aminobutyric acid
in amygdaloid kindling. Brain Res 1986; 398: 370-4
Ylinen AMA, Miettinen R, Pitkanen A, et al. Enhanced GABAergic inhibition preserves hippocampal structure and function
in a model of epilepsy. Proc Natl Acad Sci USA 1991; 88:
7650-3
Pitkanen A, Tuunanen J, Halonen T. Vigabatrin and carbamazepine have different efficacies in prevention of status epilepti-

Adis International Limited. All rtghts reserved.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

cus induced neuronal damage in the hippocampus and

amygdala. Epilepsy Res. In press
Dodrill CB, Arnett JL, Sommerville KW, et al. Evaluation of
the effects of vigabatrin on cognitive abilities and quality of
life in epilepsy. Neurology 1993; 43: 2501-7
Dodrill CB, Arnett JL, Sommerville KW, et al. Effects of differing dosages of vigabatrin on cognitive abilities and quality
of life in epilepsy. Epilepsia 1995; 36: 164-73
Gillham RA, Blacklaw J, McKee PJW, et al. Effect ofvigabatrin
on sedation and cognitive function in patients with refractory
epilepsy. J Neurol Neurosurg Psychiatry 1993; 53: 1271-5
Grunewald RA, Thompson PJ, Corcoran R, et al. Effects of
vigabatrin on partial seizures and cognitive function. J Neurol
Neurosurg Psychiatry 1994; 57: 1057-63
McGuire AM, Duncan JS, Trimble MR. Effects of vigabatrin
on cognitive function and mood when used as add-on therapy in patients with intractable epilepsy. Epilepsia 1992;
33: 128-34
Kalviainen R, Aikia M, Saukkonen AM, et al. Vigabatrin vs
carbamazepine monotherapy in patients with newly diagnosed epilepsy. Arch Neurol 1995; 52: 989-96
Kalviainen R, Aikia M, Riekkinen PJ. Vigabatrin monotherapy
in newly diagnosed patients with epilepsy: two-year comparative follow-up of efficacy, safety and cognitive effects [abstract]. Epilepsia 1995; 36 Suppl. 3: I 05
Hamoda K, Ishida S, Yagi K. Anticonvulsant effects of zonisamide on amygdaloid kindling in rats. Neuroscience 1990; 16:
407-12
Peters DH, Sorkin EM. Zonisamide: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in epilepsy. Drugs 1993; 45: 760-87
Berent S, Sackellares JC, Giordani B, et al. Zonisamide (CI912) and cognition: results from preliminary study. Epilepsia
1987; 28: 61-7

Correspondence and reprints: Dr Reetta Kiilviiiinen, Department of Neurology, University Hospital of Kuopio, POB
1777,70211 Kuopio, Finland.

CNS Drugs 1996 May; 5 (5)