INTRODUCTION
Temporal lobe epilepsy
(TLE), a common epileptic syndrome with adult onset, accounts for more than one
third of partial epilepsy and more than half of intractable epilepsy1.
The relatively high prevalence of neuropsychiatric comorbidities in TLE
patients suggests shared mechanisms and/or substrates between these two
conditions2.
The
main psychiatric disorders involved in TLE, in order of frequency, are
depression, anxiety and psychosis with prevalence ranging from 11 to 44%,
15-25% and 2-8%, respectively3. Psychiatric disorders in epilepsy
can be classified into ictal (the psychiatric symptoms are a clinical manifestation
of the seizure), peri-ictal (symptoms precede and/or follow the seizure
occurrence) and interictal (symptoms occur independently of the seizure
occurrence) disorders4.
Serotonin (5-HT) is one
of the neurotransmitters influencing the cortical and subcortical
excitatory/inhibitory balance and participates in many physiological and pathological
processes of the brain, including epilepsies. Genes coding for proteins related
to serotonin neurotransmission can regulate 5-HT availability. Of particular
interest are the gene encoding the serotonin transporter (5-HTT), responsible
for the clearance of 5-HT from the synaptic cleft, and the gene encoding the
serotonin receptor 1A (5-HT1A), that acts as an autoreceptor presynaptically
and mediates the action of serotonin postsynaptically5.
The
serotonin transporter (5-HTT) is an integral membrane protein responsible for
the reuptake of 5-HT from the synaptic cleft, modulating the serotoninergic
neurotransmission. The human 5-HTT gene is located on chromosome 17q11.1-q12,
spans 31 kb and consists of 14 exons6. Two polymorphic regions of
the 5-HTT gene, with supposed functional consequences, have been identified.
The first polymorphism is a 44 bp insertion/deletion in the promoter region,
the 5-HTT linked polymorphic region (5-HTTLPR) 7. The short variant
(S) indicates the presence of a deletion, resulting in a 484 bp allele, while
the absence of this deletion yields a long variant (L) of 528 bp. The shorter
allele impairs transcriptional activity of 5-HTT and lowers biological activity
of the transporter. Furthermore, the L variant has been reported to be
associated with greater m-RNA concentrations and serotonin uptake8. The
second polymorphism is a 17 bp variable number of tandem repeats in the second
intron (5-HTTVNTR)6. Common VNTR lengths are 9, 10, and 12 repeats.
It has been suggested that the VNTR region may act as a transcriptional
regulator of the 5-HTT gene in an allele dependent manner, with the 12 repeat
allele having stronger enhancer-like properties than the 10 repeat allele9.
The 5-HT1A gene contains a single nucleotide polymorphism (SNP) in the
promoter region (C-1019G) that seems to regulate gene expression10,11.
The G allele of C-1019G has been postulated to up-regulate autoreceptor
expression, but to decrease postsynaptic 5-HT1A expression12.
The 5-HTTLPR and 5-HTTVNTR polymorphisms in the 5- HTT gene
and the C-1019G polymorphism in the 5-HT1A gene have been studied
in various psychiatric diseases, among them depression13,14,
suicidal behavior15,16, anxiety17,18, personality
disorder19, bipolar disorder and schizophrenia20.
Recently, some authors have evaluated the association between 5- HTT variants
and epilepsy21,22. Most of these studies have shown that modulation
of the 5-HTT gene might influence epileptogenesis or the clinical
characteristics of epilepsy. Also, Savic et al. found a reduced serotonin
receptor (5-HT1A) binding potential in limbic structures in patients with
mesial TLE, supporting the hypothesis of an involvement of serotonin in the
neurobiology of TLE, perhaps suggesting a mechanism underlying affective
symptoms in these patients23.
Thus,
it is biologically possible that alterations in serotonin-related genes may be
one of the biological mechanisms involved in higher susceptibility to
neuropsychiatric comorbidities in TLE.
Aim of work: To investigate the possible effect of 5-HTTLPR
and 5-HTTVNTR polymorphisms in the 5-HTT gene and the C-1019G polymorphism in
the 5-HT1A gene in psychiatric comorbidities in Egyptian patients with temporal
lobe epilepsy.
PATIENTS AND METHODS
Study Design and Population
This is a case-control study carried out on 50 patients with non-lesional TLE. They were
recruited in the period between September 2012 and September 2013 from the
Epilepsy Outpatient Clinic of Kasr El Aini Hospital (Cairo university hospitals). According to the
results of the Present State Examination 10th revision (PSE-10) of the
Schedules of Clinical Assessment in Neuropsychiatry (SCAN)24, patients were subdivided into
two groups: 35 TLE patients with psychiatric disorder(s) we
termed them TLE-PSYCH group and 15 patients in whom PSE-10 was negative. These
two groups of patients were compared for clinical and genotypic differences.
Inclusion criteria: 50 epilepsy patients, their
diagnosis were based on the 1989 ILAE’s electroclinical classification
(Commission on Classification and Terminology of the International League
Against Epilepsy, 1989)25 and neuroimaging results. Non-Lesional
temporal lobe epilepsy and temporal lobe epilepsy with mesial temporal
sclerosis patients were included.
Exclusion criteria: Patients with extratemporal
epilepsies, mental retardation and those with systemic diseases were excluded.
Lesional temporal lobe epilepsy patients were excluded.
All patients were subjected to
EEG recording using Nihon Kohden 14-channel EEG machine; electrodes were
arranged according to 10-20 international system of electrode placement.
It was performed to all patients under standard conditions in the
Neurophysiology unit, Neurology department, Cairo University.
In all patients, brain MR images obtained by using a 1.5 Tesla Philips
Gyroscan machine (Philips Medical Systems, Best, the Netherlands)
in diagnostic radiology department, Cairo
university hospitals images were obtained using sequences
and slices to optimize visual detection of mesial temporal structures.
All patients were submitted to the Arabic version of the
Present State Examination 10th revision (PSE-10) of the Schedules of Clinical
Assessment in Neuropsychiatry (SCAN)24 The PSE-10 of the SCAN has
been translated into Egyptian colloquial Arabic by Hamdi and colleagues26.
An abridged form of the Arabic version of the PSE-10 was employed in the survey
based upon the short English form of the PSE-10 that was translated and
expanded by further questions from the Arabic version in the domains of
anxiety, phobias and obsessions, psychotic disorders, somatoform and
dissociative disorders, and mood disorders27. The final version was
back translated, tested during training of the field researchers, modified
according to feedback and tested for reliability28.
Patients then submitted to further evaluated by Hamilton
Anxiety Rating Scale (HAM-A)29, Hamilton Depression Rating Scale
(HAM-D)30 and Young Mania Rating Scale (YMRS)31 to assess
severity of anxiety, depression and manic symptoms respectively.
Genotyping
DNA was extracted from
peripheral leukocytes by genomic DNA High Pure PCR template extraction kit (Roche Diagnostics, Germany) according to the
manufacturers’ protocol. Subjects were genotyped for the 5-HTTLPR, 5-HTTVNTR
and C-1019G. 5-HTTLPR: The amplification reaction (PCR) for the 5-HTTLPR
polymorphism was carried out using primers described by Heils et al.7.
The PCR amplified products were digested with MspI restriction
enzyme (New England Biolabs) which identify the biallelic polymorphism (L and S
variants)7. The digestion products were visualized by 3% agarose gel
electrophoresis stained with ethidium bromide under UV light. For 5-HTTVNTR,
The intron 2 region of the 5-HTT gene containing the VNTR polymorphism was
amplified using primers described by Weese-Mayer et al.32. The PCR
product was visualized by 3% agarose gel electrophoresis stained with ethidium
bromide. The 5-HTTVNTR gene had three alleles: Stin2.9 (250 bp), Stin2.10 (267
bp) and Stin2.12 (300 bp). Stin2.9 (250 bp) was not detected,
but three genotypes (10/12, 10/10, 12/12) were determined in this study. For
C-1019G, An allele-specific polymerase chain reaction (ARMSPCR) analysis was
performed according to Parsey et al.33. Each sample was amplified
twice using a specific primer for the G allele and another primer for the C
allele 10. Electrophoresis was performed on 1.5% agarose gel and the
amplification product was visualized under UV light.
Statistical Methods
The
clinical variables and genotypes of the polymorphisms, 5-HTTLPR biallelic
model, and 5-HTTVNTR in the 5-HTT gene and C-1019 G in the 5-HT1A gene
were compared between TLE patients with psychiatric comorbidities and those
without it. Variables
were analysed using “Statistical Package of Social Science Software program”
version 21 (SPSS). Data were summarized using mean and standard deviation
(parametric variables), frequency, and percentage for (non-parametric
variables). Comparison between groups non-parametric
nominal variables Chi square test was preformed. Comparison between numerical
variables for more than 2 groups ANOVA and Post Hoc Tukey test was preformed. P
values less than 0.05 were considered statistically significant, and less than
0.01 were considered highly significant.
RESULTS
The
study included 50 temporal lobe patients with age ranged from 17 to 50 years
with a mean of 30.38 and SD 8.14, 25 of them were females (50%). In our study,
the most frequent psychiatric comorbidities were mood disorder (56%), anxiety
disorder (42%), drug abuse (42%) followed by somatoform disorder (24%) and
lastly psychosis (12%). The main drug of abuse was the tramadol. More than one
psychiatric co morbidity can occur in the same patients and these concomitant
occurrences were identified by PSE-10. In our study, mood and anxiety disorders
occurred together in nine patients (26% of the total).
Comparing TLE-PSYCH group with TLE-ONLY group we found a
significant lower age of the patients and lower age of onset of epilepsy in
TLE-PSYCH group (p<0.01) . Most of the patients with psychiatric disorders
(TLE-PSYCH group) were women (23(65.7%)), while only 34.3% were men, whereas in
TLE-ONLY group 13.3% were women and 86.7% were men, a significant difference
for sex (p=0.001). The history of positive consanguinity and history of status
epilepticus were significantly higher in patients with psychiatric disorders
(TLE-PSYCH group).
Mean time of epilepsy, family history of epilepsy, family
history of psychiatric disease and mesial temporal sclerosis in brain MRI did
not differ between TLE patients with and without psychiatric comorbidities in
our cohort. Clinical and demographic characteristics of the sample are
presented in Table (1).
When we
compared the genotype distribution of 5-HTTLPR, 5-HTTVNTR and C-1019G
polymorphisms in TLE-PSYCH group with TLE-ONLY group we found a higher
significant frequency of CC homozygous repeat in C-1019G polymorphism in
TLE-PSYCH group (p<0.05). There was no significant difference as regards
different genotype frequencies for 5-HTTLPR or 5-HTTVNTR polymorphism between
both groups as in Table (2).
Clinical
and genotype distribution characteristics of TLE patients according to presence
of anxiety disorders or mood disorders are summarized in Table 3. In comparing TLE with
anxiety disorders with those without it, we found significant lower age of the
patients with anxiety disorders (p=0.048). In addition, Women with TLE had more
frequently anxiety disorders than men (p=0.002). The frequency of positive
consanguinity and family history of psychiatric disease was significantly
higher in TLE with anxiety disorders (p=0.03 and0.008 respectively).The
frequency of SS repeat in 5-HTTLPR polymorphism was significantly higher in
patients with anxiety disorders (p=0.039). On the other hand, when we compared
TLE with mood disorders with those without them, we did not observe significant
differences between clinical and demographic characteristics of TLE patients
regarding the presence of mood disorders, except for significant lower age of
patient and predominance of female gender in TLE with mood disorders (p=0.039
and 0.004 respectively). Also, the frequency of 12/12 repeat in HTTVNTR
polymorphism was significantly higher in patients with mood disorders than
those without them.
Observing
the relation between the severity of the anxiety and the mood disorder in
different genotypes for 5-HTTLPR, 5-HTTVNTR and C-1019G polymorphism in
patients with psychiatric disorders (TLE-PSYCH group) we found significant
higher score of HAM-A in SS genotype for 5-HTTLPR than SL and LL genotypes
(p<0.05). On the other hand, 12/12 genotype patients had a significant
higher score of HAM-D than other genotypes for 5-HTTVNTR polymorphism
(p<0.05). There was no significant difference in means of scores of HAM-A,
HAM-D and YMRS between different genotypes for both C-1019G polymorphism as in Table
(4).
DISCUSSION
Prevalence of the association of epilepsy and psychiatric
disorders ranges from 20 to 50%, reaching 80% in selected populations like
individuals with TLE, and medically intractable patients, candidates to
surgical treatment. These indices are far superior to those found in general
population (10-20%). Differences in methods of investigation and in populations
studied are the main contributory factors for variable results. Also distinct
epidemiological definitions (punctual prevalence, cumulative prevalence,
lifelong prevalence), with their proper meanings, may contribute equally to
variability of results34.
In our
study, we observed a high rate of psychiatric disorders in our TLE patients.
Psychiatric comorbidities were present in 70% of them. The most frequent psychiatric comorbidities
were mood disorder (56%), anxiety disorder (42%), drug abuse (42%) followed by
somatoform disorder (24%) and lastly psychosis (12%). The main drug of abuse
was the tramadol. These results are matches with those of Lambert and
Robertson, Gaitatzis et al, and Bragatti et al.35-37. In Bragatti series, 63.9% of TLE patient had
psychiatric disorders, 48.2% had mood disorders followed by anxiety disorders
occurred in 30.7% of patients. Psychotic disorders and substance abuse were
observed in 8.4% and 4.8% of patients, respectively37. The high
prevalence of drug abuse in our patients was mainly due to notable widespread
tramadol addiction in our community38.
In our study, mood and
anxiety disorders occurred together in 13 patients (26% of the total). This
association has been recognized since ancient times, but its pathophysiologic
mechanisms are still poorly understood. Studies with adults and children
suffering from epilepsy have shown a high prevalence of this comorbidity in
association with epilepsy, sometimes up to 70%. Depression, anxiety and
epilepsy seem to share some biological and structural mechanisms related to
limbic system dysfunctions. This is an interesting topic which has been
intensely investigated over the last few years39.
We
found a significant lower age of the patients and lower age of onset of
epilepsy in TLE-PSYCH group compared to TLE-ONLY group. This is in accordance
with the results of Davies et al.; Gaitatzis et al.; Pellock and Swinkels et al.40,36,41,42.
In contrast, Schenkel et al. did not find significant difference between TLE
patients with and without psychiatric co morbidities regarding the age of the
patients and age of onset of epilepsy43.
Most of
our patients with psychiatric disorders (TLE-PSYCH group) were women. These
results are in agreement with Bragatti et al. and Swinkels et al.37,42.
The
history of positive consanguinity was significantly higher in patients with
psychiatric disorders (TLE-PSYCH group). Our finding might suggest that genetic
predisposing factors might be
important in the pathogenesis of
psychiatric disorders in epilepsy. This is in line with the results of Bragatti
et al.37.
History
of status epilepticus was significantly higher in patients with psychiatric
disorders especially those with mood disorders. This is matched with the
results of many others who concluded that the severity of epilepsy is one of
the most important risk factors for development of psychiatric disorders in
epilepsy time44-46.
Mean
time of epilepsy, family history of epilepsy, family history of psychiatric
disease and mesial temporal sclerosis in brain MRI did not differ between TLE
patients with and without psychiatric comorbidities in our study. This is in
accordance with the results of Schenkel et al.43.
When we
compared TLE with mood disorders with those without it, we did not observe
significant differences between clinical and demographic characteristics of TLE
patients regarding the presence of mood disorders, except for significant lower
age of patient and predominance of female gender in TLE with mood disorders.
This is in accordance with Bragatti et al., who stated that women with TLE were
significantly had mood disorder in
comparison to men but they found that
positive family history of psychiatric disorder is significantly
associated with mood disorder37.
In
comparing the genotype distribution of 5-HTTLPR, 5-HTTVNTR and C-1019G
polymorphisms in TLE-PSYCH group with TLE-ONLY group ,we found a higher
significant frequency of CC homozygous repeat in C-1019G polymorphism in
TLE-PSYCH group. There was no significant difference as regards different
genotype frequencies for 5-HTTLPR or 5-HTTVNTR polymorphism between both
groups. These results are partially matched with those of Schenkel et al., who
found that there was no significant association between these polymorphisms in
the 5-HT1A and 5-HTT genes and the combined presence of neuropsychiatric disorders
in patients with TLE (TLE-ONLY group versus TLE-PSYCH group)43. In contrast,
other studies have found that the G allele of C-1019G is a risk factor for the
development of neuropsychiatric diseases, among them depression and panic
disorder18.
When we
analyzed each psychiatric disorder individually (mood disorder, anxiety
disorder, psychosis, drug abuse and somatoform disorder), the frequency of
5-HTTLPR polymorphism was different between TLE patients with and without
anxiety disorder. The frequency of SS genotype of 5-HTTLPR polymorphism was
higher in patients with anxiety disorder than in patients without anxiety.
Caspi et al. research on the association between 5-HTTLPR alleles and
personality traits found that carriers of S alleles (S/S or S/L) were reported
to have higher neuroticism (considered a vulnerability factor for anxiety and
depression) scores than L homozygotes (L/L)47. Hariri et al.
demonstrated that S carriers had a significantly greater amygdala response than
participants with the L/L alleles, suggesting that the S allele is associated
with a greater degree of amygdala excitability48.
Also,
the frequency of 5-HTTVNTR polymorphism was different between TLE patients with
and without mood disorder. This is supported by the results of Lothe et al. who
found that changes of the serotoninergic pathway are associated with depressive
symptoms in TLE patients49.
On the
other hand, we found that the frequency of C-1019G polymorphism did not differ
significantly between TLE patients with and without anxiety disorder. This is
unlike Schenkel et al. who found that temporal lobe epileptic patients with the
C allele of C-1019G polymorphism in the 5-HT1A gene had higher frequency of
anxiety disorder43.
Our
study might help to beginning understand the molecular basis of psychiatric
comorbidities in epilepsy. In fact, this might be an initial work in a field
that remains almost unexplored. Further studies are necessary to clarify these
matters.
Conclusion
Psychiatric
comorbidities were present in 70% of our TLE patients .The most frequent
psychiatric comorbidities were mood disorders (56%). Most of our patients with
psychiatric disorders were women (65.7%). There was a higher significant
frequency of CC homozygous repeat in C-1019G polymorphism in TLE-PSYCH group.
There could be a possible role 5-HT gene polymorphisms in molecular mechanisms
involved in psychiatric comorbidities in TLE. Further large scale studies are
necessary to confirm our findings.
[Disclosure: Authors report no conflict of interest]
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