Park et al. BMC Psychiatry 2014, 14:175
http://www.biomedcentral.com/1471-244X/14/175

CASE REPORT

Open Access

Case report: bipolar disorder as the first
manifestation of CADASIL
Soyeon Park1, Boram Park1, Min Kyung Koh2 and Yeon Ho Joo1*

Abstract
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL) is an inherited cerebrovascular disease, clinically characterized by variable manifestations of migraine,
recurrent transient ischemic attack or lacunar strokes, cognitive decline, and mood disturbances. However, manic
episodes have rarely been documented as an initial symptom of CADASIL and bipolar disorder presenting as the
first manifestation in CADASIL has not been reported previously from evaluations by psychiatrists or psychological
testing by psychologists.
Case presentation: A 53 year old woman developed symptoms of mania in her 50s leading to a personality
change involving a continuously labile mood and irritability over a number of years. Neuropsychological testing
revealed an intact memory, but impairment in attention and executive function. In the Rorschach test, she showed
a high level of cognitive rigidity. Magnetic resonance imaging findings were very consistent with a diagnosis of
CADASIL, which was confirmed by genetic testing for NOTCH3 mutations. Atypical antipsychotics proved to be
helpful in treating her manic symptoms and for behavior control.
Conclusion: We present a novel case of CADASIL that first presented as bipolar disorder. We contend that when
patients show a late onset personality change or chronically irritable mood that deteriorates over many years, an
organic cause such as CADASIL must be considered. Further studies are needed to better understand the exact
impacts of cerebral tissue lesions and psychiatric symptoms in CADASIL patients.
Keywords: CADASIL, Bipolar disorder, Mood disorder, NOTCH3

Background
The genetic contributions to bipolar disorder (BD) have
been well characterized, with an increased risk, estimated
to be 8-fold higher than the prevalence in the general
population, in siblings with affected probands [1]. It is believed that BD is a complex genetic disease that is caused
by various interactions between the environment and by
multiple genes [1]. Although a high degree of heritability
is known for BD, the mode of inheritance for this disorder
appears complex, indicating that it is non-Mendelian in
nature and involves genes that have yet to be identified
[2]. One of the suggestions for why BD has not been clarified as a single genetic disease is heterogeneity. Research
on BD subtypes is still at an early stage, and the concepts
being developed to explain this disease are changing
* Correspondence: jooyh@amc.seoul.kr
1
Department of Psychiatry, University of Ulsan College of Medicine, Asan
Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 136-736, Korea
Full list of author information is available at the end of the article

continuously. Recently, the concept of a bipolar spectrum
disorder was introduced to try to understand BD from a
continuous line into the past. Hence, there have been attempts to distinguish between BD subtypes to better
understand the etiology of this disorder.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare
hereditary disease caused by mutations in the NOTCH3
gene on chromosome 19p13.1 [3]. CADASIL is a systemic
angiopathy and it is characterized by recurrent transient ischemic attacks (TIA), strokes, vascular dementia, mood
disturbances and motor disability. If CADASIL arises at an
age below 20, the most common first symptom is migraine.
However, if the first symptoms of CADASIL occur in persons over 50, they can rapidly progress to a more serious
condition such as depression [4]. Because these cases do
not show neurological abnormalities, they are commonly
diagnosed as a mood disorder only. The diagnosis of

© 2014 Park et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited.

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CADASIL is therefore often delayed or missed in psychiatric clinics.
Although there has been considerable neurological research on CADASIL, there have been fewer studies of
the mood disorders associated with this disease. Psychiatric disturbances have been mentioned by almost all
previous studies of CADASIL, but most of these reports
have only addressed the presence of psychiatric disorders
among the symptoms of the disease and have not focused specifically on the psychiatric aspects of CADASIL
[5]. Hence, prior CADASIL studies have not incorporated
a psychiatric evaluation or provided any detailed descriptions of psychiatric symptoms. In our current report, we
present a case of CADASIL that first presented as BD.
Through our analysis of this case, we provide new insights
into the issues around the initial differential diagnosis of
CADASIL and also the appropriate interventions for
these patients.

Case presentation
A 53-year-old woman visited our out-patient psychiatric
clinic in March 2013. Her daughter reported that she
had become excessively talkative, impulsive, and verbally
aggressive. The changes in her personality had begun to
appear in 2008 and her symptoms of hostility had become
more severe recently. Her premorbid personality was described as reserved, diligent, frugal, and calm and she had
worked in a market for more than 20 years. However,
during the previous 5 years, she had begun to speak garrulously and often lost the thread of a conversation and
included many irrelevant details when providing an explanation. She had become much more easily irritable and
angry, which took the form of yelling and throwing objects. She had also begun to argue over seemingly unimportant matters with her neighbors. She had also begun to
impulse buy multiple items also make many unnecessary
purchases for her family. She had also become very hyperactive in her work life and social life. She did not display
any sleep or eating disorders at the time of her visit.
The patient’s husband had an explosive temperament
and alcohol problems which were a source of great stress
and concern for her. Since 2000, she had begun to irregularly attend a local psychiatric clinic to receive medications for a depressed mood and insomnia. At the time of
these visits, she was taking both antidepressants and
sleeping pills. However, she and her family denied that she
had experienced any depressive episodes or had ever been
diagnosed with a mood disorder. She had no history of
head trauma but had hypertension and diabetes, both of
which are cardiovascular risk factors. There was also no
history of migraine, a prior TIA, or stroke reported by
the patient.
Her family history further revealed that her father had
died at 76 years of age after having suffered a stroke and

Page 2 of 6

that he had hypertension, diabetes and a history of depression including a suicide attempt. However, her mother is
76 years old and in good health. She has three younger
brothers, the oldest of whom is 51 years old and has been
diagnosed with cerebellar atrophy. He also has dysarthira
and cerebellar ataxia. Those symptoms had gradually developed within the previous 2 years. Her second brother
had suffered from depression and had committed suicide
20 years previously. Her youngest brother had no health
issues, but his 17-year-old son had been diagnosed with
epilepsy. She also has a son and a daughter. Her son suffers from migraine attacks but her daughter is healthy.
When her mental condition was assessed she showed
no evidence of delusions or hallucinations, but she did
have pressured speech, circumstantiality, labile moods,
poor impulse control, and made grandiose plans. She
demonstrated no insights into the changes in her personality and behavior. Bedside neuropsychological testing revealed total scores that were within the normal
range (K-MMSE 29/30). However, a Montreal Cognitive
Assessment test (MOCA-K 25/30) revealed a failure to
perform the trail making test (TMT) and copy cube. In
the attention subtest, she tapped on the wrong letters and
failed to correct this. In the language subtest, she could
speak more than 11 words in 60 seconds but the all of the
words began with the same sound with a different suffix,
for example, like, liked, likely, look, looked, looking. In a
delayed recall subtest, she recalled only two words correctly out of five. She was successful with Clock drawing,
the Luria’s fist-edge-palm test and the loop test.
Due to a suspected late-onset bipolar disorder with
chronic manic features in this case, neuropsychological
testing was performed by a clinical psychologist. To
evaluate this patient’s comprehensive cognitive function,
we performed the following tests: BGT, Clock Drawing
Test, Color Trail Test (CTT) 1/2, Korean Auditory Verbal
Learning Test (K-AVLT), Stroop Test, Word/Figural Fluency Test, Executive Complex Figure Test, Grooved Pegboard Test, Finger Tapping Test, Hand Dynamometer,
MMPI-II, Sentence Completion Test (SCT), Wisconsin
Card Sorting Test (WCST) and Rorschach Test.
The K-AVLT findings showed that the patient had a
normal ability to encode and retrieve verbal information.
However her abilities in terms of tracking sequential stimulations, dividing her attention and inhibitory control
function were found to be severely impaired, with a poor
score in terms of attention and executive function in the
CTT tests (<1% percentile). Cognitive productivity was
also poor as reflected in impaired word/figure fluency. In
the WCST, the patient showed 18 perseverative responses
(50% percentile) and 47 non-perseverative responses (<1%
percentile). Her potential for perseveration was therefore
low, and she showed an impaired efficient sorting tendency. The results of the Rorschach test indicated a strong

Park et al. BMC Psychiatry 2014, 14:175
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cognitive rigidity in this patient as she only responded to
the same content repetitively. Finally, the results of the
MMPI-II showed that scales 1 and 9 were all higher than
65 T, indicating that this patient was complaining of physical pain or discomfort and making efforts to cope with
difficulties in her cognitive function.
In conclusion, neuropsychological testing of our current
case revealed an intact memory, but impairment in both
attention and executive function. Although the patient’s
perseveration tendency was not clear, she revealed a high
level of cognitive rigidity in the Rorschach test. The results
of the neurological examination of this case were unremarkable and other systemic examinations showed no
abnormalities. The results of routine laboratory tests including VDRL, HIV antibodies and thyroid function were
also unremarkable apart from hyperlipidemia. MRI analysis
of the brain was performed and revealed severe leukoencephalopathy. There was a high signal intensity found by T2
weighted images (T2W1) and low signal intensity in the
left pons. In fluid-attenuated inversion-recovery (FLAIR)
images, a high signal intensity was prominent on the periventricular white matter, both basal ganglia, thalamus, and
the external capsule. These magnetic resonance imaging
(MRI) findings are very consistent with a diagnosis of
CADASIL. Since the clinical and MRI findings for this patient were highly suggestive of CADASIL, genetic testing
for NOTCH3 mutations was performed. As expected, a
heterogeneous mutation was detected in this patient that
causes an arginine to proline substitution in exon 3 of
chromosome 19 p13.2-13.1 (c.224G > C).
During her hospital treatment, her manic symptoms,
including a labile mood, talkativeness and impulsivity,
partially responded to atypical antipsychotics (quetiapine,
800 mg) and benzodiazepine (bromazepam, 6 mg) treatment. She was also prescribed with amlodipine (novasc),
metformin (diabex), and atorvastatin (lipitor) for the management of the vascular risk factors, hypertension, diabetes, and hyperlipidemia, respectively. She was able to be
discharged after two weeks in hospital. At the time of
discharge, she was no longer hostile or aggressive but
still showed slight impulsivity and mood instability
symptoms. Her initial Montgomery-Asberg Depression
Scale (MADRS) and Young Mania Rating Scale (YMRS)
scores were 24 and 37, respectively. Two weeks after
treatment, these values were lowered to 17 and 25, respectively. Her Clinical Global Impression-Severity Scale
(CGI-S) score was 6 (severely ill) at initial presentation
and 4 (moderately ill) at hospital discharge. Her Global
Assessment of Functioning (GAF) score also slightly improved from 50 to 60 after treatment.

Conclusions
CADASIL is an example of pleiotropism i.e. single gene
effects on multiple phenotypic traits. CASASIL is a

Page 3 of 6

monogenic disease caused by a dysfunction in the
NOTCH3 gene localized on chromosome 19p13.1, but
shows a wide variety of clinical symptoms. This disease
is characterized by five main symptoms: migraine with
aura, subcortical ischemic events, mood disturbance,
apathy, and cognitive impairment [6]. Psychiatric symptoms, mainly episodes of mood disturbances, are seen
in 23% of CADASIL cases [5].
Our current case of a bipolar clinical presentation of
CADASIL without remarkable neurologic deficits provides some important new insights into this disorder.
Our patient was interviewed and described by a psychiatrist. Psychiatric disturbances in patients with CADASIL are usually reported to occur during the course of
the disease [5], and are often the first recorded symptoms because the affected patients will first be admitted
to a psychiatric clinics. The initial symptoms of CADASIL vary with the age of onset, but migraine and TIA are
the most commonly reported initial symptoms [4]. Depression is the second most common first symptom in
patients who first present with CADASIL at an age of
over 50 [4]. However, manic episodes have rarely been
documented as an initial symptom of CADASIL [4,7]. A
recent CADASIL review article, has highlighted that personality and behavioral disorders, such as irritability and
aggressiveness, were reported in only 7 cases (2%) of a
previous 454 patient cohort and that BD was documented in 9 cases (2%) of a 451 patient series [5]. However, these studies were limited by the fact that clinical
manifestations were mainly defined by medical specialists or medical records and not through psychiatric evaluations. Also, manic symptoms appear to be uncommon
in CADASIL patients and may therefore have generated
less interest among clinicians.
Few studies have investigated mood disorder with a
more specific focus on psychiatric disorders in CADASIL. Layhe et al. [8] reported two CADASIL cases who
had been admitted to a gerontopsychiatric hospital with
psychopathological manifestations at the onset of the
disorder. One of these patients had experienced a
submanic episode who had become impulsive, verbally
aggressive, irritable, and sexually preoccupied. Taylor
et al. [9] have described a male CADASIL patient who
showed persistent behavioral disturbances, irritability,
and angry outbursts that lasted for 4years. Gamakaranage et al. [10] have also described a CADASIL case
with a changed personality involving mood swings, aggressive behavior, and cognitive deficit [10]. Although
this patient seemed to show symptoms of mania, this
was considered to be just a personality problem as the
causes were attributed to the persistence of manic
symptoms for many years. This patient was not interviewed by psychiatrist. Only one previous report has described a case of CADASIL with mania [11]. However, it

Park et al. BMC Psychiatry 2014, 14:175
http://www.biomedcentral.com/1471-244X/14/175

had not included detailed descriptions of neuropsycholocial evaluations or psychiatric treatment.
In our present case report, the symptoms of BD which
had begun when our patient was aged in her 50s seemed
for many years to be a personality change due to a continuously labile mood and irritability. She had specific
findings on a cerebral MRI and did not respond well to
medication. She showed an intact memory, but neuropsychological testing revealed impairment of both attention and executive function. However, detailed descriptions
of psychiatric symptoms, neuropsychological testing and
treatments are available for this patient. We propose several clinical characteristics of CADASIL presenting as BD.
All CADASIL cases for which manic symptoms have been
reported including our current case have been documented
with a labile mood, irritability, and verbal aggression, with
no euphoria or elated mood. All CADASIL patients show a
first manifestation of late-onset disease after reaching the
age of 50. In addition, as they show a chronic symptom
course which has progressed for years, they have often
been diagnosed with a personality problem. We contend
therefore that when patients show a late onset personality
change, and a chronically labile or irritable mood that deteriorates over many years, an organic cause like CADASIL
must be considered.
The most prominent neurologic deficits reported in
CADASIL patients to date manifest as a reduced processing
speed as assessed, for example, by the timed measurements

Page 4 of 6

in the TMT and the symbol digit tests. Indeed, abnormalities that are revealed by the TMT B, which measures processing speeds and set shifting, are remarkably consistent
across all published studies on CADASIL including our
current case [12]. Cognitive decline predominantly affects
frontal lobe functions and is characterized by impaired
executive function and poor concentration. Cognitive
decline may also commence insidiously before the onset
of symptomatic ischemic episodes in CADASIL [13].
These impairments are suggestive of dysfunction in the
subcortical-frontal network [12,14]. Memory and other
cognitive functions are relatively preserved at the early
stages of CADASIL [12].
Patients presenting with psychiatric symptoms should
undergo a brain MRI if they have a history of headache,
stroke-like episodes, or cognitive changes and a positive
family history of these manifestations [15]. Hyperintensities of the external capsule and the anterior pole of the
temporal lobe are highly suggestive of CADASIL [16].
Hyperintense lesions have been found in both subcortical white matter and gray nuclei and occur more frequently in BD subjects than in age-matched controls
[17]. Abnormalities converge in the prefrontal white
matter and, in particular, in the tracts that connect prefrontal regions and subcortical gray matter structures
known to be involved in emotion [17]. It is noteworthy
that the MRI changes previously known in BD are strikingly similar to those reported in CADASIL. It might be

Figure 1 Cerebral MRI with fluid-attenuated inversion-recovery (FLAIR) showing high-signal intensity lesions in the periventricular
white matter, both basal ganglia, thalamus, and external capsule (A-C), but not prominent in the anterior temporal poles (D).

Park et al. BMC Psychiatry 2014, 14:175
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postulated that psychiatric manifestations in CADASIL depend on the extent of the damage the cortical-subcortical
circuits, as evidenced by white matter lesions and lacunar
infarcts [18]. Recently, ischemic subcortical lesions are reputed to be important risk factors for the onset of mood
disorders [19]. However, information is still lacking regarding the relationship between mood disorders and lesions
detected on MRI. The NOTCH pathways have been postulated as a cause of white matter changes in BD [17].
Although some studies of CADASIL have described
phenotype-genotype correlations, the genotype cannot
be used to predict the phenotype in this disease [20]. The
R75P mutation identified in our current case is a novel
mutation in a CADASIL patient but is relatively common
in Koreans [21]. In addition, this mutation is related to arginine, whereas previous CADASIL case reports have frequently described the involvement of a cysteine residue.
However, several mutations at arginine residues in EGFlike repeats have been identified previously in other
proteins that are functionally related to NOTCH3 [21].
Whilst anterior temporal hyperintensities have been commonly observed in 75% of CADASIL cases without an
R75P mutation, they have not been observed in any patients with this mutation [21]. Consistently, our current
patient did not show prominent anterior temporal hyperintensities (Figure 1D).
However, this study was retrospective and has some
limitations. This was not confirmed GOM by a skin biopsy, and we investigated exon 2–11, 18 of NOTCH3
which was known as mutation of CASASIL. Because we
did not survey other exons from 12 to 15 or 20–23 have
been reported [22] expressing NOTCH3 and exclude the
possibility of other mutations related to cysteine.
CADASIL is likely to be an underdiagnosed disease,
particularly in psychiatric patients. It is therefore important to highlight CADASIL to psychiatrists as a potential
differential diagnosis. When BD patients show different
clinical features such as resistance to antipsychotics, and
late onset and chronic progression, the neurological signs
and detection of white-matter MRI abnormalities, as well
as a positive family history of stroke, are helpful for diagnosing CADASIL [23]. Testing which is particularly sensitive for the detection of the early cognitive changes can
then be performed such as digit span back-forwards,
TMT-B, Stroop, and WCST tests. These tests have revealed that patients with CADASIL show preservation of
encoding processes even though memory retrieval is impaired [23].
There is currently no treatment with a proven efficacy
for CADASIL. Because CADASIL is a vascular disorder
responsible for cerebral ischemic events, treatment of
vascular risk factors is needed for secondary prevention
in affected patients. Hypertension, hypercholesterolemia
and diabetes should also be treated very strictly in these

Page 5 of 6

cases. Donepezil can be prescribed for improving executive function, and other symptoms should be treated
symptomatically in CADASIL patients [24]. Yuan et al.,
have reported that valproate (VPA), an anticonvulsant
and mood stabilizer activates the NOTCH3/c-FLIP cascade, conferring cytoprotective effects on vascular smooth
muscle cells [25]. Thus, VPA may be useful in the treatment of CADASIL, particularly in patients showing BD.
In our current case, atypical antipsychotics proved to be
helpful in behavior control. Further studies are needed to
better understand the exact impacts of cerebral tissue lesions and psychiatric symptoms in CADASIL patients.
Consent

Written informed consent was obtained from the patient
for publication of this case report and any accompanying
images.
Competing interests
All authors disclose no potential conflicts of interest include employment,
consultancies, stock ownership, honoraria, paid expert testimony, patient
applications/registrations, and grants or other funding.
Authors’ contributions
S Park participated in the design of the study and drafted the manuscript. BR
Park made acquisition and interpretation of a psychiatric history of a case
report part and helped to draft the manuscript. MKK made acquisition and
interpretation of psychological tests of a case report part and helped to draft
the manuscript. YHJ conceived of the study, and participated in its design
and coordination and helped to draft the manuscript. Each author has
participated sufficiently in the work to take public responsibility for
appropriate portions of the content. All authors read and approved the final
manuscript.
Author details
1
Department of Psychiatry, University of Ulsan College of Medicine, Asan
Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 136-736, Korea.
2
Department of Psychology, Asan Medical Center, 88 Olympic-ro 43-gil,
Songpa-gu, Seoul 136-736, South Korea.
Received: 21 August 2013 Accepted: 11 June 2014
Published: 14 June 2014
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doi:10.1186/1471-244X-14-175
Cite this article as: Park et al.: Case report: bipolar disorder as the first
manifestation of CADASIL. BMC Psychiatry 2014 14:175.

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