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Red de Revistas Científicas de América Latina y el Caribe, España y Portugal
644
Rev. Colomb. Psiquiat., vol. 37
/
No. 4 / 2008
Reporte
de caso
Obsessive-Compulsive Disorder Symptoms in
Huntington’s Disease: A Case Report
Juan Carlos Molano-Eslava
1
Ángela Iragorri-Cucalón
2
Gonzalo Ucrós-Rodríguez
3
Carolina Bonilla-Jácome
4
Santiago Tovar-Perdomo
5
David V. Herin
6
Luis Orozco-Cabal
7
Abstract
Introduction
: Few cases of obsessive-compulsive disorder (OCD) symptoms preceding the
clinical onset of Huntington Disease (HD) or during later stages of the disease have been
reported in the literature, but the nature of this association and its neurobiological mecha-
nisms have not been well-investigated.
Objectives
: To review the scienti
f
c literature regarding
OCD symptoms in patients with HD and describe a case study from our clinic.
Methods
:
Extensive literature searches were performed to identify reports of patients with concurrent
HD and OCD symptoms. Results: Recent studies and the current case report suggest that
OCD symptoms may predate or coincide with motor, affective or behavioral symptoms in
patients with HD. The development of OCD and HD symptoms may involve structural and
functional changes affecting the orbital and medial prefrontal cortex, ventromedial caudate
nucleus, and pallidal sites.
Conclusions
: Some patients with HD develop symptoms asso-
ciated with OCD. Progressive and differential neuropathological changes in the ventrome-
dial caudate nucleus and related neural circuits may underlie this association. No speci
f
c
treatment strategy has been developed to treat these patients; however some medications
attenuate associated symptoms. Further testing is needed to determine the neurobiological
mechanisms of these disorders.
Key words:
Obsessive-compulsive disorder, Huntington disease.
1
Médico psiquiatra. Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá, Co-
lombia. Facultad de Medicina, Universidad de los Andes, Bogotá, Colombia.
2
Médica neuróloga. Clínica de Memoria, Clínica La Inmaculada, Bogotá, Colombia.
3
Médico del Hospital Universitario Fundación Santa Fe de Bogotá, Colombia. Facultad
de Medicina, Universidad de los Andes, Bogotá, Colombia.
4
Médica. Western Psychiatric Institute and Clinic. Pittsburg, PA, Estados Unidos.
5
Médico graduado de la Facultad de Medicina, Universidad de los Andes. Bogotá, Co-
lombia.
6
PhD, Department of Psychiatry, University of Texas Health Science Center at Houston,
Texas, Estados Unidos.
7
Médico. PhD en Neurociencias. Facultad de Medicina, Universidad de los Andes, Bo-
gotá, Colombia.
Obsessive-Compulsive Disorder Symptoms in Huntington’s Disease: A Case Report
Rev. Colomb. Psiquiat., vol. 37
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No. 4 / 2008
645
Título: Síntomas del trastorno obsesivo-
compulsivo en la enfermedad de Hunting-
ton: reporte de caso
Resumen
Introducción
: Algunos reportes de caso
indican que pacientes con enfermedad de
Huntington (EH) pueden presentar sínto-
mas obsesivo-compulsivos (TOC) antes del
desarrollo de la enfermedad y durante ésta,
pero no se ha estudiado la naturaleza de esta
asociación y sus mecanismos neurobiológi-
cos.
Objetivos
: Revisar la literatura cientí
f
ca
acerca de la asociación entre EH y síntomas
TOC y reportar el caso de un paciente con es-
tas condiciones.
Método
: Búsqueda selectiva
de literatura relevante.
Resultados
: Estudios
recientes y el caso aquí reportado sugieren
que los síntomas TOC pueden presentarse
antes de la EH y durante ésta. El desarrollo
concurrente de estas patologías puede estar
mediado por cambios estructurales y funcio-
nales de la corteza prefrontal orbital y medial,
región ventromedial del núcleo caudado y
regiones palidales.
Conclusiones
: Algunos
pacientes con EH desarrollan síntomas de
TOC. Cambios neuropatológicos progresivos
y diferenciales en el caudado ventromedial
y circuitos dependientes pueden mediar
esta asociación. No se ha desarrollado una
estrategia terapéutica para el tratamiento
de estos pacientes; sin embargo, algunos
medicamentos parecen ofrecer mejoría sin-
tomática parcial a los sujetos afectados. Se
requieren mayores estudios acerca de los
mecanismos neuropatológicos involucrados
en esta asociación.
Palabras clave:
trastorno obsesivo-convul-
sivo, enfermedad de Huntington.
Introduction
Huntington’s disease (HD) is an
autosomal, dominantly inherited,
neurodegenerative disorder which
manifests during middle adult life
(40´s). This disorder affects 4-8
individuals per 100000 people in
European populations, whereas in
Japan, less than 1 per 100000 in-
dividuals have this disorder (1). The
diagnostic hallmark of HD includes
cognitive de
f
cits, mood alterations
and motor disturbances (2) such as
chorea and other motor disorders
(dystonia, dysathria, gait disturban-
ces). However, behavioral problems
and neuropsychiatric conditions
are also often present (3,4), and ac-
cumulating evidence suggests that
obsessive compulsive disorder (OCD)
symptoms may precede the clinical
onset of HD or emerge during the
later stages of the disease. Unfortu-
nately the mechanisms underlying
these comorbid disorders and treat-
ments for the dual condition have
not been well-investigated (3).
Thus, the goal of this article is
to review the scienti
f
c literature
on OCD symptoms in patients with
HD and describe a case study from
a patient presenting to our clinic.
Additionally, we will explore the po-
tential neurobiological mechanisms
underlying this association and dis-
cuss the medications used to treat
these comorbid conditions.
HD Pathophysiology
HD is caused by expanded CAG
repeats in the 5´ region of the hun-
tingtin gene located on chromosome
4p16.3 (5-7). Wild-type chromo-
somes contain between 6-34 CAG
repeats, while HD chromosomes
Molano-Eslava J., Iragorri-Cucalón Á., Ucrós-Rodríguez G., Bonilla-Jácome C., Tovar-Perdomo S.,
et al
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contain 36-121 repeats (8). Signi-
ficant positive associations have
been described between the repeat
length and various clinical features
of HD, such as age of onset, disease
severity and age of death (9).
Huntingtin is a 3136 amino acid
protein that is extensively expressed
in the mammalian brain, particu-
larly in neuronal cell bodies and
dendrites of large neurons (10,11).
Numerous proteins have been
shown to associate with the N-ter-
minal polyglutamine fragment and
C-terminal HEAT repeats of hun-
tingtin, suggesting that it may act
as a scaffolding protein in multiple
signaling pathways (12,13) inclu-
ding those involved in neurogenesis
and cellular processes necessary to
maintain cellular viability (14-17).
Some researchers hypothesize that
increased polyglutamine fragments
in mutant huntingtin may alter pro-
tein-protein interactions, leading to
selective neuronal dysfunction and
neurodegeneration (11,18). The me-
chanisms underlying neural dege-
neration are unknown (19), however
polyglutamine fragment-induced
toxicity, huntingtin aggregation,
transcription factor alterations, ab-
normal axonal transport, mitochon-
drial dysfunction, and activation of
apoptosis may be involved (20,21).
This neurodegeneration has
been localized to fronto-striatal
systems (22). For example, there is
marked and selective neuronal dea-
th with astrogliosis in the caudate
nucleus, putamen and deep layers
(III, IV, and VI) of the cortex (23).
Of striatal neurons, medium spiny
efferent neurons (GABA-ergic) are
primarily affected in HD (24,25).
Neuropsychiatric and behavioral
Changes in Patients with HD
Recent reports suggest that
behavioral problems and neurop-
sychiatric conditions are often
present in patients with HD (4). For
example, Craufurd et al. (26) de-
monstrated that loss of energy and
initiative, poor perseverance and
quality of work, impaired judgment,
poor self-care and emotional blun-
ting are often present in HD patients.
In addition, depression, apathy and
irritability are some major affecti-
ve symptoms found in those with
HD. In fact, major depression and
intermittent explosive disorder oc-
cur in >30% of these patients (27).
Furthermore, HD patients exhibit
executive dysfunction and progres-
sive cognitive decline, resulting in in-
creased functional impairment after
controlling for motor disturbances,
(28). These cognitive and behavioral
symptoms usually emerge following
changes in cortical architecture (29),
but may also predate the onset of
motor symptoms. The mechanisms
causing early or late non-motor
symptoms remain unknown.
OCD Symptoms in Patients with
HD
In contrast, the relationship
between OCD and HD has been
Obsessive-Compulsive Disorder Symptoms in Huntington’s Disease: A Case Report
Rev. Colomb. Psiquiat., vol. 37
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No. 4 / 2008
647
little-investigated, despite the fact
that both diseases are associated
with striatal dysfunction (30) and
that the number of case reports of
obsessive-compulsive symptoms
either preceding the clinical onset of
HD or during later stages of the di-
sease is increasing (31). For example,
Dewhurst et al. (32) reported “obses-
sional features” in 7 of 102 patients
at onset of HD. Twenty years later,
Tonkonogy and Barrera (33) des-
cribed a patient with obsessive and
compulsive symptoms, namely ideas
of contamination and compulsive
hand washing, associated with affec-
tive disturbances and cognitive decli-
ne characteristic of HD. Additionally,
Cummings and Cunningham (34)
described two unrelated HD patients
with late onset OCD symptoms (i.e.,
compulsions of cleaning). De Marchi
et al. (35) described a pedigree in
which three cases of OCD and two
cases of pathological gambling were
identi
f
ed prior to clinical onset of
HD, and Scicutella (36) reported a
72-year-old patient who developed
HD and OCD. More recently, Patzold
and Brune (37) described a 42-year-
old woman successfully treated with
sertraline for obsessive thoughts
which emerged 10 years after the
onset of HD. Furthermore, Beglinger
et al. (38) demonstrated that the
probability of obsessive-compulsive
symptoms increased with severity of
HD, such that obsessions and com-
pulsions were three times greater in
patients with motor symptoms than
in patients at risk with no motor
abnormalities.
Our group was recently con-
sulted in a case of a 45-year-old
woman who met diagnostic criteria
for HD and OCD (39). The patient
sought medical attention for con-
ciliation insomnia, hyporexia, 4kg
weight loss, emotional liability,
anxiety and obsessive-compulsive
symptoms. Speci
f
cally, she repor-
ted being constantly worried about
contamination, washing her hands
and teeth repeatedly throughout the
day (20-30 times a day) and spen-
ding great part of her day cleaning
her body, during the past 18 mon-
ths. She also reported trying not
to touch light switches, money or
any surface that could be touched
by someone else. In addition, the
patient reported having dif
f
culty
concentrating, remembering recent
events and performing mathemati-
cal operations to the point she had
to quit her job a year ago. She also
reported mild involuntary choreoa-
thetoid movements of the upper
extremities and dif
f
culty walking
during the past 6 months. Her de-
ceased mother was diagnosed with
HD at age 42. Similarly, her sister,
now 58, was diagnosed with HD
during her early forties.
The neurological examination
on admission was remarkable for
choreoathetoid movements of the
right upper limb, head tilting to
the left side, and a wide-based,
unsteady gait. On the mental state
examination, the patient was alert,
oriented in time, place and person;
although hypoprosexic. There was
no evidence of hallucinations or
Molano-Eslava J., Iragorri-Cucalón Á., Ucrós-Rodríguez G., Bonilla-Jácome C., Tovar-Perdomo S.,
et al
.
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delusions. She exhibited short-term
memory de
f
cits; long-term memory
without alterations. Her intelligence
was above average but she had dis-
calculia. She spoke slowly and with
a low tone. Her thought process was
slow too and had recurrent ideas
of cleanliness or fear of becoming
infected or contaminated. Her mood
was dysphoric, with depressive
affect and severe anxiety. She felt
sad when she thought about the
possibility of having HD. The patient
was evaluated by a dermatologist
who diagnosed irritative dermatitis
probably due to her compulsive
hand-washing.
CBC count with differential,
glycemia, hepatic and renal func-
tion tests, TSH levels, VDRL and
urinalysis were normal. Magnetic
Resonance was performed which
revealed increased subarachnoid
space surrounding cortical sulci
and gyri, suggesting cortical atro-
phy. PET scan with [18F] Fluo-
rodeoxyglucose (FDG) revealed a
marked, symmetrical and bilateral,
reduction of FDG uptake in the
caudate. Neuropsychological tes-
ting (Barcelona diagnostic tests,
WAIS III, Rey
f
gure y Wisconsin
Card Sorting Test) revealed abnor-
mal attention, short-term memory
de
f
cits, discalculia, and de
f
cits in
task planning and execution, all of
which suggest cognitive de
f
cits of
subcortical origin compatible with
HD. The patient was diagnosed
with OCD, possible HD and mayor
depression. HD was con
f
rmed by
genetic testing which revealed 44
CAG repeats compared with 25
repeats of the healthy allele. The
patient was started on olanzapine
2,5mg PO BID and paroxetine 40
mg PO per day. After 4 weeks of
treatment, obsessional thoughts de-
creased signi
f
cantly and the affect
improved. Motor symptoms remain
the same.
Neurobiological Mechanisms
Underlying the Relationship
between OCD Symptoms and HD
Functional and structural ima-
ging studies have consistently de-
monstrated that HD patients exhibit
frontal and striatal hypometabolism
along with thalamic hypermetabo-
lism (40,41). Together the studies
suggest HD is not exclusively con
f
-
ned to the striatum, but also affects
striatum-elated structures, such
as the frontal cortex. Alexander et
al. (42) proposed
f
ve segregated
circuits between the basal gan-
glia and selected frontal cortical
areas. Speci
f
cally, neuropsychiatric
symptoms (cognitive, affective and
behavioral) in HD patients have
been attributed to orbitofrontal-,
anterior cingulate- and lateral pre-
frontal-striatal circuit dysfunction
(22), possibly caused by basal gan-
glia and cortical neurodegeneration
or developmental alterations, which
lead to reduced basal ganglia output
to the frontal cortex and further
frontal dysfunction (43-45).
In addition, alterations in neu-
rotransmitter systems may contri-
bute to functional and structural
Obsessive-Compulsive Disorder Symptoms in Huntington’s Disease: A Case Report
Rev. Colomb. Psiquiat., vol. 37
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No. 4 / 2008
649
changes within these circuits. For
example, numerous post-mortem
studies and in vivo studies using
PET scan have demonstrated de-
creased binding for D1 and D2
receptor-ligands in the striatum
and frontal cortex of patients with
clinical HD (46-50). Decreased bin-
ding for opiate receptors (44) and
the benzodiazepine site on GABAA
receptors (51) have also been docu-
mented in the striatum and medial
prefrontal cortex and caudate nu-
cleus, respectively.
In contrast, numerous func-
tional imaging studies showing in-
creased activity in the orbitofrontal
cortex, anterior cingulate, caudate
nucleus and thalamus in patients
with OCD (reviewed by Baxter et al.)
(52). Furthermore, structural chan-
ges of corticolimbic regions of the
frontal lobes (orbitofrontal and me-
dial prefrontal cortex), ventromedial
caudate nucleus and pallidal sites
have been associated with the deve-
lopment of obsessive and compulsi-
ve symptoms in humans (34). These
f
ndings suggest that dysfunction of
fronto-subcortical circuits plays a
signi
f
cant role in OCD, similar to
HD. For example, Baxter et al. (52)
suggested that overactivity of the or-
bitofrontal cortex and ventromedial
caudate along with hypoactivity of
lateral prefrontal cortex would tend
to disinhibit the thalamus via its
predominant direct pathway tone,
leading to compulsive behaviors.
Accordingly, recovery from OCD
after treatment with selective sero-
tonin reuptake inhibitors (SSRI) or
tricyclic antidepressants is asso-
ciated with lateralized or bilateral
reductions in orbitofrontal cortex,
anterior cingulate and caudate nu-
cleus activity (53,54).
In addition to striatal degene-
ration, dysfunction of neuropep-
tide systems may be involved in
co-occurrence of HD and OCD. For
example, HD and OCD patients ex-
hibit increased somatostatin levels
and immunoreactivity in selective
CNS regions (55,56). Furthermore,
chronic administration of serotonin
reuptake inhibitors that effectively
treats OCD symptoms decreases
somatostatin contents in selective
brain regions (57). Thus, multiple
mechanisms are likely involved in
the presentation of OCD symptoms
in HD patients.
However, as stated by Patzold
and Brüne (37): “whereas the link of
OCD and HD is intuitively obvious,
the clinical and pathophysiologic
association between the two disor-
ders is still obscure to some extent.”
Speci
f
cally, the neural mechanisms
underlying the development of OCD
in patients with HD remain un-
clear. It is possible that differential
neurodegeneration in the caudate
nucleus, frontal cortex or other
structures within fronto-subcorti-
cal circuits may explain differential
neuropsychiatric symptoms in
these patients. For example, exe-
cutive dysfunction in early stages of
Huntington’s disease is speci
f
cally
associated with striatal and insular
atrophy (58). Similarly, progression
in neuropsychiatric symptoms of
Molano-Eslava J., Iragorri-Cucalón Á., Ucrós-Rodríguez G., Bonilla-Jácome C., Tovar-Perdomo S.,
et al
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Rev. Colomb. Psiquiat., vol. 37
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HD is correlated with differential
dopaminergic dysfunction in HD
patients (59). Based on the above it
is possible to hypothesize that diffe-
rential and progressive neuropatho-
logic changes, likely involving the
ventromedial caudate or associated
prefrontal subregions and modula-
tory neurotransmitter systems, are
responsible for the development of
OCD symptoms in patients with HD.
In fact, progression of HD severity
has been linked to the development
of OCD symptoms in these patients.
In a recent study, Beglinger et al.
(38) demonstrated that the probabi-
lity of HD patients having obsessio-
ns and compulsions increased with
both greater diagnostic certainty
and greater functional impair-
ment. A future post-mortem study
characterizing the progression of
neuropathological changes within
fronto-subcortical circuits would
allow us to test this hypothesis.
Similarly, we lack evidence
about the right treatment for pa-
tients with OCD symptoms and
HD. Previous reports suggest that
patients with HD and behavioral
or affective symptoms bene
f
t from
SSRI treatment. Ranen et al. (60)
successfully treated two consecu-
tive cases of genetically con
f
rmed
Huntington’s disease in which se-
vere irritability and aggressiveness
required inpatient admission. Patel
et al. (61) administered
F
uoxetine,
an SSRI, and L-deprenyl in a 19-
year-old female with Huntington’s
disease with signi
f
cant improve-
ment of affective, behavioral, and
motor function. Interestingly, there
is only one published report of a pa-
tient with HD and OCD symptoms
treated with sertraline (37). Olan-
zapine, an atypical antipsychotic,
has been used to control motor
and behavioral disturbances in
patients with single-diagnosis HD
(62). In addition, olanzapine has
been used successfully in patients
with severe OCD alone (63) or with
schizophrenia (64), despite reports
of atypical antipsychotics evoking
OCD-like symptoms (65,66). Undo-
ubtedly, clinical studies are needed
to determine the effectiveness in
the treatment of these co-morbid
conditions.
Conclusions
OCD symptoms may precede
or coincide with motor, affective or
behavioral symptoms in patients
with HD. Both diseases are inva-
riably associated with dysfunction
of striatal neural circuits such as
prefrontal-striatal circuits. Multiple
mechanisms have been proposed to
account for striatal degeneration
in HD and related circuit dysfunc-
tion. Speci
f
cally, structural and
functional changes affecting orbi-
tal and medial prefrontal cortex,
ventromedial caudate nucleus and
pallidal sites have been suggested
to play a role in the development
OCD symptoms in HD. Anecdotal
evidence suggest that SSRIs alone
or in combination with atypical
antipsychotics like olanzapine may
be useful for these patients. Howe-
Obsessive-Compulsive Disorder Symptoms in Huntington’s Disease: A Case Report
Rev. Colomb. Psiquiat., vol. 37
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No. 4 / 2008
651
ver, these hypotheses need further
testing.
Acknowledgements
Supported by SEMILLA grant
from Los Andes University (LO-C) and
U.S. National Institute on Drug Abuse
DA023548 (DVH).
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Interest con
f
icts: None of the authors
reported interest con
f
icts in this article.
Received for assessment:
October 14, 2008
Accepted for publication:
November 20, 2008
Correspondence
Luis Felipe Orozco-Cabal
Neurociencias-Facultad de Medicina
Universidad de los Andes
Carrera 1ª
Nº 18A-10
Bogotá, Colombia
luiorozc@uniandes.edu.co
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