European Journal of Paediatric Neurology 32 (2021) 106e114

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European Journal of Paediatric Neurology

Effects of antiseizure monotherapy on visuospatial memory in

pediatric age
Francesca Felicia Operto a, *, 1, Grazia Maria Giovanna Pastorino a, 1, Carlo Di Bonaventura b,
Chiara Scuoppo a, Chiara Padovano a, Valentina Vivenzio a, Serena Donadio a,
Giangennaro Coppola a
a
Child and Adolescent Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy
b
Epilepsy Unit, Department of Human Neurosciences, “Sapienza” University of Rome, Rome, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Visuospatial abilities are fundamental for good school achievements and good daily
Received 16 December 2020 functioning. Previous studies showed an impairment of visuospatial skills in pediatric patients with
Received in revised form epilepsy; pharmacological treatment, although indispensable for the seizure control, could further affect
8 April 2021
cognitive functions. The aim of our study was to evaluate the visuospatial skills in children and ado-
Accepted 10 April 2021
lescents with different forms of epilepsy well-controlled by antiseizure monotherapy, both at baseline
and after one year follow-up, through a standardized neuropsychological assessment.
Keywords:
Methods: We recruited 207 children and adolescents (mean age ¼ 10.35 ± 2.39 years) with epilepsy, well
Visuospatial memory
Epilepsy
controlled by monotherapy with levetiracetam, valproic acid, ethosuximide, oxcarbazepine or carba-
Children mazepine and 45 age/sex-matched controls. All the participants performed the Rey-Osterrieth Complex
Antiseizure medications Figure, a standardized test for visuospatial perception and visuospatial memory assessment, at baseline
and after 12 month of drug therapy. Age, sex, executive functions, non-verbal intelligence, age at onset of
epilepsy, epilepsy duration, epilepsy type, lobe and side of seizure onset were considered in our analysis.
EEG, seizure frequency, and drug dose were also recorded.
Results: At baseline, the epilepsy group performed significantly worse than controls in the Immediate
Recall test but not the Direct Copy test, without differences between epilepsy subgroups. Immediate
Recall scores were related to age of seizure onset and epilepsy duration and executive functions. The re-
assessment after 1 year showed that the Immediate Recall mean scores were not significantly changed in
the levetiracetam and oxcarbazepine group, while they significantly worsened in the valproic acid,
ethosuximide and carbamazepine groups. The Immediate Recall scores were correlated to age, age at
onset of epilepsy, epilepsy duration, and executive functions.
Conclusions: Children with epilepsy may exhibit visuospatial memory impairment compared to their
peer, that may be correlated to some features of the epilepsy itself and to the impairment of executive
functions. Different antiseizure medications can affect visuospatial memory differently, so it is important
monitoring this aspect in pediatric patients.
© 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

1. Introduction and allow each individual to adequately interact with the external
world [1]. The visuospatial perception skills are the ability to
Visuospatial perception and visuospatial memory are two represent, modify and recall symbolic non-linguistic information.
fundamental abilities for the correct human cognitive functioning, The visuospatial memory, included by some authors in the working

* Corresponding author. Child and Adolescent Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Via Salvator Allende, Via
Allende, 84081, Baronissi, SA, Italy.
E-mail address: opertofrancesca@gmail.com (F.F. Operto).
1
These authors equally contributed to this work.

https://doi.org/10.1016/j.ejpn.2021.04.004
1090-3798/© 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
F.F. Operto, G.M.G. Pastorino, C. Di Bonaventura et al.
Abbreviations
LEV levetiracetam
CBZ carbamazepine
EEG electroencephalography
ETS ethosuximide
IQ intelligence quotient
OXC oxcarbazepine
RCFT Rey-Osterrieth Complex Figure Test
SD standard deviation
SPM Standard Progressive Matrices
VP valproic acid
WISC-V Wechsler Intelligence Scale for Children e Fifth
Edition
memory, is distinguished in a visual component, which store visual
information such as colors, shapes and orientation of objects, and a
spatial component that acquires the spatial relationships between
different elements [2,3]. These abilities are indispensable in a
complex variety of human actions, such as non-verbal communi-
cation, orientation and movement in the space, spatial represen-
tation and memorization, geometric recognition, graphic
production and in different forms of problem solving and school
achievements [4e6].
Although visuospatial skills appear very early, these cognitive
processes are not fully developed in children younger than 7 years
and continue to refine during adolescence [7,8]. Neuroimaging
studies, investigating the neural correlates of visuospatial memory,
suggested that these networks consist of some cortical areas such
as superior frontal and intraparietal cortex and also of white matter
tracts connecting them [9,10].
Although several literature studies suggest an impairment of
visuospatial skills in children and adolescents with epilepsy, the
impairment of visuospatial memory skills have not sufficiently
been documented in different form of epilepsy [11e15]. Myatchin
and Lagae (2011) [16] found that in children with well-controlled
epilepsy, compensatory recruitment of the working memory
network occurred during visuospatial memory tasks, even if the
performance seems normal. In a recent work by MacAllister et al.
(2019) [17], the authors evaluated the neuropsychological functions
of 80 children and adolescents between 6 and 15 years (mean
age ¼ 9.87 ± 2.82) with focal and generalized epilepsy versus a
control group, using the Wechsler Intelligence Scale for Children
test - Fifth Edition (WISCeV). Relative to controls, patients with
epilepsy demonstrated significantly lower mean scores in all the
WISC-V indexes, including the visuospatial perception index
(p < 0.001); furthermore, the percentage of subjects with epilepsy
who scored below the average range in the visuospatial perception
index was significantly higher in the epilepsy group than in the
control group (20% versus 1.3%; p < 0.001).
Epilepsy is one of the most frequent neurological conditions in
pediatric age, and several studies demonstrate that children and
adolescents with epilepsy present some deficits in neuropsycho-
logical functions, which can affect school learning, personal/social
functioning and the family’ quality of life [18e20].
More in detail, despite a normal global intelligence, in subjects
with epilepsy an impairment of some higher cognitive abilities
such as executive functions, visuospatial skills and social cognition
may occur. The cause of this impairment seems to be multifactorial
and associated with the type of epilepsy, the structural abnormal-
ities, the age at onset of epilepsy, the disease duration, the seizure
frequency and the antiseizure medication (ASM) [21].
107
European Journal of Paediatric Neurology 32 (2021) 106e114
Antiseizure drugs are often indispensable for the treatment of
epilepsy and are often effective in controlling seizures, however
drug therapy is not free from causing adverse events on the
cognitive profile as they can negatively impact in a nervous system
still in development, and also exacerbate pre-existing neuropsy-
chological impairments by modulating the neuronal excitability
[22,23].
The relative risk of side effects on cognition increases in relation
to the use of higher doses of antiepileptic drugs, elevated serum
levels, rapid titrations and polytherapy [24].
Although polytherapy is more associated with cognitive
impairment, antiepileptic monotherapy can also have a detrimental
effect on the cognitive profile, and some drugs have more pro-
nounced effects than others. In this regard, a randomized
controlled study showed that discontinuation of monotherapy in
seizure-free patients was associated with a cognitive improvement
in attention and memory skills [25]. Overall, older drugs, such as
phenobarbital and phenytoin, appear to have greater adverse ef-
fects on cognitive functioning than ethosuximide (ESM), valproic
acid (VPA) and carbamazepine (CBZ). Other drugs such as lamo-
trigine, levetiracetam (LEV) and oxcarbazepine (OXC) appear to
have a good tolerability profile on cognition [26,27]. Even newer
drugs, such as lacosamide and perampanel, will appear to have no
adverse effects on cognitive function in children [28].
The aim of our observational study was to evaluate the visuo-
spatial perception and visuospatial memory abilities in a popula-
tion of children and adolescents with different forms of epilepsy
well-controlled by antiepileptic monotherapy, both at baseline
and after one year follow-up, through a standardized neuropsy-
chological assessment.
Secondary objective of our study was to evaluate the impact of
some demographic and clinical variables related to epilepsy (sex,
age, executive functions, non-verbal intelligence, age at onset of
epilepsy, epilepsy duration, epilepsy type, seizure frequency, ASM
dose, side and lobe of seizure onset) on visuospatial performance.
2. Methods
2.1. Study design and participants
Our sample, composed by 207 children and adolescents (6e18
years) with a new diagnosis of epilepsy, was recruited from the
Child Neuropsychiatry Unit of University of Salerno between
January 2013 and January 2020.
The aims and procedures of the study were explained to all the
participants, and written informed consent from the parents was
obtained. The study was performed according to the rules of good
clinical practice of the Helsinki Declaration and was approved by
the local Ethics Committee.
The diagnosis was made by two different clinicians with de-
cades of experience in epilepsy, through the clinical features and
the electroencephalography (EEG) reports, according with the In-
ternational League Against Epilepsy classification. In focal epilepsy
the localization of seizure onset (lobe/side) was based on EEG
features; through EEG recording the presence of electrical status
epilepticus during sleep (ESES) were also excluded.
The eligibility criteria were the following: noneverbal intelli-
gence higher than the 5th percentile (intelligence quotient -
IQ  70) measured using the Raven's Progressive Matrices; anti-
seizure monotherapy which included one of CBZ, OXC, VPA, ESM, or
LEV; epilepsy well controlled by monotherapy (at least 75% of
seizure reduction).
The exclusion criteria were the presence of neurological, psy-
chiatric, or other relevant medical conditions which could nega-
tively affect neuropsychological performances (visual or motor
F.F. Operto, G.M.G. Pastorino, C. Di Bonaventura et al. European Journal of Paediatric Neurology 32 (2021) 106e114

deficit, cerebral palsy, intellectual disabilities, anxiety and mood
disorders, specific learning disorders, autism spectrum disorders,
attention deficit/hyperactivity disorder, psychosis).
The subjects to whom was added the second antiseizure drug,
due to poor seizure control, were also excluded. All patients were
untreated at baseline. The type of antiseizure drug and the dose
administered were determined by the treating physician for each
patient in order to achieve optimal seizure control and avoid
adverse effects. At each follow-up (approximately every 3e6
months) patients received routine laboratory test including serum
antiepileptic drug levels, and EEG recording in which ictal and
interictal epileptiform activity was assessed.
As habitual clinical practice, all the participants performed the
Rey-Osterrieth Complex Figure Test, a standardized neuropsycho-
logical test for the evaluation of the visuospatial perception and the
visuospatial memory abilities, at baseline and after 12 months of
antiseizure monotherapy; they also performed only at baseline
Raven's Progressive Matrices test, for the evaluation of non-verbal
intelligence abilities. Age, sex, seizure types, seizure frequency,
and antiseizure drug dose were also recorded. The demographic
and clinical characteristics are summarized in Table 1.
Finally, we also recruited 45 age/sex-matched controls who
underwent the Rey-Osterrieth Complex Figure Test and Raven's
Progressive Matrices during a screening program for learning dis-
abilities. The control group consisted only of healthy children who
had no Specific Learning Disorders or other relevant medical,
neurological or psychiatric conditions (the same exclusion criteria
were applied to the control group).
2.2. Rey-Osterrieth Complex Figure Test (RCFT)
Rey-Osterrieth Complex Figure Test is a widely used figural copy
and recall test for the evaluation of visuospatial perceptual and
visuospatial memory skills in both adults and children [29].
Subjects were provided with a pencil and a blank sheet of paper.
Initially, each subject was asked to copy a complex geometric figure
(Fig. 1) presented from a landscaped viewpoint as best as they can
(RCFT-Direct Copy). After 3 min, with no previous warning, each
subject was given another blank sheet and asked to recall the
design (RCFT-Immediate Recall). There was no time limit set for the
copy and recall. The drawings were scored according to the tradi-
tional system which evaluated 18 separated elements of the figure,
according to a two-point scale, for up to 36 points [30]. Two points
were attributed when the graphic element is correct and placed
properly; 1 point when the element was distorted, incomplete or
incorrectly placed; 0.5 points was given was incorrectly placed and
reproduced poorly; 0 points when the element was absent or not
unrecognizable. Raw scores are also converted into percentiles,
according to age [31].

Table 1
Demographic and clinical characteristics.

Epilepsy LEV VPA ESM OXC CBZ Control Statistics

Group Group

N Baseline 207 58 60 22 23 44 45 NA
N at T1 183 50 52 20 21 40 e NA
Sex 30 40 12 13 25 26 (58%) Chi-square
male 120 (58%) (52%) (67%) (55%) (57%) (58%) X2 ¼ 2.941
p ¼ 0.709
Age in years 10.35 (2.39) 10.83 (2.30) 10.55 (2.60) 9.55 (1.68) 9.74 (2.32) 10.18 (2.42) 9.91 (2.16) H Kruskall Wallis
M (SD) H ¼ 7.511 p ¼ 0.185
9.53 (2.41) 10.08 (2.36) 9.61 (2.67) 8.63 (1.65) 9.09 (2.09) 9.35 (2.45) e H Kruskall Wallis
Age at onset H ¼ 7.727 p ¼ 0.102
0.83 (0.67) 0.74 (0.52) 0.94 (0.90) 0.91 (0.89) 0.65 (0.49) 0.83 (0.37) e H Kruskall Wallis
Epilepsy duration in years H ¼ 4.282 p ¼ 0.369
Seizure types 95 (46%) 13 (23%) 60 (100%) 22 (100%) e e e NA
Generalized 63 (30%) 21 (36%) e e 13 (57%) 29 (66%)
Focal - aware 49 (24%) 24 (41%) e e 10 (43%) 15 (34%)
Focal - impaired awareness
Probable side of seizure 52 (46%) e e
onset 60 (54%)
Left
Right
Probable lobe of seizure 68 (61%) e e
onset 29 (26%)
Temporal 15 (13%)
Frontal
Occipital
Seizure number (per month) 12.64 12.53 (9.02) 10.93 (9.56) 21.82 (17.13) 11.22 (8.59) 11.25 (8.46) e H Kruskall Wallis
M (SD) (10.58) H ¼ 8.567 p ¼ 0.073
36 (17%) 12 (21%) 11 (18%) 2 (9%) 4 (18%) 7 (17%) - Chi-square
Seizure at T1 reduction >75% 171 (83%) 46 (79%) 49 (82%) 20 (91%) 19 (82%) 37 (83%) X2 ¼ 1.599
Seizures free % p ¼ 0.809
ASM dose (mg/d) - 1022.44 (211.96) 985.00 (226.11) 990.91 (242.82) 1000.00 (326.13) 918.18 (180.79) e NA
M (SD)
24 8 7 2 2 5 e NA
Drop-out 3 low efficacy 2 low efficacy 2 lost at follow- 2 lost at follow- 3 poor
2 poor 2 poor up up compliance
compliance compliance 2 lost at follow-
3 lost at follow- 3 lost at follow- up
up up
Non verbal Intelligence 93.10 (8.79) 94.48 (8.45) 92.33 (8.78) 92.05 (8.21) 93.35 (9.61) 92.70 (9.25) 93.73 H Kruskall Wallis
(SPM) (10.22) H ¼ 2.718 p ¼ 0.743

N ¼ sample size; T1 ¼ 12 month follow-up; M ¼ mean; SD ¼ standard deviation; ASM ¼ antiseizure medication; CBZ ¼ carbamazepine; VPA ¼ valproic acid;
ESM ¼ ethosuximide; OXC ¼ oxcarbazepine; LEV ¼ Levetiracetam; NA ¼ not admitted; SPM¼ Standard Progressive Matrices.

108
F.F. Operto, G.M.G. Pastorino, C. Di Bonaventura et al.
Fig. 1. Rey-osterrieth complex Figure.
2.3. EpiTrack junior
EpiTrack Junior [32] is a screening tool for executive functions
which is especially sensitive to drug effects and therefore particu-
larly indicated for monitoring ongoing treatment. It consists of six
subtests (inhibition, visual-motor speed, mental flexibility, visual
motor planning, verbal fluency and working memory) that
contribute to determining an age-corrected total score. The
maximum age-corrected total score is 49. A total score below 31
points indicates an executive functions impairment, according to
the following: 29e30 points ¼ mild impairment; 28
points ¼ significant impairment. Significant change in two subse-
quent measures is indicated by a gain of >3 points and a loss of >2
points.
2.4. Standard Progressive Matrices (SPM)
The Raven Progressive Matrices is a test typically used for
measuring non-verbal intelligence in subjects from 5 years to
adulthood [33]. They are available in different forms.
All participants in our study were administered the Standard
Progressive Matrices, that includes five series of 12 elements, which
require an increasing cognitive capacity to encode and analyze non-
verbal visuospatial information. Raw scores have been converted in
percentiles and age-weighted standard scores with mean ¼ 100
and standard deviation ¼ 15. Scores 5 percentile or 70 standard
score are considered in the norm [34].
2.5. Statistical analysis
All neuropsychological scores were expressed as
mean ± standard deviation (SD). The percentage of participants
scoring lower than the norm (<2 SD or <1 DS) was considered. In
order to verify the data distribution, the Kolmogorov-Smirnov
normality test was preliminarily performed. Because of the pres-
ence of some data not normally distributed, non-parametric
methods were employed for our analysis. The comparison of pro-
portions was made using the Chi-Square test with Yates's correc-
tion or with Fisher exact test, based on the sample size. The Kruskal
Wallis H test was used for the comparison of mean scores in several
independent samples. The mean scores comparison in two related
samples were performed using the Wilcoxon signed-rank test.
The two-tailed Spearman rank correlation test (with one-to-one
variable analysis) was employed to evaluate the relationship be-
tween different variables. The correlations were interpreted as
109
European Journal of Paediatric Neurology 32 (2021) 106e114
follow: <0.2, low; 0.21e0.40, fair; 0.41e0.60, moderate; 0.61e0.80,
good; 0.81e1.00, very good.
All data were analyzed using Statistical Package for Social Sci-
ence software, version 23.0 (IBM Corp, 2015). Our hypotheses were
tested using Bonferroni adjusted alpha levels of 0.0025 per test
(0.05/20).
3. Results
3.1. Sample characteristics
Six hundred and thirty-four medical records were initially
considered, 427 were excluded due to the presence of ASM poly-
therapy, intellectual disability, neurosensory deficits or complex
disabilities.
Finally, we retrospectively recruited 207 children and adoles-
cents with epilepsy aged between 6 and 18 years
(mean ¼ 10.35 ± 2.39) who underwent Rey-Osterrieth Complex
Figure Test before and during ASM monotherapy with LEV (n ¼ 58),
VPA (n ¼ 60), ESM (n ¼ 22), OXC (n ¼ 23), or CBZ (n ¼ 44).
Forty-five age/sex matched controls are also recruited. All de-
mographic and clinical features of the participants are summarized
in Table 1. Patients in the five ASM groups did not significantly differ
in demographic or clinical characteristics (sex, age, age at onset of
epilepsy, epilepsy duration and seizure frequency at baseline)
(Table 1). After 12 months of ASM therapy, all patients had 75%
seizure reduction or were seizure-free (Table 1). At the 1-year
follow-up, different ASM treatment led to comparable reductions
in seizure frequency (Table 1). The five treatment groups and the
control group did not significantly differ in non-verbal intelligence
quotient, measured by Standard Progressive Matrices (Table 1).
3.2. Baseline assessment
Overall, analyzing the results obtained in RCFT-Direct Copy,
6.76% (14/207) of patients with epilepsy showed a score under the
norm (<5 percentiles), whereas 7.25% (15/207) showed a score at
low limits of the norm (5 -15 percentiles) versus 0% (0/45) and
2.23% (1/45) of controls respectively. These differences did not
reach the statistical significance on Fisher's exact test, however a
trend towards significance could be highlighted in patients
achieving a score <5 percentile in the two groups. (F ¼ 0.0814,
p ¼ 0.058; F ¼ 0.3182, p ¼ 0.144).
The RCFT-Direct Copy mean scores of the five treatment groups
(LEV, VPA, ETS, OXC and CBZ) and of the control group did not differ
significantly from each other, as showed by Kruskall-Wallis H test
for unpaired sample (Table 2).
The Spearman correlation test showed that, in patients with
epilepsy (total sample), the RCFT-Direct Copy scores were related to
age, age at onset of epilepsy and Intelligence non-verbal quotient
(measured by Raven Progressive Matrices), while there was no
significant association with executive functions (measured by
Epitrack Junior Test), epilepsy duration, and seizure frequency
(Table 3; Fig. 2). There was also no significant difference in mean
scores based on the following variables: sex (Mann-Whitney U test
(n ¼ 207), U ¼ 3033, p ¼ 0.714), epilepsy type (Mann-Whitney U
test (n ¼ 207), U ¼ 4930.0, p ¼ 0.362), side of seizure onset (Mann-
Whitney U test (n ¼ 207), U ¼ 1670.5, p ¼ 0.518) and lobe of seizure
onset (Kruskall-Wallis H test (n ¼ 207), H ¼ 1.478, p ¼ 0.478).
Analyzing RCFT-Immediate Recall we found that 7.25% (26/207)
of patients with epilepsy showed a score under the norm (<5
percentiles), whereas 12.56% (26/207) showed a score at low limits
of the norm (5 -15 percentiles) versus 2.23% (1/45) and 4.45% (2/
45) of controls respectively. These differences did not reach the
statistical significance on Fisher's exact test (F ¼ 0.2069, p ¼ 0.110;
F.F. Operto, G.M.G. Pastorino, C. Di Bonaventura et al. European Journal of Paediatric Neurology 32 (2021) 106e114

Table 2
Visuospatial perception (RCFT-Direct Copy) in epilepsy patients at baseline and after 1 year follow-up.

ASM Direct Copy at baseline mean ± standard deviation Direct Copy after 1 year mean ± standard deviation Statistic
Wilcoxon signed-rank test

Levetiracetam 28.95 ± 5.71 29.67 ± 5.29 W ¼ 1.812 p ¼ 0.070

Valproic Acid 28.60 ± 5.29 29.03 ± 5.04 W ¼ 1.383 p ¼ 0.167
Ethosuximide 27.73 ± 3.69 28.27 ± 3.97 W ¼ 1.359 p ¼ 0.174
Oxcarbazepine 28.43 ± 4.29 28.78 ± 4.25 W ¼ 0.820 p ¼ 0.412
Carbamazepine 28.36 ± 4.62 28.95 ± 4.35 W ¼ 1.517 p ¼ 0.129
Control Group 29.82 ± 3.42 - -
Statistic H ¼ 5.868 p ¼ 0.319 - -
Kruskall-Wallis H test

ASM ¼ Antiseizure medication; statistically significant p values are in bold.

Table 3 related to age, age at onset of epilepsy, epilepsy duration, and ex-
Spearman correlation test. ecutive functions (measured by EpiTrack Junior Test) while there
EPILEPSY GROUP was no significant association with Intelligence non-verbal quo-
RCFT RCFT
tient (measured by Raven Progressive Matrices), and seizure fre-
Direct Copy Immediate Recall quency (Table 3; Fig. 2).
There was also no significant difference in mean scores based on
Executive Functions (EpiTrack Junior) r ¼ 0.133 r ¼ 0.425
p ¼ 0.055 p < 0.001 the following variables: sex (Mann-Whitney U test (n ¼ 207),
Non-verbal Intelligence (SPM) r ¼ 0.238 r ¼ 0.044 U ¼ 5375.0, p ¼ 0.055), epilepsy type (Mann-Whitney U test
p ¼ 0.001 p ¼ 0.533 (n ¼ 207), U ¼ 5022.5, p ¼ 0.487), side of seizure onset (Mann-
Age r ¼ 0.422 r ¼ 0.575 Whitney U test (n ¼ 207), U ¼ 1618.5, p ¼ 0.732) and lobe of seizure
p < 0.001 p < 0.001
Age at onset r ¼ 0.445 r ¼ 0.698
onset (Kruskall-Wallis H test (n ¼ 207), H ¼ 2.434, p ¼ 0.296).
p < 0.001 p < 0.001
Epilepsy duration r ¼ 0.021 r ¼ -0.332
p ¼ 0.786 p < 0.001 3.3. Time 1 assessment and comparison between time 1 and
Seizure frequency r ¼ 0.033 r ¼ 0.025 baseline
p ¼ 0.632 p ¼ 0.721

RCFT ¼ Rey-Osterrieth Complex Figure Test; SPM¼ Standard Progressive Matrices.
Significant results are in bold.
F ¼ 0.3795, p ¼ 0.137).
The mean scores comparison, performed by Kruskall-Wallis H
test, revealed that the RCFT-Immediate Recall mean scores of LEV,
VPA, ETS, OXC and CBZ group did not significantly differ from each
other, but they were all significantly lower compared to the control
group (Table 4).
The Spearman correlation test showed that, in patients with
epilepsy (total sample), the RCFT-Immediate Recall scores were
We performed the re-assessmant after 12 months only in pa-
tients with epilepsy (n ¼ 183); After 12 months, 9.84% (18/183) of
patients with epilepsy showed a RCFT-Direct Copy score under the
norm (<5 percentiles), whereas 8.20% (15/183) showed a score at
low limits of the norm (5 -15 percentiles); while 21.74% (45/183) of
patients with epilepsy showed a RCFT-Immediate Recall score un-
der the norm (<5 percentiles), whereas 10.14% (21/183) showed a
score at low limits of the norm (5 -15 percentiles).
After 12 months, we found that the RCFT-Direct Copy mean
scores did not significantly differ from baseline, in any of the five
treatment groups (Table 2; Fig. 3).
The comparison of the RCFT-Immediate Recall mean scores

Fig. 2. Spearman correlation: RCFT-Direct Copy scores were related to age Raven Progressive Matrices scores (a) and age at onset of epilepsy (b); RCFT-Immediate Recall scores were
related to age at onset of epilepsy (c), epilepsy duration (d) and EpiTrack Junior scores (e). RCFT ¼ Rey-Osterrieth Complex Figure Test.

110
F.F. Operto, G.M.G. Pastorino, C. Di Bonaventura et al. European Journal of Paediatric Neurology 32 (2021) 106e114

Table 4
Visuospatial memory (RCFT-Immediate Recall) in epilepsy patients at baseline and after 1 year follow-up.

ASM Immediate Recall at baseline Immediate Recall after 1 year mean ± standard deviation Statistic
mean ± standard deviation Wilcoxon signed-rank test

Levetiracetam 13.71 ± 5.45 13.30 ± 5.06 z ¼ 0.700

p ¼ 0.484
Valproic Acid 13.52 ± 6.14 11.97 ± 5.43 z ¼ -3.230
p ¼ 0.001
Ethosuximide 12.86 ± 4.73 11.27 ± 3.44 z ¼ -3.219
p ¼ 0.001
Oxcarbazepine 13.30 ± 5.80 12.35 ± 4.91 z ¼ 1.761
p ¼ 0.078
Carbamazepine 13.41 ± 5.08 11.34 ± 3.31 z ¼ -3.524
p < 0.001
Control Group 17.47 ± 5.44 - -
Statistic H ¼ 18.988 p ¼ 0.002 - -
Kruskall-Wallis H test (ASM vs Control Group)
Statistic H ¼ 0.701 p ¼ 0.951 - -
Kruskall-Wallis H test (between ASM groups)

ASM ¼ Antiseizure medication; statistically significant p values are in bold.

4. Discussion

Several non-independent factors can contribute to cognitive

Fig. 3. Comparison of RCFT-Direct Copy and RCFT-Immediate Recall mean scores at
baseline and after 12 months; CBZ ¼ carbamazepine; VPA ¼ valproic acid;
ESM ¼ ethosuximide; OXC ¼ oxcarbazepine; LEV ¼ Levetiracetam; To ¼ baseline;
T1 ¼ 12 months follow-up. RCFT ¼ Rey-Osterrieth Complex Figure Test. RCFT ¼ Rey-
Osterrieth Complex Figure Test.
showed different results, depending on the ASM group considered:
VPA, ETS, and CBZ mean scores was significantly lower at Time 1
compared to the baseline; LEV and OXC mean scores did not
significantly differ after 12 months follow-up (Table 4; Fig. 3).
No significant relationship was found between drug dose and
RCFT-Copy and RCFT-Immediate Recall scores (LEV: r ¼ 0.181
p ¼ 0.173, r ¼ 0.136 p ¼ 0.308; VPA: r ¼ 0.233 p ¼ 0.086, r ¼ 0.143
p ¼ 0.275; ETS r ¼ 0.122 p ¼ 0.590, r ¼ 0.229 p ¼ 0.305; OXC r ¼ -
0.125 p ¼ 0.569, r ¼ 0.189 p ¼ 0.389; CBZ r ¼ 0.140 p ¼ 0.364,
r ¼ 0.0289 p ¼ 0.057).
111
problems in children and adolescents with epilepsy, and it is not
always easy to consider their role separately [35]. Probably the
main factor responsible for cognitive impairment is the epileptic
process itself, and the underlying brain dysfunction; the contribu-
tion of the different epilepsy-related factors, such as age at onset,
seizure type and frequency, EEG abnormalities is complicated to
quantify. It is only in recent years that the effect of ASMs on
cognitive functioning has been recognized and emphasized. With
the introduction of the new ASMs, which have a similar efficacy in
the seizure control, the adverse effects on cognition and memory
become discriminating in the choice of the pharmacotherapy,
especially in pediatric age when these functions are preparatory to
school achievement and essential for a good adaptability to all life
contexts [35].
Our longitudinal retrospective study was based on 207 pediatric
patients, newly diagnosed with epilepsy, who underwent neuro-
psychological assessment for visuospatial perception and memory
before and after 12 months of the introduction of LEV, VPA, ESM,
OXC, or CBZ monotherapy.
The five treatment groups were homogeneous for age, sex, age
of epilepsy onset, duration of epilepsy and number of seizures at
baseline.
At baseline, a score at the low limits of the norm was found in
7.25% and 12.56% of patients in visuospatial perception and visuo-
spatial memory skills respectively, while approximately 7% of our
patients scored below the norm in both of these abilities. Visuo-
spatial perception skills mean scores did not differ from the control
group; in contrast, visuospatial memory skills mean scores were
significantly lower than controls across all five treatment. This data
is consistent with the other literature data, which showed that in
subjects with epilepsy there was a more or less severe impairment
of visuospatial memory skills while the visuospatial perception was
preserved. The study by Tallarita and colleagues (2019) [13] on 189
patients with epilepsy demonstrated that temporal lobe epilepsy
did not negatively affect visuospatial functions but significantly
impaired visuospatial memory, regardless of the lateralization of
the epileptic focus. Furthermore, the study by Myatchin et al. (2011)
[17] on 62 children with well-controlled epilepsy and normal IQ,
showed a compensatory activation of cortical Working Memory
Networks during a visuospatial task, even when performance was
normal.
F.F. Operto, G.M.G. Pastorino, C. Di Bonaventura et al.
In our sample, worse performance in visuospatial memory was
related to earlier onset and longer duration of epilepsy and exec-
utive functions, while there was no significant association with
non-verbal IQ, seizure frequency, epilepsy type, lobe and side of
seizure onset.
Our data reinforce the evidences that suggests that an earlier
age of the seizures onset can lead to a greater impairment of
cognitive functions, acting on a neuronal system still in develop-
ment [36e38].
In our study, a positive correlation was found between executive
functions and visuospatial memory skills at baseline. This rela-
tionship was not present in visuospatial perception skills.
Based on our results, it is possible to hypothesize that visuo-
spatial memory ability may depend on executive functions, which,
in turn, may be impaired in epileptic patients and may also be
affected by drug therapy [22]. It would be useful to better investi-
gate the role of individual executive functions (focused attention,
working memory) on visuospatial memory through multifactorial
analysis in future studies.
The relationship between the impairment of visuospatial
memory skills and the lobe/side of seizure onset is controversial.
Although it is generally accepted that the left temporal lobe is
involved in verbal memory skills and the right temporal lobe in
visuospatial memory skills, the correlation between lobe/side of
origin of seizures and clinically detectable performance is unclear.
In fact, while some studies reported a differential effect of the
lateralization of the epileptic focus on memory performance, in
other studies this correlation was not confirmed (Bedoin et al.,
2006; Schouten et al., 2009) [39,40]. The study by Vo € lkl-Kernstock
and colleagues (2006) [41], which specifically investigated visuo-
spatial performance in children with benign childhood epilepsy
with centro-temporal spikes, showed a significant impairment in
short- and long-term spatial memory compared to controls, which
was independent of side of seizure onset (right or left) and drug
treatment.
In our study, at 12-months reassessment, the visuospatial
perception skills were not significantly changed from baseline in all
five treatment groups, instead the visuospatial memory skills
changed depending on the type of ASMs employed.
In particular, the subjects taking VPA, ETS, and CBZ performed
significantly worse than baseline, while in those taking LEV and
OXC there were no significant changes in performance.
We did not find a significant relationship between ASM dose
and visuospatial abilities.
It is very difficult to understand the exact mechanism by which
the ASMs act on cognitive functions, first of all because the same
mechanism of action of the ASMs is not always fully known, and
secondly because it is complex to consider the loco-regional brain
differences in the expression of neurotransmitter receptors,
responsible for different cognitive functions.
Despite this, several clinical works and reviews described the
cognitive effects of ASMs in children and adults, drawing the gen-
eral conclusion that older generation ASMs have a greater negative
impact on cognitive functions than new generation ones [26,35,42].
To the best of our knowledge, there are no other comparative
studies that specifically investigate visuospatial memory functions,
in relation to ASMs treatment.
However, our results showed that also this specific cognitive
ability is more compromised in children and adolescents taking the
older ASMs (VPA, ETS and CBZ) than the newer ones (LEV and OXC).
Our finding that VPA, ESM and CBZ negatively impact cognitive/
executive functions is also consistent with previous literature. In
particular, a randomized and controlled study by Hessen and col-
leagues (2009) demonstrated that CBZ monotherapy negatively
affected cognitive abilities and that discontinuation of therapy
112
European Journal of Paediatric Neurology 32 (2021) 106e114
improved performance [43]. Furthermore, Helmstaedter et al. had
shown a mild but significantly lower cognitive outcome in patients
taking CBZ monotherapy compared to LEV after 6 months of
treatment [44].
A previous double-blind randomized controlled study on 446
children with epilepsy, showed that VPA compromises executive
functions more than the lamotrigine [45]. A more or less severe
impairment of the executive functions was also documented in a
study of a pediatric population taking VPA or ETS [46].
On the contrary, a good tolerability of LEV and OXC on the
cognitive profile had already been demonstrated by previous
studies [22,47].
In particular, a randomized and controlled study on 98 children
showed that LEV did not have a negative impact on executive
functions (memory and attention) [48].
A study of 168 children treated with OXC documented
improvement in cognitive function after approximately seven
months of therapy [49]. Another study in 70 pediatric patients with
epilepsy documented that after 18 months of OXC therapy there
was no cognitive impairment and that there was a slight
improvement in cognitive skills in some subjects [50].
Finally, the findings of the present study are generally in line
with those of our previous observational study [22], which
demonstrated a significant worsening of executive functions in
children taking CBZ and a significant improvement in those taking
LEV, after 9 months of follow-up.
It is hypothesized that focal interictal epileptiform discharges
(IED) may exert a deleterious effect on cognition in children,
nowadays, the benefits of anti-epileptic treatment aimed at
reducing IED are not established, except in specific situations like
epileptic encephalopathies with continuous spike and waves dur-
ing slow-wave sleep. In our sample, after 12 months of follow-up,
there was detected a reduction <50% in the IED frequency in
about 5% of our patients compared to baseline, however no corre-
lation was made with the neuropsychological outcome. In future
studies it would be useful to carry out a quantitative analysis of the
interictal activity and to correlate the outcome with changes in the
neuropsychological profile [51,52].
Some limitations of the study were the use of a retrospective
study design, a moderate sample size and the use of a single neu-
ropsychological test to assess visuospatial functions. In addition,
multiple correlation analysis that take into account different neu-
ropsychological variables that could affect performance, were not
considered.
It would be useful to perform multivariate analysis to evaluate
the influence of different variables (cognitive skills, executive
functions, visuospatial) on visuospatial skills. It would also be
useful to use a large battery of standardized neuropsychological
tests that evaluate other aspects that have not been taken into
consideration, such as visuospatial planning and emotional-
behavioral problems.
A strength of the study was the use of a standardized test,
including only patients taking monotherapy and who were all well-
controlled.
In conclusion, our study suggests that some of the most widely
used drugs used in pediatric epilepsy have a different tolerability on
the cognitive profile and can differently affect the visuospatial
memory skills. In particular, CBZ, VPA and ETS can contribute to
worse visuospatial memory skills, while LEV and OXC seem not to
significantly affect these cognitive abilities.
Visuospatial memory seems to be related to executive functions
abilities. Future research with larger, placebo-controlled samples
would be useful to confirm these results.
F.F. Operto, G.M.G. Pastorino, C. Di Bonaventura et al.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None of the authors has any conflict of interest to disclose.
Acknowledgments
We thank all the patients and their families who participated in
the study.
References
[1] M. Linn, A. Petersen, Emergence and characterization of sex differences in
spatial ability: a meta-analysis, Child Dev. 56 (1986) 1479e1498, https://
doi.org/10.1111/j.1467-8624.1985.tb00213.x.
[2] N.C. Aliotti, D.A. Rajabiun, Visual memory development in preschool children,
Percept. Mot. Skills 73 (1991) 792e794, https://doi.org/10.2466/
pms.1991.73.3.792.
[3] V.A. Anderson, G. Lajoie, Development of memory and learning skills in
school-aged children: a neuropsychological perspective, Appl. Neuropsychol.
3 (1996) 128e139, https://doi.org/10.1207/s15324826an0303&4_5.
[4] C.J. Young, S.C. Levine, K.S. Mix, The connection between spatial and mathe-
matical ability across development, Front. Psychol. 9 (2018 Jun 4) 755, https://
doi.org/10.3389/fpsyg.2018.00755.
[5] R. Fanari, C. Meloni, D. Massidda, Visual and spatial working memory abilities
predict early math skills: a longitudinal study, Front. Psychol. 10 (2019 Nov 6)
2460, https://doi.org/10.3389/fpsyg.2019.02460.
[6] G. Giovagnoli, S. Vicari, S. Tomassetti, D. Menghini, The role of visual-spatial
abilities in dyslexia: age differences in children's reading? Front. Psychol. 7
(2016 Dec 21) 1997, https://doi.org/10.3389/fpsyg.2016.01997.
[7] R. De Beni, F. Pazzaglia, V. Gyselinck, C. Meneghetti, Visuospatial working
memory and mental representation of spatial description, Eur. J. Cognit.
Psychol. 17 (2005) 77e95.
[8] P. Sorrentino, A. Lardone, M. Pesoli, M. Liparoti, S. Montuori, G. Curcio, et al.,
The development of spatial memory analyzed by means of ecological walking
task, Front. Psychol. 10 (2019) 728, https://doi.org/10.3389/fpsyg.2019.00728.
[9] T. Klingberg, Development of a superior frontal-intraparietal network for
visuo-spatial working memory, Neuropsychologia 44 (2006) 2171e2177,
https://doi.org/10.1016/j.neuropsychologia.2005.11.019.
[10] S.K. Krogsrud, A.M. Fjell, C.K. Tamnes, H. Grydeland, P. Due-Tønnessen,
A. Bjørnerud, et al., Development of white matter microstructure in relation to
verbal and visuospatial working memoryda longitudinal study, PloS One 13
(2018), e0195540, https://doi.org/10.1371/journal.pone.0195540.
[11] M. Cohen, Auditory/verbal and visual/spatial memory in children with com-
plex partial epilepsy of temporal lobe origin, Brain Cognit. 20 (2) (1992 Nov)
315e326, https://doi.org/10.1016/0278-2626(92)90024-g.
[12] A. Reyes, H.M. Holden, Y.A. Chang, V.S. Uttarwar, D.P. Sheppard, N.E. DeFord,
et al., Impaired spatial pattern separation performance in temporal lobe ep-
ilepsy is associated with visuospatial memory deficits and hippocampal vol-
ume loss, Neuropsychologia 111 (2018 Mar) 209e215, https://doi.org/
10.1016/j.neuropsychologia.2018.02.009.
[13] G.M. Tallarita, A. Parente, A.R. Giovagnoli, The visuospatial pattern of temporal
lobe epilepsy, Epilepsy Behav. 101 (Pt A) (2019 Dec) 106582, https://doi.org/
10.1016/j.yebeh.2019.106582.
[14] A. Traianou, P. Patrikelis, M.H. Kosmidis, V.Κ. Kimiskidis, S. Gatzonis, The
neuropsychological profile of parietal and occipital lobe epilepsy, Epilepsy
Behav. 94 (2019 May) 137e143, https://doi.org/10.1016/j.yebeh.2019.02.021.
[15] J.M. Cimadevilla, J.R. Lizana, M.D. Rolda n, R. Canovas, E. Rodríguez, Spatial
memory alterations in children with epilepsy of genetic origin or unknown
cause, Epileptic Disord. 16 (2) (2014 Jun) 203e207, https://doi.org/10.1684/
epd.2014.0661.
[16] I. Myatchin, L. Lagae, Impaired spatial working memory in children with well-
controlled epilepsy: an event-related potentials study, Seizure 20 (2) (2011
Mar) 143e150, https://doi.org/10.1016/j.seizure.2010.11.005.
[17] W.S. MacAllister, M. Maiman, M. Vasserman, T. Fay-Mcclymont, B.L. Brooks,
E.M.S. Sherman, The WISC-V in children and adolescents with epilepsy, Child
Neuropsychol. 25 (7) (2019 Oct) 992e1002, https://doi.org/10.1080/
09297049.2019.1571181.
[18] J. Williams, T. Phillips, M.L. Griebel, G.B. Sharp, B. Lange, T. Edgar, et al., Factors
associated with academic achievement in children with controlled epilepsy,
Epilepsy Behav. 2 (3) (2001 Jun) 217e223, https://doi.org/10.1006/
ebeh.2001.0166.
[19] F.F. Operto, R. Mazza, G.M.G. Pastorino, S. Campanozzi, A. Verrotti, G. Coppola,
Parental stress in a sample of children with epilepsy, Acta Neurol. Scand. 140
(2) (2019 Aug) 87e92, https://doi.org/10.1111/ane.13106.
[20] F.F. Operto, R. Mazza, G.M.G. Pastorino, S. Campanozzi, L. Margari, G. Coppola,
113
European Journal of Paediatric Neurology 32 (2021) 106e114
Parental stress in pediatric epilepsy after therapy withdrawal, Epilepsy Behav.
94 (2019 May) 239e242, https://doi.org/10.1016/j.yebeh.2019.03.029.
[21] C.B. Dodrill, Neuropsychological effects of seizures, Epilepsy Behav. 5 (Suppl 1)
(2004) S21eS24.
[22] F.F. Operto, G.M.G. Pastorino, R. Mazza, M. Carotenuto, M. Roccella, R. Marotta,
et al., Effects on executive functions of antiepileptic monotherapy in pediatric
age, Epilepsy Behav. 102 (2020 Jan) 106648, https://doi.org/10.1016/
j.yebeh.2019.106648.
[23] F.F. Operto, G.M.G. Pastorino, R. Mazza, C. Di Bonaventura, R. Marotta,
N. Pastorino, et al., Social cognition and executive functions in children and
adolescents with focal epilepsy, Eur. J. Paediatr. Neurol. 28 (2020 Sep)
167e175, https://doi.org/10.1016/j.ejpn.2020.06.019.
[24] J.A. Witt, C.E. Elger, C. Helmstaedter, Adverse cognitive effects of antiepileptic
pharmacotherapy: each additional drug matters, Eur. Neuropsychopharmacol
25 (11) (2015) 1954e1959, https://doi.org/10.1016/j.euroneuro.2015.07.027.
[25] E. Hessen, M.I. Lossius, I. Reinvang, L. Gjerstad, Influence of major antiepileptic
drugs on neuropsychological function: results from a randomized, double-
blind, placebo-controlled withdrawal study of seizure-free epilepsy patients
on monotherapy, J. Int. Neuropsychol. Soc. 13 (3) (2007) 393e400.
[26] R. Moavero, M.E. Santarone, C. Galasso, P. Curatolo, Cognitive and behavioral
effects of new antiepileptic drugs in pediatric epilepsy, Brain Dev. 39 (6)
(2017) 464e469, https://doi.org/10.1016/j.braindev.2017.01.006.
[27] F.F. Operto, G.M.G. Pastorino, R. Mazza, M. Roccella, M. Carotenuto, L. Margari,
et al., Cognitive profile in BECTS treated with levetiracetam: a 2-year follow-
up, Epilepsy Behav. 97 (2019 Aug) 187e191, https://doi.org/10.1016/
j.yebeh.2019.05.046.
[28] F.F. Operto, G.M.G. Pastorino, R. Mazza, C. Di Bonaventura, S. Matricardi,
A. Verrotti, et al., Perampanel tolerability in children and adolescents with
focal epilepsy: effects on behavior and executive functions, Epilepsy Behav.
103 (Pt A) (2020 Feb) 106879, https://doi.org/10.1016/j.yebeh.2019.106879.
[29] S.R. Davies, A.R. Field, T. Andersen, C. Pestell, The ecological validity of the
Rey-Osterrieth Complex Figure: predicting everyday problems in children
with neuropsychological disorders, J. Clin. Exp. Neuropsychol. 33 (7) (2011
Aug) 820e831.
[30] M.D. Lezak, Neuropsychological Assessment, fourth ed., Oxford University
Press, New York, 2004.
[31] M. Conson, M. Siciliano, C. Baiano, I. Zappullo, V.P. Senese, G. Santangelo,
Normative data of the Rey-Osterrieth Complex Figure for Italian-speaking
elementary school children, Neurol. Sci. 40 (10) (2019 Oct) 2045e2050,
https://doi.org/10.1007/s10072-019-03929-w.
[32] C. Helmstaedter, K. Schoof, T. Rossmann, G. Reuner, A. Karlmeier,
G. Kurlemann, Introduction and first validation of EpiTrack Junior, a screening
tool for the assessment of cognitive side effects of antiepileptic medication on
attention and executive functions in children and adolescents with epilepsy,
Epilepsy Behav. 19 (1) (2010) 55e64, https://doi.org/10.1016/
j.yebeh.2010.06.042.
[33] J. Raven, J.C. Raven, J.H. Court, Manual for Raven's Progressive Matrices and
Vocabulary Scales, Harcourt Assessment, San Antonio, TX, 2003 updated 2004.
[34] L. Picone, A. Orsini, L. Pezzuti, Le Matrici Progressive di Raven: contributo alla
taratura italiana per soggetti tra i 6 e i 18 anni, Giunti Psychometrics S.r.l. -
Firenze, 2018.
[35] L. Lagae, Cognitive side effects of anti-epileptic drugs. The relevance in
childhood epilepsy, Seizure 15 (4) (2006 Jun) 235e241, https://doi.org/
10.1016/j.seizure.2006.02.01335.
[36] S.C. Tromp, J.W. Weber, A.P. Aldenkamp, J. Arends, I. vander Linden,
L. Diepman, Relative influence of epileptic seizures and of epilepsy syndrome
on cognitive function, J. Child Neurol. 18 (6) (2003 Jun) 407e412, https://
doi.org/10.1177/08830738030180060501.
[37] T.S. Kellermann, L. Bonilha, J.J. Lin, B.P. Hermann, Mapping the landscape of
cognitive development in children with epilepsy, Cortex 66 (2015 May) 1e8,
https://doi.org/10.1016/j.cortex.2015.02.001.
[38] H. O'Reilly, C. Eltze, K. Bennett, K. Verhaert, R. Webb, A. Merrett, et al.,
Cognitive outcomes following epilepsy in infancy: a longitudinal community-
based study, Epilepsia 59 (12) (2018 Dec) 2240e2248, https://doi.org/
10.1111/epi.14589.
[39] N. Bedoin, V. Herbillon, I. Lamoury, P. Arthaud-Garde, K. Ostrowsky, J. De
Bellescize, et al., Hemispheric lateralization of cognitive functions in children
with centrotemporal spikes, Epilepsy Behav. 9 (2) (2006 Sep) 268e274,
https://doi.org/10.1016/j.yebeh.2006.06.002.
[40] D. Schouten, J.G. Hendriksen, A.P. Aldenkamp, Performance of children with
epilepsy on the Rey-Osterrieth complex figure test: is there an effect of
localization or lateralization? Epilepsy Res. 83 (2e3) (2009 Feb) 184e189,
https://doi.org/10.1016/j.eplepsyres.2008.11.002.
[41] S. Vo€lkl-Kernstock, U. Willinger, M. Feucht, Spacial perception and spatial
memory in children with benign childhood epilepsy with centro-temporal
spikes (BCECTS), Epilepsy Res. 72 (1) (2006 Nov) 39e48, https://doi.org/
10.1016/j.eplepsyres.2006.07.004.
[42] G. Coppola, G. Iapadre, F.F. Operto, A. Verrotti, New developments in the
management of partial-onset epilepsy: role of brivaracetam, Drug Des. Dev.
Ther. 11 (2017 Mar 6) 643e657, https://doi.org/10.2147/DDDT.S103468.
[43] E. Hessen, M.I. Lossius, L. Gjerstad, Antiepileptic monotherapy significantly
impairs normative scores on common tests of executive functions, Acta
Neurol. Scand. 119 (3) (2009) 194e198, https://doi.org/10.1111/j.1600-
0404.2008.01109.x.
[44] C. Helmstaedter, J.A. Witt, Cognitive outcome of antiepileptic treatment with
F.F. Operto, G.M.G. Pastorino, C. Di Bonaventura et al.
Levetiracetam versus carbamazepine monotherapy: a non-interventional
surveillance trial, Epilepsy Behav. 18 (1e2) (2010) 74e80, https://doi.org/
10.1016/j.yebeh.2010.02.011.
[45] T.A. Glauser, A. Cnaan, S. Shinnar, D.G. Hirtz, D. Dlugos, D. Masur, et al.,
Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy,
N. Engl. J. Med. 362 (9) (2010) 790e799, https://doi.org/10.1056/
NEJMoa0902014.
[46] D. Masur, S. Shinnar, A. Cnaan, R.C. Shinnar, P. Clark, J. Wang, et al., Pre-
treatment cognitive deficits and treatment effects on attention in childhood
absence epilepsy, Neurology 81 (18) (2013 Oct 29) 1572e1580, https://
doi.org/10.1212/WNL.0b013e3182a9f3ca.
[47] KimD, J.H. Seo, E.Y. Joo, H.W. Lee, ShinWC, S.B. Hong, Cognitive and psycho-
social effects of oxcarbazepine monotherapy in newly diagnosed partial epi-
lepsy, Clin. Neuropharmacol. 37 (4) (2014 Jul-Aug) 100e107, https://doi.org/
10.1097/WNF.0000000000000038.
[48] P.M. Levisohn, M. Mintz, S.J. Hunter, H. Yang, J. Jones, N01103 Levetiracetam
Study Group. Neurocognitive effects of adjunctive levetiracetam in children
114
European Journal of Paediatric Neurology 32 (2021) 106e114
with partialonset seizures: a randomized, double-blind, placebo-controlled,
non-inferiority trial, Epilepsia 50 (2009) 2377e2389.13.
[49] M. Tzitiridou, T. Panou, G. Ramantani, A. Kambas, K. Spyroglou, C. Panteliadis,
Oxcarbazepine monotherapy in benign childhood epilepsy with cen-
trotemporal spikes: a clinical and cognitive evaluation, Epilepsy Behav. 7 (3)
(2005) 458e467.
[50] S.H. Eun, H.D. Kim, H.J. Chung, H.C. Kang, J.S. Lee, J.S. Kim, et al., A multicenter
trial of oxcarbazepine oral suspension monotherapy in children newly diag-
nosed with partial seizures: a clinical and cognitive evaluation, Seizure 21 (9)
(2012) 679e684, https://doi.org/10.1016/j.seizure.2012.07.007.
[51] P. Van Bogaert, C. Urbain, S. Galer, N. Ligot, P. Peigneux, X. De Tie ge, Impact of
focal interictal epileptiform discharges on behaviour and cognition in chil-
dren, Neurophysiol. Clin. 42 (1e2) (2012 Jan-Feb) 53e58, https://doi.org/
10.1016/j.neucli.2011.11.004.
[52] G.L. Holmes, P.P. Lenck-Santini, Role of interictal epileptiform abnormalities in
cognitive impairment, Epilepsy Behav. 8 (3) (2006 May) 504e515, https://
doi.org/10.1016/j.yebeh.2005.11.014.