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Psychiatric Comorbidities of Epilepsy: A Review
José Augusto Bragatti*, Carolina Machado Torres, Gustavo Rassier Isolan and Marino Muxfeldt Bianchin
Division of Neurology, Hospital de Clínicas de Porto Alegre
Abstract
People with epilepsy (PWE) have an increased risk for cognitive, behavioral, and psychosocial disorders. The
presence of comorbidities may directly affect quality of life of PWE. For example, there is an increased risk for suicide
in PWE, compared to the general population. Association between epilepsy and mental disorders is a condition known
since Antiquity, and its ranges from 20 to 50%, reaching 80% in selected populations, like individuals with temporal
lobe epilepsy (TLE), and medically intractable patients, candidates to surgical treatment, and these indices are far
superior to those found in general population (10-20%). Risk factors for the main psychiatric comorbidities in PWE
(depression, anxiety and psychosis) are classiied in (1) neurobiological, (2) psychosocial, and (3) pharmacological
factors. There is a bidirectional relationship between epilepsy and mental disorders, namely, not only the epileptic
disorder can antedate settlement of psychiatric symptoms in a given patient, but also the diagnosis of mood and
behavioral disorders may be made before a irst epileptic seizure. This bidirectionality suggests that structural and
functional modiications of one disease increase the risk for the development of the other. In this review, we included
the most recent articles concerning the terms “mental disorders”, “epilepsy”, and “risk factors” in PubMed. Book
chapters were also referred for this work. We gave preference for population-based studies, especially those with
more than 100 patients studied.
Keywords: Epilepsy; Comorbidity; Mental disorders; Risk factors;
Physiopathology
Introduction
Ian Curtis, the famous Joy Division band’s vocalist and song writer
had a transient personality. He could show diferent behaviors at
diferent times and with diferent people. Sometimes he was angry and
spiteful, but more oten was compliant and kind. He was diagnosed
as epileptic when he was 23 years old. His its varied in frequency and
intensity, and anticonvulsant medication, which he took regularly,
seemed to make his mood swings more radically. His frenetic style on
stage simulated his own real epileptic seizures. Ian Curtis killed himself
at his home in Macclesield, England. He was 24 years old. he history
of his life was recently portrayed in the movies “Control”, launched in
2007 [1].
his case exempliies how an epileptic disorder can transform
people`s lives in true tragedies, harming their quality of life, changing
personality traits and eventually increasing malady and causing death.
Epilepsy is quite common also in “anonimous” individuals, and
comprehension of its comorbidities, especially those pertaining to the
psychiatric sphere, is a basic element for its management.
Epilepsy is a frequent neurological disorder with a worldwide
distribution, although most people with epilepsy (PWE) live in
underdeveloped countries. he term Epilepsy comprises many
conditions typiied by a tendency to spontaneous recurrence of
epileptic seizures. Epilepsy occurs in all ages and can be associated to
several cognitive, social and psychiatric troubles [2].
Epileptic seizures are clinical expressions (symptoms) that
begin abruptly and have a great variability in presentation form. A
seizure can present with motor, sensorial, autonomic and/or state of
consciousness changes [3]. he common physiopathological substrate
for all types of epileptic seizures is disequilibrium between excitatory
and inhibitory inluences onsettled neuronal pathways. In summary,
there is a state of hyperexcitability supplied by predominant excitatory
strengths. Epilepsies and epileptic seizures are divided in generalized
(when neuronal hyperexcitability originates in both cerebral
J Neurol Neurophysiol
hemispheres simultaneously) and focal (localized unilateral neuronal
hyperexcitability) [4,5].
he most common epileptic disorder is the Temporal Lobe Epilepsy
(TLE) that alicts 40% of adult PWE [6]. Temporal lobe seizures belong
to three distinct types: simple partial (aura only), complex partial (most
commonly absences with automatisms), and secondarily generalized.
TLE is divided in mesial (onset on hippocampus and amygdala) and
lateral (onset on temporal neocortex). Mesial TLE has high indices of
association with psychiatric disorders, because it involves the Lymbic
System, the main integrator of emotional processes [7,8]. he most
common pathology causing mesial TLE is hippocampal sclerosis [3].
he epileptic seizure temporally subdivides the clinical state of the
PWE into two distinct periods of time: ictal (or peri-ictal) and interictal
(when there isn’t any sustained-release excessive rhythmic neuronal
discharge). he essential focus of pharmacologic treatment of epilepsy
is the hamper of ictal phenomenon. In general, this is achieved in about
two thirds of cases [2]. Nevertheless, study of the interictal condition of
PWE is also very important, and has improved the comprehension of
epileptic phenomenon as a whole.
One of the most important issues not linked to the pharmocological
control of seizures is the assessment of comorbidities in PWE.
hese patients have an increased risk for cognitive, behavioral, and
psychosocial disorders. [8,9] By the way, not only a poor control of
*Corresponding author: José Augusto Bragatti, Division of Neurology, Hospital
de Clínicas de Porto Alegre, Brazil, Tel: +5551-3222-4690; Fax: +5551-32224690; E-mail: jbragatti@hcpa.ufrgs.br
Received July 24, 2011; Accepted December 09, 2011; Published December
18, 2011
Citation: Bragatti JA, Torres CM, Isolan GR, Bianchin MM (2011) Psychiatric
Comorbidities of Epilepsy: A Review. J Neurol Neurophysiol S2. doi:10.4172/21559562.S2-002
Copyright: © 2011 Bragatti JA, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Epilepsy: Current Trends
ISSN: 2155-9562 JNN, an open access journal
Citation: Bragatti JA, Torres CM, Isolan GR, Bianchin MM (2011) Psychiatric Comorbidities of Epilepsy: A Review. J Neurol Neurophysiol S2.
doi:10.4172/2155-9562.S2-002
Page 2 of 10
seizures, but also the presence of comorbidities may directly afect
quality of life of PWE. here is an increased risk for suicide in PWE,
compared to the general population, and this risk is even greater in
patients with a history of a psychiatric disorder, especially with the
association between depression and anxiety [10].
Epilepsy associated with mental disorders is a condition already
known since Antiquity. Most part of stigma that follows PWE is
descendent from the assignment of supernatural entities, like gods,
witches, and devils, to the epileptic disorder [11].
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. hese indices are far superior to those found in
general population (10-20%). Diferences in methods of investigation
and in populations studied are the main contributory factors for
variable results. Also distinct epidemiological deinitions (punctual
prevalence, cumulative prevalence, lifelong prevalence), with their
proper meanings, may contribute equally to variability of results
[12,13].
Risk factors for the main psychiatric comorbidities in
PWE (depression, anxiety and psychosis) are classiied in (1)
neurobiological, (2) psychosocial, and (3) pharmacological factors.
Major neurobiological factors are: type, frequency, duration, age of
onset, and lateralization of epileptic seizure, genetic predisposition,
gender, and presence of structural lesion. Issues concerning
surgical treatment of epilepsy, like lateralization, type of resection,
histopathological diagnosis, and surgical prognosis have been studied
also. Other factors like hippocampal volume loss, temporal and frontal
lobe glucose hypometabolism, and neurotransmitter and hormonal
substances changes, may also be highlighted. As psychosocial factors
we could name the “learned despair”, restraints to normal daily living
activities, low self-esteem, educational and Professional diiculties,
stigmatization, and social rejection. Among pharmacological factors,
adverse efects of central nervous system (CNS) depressor antiepileptic
drugs (DAEs), withdrawal of a mood stabilizer drug, polytherapy,
starting a new DAE, and dose adjusting have been cited [14,15].
here is a heterogeneous association between epilepsy subgroups
and psychiatric disorders. In most patients, several chronic and
acute risk factors can be identiied. hese factors are diicult to study
retrospectively, and establishment of a cause and efect relationship
may not always be possible. Literature data is highly controversial,
and there is a huge diiculty to compare studies, because of the great
variability in deinition of essential terms like “epilepsy”, “psychiatric
disorder”, and the proper explored risk factors.
It is important to highlight that there isn’t a unidirectional
relationship between epilepsy and mental disorders, namely, not
only the epileptic disorder can antedate settlement of psychiatric
symptoms in a given patient, but also the diagnosis of mood and
behavioral disorders may be made before a irst epileptic seizure. his
bidirectionality suggests that structural and functional modiications
of one disease increase the risk for the development of the other [16].
here is increasing evidence that both in epilepsy and in
mental disorders, changes in interaction between serotonergic and
noradrenergic neurons with glutamatergic systems are associated
to abnormal neuronal circuitries and hyperexcitability. his
hyperexcitability could evoke both seizure activity and emotional
dysfunctions [15]. Furthermore, decrease in synaptic levels of
J Neurol Neurophysiol
neurotransmitters, as well as elevation in glucocorticoid levels could
inluence intracellular signaling pathways, like cyclic Adenosine
Monophosphate (cAMP), and originating disorders of neurotrophic
factors, like Brain-Derived eurotrophic Factor (BDNF) [17,18].
herefore, the association between TLE and psychiatric disorders
seems to be highly prevalent. his comorbidity afects directly
clinical prognosis of the epileptic seizures, and also the quality of
life of the patients with this type of epilepsy. It appears that there are
common physiopathological mechanisms in both TLE and mental
disorders, in general afecting neuronal circuitries of Lymbic System.
Genetic disorders, like polymorphisms of receptor genes of many
neurotransmitters, and also of neurotrophins, like BDNF, might be
involved in this association.
In this review, we included the most recent articles concerning the
terms “mental disorders”, “epilepsy”, and “risk factors” in PubMed.
Book chapters were also referred for this work. We gave preference for
population-based studies, especially those with more than 100 patients
studied.
Concepts in Epilepsy
he term Epilepsy comprises several syndromes which the main
characteristic is an enduring redisposition to recurrent non-provoked
epileptic seizures [2]. Epileptic seizures are sudden and brief attacks
of altered consciousness, motor, sensitive, psychic, cognitive or
autonomic dysfunctions, or an inappropriate behavior, caused by
excessive or synchronic abnormal neuronal activity in the brain [3].
he epilepsies and epileptic seizures are classiied in focal and
generalized [4,5]. Regarding focal epilepsies, the seizure clinical
expression is determined by the topographical localization of the
neuronal discharge, as well as its extent of spread in the brain. For
the sake of conceptualization and pre-surgical neurophysiologic
assessment of epilepsies, the region that yields the neuronal discharge
is named Ictal Onset Zone, and the regions that generate the seizure’s
clinical features are named Symptomatogenic Zones. his is an
important distinction, because the region where the discharge starts
is not always able to produce clinical manifestations (“silent cortex”).
In this case, surgical removal of the symptomatogenic zone would not
be curative, because the real source of the epileptic disorder would
not be included in the removed tissue [19]. he physiopathology of
generalized seizures is diverse, depending on a genetically-determined
thalamocortical circuitry dysfunction [20].
Regarding etiology, epilepsies are divided in idiopathic (without
structural brain lesion), symptomatic (with a structural lesion seen in
neuroimaging exams) and cryptogenic (with a presumable etiology,
not diagnosed at all) [5]. Estimated incidence of epilepsy in developed
countries is about 50/100,000/year [21], and these numbers may double
in poor countries [22]. In general, we ind a bimodal distribution, with
peaks of incidence in the irst year of life and ater 60 years of age.
Prevalence of active epilepsy in most regions of the world is in turn
of 5-10/1,000, although it may be even greater in some localized areas
[23,24]. General prognosis for complete seizure control is good, since
70% of patients acquire remission ater ive years of diagnosis [25,26].
Nevertheless, both adults and children with epilepsy an increased risk
for death, when compared with normal individuals [27,28].
Temporal Lobe Epilepsy
Temporal lobe epilepsy represents most patients with symptomatic
or cryptogenic focal epilepsies. Types of seizures in TLE include simple
Epilepsy: Current Trends
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Citation: Bragatti JA, Torres CM, Isolan GR, Bianchin MM (2011) Psychiatric Comorbidities of Epilepsy: A Review. J Neurol Neurophysiol S2.
doi:10.4172/2155-9562.S2-002
Page 3 of 10
partial, complex partial and secondarily generalized seizures. Seizures
most oten originate in amygdalo-hippocampal region, in the medial
and basal portion of temporal lobe. Hence, mesial temporal epilepsy
(MTE) is the most frequent focal epilepsy [29-32].
diferent phases of the moon. In the Arabic world, the epilepsy-mental
disorders-devils association persisted, and prophets, like Mohammed
and Saint Paul, that periodically heard voices and fell on the loor,
supposedly had epilepsy [39].
In MTE, seizure begins in more than 90% of the cases with an
unnatural rising epigastric sensation. Other autonomic, psychic (i.e.:
fear) and sensitive (i.e.: olfactory sensation) symptoms could occur
also. Complex partial seizures of MTE almost always implicate motor
arrest or automatisms (oroalimentary or gestural), early in the course
of seizure. Ictal features with lateralizatory value include: dystonic
posture of one superior limb (contralateral to the epileptic focus),
early shit of the head (ipsilateral), late version of head, on transition
to secondary generalization (contralateral). Intelligible vocalizations
suggest onset of seizure in the non-dominant hemisphere. Most oten,
temporal lobe seizures last about two minutes, and are followed by a
post-ictal confusional state. Post-ictal aphasia suggests seizure activity
in the dominant hemisphere. MTE is the most common medically
refractory focal epilepsy, and also one of the most surgically treatable
[33].
In the XIXth century and in the beginning of the XXth century,
epilepsy was a common diagnosis in asylums housing patients
with mental disorders. he most sicker individuals were treated
by psychiatrists, whereas those with less severe pictures stayed in
the community, where they were treated by general physicians or
neurologists [40].
Lateral (neocortical) TLE is less frequent, and generally is
characterized by an auditory aura [34]. Most oten, seizures yielded in
the lateral portion of temporal lobe are shorter in duration. Vertiginous
hallucinations were described with temporo-parietal discharges.
Most frequently structural lesions associated with TLE
are: hippocampal sclerosis, benign tumors (i.e.: ganglioglioma,
neuroepithelial dysembrioplasic tumors), vascular malformations
(i.e.: cavernoma), and malformations of cortical development (i.e.:
focal cortical dysplasia). Hippocampal sclerosis coexisting with an
extratemporal lesion is called dual pathology, a condition that carries
a greater degree of diiculty for diagnosis, and worst prognosis [35].
Considering the importance of limbic circuitries for the
neuropsychiatric diseases, it is not a surprise the observation that many
patients with TLE present concomitant psychiatric disorders, like
depression and anxiety [36].
Comorbidities in Epilepsy
he term comorbidity refers to a more than occasional concomitant
presence of two medical conditions in the same individual [37].
Comorbidity does not implies directionality or a cause-and-efect
relationship, and diseases may coexist randomly, or also share common
genetic and/or environmental mechanisms [9]. Epilepsy is frequently
associated to cognitive, psychiatric or social troubles [38].
Psychiatric Comorbidities in Epilepsy
Historical
Association between epilepsy and psychiatric disorders has been
described since the beginnings of Neurology and Psychiatry practices,
and there are many examples found in literature. Hippocrates, about
400 b.c., observed a dichotomy between epilepsy and melancholia, and
purposed that these two entities could be linked by a probable common
physiopathological mechanism [11].
he history of the epilepsy-psychiatry interface had its beginning
imprinted by the empirical association of these conditions with gods,
witches, devils, and supernatural phenomena. he Greeks referred to
epilepsy as the “sacred disease”. In those years, Hippocrates that rush
of fury that led Hercules to kill his children had an epileptic nature.
he Romans referred to epilepsy as “morbidus lunaticus”, related to the
J Neurol Neurophysiol
In the 1920’s decade, Emil Kraepelin made observations that
are considered the basis for the modern psychiatric diagnostic
classiication. Kraepelin described precisely the afective changes of
PWE, years before the age of electroconvulsive therapy. Dysphoric
events, characterized by irritability, with or without bursts of fury,
were considered by him the most frequent psychiatric disorder in
PWE. Depression, anxiety, headache, and insomnia were very frequent
complementary symptoms, although euphoric mood was less common
[41].
Heinrich Landolt identiied diferent types of psychotic episodes and
their correlations with epileptic seizures and the electroencephalogram
(EEG), introducing the concept of “Alternant Psychosis or Forced
Normalization” [42]. His work was later complemented by Slater and
Beard, with the article “Schizophrenia-Like Psychosis of Epilepsy”,
where it was purposed an agonic relation between epileptic seizures
and psychotic states [43].
More recently, the introduction of advanced techniques of
neuroimaging, like Positron Emission Tomography (PET), Magnetic
Resonance Imaging (MRI), and the spectroscopy, combined with
animal models and reined behavioral tests, made it possible the
identiication of common physiopathological mechanisms to both the
epilepsies (especially TLE) and psychiatric disorders (especially major
epression).
Epidemiology
here are few community-based studies on prevalence of
psychiatric conditions in PWE. Most of these studies involve speciic
epileptic populations, in tertiary centers for attention to PWE.
Community-based epidemiologic studies suggest a lifelong prevalence
of psychiatric disorders in PWE, both adults and children, between 20
and 50% [13,44-52]. Recently, Tellez-Zenteno et al. [9] using data from
the Canadian Community Health Survey, with administration of the
World Mental Health Composite International Diagnostic Interview
(CIDI), found a lifelong psychiatric disorder diagnosis in 35% of PWE,
compared with 20% of non-epileptic individuals.
he great variability of results obtained has been ascribed to
diferences in the methodology applied and in populations studied. It is
well known that psychiatric pathologies could be overrated in selected
populations, like TLE or refractory patients [53], in whose prevalence
of mental disorders may reach 80% [54].
Methods of psychiatric assessment
Psychiatric assessment can be made basically by two types of
interviews: structured interviews and self-applicable questionnaires
(non-structured) [12]. Non-structured interviews have been
progressively replaced by structured interviews in the last years, to obtain
a greater diagnostic accuracy. Structured interviews are composed by a
Epilepsy: Current Trends
ISSN: 2155-9562 JNN, an open access journal
Citation: Bragatti JA, Torres CM, Isolan GR, Bianchin MM (2011) Psychiatric Comorbidities of Epilepsy: A Review. J Neurol Neurophysiol S2.
doi:10.4172/2155-9562.S2-002
Page 4 of 10
set of key questions intending the fulillment of well-deined diagnostic
criteria included in the Diagnostic and Statistical Manual, Fourth
Edition (DSM-IV). Main representatives are the Structured Clinical
Interview for DSM Disorders (SCID) [55] and the Mini-International
euro psychiatric Interview (MINI) [56]. Self-applicable questionnaires,
like the Beck Depression Inventory (BDI) [57], and the Center for
Epidemiologic Studies Depression Scale (CES-D) [58], in general are
less extensive and are based upon subjective criteria. Results obtained
by self-applicable tests tend to be overrated regarding prevalence of
psychiatric disorders.
patients with other non-neurological chronic diseases [7,38,54,60].
Notwithstanding, it is still controversial if patients with TLE have
increased risk for development of a mental disorder when compared
with patients with other types of epilepsy. Two important studies didn’t
ind any diferences in the risk of patients with TLE, focal extratemporal,
and idiopathic generalized epilepsies [61,62]. It is possible that greater
prevalence of psychiatric disorders in patients with TLE could depict
just the dominant prevalence of TLE related to other epilepsies [63].
Despite this conjecture, it is plausible to believe that the same
neuronal circuitries involved in the physiopathogenic mechanisms
of TLE are also responsible for the production of psychiatric
symptoms [15]. Purposed mechanisms for this frequent association
could be arbitrarily divided in clinical, biological and environmental
causes. Regarding clinical factors, it has been enrolled: number of
epileptic seizures since onset of disease, efects of antiepileptic drugs,
lateralization of the epileptic focus, gender and psychiatric familial
history [8].
Nevertheless, studies of lifelong prevalence of psychiatric disorders
in PWE point to upper indices, compared to those found in general
population [59]. For a comparison between several studies, see Tables
1 and 2. In community-based studies (Table 1), prevalences varied
between 5.9% e 54.5%. Only one study (Davies et al.) used structured
interview for psychiatric diagnosis. his study found a superior
number (37%), compared with other older population-based studies
that used unstructured interviews. Regarding studies of selected
populations (performed in tertiary centers, in general as part of a presurgical evaluation), prevalence varied between 6.7% and 80%. Clearly,
patients with diicult-to-control seizures, and especially those studied
with structured interviews, trend to show increased frequencies of
psychiatric comorbidities.
Biological factors concern chemical and structural changes
in the Lymbic System circuitry, the site of processing of behavior
and emotions [14]. Environmental factors possibly involved with
psychiatric comorbidities in epilepsy include: loss of independence,
social stigma, inancial and legal restraints (i.e.: driving license) [64]. In
a prospective study achieved in the New York University, Devinsky et
al. assessed the impact of several clinical variables on the quality of life of
patients with intractable epilepsy, in pre-surgical evaluation. Presence
of depression, assessed by the BDI, was the only predictive factor for
Risk factors
Many papers have been demonstrated that patients with TLE
have an increased risk for psychiatric disorders, when compared to
AUTHORS
N
INSTRUMENT
POPULATION
PSYCHIATRIC
DISORDERS
MOOD
DISORDERS
ANXIETY
DISORDERS
PSYCHOSIS
SUBSTANCEE
ABUSE
Pond and
Bidwell, 1960
UK
245
Unstructured
psychiatric
interview
Children with
epilepsy –
community-based
29%
-
-
-
-
Gudmundsson,
1966
Iceland
654
Clinical interview
(unstructured)
Epilepsy
(communitybased)
54.5%
-
-
9%
-
Graham and
Rutter, 1970
UK
63
Unstructured
psychiatric
interview
Children with
epilepsy –
community-based
28.6%
-
-
-
-
Forsgren, 1992
Sweden
713
Chart review
(unstructured)
Epilepsy –
community-based
5.9%
-
-
0.7%
-
Bredkjaer et al.,
1998
Denmark
67
ICD-8
Epilepsy –
community-based
16.8%
-
-
-
-
Hackett et al.,
1998
India
26
ICD-10
Epilepsy –
community-based
23.1%
-
-
-
-
Davies et al.,
2003
UK
67
SCID
Epilepsy –
community-based
37%
-
-
-
-
Ettinger et al.,
2004
USA
775
CES-D
Epilepsy –
community-based
-
36.5%
-
-
-
Strine et al.,
2005
USA
427
Kessler 6 scale
Epilepsy –
community-based
-
32.6%
14.4%
-
-
Kobau et al.,
2006
USA
131
Health Style Survey
(self- reported
depression and
anxiety)
Epilepsy –
community-based
-
39%
39%
-
-
Tellez-Zenteno
et al., 2007
Canada
253
CIDI
Epilepsy –
community-based
23.5%
17.4%
12.8%
-
-
Table 1: Prevalence of psychiatric comorbidities in PWE. Population-based studies.
J Neurol Neurophysiol
Epilepsy: Current Trends
ISSN: 2155-9562 JNN, an open access journal
Citation: Bragatti JA, Torres CM, Isolan GR, Bianchin MM (2011) Psychiatric Comorbidities of Epilepsy: A Review. J Neurol Neurophysiol S2.
doi:10.4172/2155-9562.S2-002
Page 5 of 10
Edeh and Toone,
1987
UK
88
CIS
Epilepsy – selected
by
general practitioners
(GP)
48%
22%
15%
3.4%
-
Gaitatzis et al.,
2004
UK
5834
ICD-9
Epilepsy – selected
from a database
generated by GP
41%
18.2%
11.1%
9%
2.4%
Mensah et al.,
2006
UK
499
HADS
Epilepsy – from GP
-
11.2%
-
-
-
Perini et al., 1996
Italia
38
SADS, BDI,
STAIX1, STAIX2
JME and TLE
(selected)
patients
80% (TLE),
22% (JME)
55% (TLE),
17% (JME)
15% (TLE),
11% (JME)
-
-
Swinkels et al.,
2001
Netherlands
209
CIDI
Epilepsy – tertiary
epilepsy center
-
24.9%
29.7%
0.5%
0.5% 20.1%
Havlová, 1990
Czech Republic
225
Chart review
(unstructured)
Cohort of epileptic
children
6.7%
-
-
-
-
Stefansson et al.,
1998
Iceland
241
ICD-9
Epileptic patients
receiving beneits
35.3%
-
-
6.2%
5%
Jalava and
Sillanpaa, 1996
Finland
94
Chart review and
ICD-9
Epilepsy – selected
from
different sources
24%
-
-
3.1%
-
Gureje et al.,
1991
Nigeria
204
CIS
Epilepsy – tertiary
center
37%
-
-
30%
-
Araújo Filho et
al., 2008
Brazil
270
SCID
Refractory TLE and
JME
from a tertiary
epilepsy center
50% (TLE),
49% (JME)
25.8% (TLE),
19% (JME)
14.1% (TLE),
23% (JME)
15.8% (TLE),
3% (JME)
2%
(JME)
Bragatti et al., in
press
Brazil
98
SCID
TLE – selected from
a tertiary epilepsy
center
54.1%
42.9%
18.4%
6.1%
6.1%
Table 2: Prevalence psychiatric comorbidities in PWE. Studies in selected populations.
achievement of low indices of quality of life, assessed by the Quality of
Life in Epilepsy (QOLIE-31) survey. Neither other factor (frequency of
seizures, localization, age, gender, marital status, duration and type of
seizure, or number of DAE) was predictor for quality of life [65].
PWE have a signiicantly increased risk for suicide related to
general population. Two big studies, made in Canada [9] and Denmark
[10], showed that PWE has 2 to 3 times more risk of suicide than
control individuals. Danish study found a risk of suicide even greater
between epileptic patients with a speciic comorbidity: mood disorder
plus anxiety.
Speciic Psychiatric Disorders
Mood disorders
Main neurobiological risk factors for depression in PWE that
has been studied are: lateralization of epileptic focus, frontal lobe
hypometabolism, and hippocampal volume.
Regarding lateralization, Hurwitz et al. [66] found association
between let-sided epileptic focus and depressive mood. In this study,
seizures yielded by the right hemisphere were followed by laughter and
seductive behavior. As a seizure activity localized in one hemisphere
probably “releases” the opposite hemisphere, the authors postulated
that the dominant hemisphere could be responsible for negative
emotional states, and the non-dominant hemisphere could yield the
opposite efect. Other theory hypothesizes that a seizure activity in the
non-dominant hemisphere could result in neglect of negative emotions
[63]. Many controlled studies comparing seizure focus with degrees
of depression found increased frequencies of depression with a focus
J Neurol Neurophysiol
in the let hemisphere, independent of seizure type [67-70], although
other studies didn’t ratify this correlation [71]. A complex interaction
between several factors would be employed in this association.
Recent works using PET and SPECT have shown an association
between epilepsy and frontal lobe dysfunction with hypo metabolism.
Bromield et al. [72] studied 23 patients with complex partial seizures,
candidates for surgery, regarding depressive features (BDI > 11),
compared to normal controls. Patients with a let-sided temporal focus
presented more depressive symptoms as well as a bilateral inferior
frontal lobe hypo metabolism. Victor of et al. [70] studying 53 epileptic
patients candidates for surgical treatment, observed that an ictal onset
on the let was associated to an increased frequency of depression (79%
x 50%, non-signiicant). It has not been found any correlation between
current afective state and metabolism in the frontal lobes, but it was
interesting to observe that a history of depressive episodes (identiied by
SCID) signiicantly correlated with a let frontal lobe hypo metabolism.
Hermann et al. [73] didn’t ind any correlation between humor and
laterality, but a let-sided focus was signiicantly associated to the
severity of frontal dysfunction (measured by Wisconsin Card Sort Test)
and dysphoria. Contrarily, a right-sided focus was inversely associated
to frontal dysfunction and dysphoria (non-signiicant results).
Our group studied 97 patients with TLE regarding risk factors
for afective disorders [74]. A positive family history of psychiatric
disorders (O.R. = 3.8; p = 0.003) and interictal EEG epileptiform
discharges involving the let temporal lobe (O.R. = 2.9; p = 0.041)
were signiicantly associated with an increased risk for an afective
disorder in population studied. his article reinforced the importance
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Citation: Bragatti JA, Torres CM, Isolan GR, Bianchin MM (2011) Psychiatric Comorbidities of Epilepsy: A Review. J Neurol Neurophysiol S2.
doi:10.4172/2155-9562.S2-002
Page 6 of 10
of biological factors, speciically genetic and anatomical substrates, for
the development of humor disorders in PWE.
Few studies evaluated the association between hippocampal
volume loss, depression and epilepsy. Quiske et al. [75] found higher
BDI scores in patients with TLE and hippocampal sclerosis, when
compared to patients with normal MRI. Another study also identiied
an association between higher scores for depression and increased
volume of let hippocampus, in patients with right hippocampal
sclerosis [76]. Also studies with PET showed an association between
higher scores for depression in PWE with metabolic alterations in
temporal lobes, compared to PWE with normal PET [77].
Anxiety disorders
he main types of anxiety disorders described in DSM-IV are:
generalized anxiety disorder, panic disorder, phobia, and obsessivecompulsive disorder. he risk factors pointed for the association
between epilepsy and anxiety are: frequency of seizures, surgical
treatment for epilepsy, age, type of seizure, and perception of stigma
[78,79].
Frequency of seizures was associated to anxiety in some works
[80,81], but this is not an unanimity [82]. Studies combining PET
with electrophysiological data indicate the right temporal lobe as the
main structure responsible for pathogenesis of anxiety in epilepsy [83].
Probably, more than the frequency of seizures, fear of falling down or
to die is the real critical factor for the development of anxiety in PWE.
Surgical treatment for epilepsy may increase the frequency of anxiety
disorders in these patients, especially those that experience a greater
than 75% reduction in their seizures ater surgery [84].
Regarding age, minimal efects were observed, although a late onset
of epilepsy could be associated with higher degrees of anxiety [85]. Risk
for anxiety seems to be greater in focal epilepsies (especially TLE) than
in generalized epilepsies [86]. Higher indices of anxiety were found in
patients with poor pharmacological control of their seizures [87,88].
An important factor linked to anxiety in PWE is the stigma perception
[89,90], and this factor is heavier in young patients [83,91].
Psychotic disorders
Literature regarding risk factors for psychotic disorders in epilepsy
is highly controversial, and most studies are restricted to interictal
psychosis [92].
Regarding duration of epilepsy, in most series, time for the irst
psychotic manifestation from the onset of epilepsy is about 11 to 15
years, raising an etiological meaning to the epileptic disorder, through
a mechanism “kindling-like” [40]. TLE is the epilepsy most associated
with psychosis in almost all case series. In a non-systematic revision of
10 studies, 76% patients sufering from psychosis had TLE [40]. Major
criticism to these studies is that their results may relect just the higher
prevalence of TLE in the community. Severity of epilepsy is one of the
most important risk factors for psychosis, and it could be measured
by duration and multiplicity of seizures, history of status epilepticus,
and poor clinical response to treatment [40]. Flor-Henry [93] originally
suggested that let temporal lobe dysfunction was a risk factor for
schizophreniform psychosis. Trimble’s analysis of 14 studies with 341
patients with TLE found that 43% had a let-sided epileptic focus, 23%
on the right, and 34% had bilateral changes [40]. his data regarding
laterality were supported by neuroimaging studies, especially SPECT
and MRI. Mellers et al. [94], using a verbal luency activation paradigm
and SPECT, compared patients with schizophrenia-like psychosis (n =
J Neurol Neurophysiol
12), schizophrenia (n = 11), and non-psychotic epileptic patients (n =
16). Psychotic epileptic patients showed and increased blood low in the
superior temporal gyrus, during activation, related to the other groups.
Maier et al. [95] compared the amygdalo-hippocampal volumes and
hippocampal N-Acetyl Aspartate (NAA) (by spectroscopy) of patients
with TLE, with (n = 12) and without schizophreniform psychosis (n
= 12), non-epileptic schizophrenics (n = 26), and normal individuals
(n = 38). Psychotic patients showed signiicant reduction of NAA in
the let temporal lobe, with a more accentuated phenomenon observed
in epileptic patients. PWE showed bilateral volume reduction, whereas
psychotic patients had a more prominent atrophy of the let amygdalohippocampal complex.
Interictal psychosis seems to be diferent from schizophrenia,
especially because interictal psychosis courses with more afective
symptoms and has a better prognosis. Although hippocampal
alterations could be related to both disorders, bilateral increase of
amygdales (with less volumetric changes in hippocampi) is typical
of interictal psychosis, suggesting a great diference between both
conditions. his hypothesis was supported by a recent study, with 26
patients with epileptic psychosis, 24 non-psychotic patients with TLE,
and 20 normal controls. Psychotic patients had signiicant bilateral
increases of amygdales, in comparison with the other groups. hese
indings were not correlated with lateralization of the focus, and neither
with the duration of epilepsy [96].
Pshysiopathology
Bidirectional relation
It is demonstrated that some speciic humor and behavioral
disorders may show a bidirectional relation with the onset of epileptic
seizures, namely, a psychiatric diagnosis may precede onset of seizures,
especially in three situations: major depression, suicidal ideation, and
Attention Deicit Disorder with Hyperactivity (ADDH).
Case-control studies [97,98] as well as longitudinal studies [99],
in children, showed an increased risk of 2.5 fold for patients with a
diagnosis of ADDH sufer a irst epileptic seizure.
hree controlled studies assessed the temporal relation between
depression and epilepsy. One population-based case-control study
found a 7-fold increased risk for and adult with depression to develop
epileptic seizures, ompared to normal individuals. he risk increased
to 17-fold with focal epilepsies [49]. Hesdorfer et al. [100] observed
the same temporal relation between depression and a irst seizure, with
a 6-fold increased risk. Data from these two studies were conirmed
in a population-based controlled study, proceeded in Island, with
324 patients above 10 years of age, with a irst non-provoked seizure
or newly diagnosed epilepsy, and 647 controls: major depression,
diagnosed ater DSM-IV criteria, increased the risk for epilepsy in 1.7fold. his same atudy showed that a suicide temptation is associated
with a 3.5-fold increased risk for epilepsy [16].
Common physiopathologic mechanisms
his bidirectionality suggests a common underlying susceptibility
to epilepsy and humor disorders. Literature is plentiful of studies
on molecular and cellular biology and anatomy of the brain in both
diseases [101]. hosemechanisms are strongly interconnected, and
functional and structural alterations in one disease may give rise to the
other.
Animal models: One of the best studied models in TLE uses
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Page 7 of 10
convulsant substances, like kainate and pilocarpine, in general,
systemically injected. Ater induce a status epilepticus in the animal, in
this model, it follows a period of latency along some weeks, with further
development of spontaneous seizures [102]. Other experimental model
utilized is the electrical kindling, but this method does not seem to
reproduce the typical physiopathological events of TLE, compared
to the pharmacological method. With kindling, seizures do not
occur spontaneously, a hippocampal sclerosis does not develop, and
there is no latency period between initial precipitant injury and the
development of seizures.
Recently, Mazaratti et al. [103] investigated if a kindling-induced
chronic increase of susceptibility to seizures could result in a depressive
behavior in rats. Two to four weeks ater application of 84 subconvulsant
electrical stimuli (each ive minutes) in ventral hippocampus of adult
Wistar rats, the authors applied two tests: Forced Swim Test (FST) and
a gustative test (preference for sugar). Immobility in the tank on FST
is equivalent to depression, as the animal does not show any initiative
to escape in a stress situation. he second test aims to reproduce the
loss of ability to seek pleasure, a frequent ymptom in depression. he
study showed that rats submitted to kindling exhibited a signiicant
increase in time of immobility on FST, associated to a loss of preference
of sweet taste, compared to controls. he authors concluded that
the alterations in neuronal plasticity caused by kindling would be
followed by a depressive behavior. he role of neurotransmitters in the
physiopathologic mechanisms of humor disorders is recognized since
some decades ago [104].
he roles of gama-aminobutyric acid (GABA) and glutamate in
epileptogenesis were already demonstrated in several studies in animals
and humans. he Genetically Epilepsy-Prone Rat (GEPR) provides an
experimental model for both epilepsy and depression. In this model,
mutated animals are highly sensible to auditory stimuli, to which
they answer with generalized tonic-clonic seizures. Moreover, GEPRs
show endocrinologic changes similar to those identiied in depressive
patients: increased corticosteroid plasmatic levels, decreased secretion
of growth hormone, and hypothyroidism [105]. Defective arborizations
of noradrenergic and serotonergic circuitries were observed in those
animals. An increase in the levels of these neurotransmitters could
prevent seizures, whereas diminished levels have the opposite efect
[105]. One classic study showed that luoxetine, a selector synaptic
serotonin reuptake inhibitor, provoked a dose-dependent reduction in
the frequency of seizures in GEPRs, which correlated with extracellular
thalamic serotonin concentrations [106].
Studies in humans: Animal serotonergic transmission was
demonstrated in the brain of depressed patients [107,108], the same
feature found in studies with PET, in patients with TLE [109,110]. In
a more recent study, Hasler et al. [111] compared the level of 5-HT1A
receptor binding to a speciic antagonist, in 37 patients with TLE,
with and without major depression (diagnosis by SCID), using PET.
Beyond a decreased binding to 5-HT1A receptors in the epileptic focus,
patients with major depression exhibited a more extensive reduction in
binding, involving non-lymbic areas, distant from the epileptic focus.
One of the most important proteins involved in the functioning
of Lymbic System is the BDNF. his element may inluence both
neuronal electrical activity and memory and behavior functions, which
are directly related to hippocampus in its connections. Changes in
BDNF are associated to hippocampus atrophy, alterations in memory,
and temporary amygdalar hypertrophy, with alteration in fear process.
Moreover, studies with PET suggest a glucose hypometabolism in
J Neurol Neurophysiol
temporal and frontal lobes in the TLE-depression association [112].
A functional polymorphism of BDNF gene, the Val66Met, has
been studied as a predisposition factor for many neurological and
psychiatric disorders, with variable results. Regarding epilepsy, it
seems that there isn’t any direct relation with the polymorphism [113].
Notwithstanding, depression, anxiety, psychosis and eating disorders
have been oten associated to the presence of Val66Met polymorphism
in the BDNF gene [112]. A recent meta-analysis airmed the association
of Val66Met to substance-related disorders, eating disorders, and
schizophrenia [114].
Our group also studied the association between 5HTTLPR
and 5HTTVNTR allele variants in serotonin transporter gene and
epileptogenesis in TLE. We compared 175 patients with TLE and 155
healthy control individuals, and observed an association between the
presence of 5HTTLPR and 5-HTTVNTR less transcriptional eicient
combined genotypes and TLE. Our results agreed with several other
studies showing that low transcriptional activity 5-HTT genotypes are
associated with neuropsychiatric disorders, such as depression, suicidal
behavior, attention deicit hyperactivity disorder, and personality
disorder [115].
Discussion
here is a growing evidence for psychiatric comorbidities in
epilepsy. Studies on prevalence have demonstrated advances in
methodological issues, improving reliability of results. Future research
need to focus on physiopathologic mechanisms, especially regarding
functional and structural alterations involving human neuronal
circuitries in the Lymbic System. Although many studies on a possible
association between epilepsy and the polymorphism of the BDNF
gene, Val66Met, did not ind any positive result, strong evidence exists
linking this polymorphism to psychiatric disorders. Likely, serotonin
allelic variants may also inluence the modulation of serotoninergic
system, and eventually epileptogenesis in TLE. For those reasons, it
remains plausible to continue researching genetic variants in this ield.
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ISSN: 2155-9562 JNN, an open access journal
Citation: Bragatti JA, Torres CM, Isolan GR, Bianchin MM (2011) Psychiatric Comorbidities of Epilepsy: A Review. J Neurol Neurophysiol S2.
doi:10.4172/2155-9562.S2-002
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