YEBEH-05846; No of Pages 5

Epilepsy & Behavior xxx (2018) xxx–xxx

Contents lists available at ScienceDirect

Epilepsy & Behavior

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

Neuropsychological profile of mild temporal lobe epilepsy

Maria Grazia Vaccaro a,1, Michele Trimboli a,1, Cristina Scarpazza b,c, Liana Palermo d, Antonella Bruni a,
Antonio Gambardella a, Angelo Labate a,⁎
a
Department of Medical Sciences, Institute of Neurology, University Magna Græcia, Catanzaro, Italy
b
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK
c
Department of General Psychology, University of Padua, Italy
d
Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Italy

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

Article history: Objective: In the current literature, whether patients with mild mesial temporal lobe epilepsy (mMTLE) have typ-
Received 22 February 2018 ical neurocognitive profile similar to patients with treatment-refractory seizures still remains unknown. The pur-
Revised 25 May 2018 pose of the present work was to analyze the neuropsychological profile in a group of consecutive patients with
Accepted 7 June 2018 mMTLE.
Available online xxxx
Methods: Forty consecutive patients whose conditions were diagnosed with mMTLE and 30 healthy controls (HC)
were evaluated with an extensive neuropsychological battery. In addition, self-report questionnaires were also
Keywords:
Mild temporal lobe epilepsy
administered to evaluate the subjective impairments in prospective and retrospective memories. Finally, the
Cognitive profile levels of depression and anxiety were evaluated using the Beck Depression Inventory II (BDI-II) and the State–
Verbal memory Trait Anxiety Inventory — Form Y1 (STAI-YI e 2).
Prospective memory Results: Patients with mMTLE patients showed higher BDI-II scores (15.9 ± 13.9 vs 7.2 ± 6.7; p =, 002), and
Retrospective memory higher STAI-Y1 (41.2 ± 14.6 vs 32.6 ± 9.8; p =, 005) together with both objective and subjective memory
deficits. Although BDI-II and STAI scores strongly correlated to the outcome in Rey Auditory Verbal Learning
Test (RAVLT) and prospective and retrospective memory questionnaire (PRMQ) (p b 0.0021), these results did
not change without depression scores.
Conclusion: We showed that a specific neurocognitive profile in patients with mMTLE exists. The neuropsycho-
logical features are mood depression, verbal memory immediate and delayed deficits, and subjective prospective
and retrospective memory deficits.
© 2018 Elsevier Inc. All rights reserved.

1. Introduction 90% of patients, seizures are well-controlled with a single antiepileptic

Temporal lobe epilepsy (TLE) is the most common type of partial ep-
ilepsy in adulthood [1]. According to the International League Against
Epilepsy (ILAE) classification, two different TLE categories have been
distinguished: mesial TLE (MTLE) and lateral TLE (LTLE). Mesial tempo-
ral lobe epilepsy represents the vast majority (more than 70%) and
comprises two subtypes: mild mesial temporal lobe epilepsy (mMTLE)
and refractory mesial temporal lobe epilepsy (rMTLE) [2–4]. Mild mesial
temporal lobe epilepsy is defined as “benign” because it is characterized
by at least 24 months of seizure freedom with or without antiepileptic
medication, seizures that begin during adolescence up to middle age,
and an average age of onset at around 34 years [5–7]. In more than
⁎ Corresponding author at: Cattedra di Neurologia, Università degli Studi “Magna
Graecia”, Campus Universitario Germaneto, Viale Europa, 88100 Catanzaro, Italy.
E-mail address: labate@unicz.it (A. Labate).
1
These authors contributed equally.
drug (AED) at low dosage, and some patients do not take medications.
At long-term follow-up, seizures in one-third of patients with mMTLE
will develop refractoriness to AEDs over time [7]. Although mMTLE
and rMTLE share very similar electroclinical and neuroimaging features,
a cognitive profile has been described only in rMTLE. A typical cognitive
impairment in rMTLE (possible candidates to surgery) is characterized
by memory deficits, impaired executive functions, language, processing
speed, intelligence, and motor dexterity [8,9]. There are several studies
investigating the relationship between patients with rMTLE and mem-
ory impairment; one of them suggests that hippocampal sclerosis influ-
ences verbal memory [10], and a second one found that the mood and
memory disturbances are the most salient comorbid conditions in pa-
tients with rMTLE [11,12]. Conversely, a typical cognitive mMTLE profile
has not been fully described so far. Only few studies with limited pa-
tients suggested that mMTLE shows verbal memory deficits [13–15].
Therefore, the aim of our study was to describe a cognitive profile
using a large cognitive battery in a consecutive group of patients with
mMTLE.

https://doi.org/10.1016/j.yebeh.2018.06.013
1525-5050/© 2018 Elsevier Inc. All rights reserved.

Please cite this article as: Vaccaro MG, et al, Neuropsychological profile of mild temporal lobe epilepsy, Epilepsy Behav (2018), https://doi.org/
10.1016/j.yebeh.2018.06.013
2 M.G. Vaccaro et al. / Epilepsy & Behavior xxx (2018) xxx–xxx
2. Materials and method
2.1. Participants
In this study, 40 consecutive patients with a diagnosis of mMTLE
were enrolled from February 2015 to June 2017. Patients were recruited
from the Outpatients Epilepsy Centre of Magna Graecia University of Ca-
tanzaro, Italy. The mMTLE of all patients was diagnosed according to the
ILAE classification of seizures [16] by two trained epileptologists (AG
and AL). Exclusion criteria were as follows: patient age is less than 18
or more than 70 years; patient has other neurological, psychotic disor-
ders (excluding depression and anxiety) or comorbidities; and patient
has generalized epilepsy, other partial epilepsies, or rMTLE. We decided
not to exclude patients with clinically relevant depression or anxiety as
these psychiatric symptoms are often associated with epilepsy [17–20].
Thirty healthy individuals matched in age, gender, and level of educa-
tion to the patients with mMTLE were also recruited. Healthy individ-
uals with Mini Mental State Examination (MMSE) [21] score equal or
less than 25/30, neurological or psychiatric diseases, and drug addiction
were excluded. Both patients and healthy controls (HC) provided writ-
ten informed consent to participate in the study. The study was ap-
proved by the local Research Ethics Committee in accordance with the
Helsinki Declaration. In each patient, the diagnosis of MTLE was mainly
based on typical temporal auras or interictal electroencephalographic
(EEG) discharges with a maximum over the temporal lobes. Any sug-
gestion of seizure onset outside the mesial temporal structures by semi-
ology or EEG findings was an exclusion criterion. Lateralization was
based on lateralized EEG discharges, with or without lateralized seizure
features. Epileptiform discharges were diagnosed in the presence of
focal spikes or sharp waves followed by slow waves, and they always in-
volved the temporal regions.
All patients underwent 3-Tesla magnetic resonance imaging (MRI)
test to evaluate the presence of abnormal temporal lobe features,
mainly the presence of hippocampal sclerosis. Multiple scalp EEG re-
cordings were used to detect interictal EEG abnormalities. At baseline,
all participants underwent a battery of standardized neuropsychological
(NPC) tasks and several neuropsychiatric interviews. All tests and ques-
tionnaires were administered by the same neuropsychologist expert
(MGV) blinded to clinical information.
2.2. Neuropsychological battery
The general cognitive functions of all patients and HC were evalu-
ated by a battery of standardized neuropsychological tests. The follow-
ing tests were administered: MMSE [21] was used to screen cognitive
impairment; the Controlled Oral Word Association Test (COWAT) was
used as a measure of lexical stock, ability to access the lexicon, and cog-
nitive flexibility [22–25]; Stroop Color and Word Test (Stroop) [26,27]
Table 1
Demographic, clinical, and neuroimaging features of healthy controls (HC) and patients with mild mesial temporal lobe epilepsy (mMTLE).
Gender (F)a
Age (years)b
Education (years)c
Duration of illness (years)b
Febrile seizures, n
Simple partial seizures (e.g., dejàvù)/m (n), mean (CI)
Number of AEDs (mean ± SD)
MRI evidence of hippocampal sclerosis (n)
BDI-IIb
STAI-YIb
STAI-YIIb
Results were expressed using row number percentage (a) for dichotomous variable and mean ± standard deviation (b) or median [range] (c) for continuous variables depending on
whether or not the data were normally distributed. Statistical analyses were performed using chi-square (a) for dichotomous variable, two independent samples t-test (b) or Mann–Whit-
ney (c) for continuous variables depending on whether or not the data were normally distributed. CI: confidence interval; m: month; n: number.
Please cite this article as: Vaccaro MG, et al, Neuropsychological profile of mild temporal lobe epilepsy, Epilepsy Behav (2018), https://doi.org/
10.1016/j.yebeh.2018.06.013
evaluated attention with an interference procedure (times in s); the
Modified Wisconsin Card Sorting Test (MWCST) [28] was a modification
of the original Wisconsin Card Sorting Test, and it tested the abstract
reasoning, decision making, planning, conceptual shifting, learning
new rules, and the ability to change cognitive strategies depending on
changes in environmental conditions [29]; the Digit Span: Forwards
and Backwards task [30] was used to assess the short-term verbal mem-
ory; the Rey–Osterrieth Complex Figure Test (ROCFT) [31,32] was used
to investigate visuospatial constructional functions, visuographic mem-
ory, and some aspects of planning and executive functions, with imme-
diate and delayed recalls; the Rey Auditory Verbal Learning Test
(RAVLT) [33,34], which includes measures of immediate and delayed
recalls, was used to assess verbal learning and memory; and the Short
Tale (ST) [35,31], which includes measures of immediate and delayed
recalls, was used to assess the episodic memory. In addition, the self-re-
ported prospective and retrospective memory questionnaire (PRMQ)
[36] was used to measure the subjective impairment in daily life in pro-
spective memory (PM) and retrospective memory (RM). It is a self-re-
port questionnaire, and it is made up of sixteen items: eight asking
about PM (i.e., the ability to remember to accomplish an intended action
at some point in the future such as remembering to take a tablet after
lunch) and eight about RM failures. Participants were asked to rate
how often they believe to fail in daily life activities requiring PM or
RM from very often (rated as 5 in a Likert scale) to never (rated as 1
in a Likert scale) [37,38]. In this way, the higher the PRMQ score is, the
higher the subjectively perceived problems in PM and RM are. Although
the PRMQ is widely used in literature [39–44], it has never been used to
study the cognitive impairment in epilepsy. The Beck Depression Inven-
tory Second Edition (BDI-II) [45] was used to evaluate depressive symp-
toms of both groups; the State–Trait Anxiety Inventory — Form Y1
(STAI-YI) provides scores for state anxiety; and State–Trait Anxiety In-
ventory — Form Y2 (STAI-YII) [46] provides scores for trait anxiety
levels. The entire neuropsychological battery lasted around 60 to 90
min.
2.3. Statistical analysis
Categorical variables are expressed as count (percentage) and con-
tinuous variables as mean (SD) or median (range), as appropriated. Be-
tween-group differences were tested using the chi-square for
categorical variables and the two independent samples t-test or the
Mann–Whitney U tests for categorical and continuous variables, de-
pending on whether the data were or were not normally distributed.
The normal distribution of the data was tested using the Kolmogorov–
Smirnov test (d-value) on each variable. The partial eta squared (η2p)
was reported as an estimate of effect size [47]. Note that 0.2 is consid-
ered a small effect, 0.5 a medium effect, and 0.8 a large effect [47]. The
results from the neuropsychological tests were corrected for multiple
HC mMTLE p value
n = 30 n = 40
20 (66.6%) 27 (67.5%) 0.941
43.4 ± 16.5 44.3 ± 12.9 0.790
13 [5–17] 13 [5–17] 0.763
– 15.8 ± 11.6 –
– 22 –
– 0.7 (0.2–6.2) –
– 1.1 ± 0.6 –
– 8 –
7.2 ± 6.7 15.9 ± 13.8 0.002
32.6 ± 9.8 41.2 ± 14.6 0.005
35.4 ± 11.4 41.6 ± 13.2 0.046
 M.G. Vaccaro et al. / Epilepsy & Behavior xxx (2018) xxx–xxx 3

Table 2
Neuropsychological profile of healthy controls (HC) and patients with mild temporal lobe
epilepsy (mMTLE).

HC mMTLE p K–S d Cohen's

n = 30 n = 40 d

MMSEa 27.9 ± 1.6 27.1 ± 1.5 0.06 0.12 0.51

ROCF copya 24.3 ± 4.2 27.8 ± 5.2 0.004 0.13 0.75
ROCF delay 30 sa 14.4 ± 4.9 12.5 ± 5.7 0.152 0.08 0.35
ROCF delay 20 mina 13.8 ± 4.7 12.1 ± 5.1 0.156 0.06 0.34
RAVLT immediate recalla 51.0 ± 41.4 ± 9.4 0.001* 0.07 0.92
12.2
RAVLT delayed recalla 11.6 ± 3.4 8.5 ± 3.8 0.001* 0.11 0.85
SRT total scorea 11.7 ± 2.9 9.0 ± 4.2 0.005 0.11 0.72
SRT immediate recalla 5.4 ± 1.8 4.4 ± 2.1 0.055 0.16 0.50
SRT delayed recalla 6.2 ± 1.6 4.5 ± 2.5 0.003 0.15 0.78
COWATa 38.2 ± 29.7 ± 0.015 0.12 0.79
14.4 12.1
MCST categoriesb 5 [1–6] 5 [1–6] 0.19 0.21°
MCST perseverative 2 [0–21] 4 [0–15] 0.03 0.207°
errorsb
MCST total errorsa 6.6 ± 7.2 8.4 ± 6.2 0.292 0.15 0.27
Digit span forwarda 5.4 ± 1.1 4.6 ± 1.1 0.007 0.18 0.72 Fig. 1. Correlation between BDI-II and PRMQ retrospective (PRMQ R).
Digit span backwarda 3.5 ± 1.0 2.7 ± 1.0 0.003 0.19 0.9
Stroop test interferencea 26.7 ± 8.1 27.7 ± 0.737 0.11 0.08
14.6
0.001). The results of these neuropsychological tests strongly correlated
PRMQ prospectivea 17.2 ± 5.4 22.5 ± 5.7 0.001* 0.12 0.95
PRMQ retrospectivea 17.0 ± 4.1 22.3 ± 5.8 b0.001* 0.14 1.04 with the BDI-II score but not with the STAI-YI and STAI-YII scores (Table
3). In particular, the RAVLT delayed score negatively correlated with the
Results were expressed using mean ± standard deviation (a) or median [range] (b) de-
pending on whether or not the data were normally distributed. Statistical analyses were BDI-II (r = − 0.386, p = 0.001; indicating that the higher the depres-
performed using two independent samples t-test (a) or Mann–Whitney test (b) depend- sion score, the lower the delayed recall) (Fig. 1). Similarly, the PRMQ
ing on whether or not the data were normally distributed. K–S: Kolmogorov–Smirnov. scores positively correlated with the BDI- II (r = 0.449 and r = 0.461
Asterisk (*) denotes statistical significance after multiple comparison correction. Open cir- for the prospective and retrospective indces, respectively, both p b
cle (°) denotes that the data are not normally distributed
0.001; indicating that the higher the depression score, the higher the
perceived prospective and retrospective memory difficulties) (Figs.
comparisons (Bonferroni's correction) and considered significant if p b 2 and 3). The correlation between RAVLT immediate score and BDI-II
0.05/18 = 0.0027 (as 18 different neuropsychological tests were ad- is not significant after Bonferroni correction (r = 0.338, p = 0.005).
ministered). Clinical and neuropsychological data were correlated One way analysis of covariance (ANCOVA) on neuropsychological per-
using Pearson's correlation. formance, using group as independent factor (two levels: controls and
patients with mMTLE) and controlling for BDI score, was performed in
3. Results order to rule out the hypothesis that the worse neuropsychological per-
formance of patients with mMTLE was due to their higher depression
Neither patients nor HC were excluded or dropped out during the and not to a real impairment in cognitive functioning. Interestingly,
study. None of the controls showed interictal or ictal EEG abnormalities; the results still remained significant (RAVLT delayed: F = 5.24, p =
interictal spikes or sharp waves were detected on the left side (22/40) 0.025; PRMQ P: F = 5.39, p = 0.024; PRMQ R: F = 8.047, p = 0.006),
or right side (18/40) in the patient group. As summarized in Table 1, pa- thus, confirming that patients with mMTLE performed worse than con-
tients with mMTLE did not differ from HC in the sociodemographic fea- trols in these neuropsychological tests.
tures, age, gender, and level of education. Patients with mMTLE showed
significantly higher depression (p = 0.002) and anxiety (p = 0.005 and 4. Discussion
p = 0.046) scores compared with the HC as expressed by the BDI-II,
STAI-YI, and STAI-YII questionnaire scores, respectively (Table 1). The purpose of the present study was to describe NPC features in a
In detail, at the neuropsychological assessment, patients with consecutive group of patients with mMTLE. In fact, mMTLE has been ex-
mMTLE showed lower performance than controls in the majority of tensively described [4,48,14,15] and represents a syndrome itself. How-
the neuropsychological tests particularly at RAVLT, short tale test ever, a typical cognitive profile of this peculiar population is still
(SRT), Digit Span, and PRMQ questionnaire as summarized in Table 2. unknown. We, thus, proceed to comparing patients with mMTLE with
After correction for multiple comparisons, significant differences be- HC to study whether, even if mMTLE is defined as mild or “benign”,
tween patients and controls were captured at RAVLT immediate recall they carry a typical cognitive profile at onset. In fact, neurologically
(51.0 ± 12.2 and 41.4 ± 9.4, t = 3.648, degrees of freedom (df) = 68, healthy patients with mMTLE might manifest important neuropsycho-
p = 0.001), RAVLT delayed recall (11.6 ± 3.4 and 8.5 ± 3.8, t = 3.400, logical deficits since onset independent from depression or anxiety.
df = 68, p = 0.001), PRMQ prospective (PRMQ P) (17.2 ± 5.4 and We clearly showed that firstly, the NPC assessment is important
22.5 ± 5.7, t = −3.631, df = 68, p = 0.001), and PRMQ retrospective even in patients with milder and subtle form of epilepsy and secondly,
(PRMQ R) (17.0 ± 4.1 and 22.3 ± 5.8, t = − 4.034, df = 68, p b patients' awareness of memory impairment could prevent a negative

Table 3
Correlations between clinical and neuropsychological features.

RAVLT immediate RAVLT delayed PRMQ prospective PRMQ retrospective

BDI-II r = −0.338, p = 0.005 r = −0.386, p = 0.001* r = 0.499, p b 0.001* r = 0.461, p b 0.001*

STAI-YI r = −0.084, p = 0.502 r = −0.197, p = 0.111 r = 0.297, p = 0.026 r = −0.260, p = 0.053
STAI-YII r = −0.077, p = 0.543 r = −0.198, p = 0.113 r = 0.361, p = 0.007 r = 0.332, p = 0.014

Asterisk (*) denotes statistical significance after multiple comparison correction.

Please cite this article as: Vaccaro MG, et al, Neuropsychological profile of mild temporal lobe epilepsy, Epilepsy Behav (2018), https://doi.org/
10.1016/j.yebeh.2018.06.013
4 M.G. Vaccaro et al. / Epilepsy & Behavior xxx (2018) xxx–xxx
Fig. 2. Correlation between BDI-II and PRMQ prospective (PRMQ P).
impact of cognitive deficits on everyday life allowing physicians to set
rehabilitation programs [49]. Interestingly, we observed that patients
with mMTLE showed a cognitive impairment that can be part of the syn-
drome itself. Indeed, we found verbal memory deficits at RAVLT delay as
well as subjective memory deficits in the daily life using a self-reported
questionnaire exploring PM and RM [37–39]. Although PM and RM im-
pairments might have very serious implications for the health of pa-
tients with epilepsy such as forgetting to take tablets [50], PM and RM
subjective assessments in patients with mMTLE have received little at-
tention to date. In contrast to Rayner's [51,52] results, showing that sub-
jective memory complaints in patients with refractory focal epilepsy
were often due to mood dysfunction, our results suggested that subjec-
tive memory complaints are independent from mood dysfunction. An-
other intriguing finding in our study is that patients with mMTLE
showed higher score on BDI-II compared with HC. However, when con-
trolling for the BDI-II score, we found the same significant difference be-
tween controls and patients on memory performance, suggesting that
memory deficits are not due to depressive symptoms. We can hypothe-
size that our results are mainly related to the underlying epileptic pro-
gression itself that might cause additional damage to temporal
structures dealing to remodeling of synaptic organization and memory
deficit because epilepsy in our cohort is very mild with few simple par-
tial seizures at long-term follow-up. In accordance with this hypothesis,
good evidence from experimental and imaging studies indicate that
Fig. 3. Correlation between BDI-II and RAVLT.
Please cite this article as: Vaccaro MG, et al, Neuropsychological profile of mild temporal lobe epilepsy, Epilepsy Behav (2018), https://doi.org/
10.1016/j.yebeh.2018.06.013
long-term alteration in neuronal plasticity and memory function may
be the consequence of even single or brief repetitive seizures and
cause secondary hippocampal volume loss [7,53,54]. Furthermore, we
cannot exclude that AEDs might have negatively influenced the cogni-
tive profile of patients with mMTLE. Indeed, there is a possibility that
a longer exposure to AEDs might also contribute to verbal learning im-
pairment in our patients. However, this should not represent our case
because the vast majority of our sample was taking a single AED at
low dosages that carries a modest, dose-related, adverse cognitive effect
compared with the contribution of high dosages and polytherapies [55].
Few limitations need to be accounted for. The sample size was not
very large; however, the cohort with mMTLE was very homogeneous
representing a specific syndrome. Secondly, we used PRMQ that is a
measure of self-rated memory failures and therefore cannot be treated
as though it were a direct measure of memory performance [38], but
the results of memory deficits are confirmed by objective neuropsycho-
logical assessment particularly with verbal memory test (RAVLT).
To our knowledge, the current work might represent the first neuro-
psychological study carried out in consecutive patients with mMTLE.
We demonstrated that even with patients with mMTLE and a very
mild profile, there are cognitive dysfunctions mainly on memory defi-
cits as part of the clinical spectrum of this syndrome. We believe that
this information is crucial because neuropsychology plays a very impor-
tant role in the treatment of epilepsy [56-60], providing information on
the effects of seizures on higher cortical functions through the measure-
ment of behavioral abilities and disabilities. Larger longitudinal long-
term studies together with advanced neuroimaging correlation com-
paring patients with refractory TLE are necessary to better characterize
the NPC profile in mMTLE and to look for potential biomarkers of
refractoriness.
Acknowledgments
The authors wish to thank Dr. Genevieve Rayner for providing En-
glish language proofreading for an early version of the manuscript.
Disclosure of conflicts of interest
The authors have no conflicts of interest.
This research did not receive any specific grant from funding agen-
cies in the public, commercial, or not-for-profit sectors.
Ethical publications statement
We confirm that we have read the journal's position on issue in-
volved in ethical publication and affirm that this report is consistent
with those guidelines.
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