REVIEW

Review

Neuropsychological effects of epilepsy and antiepileptic drugs

Patrick Kwan, Martin J Brodie

Epilepsy and its treatment can have deleterious cognitive and behavioural consequences. Affected individuals have a
higher prevalence of neuropsychological dysfunction than the general population because of complex interactions
among several multifaceted and overlapping influences—for example, underlying neuropathologies, ictal and interictal
neuronal discharges, a plethora of antiepileptic drugs, and numerous psychosocial issues. Research into the clinical
relevance of these factors has been dogged by a range of methodological pitfalls including lack of standardisation of
neuropsychological tests, small numbers and multiple testing, and statistical failure to appreciate differential effects of
interactive elements in individual patients. Although antiepileptic drugs can impair neuropsychological functioning, their
positive effect on seizure control might improve cognition and behaviour. Each person should be assessed individually
with respect to factors unique to his or her seizure disorder and its treatment.

Cognition can be defined as an individual’s ability to think, Pitfalls in research methods

or more precisely, to use information about and from the
environment in an adaptive manner. This skill involves a
wide range of mental processes including perception,
memory, learning, attention, vigilance, understanding, and
interpretation. Behaviour, in the broadest sense,
encompasses all activities concerning autonomic responses
and integrated reactions to dynamic situations, the
experiencing and expressing of emotions, and the forming
and maintaining of interpersonal relationships. Cognition
and behaviour, therefore, are the ways in which an
individual interacts with the world and its inhabitants.
People with epilepsy have long been recognised to have
greater cognitive and behavioural dysfunction than the
general population. Well before Gowers commented in
1881 that “the mental state of epileptics, as is well known,
frequently presents deterioration, and this constitutes one
of the consequences of the disease which is most dreaded
and is often most serious”,1 seizures were regarded as
characteristic features of witches and their spellbound
victims. Although society has moved away from such
extreme stigmatisation, the high prevalence of psychosocial
problems in people with epilepsy is still clearly evident,
despite the fact that most have normal intelligence and no
great cognitive impairment or behavioural dysfunction.2
Cognitive and behavioural disturbances in epilepsy are a
consequence of a range of multifaceted and overlapping
influences including underlying neuropathologies,
neuronal discharges (ictal and interictal), antiepileptic
drugs, and psychosocial issues such as public attitudes and
the patient’s low assessment of self worth (figure). Many
studies carried out over the past few decades have explored
the significance of these factors. But before these findings
are reviewed, it is important to consider some of the pitfalls
in their methods.
Lancet 2001; 357: 216–22
Epilepsy Unit, University Department of Medicine and
Therapeutics, Western Infirmary, Glasgow G11 6NT, Scotland
(P Kwan MD, Prof M J Brodie MD)
Correspondence to: Prof M J Brodie
(e-mail: Martin.J.Brodie@clinmed.gla.ac.uk)
Although most of the following criticisms refer to studies
that investigate cognitive and behavioural side-effects of
antiepileptic drugs, they are equally applicable to those
that explore the influence of the other factors mentioned
above. Vermeulen and Aldenkamp, in reviewing 89 studies
done over 25-years, concluded that no satisfactory answer
could be given to the question of adverse cognitive effects
of antiepileptics because most of these studies did not
“pass fairly basic standards of methodology, design and
analysis”.3 Even in randomised controlled trials designed
to investigate the neuropsychological effects of
antiepileptic drugs, the reporting of basic methods was
judged as poor, and there was no uniform approach to the
use of tests, hindering coherent interpretation of data.4
The main methodological difficulties can be classified
into five groups, the first two relating to the identification
of suitable controls. First, selection bias can have a major
influence, especially in non-randomised, retrospective
studies. Any variations, for example, between patients
being treated with different drugs could be a result of
differences in intrinsic characteristics of the two
populations rather than an effect of the antiepileptics.
Dodrill drew attention to this pitfall when he found lower
IQ scores in patients receiving valproic acid than in those
taking other antiepileptic drugs. However, this difference
already existed 5 years previously, when none of the
patients were receiving valproic acid.5 Baseline
measurements are, therefore, essential, and patients with
severe epilepsy or underlying neurological impairment, or
even intellectual decline, could be treated with higher
doses or greater numbers of antiepileptics than less
affected individuals.
A second, overlapping issue is non-equivalence in
critical clinical variables, which refers to the presence of
uncontrolled confounding factors that can exert effects on
cognition or behaviour to different degrees. This indicates
a failure to appreciate the complex interactions among the
factors mentioned above. The patient’s age; sex; and
treatment dose, concentration, and duration, &c are
important determining factors. One often-quoted example
is the study by Dodrill and Troupin6 in which
carbamazepine was found to have fewer cognitive and
behavioural side-effects than phenytoin. This difference
disappeared when patients with toxic phenytoin
concentrations were excluded from analysis.7 Moreover,
the type, duration, severity, and frequency of seizures; the

216 THE LANCET • Vol 357 • January 20, 2001

For personal use only. Not to be reproduced without permission of The Lancet.

Epileptic discharges
Ictal
Interictal
Subclinical
Neuropathology Focal versus generalised
Pattern of spread
Laterality Frequency
Anatomical site
Status epilepticus
Nature of pathology
Age of onset
Single or multiple lesions
Duration of epilepsy
Psychosocial factors Antiepileptic drugs
Public attitudes Monotherapy versus
Self-esteem polytherapy
Education opportunities Established versus new
Employment status Dosage
Marriage status Concentration in serum
Factors contributing to cognitive and behavioural impairment in
epilepsy
underlying neuropathology; and the anatomical site of the
lesion can also have cognitive and behavioural effects.2 All
other influences need to be carefully controlled when only
a single factor is examined in a study. Some investigators
have attempted to avoid these confounding variables by
enrolling healthy volunteers. In these studies, however,
drug exposure is typically short and whether the results can
be applied to an epileptic patient population is debatable.3
Third, neuropsychological tests should be chosen and
administered appropriately to detect putative changes with
adequate sensitivity. Tests involving vigilance, divided
attention, psychomotor speed, complex eye-hand
coordination, mood, and subjective symptoms are thought
to be particularly sensitive to antiepileptic drug effects.
The timing of the testing in relation to the last seizure, and
practice effects can affect results. More than 100
neuropsychological tests have been used, and no attempt
at standardisation has been undertaken.3
Fourth, statistical problems are found in many studies,
such as the use of multiple analyses without any correction
factor, thereby concluding differences when none exist
(type I error). In studies with small sample sizes, however,
lack of significance might in fact be due to poor statistical
power (type II error).
Last, application of results from the neuropsychology
laboratory to the individual patient, and vice versa, needs
to be exercised with care. A statistically well-tolerated
antiepileptic drug could cause substantial cognitive effects
noticed by the patients, and subjective assessment of
memory has been found to correlate poorly with objective
THE LANCET • Vol 357 • January 20, 2001
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REVIEW
neuropsychological test results.8 Perceived cognitive
functioning is strongly correlated with mood, and only
weakly correlated with formal memory test scores.9
Therefore, external factors, such as psychosocial
difficulties, could be invoked to account for memory
complaints.
Cause and neuropathology
Most generally agree that there is no universal epileptic
personality trait. There is, however, a diverse range of
clinical changes indicating anatomical foci, patterns of
seizure spread, and biological and psychological
differences among patients. In localisation-related
epilepsy, a range of cognitive defects have been suggested,
which mainly relate to the presumed physiological function
of the anatomical site of seizure focus—for example,
greater memory deficit has been found in patients with
temporal-lobe epilepsy. In particular, left temporal foci are
more commonly associated with verbal memory deficits,
whereas non-verbal, or visual memory, difficulties are most
typically found with seizure onset in the right temporal
lobe.2
Different pathologies underlying the epileptic focus,
even at the same anatomical site, can have different
cognitive consequences. In surgical series of temporal
lobectomy for epilepsy, hippocampal sclerosis was
associated with greater impairment in intelligence,
academic achievement, language and visuospatial
functions, and memory than other pathologies.10
Moreover, the greater the degree of left hippocampal
sclerosis, the more severe were the deficits in verbal
memory.11
For a given pathology, the severity of cognitive
impairment can also be related to the extent of the lesion.
For instance, in a study of children and adolescents with
refractory partial seizures caused by malformations of
cortical development, diffuse cortical dysplasia was
associated with a more severe deleterious effect on
intellectual functioning than circumscribed lesions.12
Neuronal discharges
Ictal cognitive and behavioural features are well
recognised. John Hughlings Jackson first developed the
concept of temporal-lobe epilepsy, correlating clinical
behaviour with pathological lesions in a series of elegant
case reports, toward the end of the 19th century. The
introduction of electroencephalography (EEG) provided a
powerful tool to delineate the characteristic ictal, as well as
interictal, patterns observed in this type of epilepsy,
correlating them with observable behavioural
manifestations including mental, emotional, sensorial,
motor, and autonomic features. Thus, the term
psychomotor epilepsy was coined in the 1930s. The most
common ictal psychic symptoms are fear and anxiety,
which can often be confused with panic attacks. Ictal
aggression, however, is thought to be extremely rare and
usually verbal or directed towards inanimate objects, if
physical.13
The biggest impact of seizures on cognition, however, is
through postictal effects, possibly via the disruptive
influence of neuronal discharges on long-term potentiation
involved in learning.14 Negative effects on cognitive-test
scores are detectable for variable periods after a seizure,
which could explain persistent cognitive changes in some
patients with epilepsy. Studies show that seizure type has a
determining effect on the patient’s cognitive profile, but
the findings are inconsistent. Individuals with generalised
seizures tend to do less well on tasks needing sustained
attention, and have poorer mental abilities than those with
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focal seizures, whereas generalised absence seizures are less
damaging on cognitive function than tonic-clonic seizures.5
In the first Veterans Administration Cooperative Study,
Smith and co-workers noted that patients with secondarily
generalised seizures had lower intellectual ability than
those with partial or idiopathic generalised seizures.15 To
avoid the confounding factor of medication, a Finnish
study recruited newly diagnosed untreated patients and
found no difference in tests of motor function, attention,
and memory between individuals with partial onset and
generalised seizures, although all patients scored worse
than healthy controls.16
The earlier in life that epilepsy begins, the lower the
subsequent mental abilities tend to be.5 This phenomenon
could be a consequence of greater seizure-induced damage
and the often diminished educational attainment, as well
as a tendency for these patients to have been treated with
more antiepileptic drugs with harmful cognitive and
behavioural effects than patients with better mental
performance. The possibility of progressive seizure-
induced damage has been most vigorously studied in
temporal-lobe epilepsy. Experimental and clinical evidence
suggests that seizures could produce progressive neuronal
damage, resulting in cumulative neuropsychological
disabilities.17 This effect might account for the observation
that patients with long-term epilepsy have severe cognitive
impairment, an effect that persists after successful anterior
temporal lobectomy.18 Additionally, in-vivo data suggest
that seizures affecting the immature brain can predispose
animals to extensive neuronal injury and memory
impairment after seizures in adulthood.19 Not surprisingly,
high seizure frequency and episodes of status epilepticus
are associated with more severe cognitive and psychosocial
impairment.
Interictal behavioural changes remain controversial.
Some studies have found an inverse correlation between
total seizure number and level of psychosocial functioning,
whereas others showed that patients with emotional
difficulties had fewer seizures. An increased rate of
generalised anxiety and panic disorders is found in patients
with epilepsy, especially those having partial seizures of
limbic origin. Interictal anxiety symptoms were reported
by as many as 66% and depression by 80% of patients.
Mood changes, most commonly depression, can also
manifest as prodromal symptoms preceding epileptic
seizures. Whether patients with epilepsy are at higher risk
than healthy individuals of developing psychosis or
aggression is more debatable. In one surgical study,
aggression was reduced in some violent patients after
temporal lobectomy, suggesting that the dysfunctional
temporal lobe contributed to the antisocial behaviour.20
Subclinical or interictal discharges—ie, epileptiform
EEG discharges not accompanied by obvious clinical
events—can be associated with impaired cognitive function
(transitory cognitive impairment, TCI), which is
detectable with appropriate psychological testing. In one
study employing a sensitive test procedure, TCI was
recorded in around 50% of patients with frequent
subclinical discharges.2 Most studies suggest TCI is more
common during prolonged (>3 s) generalised spike-wave
discharges than during short or focal discharges, but the
relation between the duration of discharges and severity of
cognitive impairment, or between the laterality of
discharges and nature of dysfunction,21 has not been well
examined. Simple motor and attentional tasks seem to be
little affected by such interictal discharges, whereas TCI is
more evident when higher cortical functions are measured.
In children, such discharges are associated with faster but
less accurate reading22 and impaired success on a subtest
218
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concerned with verbal short-term memory.23 The type of
cognitive activity and its degree of difficulty also affect the
frequency of epileptiform discharges.22 Another study
examined the real life situation of driving and found
impairment in half the patients during subclinical
discharges. Some of the interictal cognitive and
behavioural changes in patients could, therefore, be the
result of TCI.
Antiepileptic drugs
Huette first described the cognitive and behavioural side-
effects of bromide in 1850 before its suggested use as an
anticonvulsant in 1857 by Sir Charles Locock. Data have
since been obtained from normal volunteers, comparisons
between treated and untreated patients, measurement of
concentration-effect relations, and substitution and
withdrawal studies. Early observations did not detect any
mental effects of phenobarbital, but the investigators
failed to control for the confounding factor of improved
seizure control. More recent studies have shown
consistently that antiepileptic treatment can have adverse
cognitive consequences, although the effect can be
subtle.24,25 Associations between particular drugs and
deterioration in specific functions are not well defined.
Indeed, recent data from children suggest that the adverse
effects of antiepileptics on cognition and behaviour could
have been over-rated in the past. One study attempted to
address the issue of possible insidious cognitive
deterioration with antiepileptic treatment.26 No mental
losses were shown over 5 years in patients on established
drugs with concentrations within the target ranges and in
the absence of an active seizure disorder.
Adverse effects were especially prominent in patients
receiving polytherapy. For instance, one study found
carbamazepine monotherapy to have little effect on
cognition and psychomotor functions, but significant
impairment when carbamazepine was added to an existing
monotherapy regimen.27 Other studies have shown that
reducing the number of antiepileptic drugs, or changing to
monotherapy, resulted in cognitive and behavioural
improvement.28 Such increased neurotoxicity with
polytherapy is most commonly attributed to
pharmacokinetic interactions, particularly among the
established drugs, via effects on hepatic drug metabolism.
However, increased neurotoxicity has also been noted
with certain combinations in the absence of alteration in
drug concentration, suggesting the operation of
pharmacodynamic interactions. One such example is the
combination of carbamazepine and lamotrigine.29
Whether the increased toxicity is purely additive or supra-
additive is unclear.
Another potentiating factor is high circulating
antiepileptic drug concentrations. Most studies have
shown that cognitive functioning is best when drug
concentrations are within standard target ranges, and that
high drug dosages and concentrations are associated with
impaired intellectual functioning.2 Some investigators
have gone further to suggest that toxicity in polytherapy
could be related to total drug load, rather than to the
number of drugs given.30 This hypothesis, however,
remains untested. Bearing in mind their limitations as
systematically reviewed recently,3,4 an attempt will be
made to summarise the findings for a number of
established and new antiepileptic drugs (table).
Established drugs
Among the established antiepileptics, phenobarbital
seems to have the greatest potential for cognitive and
behavioural toxicity. Dose-related impairment occurs in
THE LANCET • Vol 357 • January 20, 2001

Drug Cognitive effects Behavioural effects
Phenobarbital ++ ++
Phenytoin + 0
Carbamazepine + 0
Sodium valproate +? 0 Comparative studies of established drugs
Clobazam + +
Clonazepam ++ + Several studies have investigated the differential cognitive
Lamotrigine 0 0
Vigabatrin 0 +
Gabapentin 0 0
Topiramate + +?
Tiagabine 0 0
Oxcarbazepine +? 0 enrolled 622 newly diagnosed patients, carbamazepine had
Zonisamide 0 +?
Levetiracetam 0 0
0=no effect; +?=possible effect; +=mild effect; ++=marked effect.
Cognitive and behavioural side-effects of antiepileptic drugs
attention and vigilance, reaction time, short-term
memory, and performance IQ. When phenobarbital was
given to children to prevent recurrent febrile convulsions
in a double-blind, placebo-controlled study, there was a
negative correlation between the drug’s concentration in
serum and five Binet subscores.31 More importantly, the
adverse effects of phenobarbital on language skills seem to
persist into school age.32 As well as the cognitive side-
effects, phenobarbital can produce a hyperkinetic
syndrome in children, and is implicated in the aggravation
of other behavioural disorders by causing hyperactivity,
lethargy, irritability, and depression.
Phenytoin can cause decline in concentration, memory,
mental speed, visuomotor functions, and intelligence.24
Although deficits seem to be dose related, they were seen
even at drug concentrations within the target range.
Suggested behavioural dysfunctions with phenytoin
include decreased motor speed, anxiety, aggression,
depression, and fatigue.
The initial enthusiasm for the positive psychotropic
effects of carbamazepine was founded on studies with
serious methodological problems. Recent studies have
shown mild adverse cognitive and psychomotor effects,
some of which are likely to be caused partly by the active
metabolite carbamazepine-epoxide.24,27 When a high dose
of carbamazepine was given to healthy volunteers,
impairment was noted in critical flicker fusion threshold
(which indicates central integration of the central nervous
system), choice reaction time, and card sorting,
accompanied by subjective complaint of sedation.33
Similar results were obtained when patients established on
a stable carbamazepine regimen took an extra dose
compared with matched placebo. However, when the
drug was given to newly diagnosed patients, the initial
impairment in psychomotor function disappeared after
4 weeks of treatment, suggesting rapid development of
tolerance to its acute detrimental cognitive effects.34
Valproic acid seems to have a good cognitive and
behavioural profile.35 However, when concentrations in
serum are within the target range, the drug can impair
attention, visuomotor function, complex decision-making,
and psychomotor speed. A few case reports have
described reversible parkinsonism and cognitive
impairment with its chronic usage.
As with other benzodiazepines, clonazepam and
clobazam commonly cause cognitive impairment and
sedation, which lead to withdrawal of medication.36
Clonazepam treatment is associated with a high rate of
drowsiness and behavioural changes, including decreased
attention, hyperactivity, irritability, and aggression,
particularly in children.37 Clobazam is less likely than
clonazepam to cause psychomotor impairment or
sedation, possibly because of its slightly different chemical
THE LANCET • Vol 357 • January 20, 2001
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REVIEW
structure.36 Mood changes, occasional irritability,
depression, aggression, and disinhibition have been
reported with its use.36
effects of established antiepileptics. Earlier data tended to
highlight the more detrimental effects of phenytoin
compared with carbamazepine and valproic acid.25 In the
first Veterans Administration Cooperative Study, which
fewer cognitive adverse effects than phenytoin,
phenobarbital, and primidone with the total behavioural
toxicity battery.38 Dodrill and Troupin found similar
efficacy between phenytoin and carbamazepine, but
significant differences in favour of carbamazepine on four
cognitive and one personality measure from a total of 35
neuropsychological tests.6 However, when patients with
toxic concentrations of phenytoin in serum (>120 ␮mol/L)
were eliminated from the analysis, all statistical differences
disappeared.7 Similarly, examination of the raw data from
the first Veterans Administration Cooperative Study
revealed no difference among the various antiepileptic
drugs.25
Most of the recent studies show comparable cognitive
effects among the established antiepileptic drugs. Brodie
and colleagues28 and Gillham and co-workers24 examined
patients on monotherapy with phenytoin, carbamazepine,
or valproic acid. Patients taking antiepileptics had lower
psychometric scores than those still untreated. No
individual test discriminated among the drugs, although
the carbamazepine-treated patients had lower composite
psychomotor scores, and those on phenytoin scored less
well on the composite memory scale. Duncan and
colleagues assessed the possible differential cognitive
effects of withdrawal of these three drugs. Only one of 64
tests showed differential improvement.39 Phenytoin and
carbamazepine produced much the same impairments in
healthy adults treated for 1 month. A review of 16 studies
comparing the cognitive effects of phenytoin and
carbamazepine supported no differential impact between
the two drugs.40 Similarly, differential effects of phenytoin
and valproic acid were recorded in only three of 32
measurements in a 2-year follow-up study.41
Even in the elderly, who are particularly susceptible to
drug-induced cognitive side-effects, little difference was
noted among phenytoin, carbamazepine, and valproic acid
at therapeutic doses.42,43 In the second Veterans
Administration Cooperative Study, carbamazepine and
valproic acid produced similar subtle negative cognitive
effects as suggested by the absence of practice effects that
were found in normal controls.44 With the exception of
phenobarbital, all established drugs seem to cause similar
dose-related cognitive side-effects, although individual
variability in tolerating these drugs at different doses is
extensive. The exception could be with valproic acid,
which seems marginally better tolerated than
carbamazepine and phenobarbital.24
Newer drugs
Although data on the newer antiepileptics are still limited,
initial evidence suggests a more favourable cognitive and
behavioural profile for some of these agents than for the
established drugs. Such differences could influence the
choice of drug.
Studies with lamotrigine in healthy volunteers and
epileptic patients have not revealed detrimental cognitive
effects with this treatment. In healthy volunteers,
lamotrigine did not affect attention, psychomotor speed,
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REVIEW
language, memory, or mood.45 In a double-blind add-on
study, there was no difference between patients
randomised to placebo or to the drug with respect to
concentration, psychomotor performance, and repetitive
mental activity.46 In a large, randomised, double-blind
monotherapy trial in which newly diagnosed patients
received lamotrigine or carbamazepine, similar efficacy was
shown with the two drugs, whereas patients treated with
lamotrigine had a lower drop-out rate. Fewer patients
complained of drowsiness with the new drug than with
carbamazepine. Further analysis revealed lack of
neuropsychological effects of lamotrigine.47 Better
tolerability in favour of lamotrigine has been confirmed in
a second double-blind comparative study in the elderly.48
Some patients have reported favourable effects of the drug
on psychological well-being that were not explained by
simple effects on seizure control, which could be a
consequence of suppression of interictal discharges or its
mood-improving properties. Positive and negative
psychotropic effects have been recorded in learning-
disabled patients treated with lamotrigine.
Vigabatrin is one of the most extensively studied of the
newer antiepileptics. Most randomised, placebo-
controlled, add-on studies generally revealed no adverse
effects on cognition or mood, even with doses up to 6 g
daily,49 and some even reported slightly improved function.
In a small monotherapy trial, patients randomised to
vigabatrin scored better in tests for memory and motor
speed than those taking carbamazepine. A greater degree
of sedation was reported during the first 6 weeks of
treatment in one study to which tolerance subsequently
developed. However, agitation, ill-temper, disturbed
behaviour, and depression have been reported.50 Paranoid
and psychotic symptoms can develop, and hyperkinesia
and agitation can occur in children.
Gabapentin is a particularly well-tolerated drug.50 In
healthy young adults it caused no,45 or few51 cognitive side-
effects when compared with other antiepileptics. In a
randomised, placebo-controlled, dose-ranging, cross-over
study, gabapentin did not affect psychomotor or memory
scores, nor did it produce any change in subjective
measures of well-being.52 Some sedation was reported at
the highest dose (2·4 g daily). Another study also reported
no adverse effects of gabapentin on cognition or quality of
life in epileptic patients.53 Dimond and co-workers assessed
the influence of this antiepileptic on mood and general
well-being using data from five double-blind trials, and
found improved quality of life in some patients irrespective
of seizure control, suggesting a possible independent
positive effect on mood.54 A few case reports of
hyperactivity and aggressive behaviour have been
associated with use of gabapentin in children with learning
disabilities.
Compared with lamotrigine and gabapentin, topiramate
caused clinically significant declines in attention and word
fluency after acute doses, and poorer psychomotor speed
and attentional performance after 1 month’s treatment in
healthy young adults.45 Controlled trials of topiramate as
adjunctive therapy have reported cognitive impairment
including slowed thinking, somnolence, fatigue, confusion,
and poor concentration.36 Clinical series from specialist
centres have also reported cognitive and behavioural side-
effects such as impaired concentration and memory,
mental slowing, and word-finding difficulties. Severe
psychiatric side-effects including depression, paranoia, and
acute confusional psychosis have been reported with
topiramate. However, such neurocognitive effects might
lessen over time and could be avoided by slower titration.
In a recent study, the cognitive functions of patients
220
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randomised to addition of either topiramate or valproic
acid to existing carbamazepine monotherapy were
measured.55 Researchers used a starting daily topiramate
dose of only 25 mg and a slow titration regimen, and did
neuropsychometric testing 8 weeks after the last dose
increase to allow habituation. There was little difference in
cognitive effects between the two drugs.
Four studies have been published that assess the
neuropsychological impact of tiagabine. Two randomised,
placebo-controlled studies found no significant changes in
cognitive function with adjuvant tiagabine treatment.56,57
Reported behavioural changes such as aggression,
irritability, lethargy, and drowsiness, were transient and
usually occurred during the titration period. Two studies,
one of which was placebo-controlled, used doses up to
56 mg daily and did not find any clinically important
changes with the addition of tiagabine on scores of
cognition and mood.58,59
Few data are available on the possible cognitive and
behavioural effects of oxcarbazepine. In a double-blind,
cross-over study in healthy volunteers, oxcarbazepine
produced a slight psychomotor stimulant effect with no
effect on long-term memory.60 In a small double-blind,
placebo-controlled interaction protocol, the drug was
given as add-on therapy to patients already receiving either
phenytoin, carbamazepine, or valproic acid as
monotherapy. Oxcarbazepine did not cause important
changes in cognitive function testing.61 Another study
assessed memory, attention, and simple psychomotor
speed in patients receiving either oxcarbazepine or
phenytoin as monotherapy and found no difference in
cognitive side-effects between the two drugs.62
Zonisamide has recently been licensed in the USA,
although it has been available in Japan and Korea for many
years. In double-blind, placebo-controlled studies of
zonisamide, mild degrees of somnolence, confusion,
abnormal or slowed thinking, nervousness, and fatigue
have been reported without leading to drug withdrawal in
most cases. One small study assessed cognitive functioning
before and after initiation of zonisamide in patients with
refractory partial epilepsy.63 High concentrations in plasma
were associated with impaired verbal learning, but did not
affect psychomotor abilities. Recently, case reports and
retrospective surveys of acute psychosis during treatment
with zonisamide have appeared in the literature.
Levetiracetam has been licensed in the USA and
approved recently by the European regulators. In clinical
trials, this drug was associated with a higher rate of
somnolence and dizziness than placebo. However, patients
randomised to levetiracetam reported higher ratings in
overall health-related quality of life, including cognitive
functioning, which was partly due to improved seizure
control.64 One small study found no change in
psychomotor or memory ability after levetiracetam was
added to the existing antiepileptic regimen for 1 week.65
Psychosocial factors
Epilepsy has long been a misunderstood and stigmatising
disorder. Although in western societies it is no longer
thought of as the product of demonic possession,
misconception and prejudice remain. In a survey carried
out in the USA in 1979, 92% of those interviewed thought
epilepsy was not a form of insanity, but only 79% believed
epilepsy patients should be employed, and only 89%
would not object to their children playing with others who
had epilepsy.66 Although there has been much
improvement in public opinion over the past few decades,
distorted and sensationalised depiction of seizures in the
media continue to fuel public misconception. Perception
THE LANCET • Vol 357 • January 20, 2001

of stigma by patients still contributes to their poor quality
of life. Baker and colleagues recently surveyed more than
5000 patients living in 15 European countries and found
that 51% felt stigmatised.67 Such feelings undoubtedly
affect personal development, including self-esteem, mood,
behaviour, and cognitive abilities. A restricted lifestyle in
areas such as driving and employment, dependent
behaviour, poor academic achievement, and low rate of
marriage can all contribute to a downward spiralling of
quality of life.
Conclusion
A better appreciation of the complex cognitive and
behavioural dimensions of epilepsy would allow clinicians
to provide a more holistic and patient-centred approach to
management. Underlying neuropathology, and ictal and
subclinical neuronal discharges, can have adverse cognitive
and behavioural consequences. Some of these psychosocial
disabilities can be cumulative or even irreversible. Studies
of surgical outcomes indicate that even when surgery is
successful in eliminating seizures, patients with a long
history commonly do not gain employment, marry, or have
children, but remain dependent on family and the welfare
system. Such irreversibility could also explain why patients
with childhood-onset epilepsy suffer social and educational
disadvantages even after entering remission in adulthood.68
Early targeting of rational combination therapy or surgery
has been advocated to prevent the progression to refractory
epilepsy with attendant pharmacoresistance, cognitive
decline, and psychosocial disability.
Neuropsychological effects of antiepileptic-drug
treatment in each patient must, therefore, be assessed
individually in the context of these overlapping and inter-
related factors. Drugs per se can impair
neuropsychological functions, but their effect on seizure
control could, in turn, improve cognition and behaviour.
Interactions among these factors could account for the
wide interindividual variability in cognitive and
behavioural effects of a particular antiepileptic. Therefore,
it is essential that all contributory factors are considered
and controlled for when studying the neuropsychological
functioning of patients with epilepsy.
Although direct evidence is lacking, pharmacogenetic
differences might also contribute to variation in tolerability
(as well as efficacy) of treatment among individuals, as is
now recognised across a range of medical disciplines such
as asthma, Alzheimer’s disease, and coronary heart disease.
This could be effected via polymorphisms in drug-
metabolising genes, or other genes involved in an
antiepileptic drug’s pharmacokinetic or pharmacodynamic
effects. Delineation of the influence of genetics in drug
efficacy and tolerability could allow pharmacogenetic
profiling to personalise treatment so that the right drug is
given to the right patient.
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