Epilepsy & Behavior 112 (2020) 107453

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Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

How predictable is cognitive performance in Brazilian patients with

pharmacoresistant mesial temporal lobe epilepsy?
Helena Dresch Vascouto a,b, Maria Emília de Oliveira Thais c, Camila Osório c, Hiago Murilo Melo a,b,
Maria Luiza Benevides a, Wuilker Knoner Campos a,b, Ricardo Guarnieri a,c,d, Jean Costa Nunes a,
Katia Lin a,c,e,f, Roger Walz a,b,c,e,f,⁎
a
Applied Neuroscience Center (CeNAp), Department of Clinical Medicine, University Hospital - UFSC (HU - UFSC), Federal University of Santa Catarina (UFSC), Florianópolis, SC, Brazil
b
Graduate Program in Neuroscience, Federal University of Santa Catarina (UFSC), Florianópolis, SC, Brazil
c
Graduate Program in Medical Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, SC, Brazil
d
Psychiatry Unit, Department of Clinical Medicine, University Hospital - UFSC (HU - UFSC), Federal University of Santa Catarina (UFSC), Florianópolis, SC, Brazil
e
Epilepsy Center of Santa Catarina (CEPESC), Department of Clinical Medicine, University Hospital - UFSC (HU - UFSC), Federal University of Santa Catarina (UFSC), Florianópolis, SC, Brazil
f
Neurology Unit, Department of Clinical Medicine, University Hospital - UFSC (HU - UFSC), Federal University of Santa Catarina (UFSC), Florianópolis, SC, Brazil

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

Article history: Objective: The objective of the study was to investigate the independent association between clinical, demographic,
Received 29 June 2020 psychiatric, radiologic, electrophysiological, and pharmacologic variables and cognitive performance of Brazilian
Revised 26 August 2020 patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE).
Accepted 27 August 2020 Methods: Ninety-three patients with pharmacoresistant MTLE related to hippocampal sclerosis (HS) were included
Available online xxxx
in the study. Multiple linear regressions were done to identify predictor variables for 24 cognitive tests. Independent
variables analyzed were sex, hand dominance, age, years of education, marital status, work activity, history for an
Keywords:
Cognitive prognosis
initial precipitant injury (IPI), family history of epilepsy, lesion side, antiseizure medication (ASM) treatment type,
Refractory epilepsy ASM serum levels, benzodiazepine (BDZ) treatment, age at epilepsy onset, disease duration, monthly frequency of
Cognitive performance seizures, and Hospital Anxiety and Depression Scale (HADS) scores.
Cognitive impairment Results: Years of education was an independent and positive predictor in 22 of the 24 cognitive tests evaluated. Male
sex was also a positive predictor of one cognitive test. Variables negatively associated with cognitive performance
were left side lesion (10 tests), disease duration (5 tests), polytherapy (3 tests), ASM serum levels (3 tests), and
BDZ treatment or not working (1 test each). The regression model explained between 6% and 44% of the cognitive
test scores variation.
Significance: In Brazilian patients with pharmacoresistant MTLE-HS, up to 44% of cognitive test scores variation is
predictable by clinical, demographic, psychiatric, radiologic, electrophysiology, and pharmacological variables. The
identification of predictors of cognitive performance may be helpful for better planning of patient care.
© 2020 Elsevier Inc. All rights reserved.

1. Introduction conditions [2,3]. Investigation of factors influencing the prognosis is

Epilepsy affects 65 million people worldwide and accounts for 1% of
the global burden of disease [1]. The prevalence of epilepsy is 5 to 10
cases per 1000 inhabitants in developed countries and maybe even
higher in resource-poor countries [2,3]. In Brazil, a prevalence study of
epilepsy shows a rate of 9.2 cases per 1000 inhabitants [4]. Studies
suggest that a higher prevalence of epilepsy in resource-poor countries
could be associated with increased parasitic and infectious diseases,
inadequate health services, treatment gap, or poor sociodemographic
⁎ Corresponding author at: Departamento de Clínica Médica, Hospital Universitário, 3rd
andar, Universidade Federal de Santa Catarina, Trindade, Florianópolis, Santa Catarina CEP
88.040-970, Brazil.
E-mail addresses: rogerwalz@hotmail.com, roger.walz@ufsc.br (R. Walz).
useful to improve the patient's care and quality of life [5].
Mesial temporal lobe epilepsy (MTLE) is the most common form of
epilepsy, often pharmacoresistant and surgically treated [6]. Hippocampal
sclerosis (HS) is the most common pathological substrate of MTLE,
although abnormalities can also extend to other limbic system structures,
extramesial temporal lobe, subcortical, and extratemporal lobe regions
[7,8]. Because of the implications of mesial temporal lobe (MTL)
structures for memory consolidation, memory impairment has been
considered the core deficit observed in patients [9,10]. Studies with
temporal lobe epilepsy (TLE) support the material-specific model of
memory, suggesting that the left temporal lobe (language-dominant)
mediates verbal memories, while the right temporal lobe mediates
nonverbal memories [11,12]. Castro and colleagues [13] reported that
profiles of selective verbal and nonverbal memory deficits are highly

https://doi.org/10.1016/j.yebeh.2020.107453
1525-5050/© 2020 Elsevier Inc. All rights reserved.
2 H.D. Vascouto et al. / Epilepsy & Behavior 112 (2020) 107453
specific for the left and right lesion side but infrequently encountered in
their sample of Brazilian patients with MTLE.
Cognitive impairment has a significant impact on a patient's quality of
life, vocational, and educational adjustment [14,15]. The development of
predictive models helps to identify risk factors involved in cognitive
impairment. A Canadian study published by Strauss et al. [16] investi-
gated the predictors of cognitive ability in patients with TLE or extra-
TLE. Age at seizure onset was the best single indicator of full-scale
intelligence quotient (FSIQ) and general memory. Laterality and location
of dysfunction and cerebral speech dominance were also relevant and
independent indicators of cognitive characteristics. Jokeit and Ebner [17]
also investigated the independent association of clinical variables and
the FSIQ in patients with TLE. Education level and duration of epilepsy
were the best predictors for the intelligence, explaining 34% of the FSIQ
variance. These studies show a limited capacity of demographic and
clinical variables to predict the cognitive tests applied in patients with
epilepsy from developed countries.
No studies investigated predictors of cognitive performance in
patients with epilepsy from undeveloped countries, including Brazil.
Considering the socioeconomic profile particularities, and the previously
described predominance of the nonlateralization profile of memory defi-
cits [13], we investigated the demographic and clinical variables indepen-
dently associated with the neuropsychological performance on different
cognitive domains of Brazilian patients with pharmacoresistant MTLE.
2. Methods
2.1. Subjects
Ninety-three consecutive patients with pharmacoresistant MTLE-HS
were evaluated between August 2008 and July 2012 at the Centro de
Epilepsia de Santa Catarina (CEPESC) by neurologists, neurophysiologists,
neurosurgeons, psychiatrists, nurses, and neuropsychologists. Variables
of interest were prospectively collected during hospitalization of patients
for preoperative evaluation by a protocol approved by the Research Ethics
Committee for Human Research of the Federal University of Santa
Catarina (No. 515) and Governador Celso Ramos Hospital (No. 20012/
0007). All subjects signed an informed consent form and voluntarily
agreed to participate in this study.
All patients had a focal seizure with impaired awareness at least
once a month, despite treatment with 2 antiseizure medications (ASMs)
in monotherapy [18]. The diagnostic process of MTLE was confirmed
by a full interview, including clinical history, neurological examination,
psychiatric and neuropsychological evaluation, seizure semiology,
video-electroencephalogram (VEEG) analysis, interictal and ictal,
magnetic resonance image (MRI) (1.5 T), and psychosocial assessment
[5,19–22].
The MRI findings of HS include hippocampus atrophy (T1-weighted)
and increased signal (fluid attenuated inversion recovery (FLAIR)) by
visual inspection. T2-weighted signal and disrupted hippocampus
structure by T1-weighted signal were also found. Patients with bilateral
asymmetric abnormalities showed the MRI findings of HS described
above on one side and less evident atrophy, signal abnormalities, or
both on the other side. We excluded patients with low-grade tumor
and cortical dysplastic lesions in the MTL, non-MTL and extra-MTL
lesions, focal motor-sensory abnormalities on physical examination,
generalized or extratemporal interictal spikes, and marked cognitive
impairment on neuropsychological testing because such features place
the diagnosis of MTLE in doubt [5,19].
The VEEG recording (Bio-logic, System Corp) was done using scalp
electrodes according to the international 10/20 system associated with
the temporal 10/10 system. The visual interictal analysis was assessed
in a one-hour sleep sample (between 5:00 and 7:00 a.m.) and a one-
hour sample during wakefulness (between 8:00 and 10:00 a.m.) in
the first, second, and third days of VEEG monitoring. Patients had a
mean of 4 seizures (± 2.5) during 2 to 6 days of VEEG investigation.
Patients could have focal slowing, interictal spikes, and sharp waves
over the anterior, inferior, and mesial temporal regions on interictal
scalp EEG.
2.2. Clinical and demographic variables
The clinical and demographic characteristics analyzed were sex,
hand dominance, age, years of education, marital status, work activity,
history for an initial precipitant injury (IPI), family history of epilepsy
in first- and second-degree relatives, lesion side (side of the mesial tem-
poral atrophy on the MRI), type of ASM treatment, ASM serum levels,
benzodiazepine (BDZ) use, age at epilepsy onset (recurrent seizures),
disease duration, monthly frequency of seizures (which impaired
awareness in the year before the presurgical evaluation), and Hospital
Anxiety and Depression Scale (HADS) scores.
Working status was classified as a) working group: patients that
were working at the presurgical evaluation; b) unemployed group:
patients who were not working but were not retired; and c) health
insurance group: not working and receiving health disability insurance.
Among the 100 patients, 33 completed at least Elementary school
(9 years education), and only three were in the school at the time of
presurgical evaluation. The remaining 67 patients were considered with
a low educational level (<9 years of education).
Patients were considered to be under monotherapy if they were
using only one ASM. Patients using two or more ASMs, associated or not
with BDZs, were classified as being under polytherapy. The ASM used
were phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PHT),
oxcarbazepine (OCBZ), or valproate (VPA). The BDZ was clobazam or
clonazepam. The serum levels of ASM were determined at 7:00 a.m. be-
fore the morning ASM administration, in the day of cognitive evaluation
(see below).
2.3. Hospital Anxiety and Depression Scale (HADS)
The HADS is widely used to measure psychological distress in the
nonpsychiatric inpatient population, validated for Brazilian patients
with MTLE-HS [21,22]. It consists of 14 multiple-choice items divided
into anxiety and depression subscales. The items are rated on a
4-point Likert scale scored from 0 to 3, resulting in a final score ranging
from 0 to 21, with higher scores meaning worse anxiety or depression.
2.4. Cognitive testing
The standardized tests were applied by the neuropsychologist of our
team, blinded for all clinical, neurosurgical, and laboratory variables
previously described. Neuropsychological testing started between
09:00 a.m. and 10:00 a.m. of the second day of hospitalization. Raw
scores were used for all cognitive tests. Adjustments for demographic
data (i.e., age, sex, education) were done including these variables in
multiple regression models (see Section 2.5, Statistical analysis).
The sequence of the tests remained the same in all assessments: Cat-
egory Fluency [23], Letters Fluency [23], Rey Auditory Verbal Learning
Test (RAVLT) total and immediate recall [23], Rey–Osterrieth Complex
Figure (ROCF) copy and immediate recall [23], Block Design [24], Picture
Completion [24], RAVLT delayed and recognition [23], ROCF delayed
[23], Logical Memory I [25], Visual Reproduction I [25], Digit Span [24],
Vocabulary [24], Matrix Reasoning [24], Logical Memory II [25], Visual
Reproduction II [25], Similarities [24], Verbal Paired Associates I [25],
Information [24], Five-Point Test [23], Verbal Paired Associates II [25],
and Boston Naming Test [23].
2.5. Statistical analysis
Continuous variables were expressed as mean ± standard deviation
(SD), and categorical variables were expressed as frequency and
percentage values. The association between the clinical, demographic,
 H.D. Vascouto et al. / Epilepsy & Behavior 112 (2020) 107453 3

neuroradiological, and electrophysiological variables (independent var- Table 1

iables) and each cognitive test (dependent variable) were determined Clinical, demographic, psychiatric, radiologic, electrophysiology, and pharmacologic
variables characteristics of Brazilian patients with pharmacoresistant MTLE.
by the Student t-test “p” test, one-way analysis of variance (ANOVA),
or chi-square tests. The univariate analysis aims to reduce the number Variable All patients
of variables included in the final multiple regression model. n = 93 (%)

The variables associated with the cognitive tests (dependent Sex

variables) in the univariate analysis with a “p” level of significance Female 53 (57.0)
Male 40 (43.0)
lower than 0.05 were included in linear multiple regression analysis to
Hand dominance
identify the independent predictors for each cognitive test performance. Right 85 (91.4)
No adjustments for multiple comparisons were made to avoid false- Nonright 8 (8.6)
negative results (type II errors). Considering the clinical and biological Marital statusa
plausibility of an association between the lesion side and cognitive perfor- Single 41 (45.1)
Married 39 (42.9)
mance, to avoid a type II error, a “p” value up to 0.08 was considered Divorced or widower 11 (12.1)
significant in our analysis. In these analyses, the continuous and categor- Working status
ical variables were considered covariates. Numeric values were attributed Working 28 (31.1)
to the categorical variables included in the model. The dichotomous vari- Health insurance 15 (16.7)
Not working 47 (52.2)
ables (sex, BDZ use, and hand dominance) were enumerated as 0 or 1. The
History of IPIb
values 0, 1, and 2 were attributed to variables showing three categories No 29 (31.2)
(marital status, work activity, side of the mesial temporal lesion on the Yes 59 (63.4)
MRI) and the values 0, 1, 2, and 3 for the variable showing four categories Unknown 5 (5.4)
(family history of epilepsy). Family history of epilepsyc
No 40 (43)
The “B,” “adjusted r2,” and “r2” coefficients of the final model that
Second-degree or distant 32 (34.4)
better explain the variation of each cognitive test are presented. A “p” First-degree 15 (16.1)
level of 0.05 was considered significant. The final regression model Unknown 6 (6.5)
was determined by evaluation of the presence of outliers, data points Side of the mesial temporal lobe lesion
Right 39 (41.9)
independency, normal distribution of residuals, constant variance, and
Left 47 (50.5)
acceptable tolerance of collinearity. The analysis was performed by Bilaterald 7 (7.5)
software SPSS 20.0 (Chicago, IL). ASMs treatmente
Monotherapy 35 (37.6)
3. Results Polytherapy 58 (62.4)
Benzodiazepines
No 47 (50.5)
The univariate analysis investigated the association among these Yes 46 (49.5)
variables, and each cognitive test was done by Student “t”-test, one-way
Mean ± SE
ANOVA, or chi-square tests (data not shown). The clinical, demographic,
Age (in years) 36 ± 1
psychiatric, radiologic, electrophysiology, and pharmacologic variables Years of education 7 ± 0.3
showing an association with each cognitive test for a “p” level of signifi- Disease duration (in years) 23 ± 1
cance ≤0.05 were initially included in the multiple linear regression anal- Age at epilepsy onset (in years) 9 ± 0.9
Monthly frequency of seizuresf 8 ± 0.8
ysis. The clinical, demographic, psychiatric, radiologic, electrophysiology,
HADS-Anxiety 7.3 ± 0.42
and pharmacologic variables of the sample are shown in Table 1. HADS-Depression 6.0 ± 0.41
The final multiple linear regression models that best explain the ASM (mcg/mL)g
variation of each cognitive test scores are presented in Table 2. Years of CBZ, n = 69 5 ± 0.4
education remains an independent and positive predictor in 22 of the OCBZ, n = 9 1.2 ± 0.5
PB, n = 32 6.8 ± 1.2
24 cognitive tests evaluated. Male sex was also positively associated
PHT, n = 15 1.4 ± 0.4
with one cognitive test score. Variables negatively associated with VPA, n = 17 9.2 ± 2.4
the cognitive performance were the presence of left side lesion on MRI a
Four patients did not inform their marital status, and two patients were a widower.
(10 cognitive tests), disease duration (5 tests), polytherapy (3 tests), b
History for an initial precipitant injury (IPI).
ASM serum levels (3 tests), and BDZ treatment or unemployment c
Family history epilepsy was unknown in three patients.
(1 test each). The “r2” coefficient for the linear regression models that ex- d
All the bilateral MRI lesions were HS (n = 07). They were symmetric HS (n = 02),
plain the cognitive test scores variation was 0.06 to 0.19 for five cognitive asymmetric HS with left HIP volume < right (n = 02), or asymmetric HS with right HIP
volume < left (n = 03).
tests, 0.20 to 0.30 for nine, 0.31 to 0.37 for eight, and 0.41 to 0.44 for two. e
Two patients were using serotonin reuptake inhibitor and one risperidone.
A summary of final regression models results separated by cognitive f
Monthly frequency of seizures with impaired awareness including focal to the bi-
domains (verbal and nonverbal memory, attention, executive function, lateral tonic–clonic (rare) and focal seizures with impaired awareness (dysperceptive
language, and perceptual-motor skills) are showed in Table 3. Verbal seizures).
g
CBZ = carbamazepine, OCBZ = oxcarbazepine, PB = phenobarbital, PHT = phe-
memory was positively associated with years of education on all
nytoin, VPA = valproic acid. The serum levels not determined for lamotrigine (8 pa-
cognitive tests of the domain (8 tests) and negatively associated with tients) and oxcarbazepine (6 patients).
left side lesion (5 tests). Nonverbal memory was positively associated
with years of education (3 tests) and negatively with left side lesion,
disease duration, or polytherapy (1 test each). Attention includes one
all cognitive tests of the domain (4 tests) and negatively associated
cognitive test that was negatively associated with left side lesion and
with disease duration (2 test), left side lesion, polytherapy, serum levels
disease duration. Executive function also includes one cognitive test
of CBZ, and BDZ treatment (1 test each).
that was positively associated with years of education. Language was
positively associated with years of education in all cognitive tests of
the domain (6 tests) and male sex (1 test) and negatively associated 4. Discussion
with left side lesion (2 tests), ASM serum levels (2 tests), polytherapy,
disease duration, and not working status (1 test each). Perceptual- This is the first study investigating multiple predictors of cognitive
motor skills were also positively associated with years of education in performance of Brazilian patients with pharmacoresistant MTLE-HS.
4 H.D. Vascouto et al. / Epilepsy & Behavior 112 (2020) 107453

Table 2 Table 2 (continued)

Linear multiple logistic regressions are showing the independent predictor variables for
cognitive test performance in patients with pharmacoresistant MTLE. Cognitive test R2 Adjusted R2 B coefficient “p” levela

Constant 28.0 <0.0001

Cognitive test R2 Adjusted R2 B coefficient “p” levela
Left side lesion - 2.2 0.03
Vocabulary 0.37 0.35 Polytherapy - 2.3 0.06
Constant 13.1 <0.0001 Years of education 1.6 <0.0001
Left side lesion −1.7 0.06 Letter fluency 0.23 0.21
Years of education 1.4 <0.0001 Constant 15.6 <0.0001
Block design 0.24 0.23 Serum level of phenobarbital - 0.2 0.002
Constant 10.5 <0.0001 Years of education 0.7 0.005
Years of education 1.6 <0.0001 Categorical fluency 0.14 0.12
Similarities 0.42 0.42 Constant 11.4 <0.0001
Constant 6.8 <0.0001 Not working - 0.7 0.05
Years of education 1.0 <0.0001 Years of education 0.3 0.02
Picture completion 0.35 0.33 Five points 0.34 0.33
Constant 10.6 <0.0001 Constant 6.4 0.003
Left side lesion - 1.3 0.04 Years of education 1.7 <0.0001
Serum levels of carbamazepine −0.3 0.02 Digit span 0.12 0.10
Years of education 0.8 <0.0001 Constant 13.1 <0.0001
Matrix reasoning 0.24 0.22 Left side lesion −0.8 0.02
Constant 7.0 <0.0001 Disease duration −0.1 0.02
Disease duration −1.1 0.02 a
“p” level of 0.05 was considered significant.
Years of education 0.5 <0.0001
Information 0.36 0.33
Constant −1.7 0.3
Table 3
Male sex 2.2 <0.0001
Cognitive domain of each cognitive test and the respective independent predictor vari-
Serum levels of carbamazepine −0.1 0.06
ables of performance in patients with pharmacoresistant MTLE-HS.
Disease duration 0.1 0.006
Years of education 0.5 <0.0001 Cognitive domain Cognitive tests Predictor variables
Logical memory I 0.32 0.32
Constant 14.8 <0.0001 Verbal memory Logical Memory I ↑ Years of education
Years of education 2.0 <0.0001 Logical Memory II ↓ Left side lesion
Logical memory II 0.37 0.35 ↑ Years of education
Constant 6.0 0.004 Verbal Paired Associates ↓ Left side lesion
Left side lesion - 2.2 0.02 I ↑ Years of education
Years of education 1.3 <0.0001 Verbal Paired Associates ↓ Left side lesion
Verbal pair associates I 0.30 0.29 II ↑ Years of education
Constant 5.0 0.005 RAVLT Total ↓ Left side lesion
Left side lesion −2.1 0.008 ↑ Years of education
Years of education 0.9 <0.0001 RAVLT Immediate ↓ Left side lesion
Verbal pair associates II 0.27 0.25 ↑ Years of education
Constant 1.8 0.006 RAVLT Delayed ↑ Years of education
Left side lesion −0.9 0.002 RAVLT Recognition ↑ Years of education
Years of education 0.2 0.001 Nonverbal memory ROCF Immediate ↑ Years of education
RAVLT total 0.20 0.18 ROCF Delayed ↓ Disease duration
Constant 30.5 <0.0001 Visual Reproduction I ↑ Years of education
Left side lesion −2.0 0.06 Visual Reproduction II ↓ Polytherapy
Years of education 0.9 <0.0001 ↓ Left side lesion
RAVLT immediate 0.25 0.23 ↑ Years of education
Constant 4.8 <0.0001 Attention Digit Span ↓ Left side lesion
Left side lesion - 1.0 0.001 ↓ Disease duration
Years of education 0.2 0.001 Executive function Five-Point Test ↑ Years of education
RAVLT delayed 0.19 0.18 Language Boston Naming Test ↓ Left side lesion
Constant 2.4 <0.0001 ↓ Polytherapy
Years of education 0.3 <0.0001 ↑ Years of education
RAVLT recognition 0.06 0.05 Category Fluency ↓ Not working
Constant 6.4 <0.0001 ↑ Years of education
Years of education 0.4 0.01 Letters Fluency ↓ Serum level of phenobarbital
Visual reproduction I 0.31 0.30 ↑ Years of education
Constant 36.1 <0.0001 Vocabulary ↓ Left side lesion
Years of education 3.3 <0.0001 ↑ Years of education
Visual reproduction II 0.27 0.24 Information ↑ Male sex
Constant 23.3 0.002 ↓ Serum levels of
Polytherapy −7.5 0.01 Carbamazepine
Left side lesion −4.1 0.08 ↓ Disease duration
Years of education 2.3 <0.0001 ↑ Years of education
ROCF copy 0.36 0.33 Similarities ↑ Years of education
Constant 31.1 <0.0001 Perceptual-motor Block Design ↑ Years of education
Disease duration −0.1 0.03 skills Picture Completion ↓ Left side lesion
Benzodiazepines treatment - 3.1 0.007 ↓ Serum levels of
Polytherapy - 1.7 0.05 Carbamazepine
Years of education 0.8 <0.0001 ↑ Years of education
ROCF immediate 0.22 0.21 Matrix Reasoning ↓ Disease duration
Constant 5.3 <0.0001 ↑ Years of education
Years of education 0.8 <0.0001 ROCF Copy ↓ Disease duration
ROCF delayed 0.08 0.07 ↓ Benzodiazepines treatment
Constant 16.5 <0.0001 ↓ Polytherapy
Disease duration −0.19 0.006 ↑ Years of education
Boston Naming Test 0.44 0.42 Note: “↑”positive association; “↓” negative association.
 H.D. Vascouto et al. / Epilepsy & Behavior 112 (2020) 107453
About 6% to 44% of the cognitive test scores variation could be predicted
by clinical, demographic, psychiatric, radiologic, electrophysiology, and
pharmacologic characteristics investigated during the presurgical eval-
uation. Years of education were positively and independently associated
with 22 of 24 cognitive tests. Male sex was also positively associated
with one cognitive test score. Variables negatively related to cognitive
performance were in different combinations: the presence of left side
lesion on MRI, disease duration, polytherapy, ASM serum levels, BDZ
treatment, and not working status.
We demonstrated that patients with less formal education exhibited
worse cognitive performance in almost all cognitive tests. Education can
be considered as a stimulus for cognition, with a strong effect on the
intelligence measurements [26], on the performance of verbal tests
since they mostly depend on general knowledge learned at school
[27], and even on those tests that appear to be unaffected by schooling,
as visual memory or visuoconstruction abilities [28,29]. As the mean of
the educational level is 7 years, we believe that low scores probably
represented the effects of low education prevalent in our sample.
More than half of our patients (67%) discontinued their study before
completing Elementary school. The maintenance of patient education
in Brazil is not only impaired by seizures themselves but also by
socioeconomic factors, such as poverty, barriers to school access, or
erroneous beliefs of their intellectual limitations [30]. Pedagogical inter-
ventions in our country are necessary to decrease dropout rates of
children with epilepsy since their presence at school has a significant
impact on overall cognitive development.
Left side lesion was the variable negatively associated with the highest
number of cognitive tests in our study. Considering the clinical and
biological plausibility of an association between lesion side and cognitive
performance, to avoid a type II error, a “p” value higher but close to 0.05
was considered significant in our analysis. Language tests related to
lexical and semantic processing (Boston Naming Test and Vocabulary)
were negatively associated with left-sided MTLE in our sample, consistent
with neuroimaging studies in epilepsy [31]. Other language tests were
expected to show an association with left side injury, considering the
dominance of the left hemisphere for language in right-handed patients
with epilepsy (91.4% in our sample) [32]. Our findings also support the
material-specific model of memory since most of the performance on
verbal memory tests was associated with the left MTL abnormality.
These patterns of selective of verbal memory to the left hemisphere are
consistent with Castro et al.'s [13] study, although we have not investi-
gated the frequency of the lateralization profile in our patients. Regarding
nonverbal memory, we found discrepant results between similar cogni-
tive tests (Visual Reproduction II and ROCF Delayed). Several studies
also reported conflicting findings of the lateralization of nonverbal mem-
ory in patients with TLE, possibly because the measures used may not be
adequately sensitive to assess nonverbal memory (interference from
verbal encoding) or because of greater sensitivity to specific nonmaterial
components (motor or visuoconstructive skills) [33,34].
We showed that the duration of epilepsy was negatively associated
with cognitive performance in our work, also demonstrated by other
studies [17,35]. Hermann et al. [35] showed by the analysis of test–retest
patterns that chronic TLE is also associated with a cognitive decrease in
patients over time. Longer duration of epilepsy may increase the patient's
exposure to adverse factors (such as high seizure frequency or chronic use
of ASMs), which induce neurophysiological and structural changes under-
lying cognitive impairment [17,36]. Therefore, duration of epilepsy is an
important indicator of cognitive functioning, although not specific to all
cognitive domains.
Both polytherapy treatment and the circulating serum levels of
ASMs were negatively associated with three cognitive tests, indicating
a selective effect of the ASMs on cognitive tests or domains, similar to
that observed in patients with TLE from Switzerland [37]. We are not
able to explain the association of BDZ treatment with only one cognitive
test. Further studies are necessary to better understand the pharmaco-
logical treatment alone since our patients were already using more
5
than one drug (polytherapy) and even with nonstandardized doses or
time of use.
Sex differences in specific cognitive abilities in patients with TLE
have been reported [38]. We found only one positive association
between male sex and information test in our sample, similar to that
found in a healthy sample of a Dutch study [39]. We did not find an
association between age at seizure onset and cognitive performance,
differently from other studies [40,41]. The lack of association of the
age at seizure onset may be related to its collinearity with the disease
duration in our patients. Similarly, the work activity status of patients
shows collinearity with their education level.
Although our study was the first to analyze the depressive and anx-
iety symptoms as a predictor of cognitive performance in patients with
MTLE-HS, we found a limited association between emotional symptoms
and cognitive performance, similar to that reported in a previous study
with patients with TLE [42]. Furthermore, we demonstrated that charac-
teristics of epilepsy (i.e., lesion side) have a greater impact on cognition
than the emotional problems.
The positive aspects of our study were a) prospective design;
b) homogeneity and sample size; c) inclusion of variables not previously
investigated by other authors, as psychiatric symptoms, work activity,
and marital status; d) objective determination, of how much the
combination of analyzed variables can predict each cognitive test
score variation.
In conclusion, in Brazilian patients with pharmacoresistant MTLE, up
to 44% of cognitive test scores variation is predictable by clinical, demo-
graphic, psychiatric, radiologic, electrophysiology, and pharmacological
variables. Biologic and environmental factors contribute significantly to
the cognitive performance of our patients. The identification of other
predictors for cognitive performance is a challenge and may be helpful
for better planning of patient care.
Ethical publication statement
We confirm that we gave read the Journal's position on issues in-
volved in ethical publication and affirm that this report is consistent
with those guidelines. The Ethics Committee approved the research
protocol for Human Research of Universidade Federal de Santa Catarina
(365-FR304969) and Governador Celso Ramos Hospital (No. 20012/
0007). All procedures performed in studies involving human partici-
pants were following the ethical standards of the institutional and na-
tional research committee and with the 1964 Helsinki declaration and
its later amendments or comparable ethical standards.
Declaration of competing interest
The authors have no conflict of interest, source of funding, or financial
ties to disclose, and no current or past relationship with companies or
manufacturers who could benefit from the results of the present study.
Acknowledgment
This work was supported by PRONEX Program (Programa de
Núcleos de Excelência - NENASC Project) of FAPESC-CNPq-MS, Santa
Catarina Brazil (process 56802/2010). KL and R.W. are Researchers Fel-
lows from CNPq (Brazilian Council for Scientific and Technologic Devel-
opment, Brazil). KL is supported by PRONEM (Programa de Apoio a
Nucleos Emergentes – KETODIET – SC Project – Process No
2020TR736) from FAPESC/CNPq, Santa Catarina Brazil. HDV and HMM
are supported by CAPES/DS scholarship.
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