Stroke

BRIEF REPORT

Association Between the Onset Pattern of Adult

Moyamoya Disease and Risk Factors for Stroke
Yudai Hirano, MD; Satoru Miyawaki , MD, PhD; Hideaki Imai, MD, PhD; Hiroki Hongo, MD; Kenta Ohara, MD;
Shogo Dofuku, MD; Yu Teranishi, MD, PhD; Hirofumi Nakatomi, MD, PhD; Nobuhito Saito, MD, PhD

BACKGROUND AND PURPOSE: Few previous studies have comprehensively explored the relationship between the onset
pattern of adult moyamoya disease and risk factors for stroke. We performed a retrospective analysis focusing on risk
factors for stroke and related findings on magnetic resonance imaging/angiography with respect to the pattern of disease
onset. We also examined whether risk factors for stroke were associated with an increased risk for symptomization in
asymptomatic patients.

METHODS: A total of 178 adult patients with moyamoya disease (asymptomatic, n=84; ischemic, n=71; hemorrhagic, n=23)
at the University of Tokyo Hospital from 2000 to 2018 were included in this study. Data pertaining to patient background
and magnetic resonance imaging findings were analyzed retrospectively. In the asymptomatic group, the effects of stroke-
associated risk factors on symptom onset were analyzed.

RESULTS: Comparisons among the 3 groups revealed no significant difference in the frequency of risk factors for stroke.
The proportion of patients with magnetic resonance imaging/angiography findings indicating anterior choroidal artery
anastomosis or microbleeds was significantly higher in the hemorrhagic group than in the asymptomatic or ischemic group.
Among asymptomatic patients, the hazard ratios for symptomization with hypertension and dyslipidemia were 6.69 ([95% CI,
1.23–36.4] P=0.028) and 8.14 ([95% CI, 1.46–45.2] P=0.017), respectively.
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CONCLUSIONS: The development of anterior choroidal artery anastomosis and microbleeds on magnetic resonance
imaging/angiography was significantly associated with hemorrhagic onset. Hypertension and dyslipidemia may
increase the risk of cerebrovascular events in asymptomatic patients, and thus, early intervention to these factors
may be important.

Key Words:  magnetic resonance imaging ◼ moyamoya disease ◼ natural history ◼ risk factors ◼ stroke

T
he main pathological condition of moyamoya dis-
ease is chronic progressive stenosis of the internal
carotid artery at its terminal portion, which devel-
ops into an abnormal vascular network (moyamoya ves-
sels) of collateral circulation at the base of the brain.1
Onset may be ischemic or hemorrhagic, and there are
many unclear points regarding the factors that deter-
mine them. Various reports have recently investigated
the associations between imaging characteristics and
the clinical features of moyamoya disease.2,3 Few stud-
ies published to date have investigated the association
between general risk factors for stroke and various pat-
terns of disease onset.4,5
In this study, we intended to clarify the importance of
risk factors for stroke in adult patients with moyamoya
disease. First, we analyzed whether the prevalence of
risk factors for stroke and magnetic resonance imag-
ing/angiography (MRI/A) findings correlated with the
pattern of disease onset. We also investigated whether
risk factors for stroke contribute to increased risk for
cerebrovascular events in asymptomatic moyamoya
patients.

 
Correspondence to: Satoru Miyawaki, MD, PhD, Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655,
Japan. Email miyawaki-tky@umin.ac.jp
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.120.030653.
For Sources of Funding and Disclosures, see page 3127.
© 2020 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

3124   October 2020 Stroke. 2020;51:3124–3128. DOI: 10.1161/STROKEAHA.120.030653

 Hirano et al Impact of Stroke Risk Factors on Moyamoya Onset

detailed diagnostic criteria were as follows: hypertension; sys-

Nonstandard Abbreviations and Acronyms tolic blood pressure ≥140 mm Hg or history of treatment with
antihypertensive drugs: diabetes mellitus; fasting blood glucose

AChA anterior choroidal artery
AMORE Asymptomatic Moyamoya Registry
MRI/A magnetic resonance imaging/
angiography
METHODS
Study Population
The data that support the findings of this study are available
from the corresponding author upon reasonable request. This
study was approved by the Ethics Committee of the Faculty
of Medicine, The University of Tokyo (approval number 2231),
which waived the requirement for individual informed consent.
Patients were provided with an opportunity to indicate whether
they wanted to share their clinical information. Our study protocol
followed the opt-out rule. Patients ≥20 years of age who visited
The University of Tokyo Hospital during the period from 2000 to
2018 for the definitive diagnosis of moyamoya disease according
to clinically accepted guidelines6 were included. Cases suspected
to have quasi-moyamoya disease or with insufficient patient
information or MRI/A findings were excluded. Quasi-moyamoya
disease refers to moyamoya vasculopathy associated with vari-
ous disease entities (eg, arteriosclerosis, autoimmune disease,
meningitis, brain tumor, Down syndrome, neurofibromatosis type
I, head trauma).6 The subjects were divided into 3 groups based
on the onset pattern: asymptomatic, ischemic, or hemorrhagic
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Brief Report
>126 mg/dL, occasional blood glucose >198 mg/dL, or the
use of hypoglycemic drugs: dyslipidemia; low-density lipopro-
tein cholesterol in fasting blood ≥140 mg/dL, high-density lipo-
protein cholesterol <40 mg/dL, triglyceride level >150 mg/dL,
or oral treatment with a lipid-lowering drug: alcohol intake; >40
g/day, smoking; ≥6-month history of smoking. MRI/A findings
were evaluated by focusing on the development of anterior
choroidal artery (AChA), posterior cerebral artery involvement,
and microbleeds (Methods in the Data Supplement).
Statistical Analysis
All statistical analysis was performed using JMP Pro 14
(Statistical Discovery From SAS, https://www.jmp.com/ja_jp/
software/data-analysis-software.html). The χ2 test was used to
compare qualitative data. For data with a non-normal distribu-
tion, the Kruskal-Wallis test was used to compare age groups.
Multivariate logistic regression analysis was performed to cal-
culate odds ratios and 95% CI. For time series data, Kaplan-
Meier curves were drawn, and P ​​values were calculated using
a log-rank test. Hazard ratios were calculated using the Cox
proportional hazard model.
RESULTS
Basic Patient Information
Among 178 subjects, we found 84 asymptomatic cases

(Figure I in the Data Supplement). Patients with asymptomatic (47%), 71 ischemic cases (40%), and 23 hemorrhagic
moyamoya disease did not receive prophylactic antiplatelet medi- cases (13%). Background factors and imaging findings
cation. Those who were treated as outpatients received standard for each group are presented in Table 1.
medical treatment to control stroke risk factors.

Definition of Risk Factors for Stroke and
Imaging Findings
We considered hypertension, diabetes mellitus, dyslipidemia,
smoking, and alcohol intake7 as risk factors for stroke. The
Table 1.  Clinical Characteristics of the Study Population
Comparison of Background Factors Among
Groups
There were no significant differences in general risk
factors for stroke among the 3 groups. As for imaging

Factor All Patients (n=178) Asymptomatic (n=84) Ischemic (n=71) Hemorrhagic (n=23) P Value
Mean age at diagnosis, y; mean±SD 45.4±11.7 47.8±11.5 43.2±11.1 43.2±12.6 0.032
Female sex 122 62% 54 64% 52 73% 16 70% 0.486
Hypertension 63 35% 31 37% 24 34% 8 35% 0.920
Diabetes mellitus 9 5% 4 5% 5 7% 0 0% 0.402
Dyslipidemia 19 11% 9 11% 9 13% 1 4% 0.532
Alcohol 24 13% 9 11% 12 17% 3 13% 0.531
Smoking history 20 11% 8 10% 10 14% 2 9% 0.615
Family history of stroke 34 19% 18 21% 15 21% 1 4% 0.156
Family history of moyamoya disease 25 14% 17 20% 7 10% 1 4% 0.064
Suzuki grade ≥4 30 17% 15 18% 12 17% 3 13% 0.861
Development of AChA 24 13% 10 12% 4 6% 10 43% <0.0001

Posterior cerebral artery involvement 34 19% 13 15% 17 24% 4 17% 0.400

Microbleeds 24 13% 9 11% 5 7% 10 43% <0.0001

AChA indicates anterior choroidal artery.

Stroke. 2020;51:3124–3128. DOI: 10.1161/STROKEAHA.120.030653 October 2020   3125

 Hirano et al
findings, the proportion of patients who developed AChA
anastomosis or microbleeds was significantly higher in
the hemorrhagic group than in the asymptomatic group
Brief Report
(P=0.0042 and P=0.0008, adjusted for age and sex) or
the ischemic group (P<0.0001 and P=0.0002, respec-
tively; Table I in the Data Supplement).
Clinical Course of Asymptomatic Moyamoya
Disease
Among 84 patients with asymptomatic moyamoya dis-
ease (mean observation period, 42.2 months) who were
followed from the time of diagnosis, 7 subjects became
symptomatic (new infarctions, n=2; transient ischemic
attacks, n=5; hemorrhage, n=0). The rate of symptom
appearance was 2.4% per year (Figure [A]). The onset of
symptoms was significantly earlier in patients with hyper-
tension (5.5% versus 0.6% per year; P=0.040) and in
patients with dyslipidemia (8.0% versus 1.4% per year;
P=0.008; Figure [B through D]). After adjustments for
age and sex, the hazard ratio for symptomization was
6.69 ([95% CI, 1.23–36.4] P=0.028) for hypertension
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Figure. Kaplan-Meier curve.
Kaplan-Meier curve for symptomization of all asymptomatic moyamoya disease patients (84 patients; A) and for subgroups of patients after
stratification for the presence/absence of a given stroke risk factor (B–D). DL indicates dyslipidemia; DM, diabetes mellitus; and HT, hypertension.
3126   October 2020
Impact of Stroke Risk Factors on Moyamoya Onset
and 8.14 ([95% CI, 1.46–45.2] P=0.017) for dyslipid-
emia (Table 2). The hazard ratio for having multiple stroke
risk factors (hypertension, diabetes mellitus, and dyslipid-
emia) was 8.00 ([95% CI, 1.36–47.0] P=0.021; Table 2).
DISCUSSION
There was no significant difference in the frequency of
risk factors for stroke or patient background among the
asymptomatic, ischemic, and hemorrhagic groups. On the
contrary, analysis of the natural history of asymptomatic
moyamoya disease revealed that hypertension and dys-
lipidemia were risk factors for cerebrovascular events in
patients with asymptomatic moyamoya disease.
Association Between Moyamoya Disease Onset
Pattern and Imaging Findings
To assess choroidal anastomosis, which is most likely
associated with hemorrhagic onset, we evaluated the
degree of AChA on MRA.2 In this study, the development
of AChA or microbleeds was significantly more frequent
Stroke. 2020;51:3124–3128. DOI: 10.1161/STROKEAHA.120.030653
 Hirano et al
Table 2.  Risk Factors for Stroke and Symptomization in
Patients With Asymptomatic Moyamoya Disease
Factor aHR (95% CI)
Hypertension 6.69 (1.23–36.4)
Diabetes mellitus 2.29 (0.25–21.3)
Dyslipidemia 8.14 (1.46–45.2)
≥2 risk factors 8.00 (1.36–47.0)
The extent to which each stroke factor affected the appearance of symptoms
was determined with the Cox proportional hazard model. The aHR was calculated
after correction for age and sex. aHR indicates adjusted hazard ratio.
in the hemorrhagic group, which is consistent with pre-
vious reports.2,3 The results of this study suggest that
these findings can be used to predict subsequent hem-
orrhage and that regular monitoring with MRI/A should
be performed to prevent the development of hemor-
rhagic events. Various analyses have been conducted on
the relationship between imaging findings and the onset
patterns of moyamoya disease, and further innovative
researches are expected.2,8
Clinical Course of Asymptomatic Moyamoya
Disease
About half of the subjects in this cohort were asymp-
tomatic because, in recent years, the widespread use of
magnetic resonance imaging in Japan has allowed doc-
tors to identify moyamoya disease in patients who pres-
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ent only with nonspecific symptoms such as headache
and dizziness.9
The relationship between stroke events and image
findings in asymptomatic moyamoya disease has recently
been clarified. As mentioned above, the presence of cho-
roidal anastomosis predicts the onset of hemorrhage.2
On the other hand, there are few reports on risk factors
for stroke and clinical course.10
We found that hypertension and dyslipidemia were
risk factors for cerebrovascular events in asymptomatic
patients. In addition, the presence of multiple risk factors
for stroke increases the risk of symptomization. There-
fore, it is important to manage risk factors for stroke,
even in asymptomatic patients who present for outpa-
tient treatment. The results of this study should clarify the
heterogeneous clinical course of moyamoya disease. We
did not perform detailed analyses to determine whether
we had properly controlled for stroke risk factors. Future
studies on the role of preventive medicine in the treat-
ment of moyamoya disease should analyze whether strict
medical control of risk factors for stroke reduces the risk
for symptomization.
Limitations and Future Prospects
This study had a small sample size and included a sin-
gle-institution cohort. In Japan, to clarify the clinical fea-
tures, prognosis, and treatment strategy of asymptomatic
Stroke. 2020;51:3124–3128. DOI: 10.1161/STROKEAHA.120.030653
Impact of Stroke Risk Factors on Moyamoya Onset
moyamoya disease, prospective multicenter efforts to
establish the AMORE (Asymptomatic Moyamoya Regis-
try) are currently underway.11
Brief Report
P Value
0.028
0.466
Conclusions
0.017
While conventional risk factors of stroke did not differ
0.021
significantly among the groups, AChA development and
microbleeds in MRI/A are factors that predict hemor-
rhagic onset. Hypertension and dyslipidemia have been
shown to be risk factors for cerebrovascular events in
asymptomatic moyamoya disease patients. Early inter-
vention to combat these stroke factors may prevent or
delay onset.
ARTICLE INFORMATION
Received March 31, 2020; final revision received May 21, 2020; accepted July
22, 2020.
Affiliations
Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Japan
(Y.H., S.M., H.H., K.O., S.D., Y.T., H.N., N.S.). Department of Neurosurgery, Tokyo
Shinjuku Medical Center, Japan (H.I.).
Acknowledgments
We thank Takuya Kawahara, MPH, PhD, for his advice regarding statistical
analysis.
Sources of Funding
This work was supported by a Grant-in-Aid for Scientific Research (B; No.
17H04301) to Dr Saito and a Grant-in-Aid for Scientific Research (C; No.
19K09473) to Dr Miyawaki from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, grants from Mitsui Life Social Welfare Foundation to Dr
Miyawaki, and grants from the MSD Life Science Foundation (Public Interest
Incorporated Foundation) to Dr Miyawaki.
Disclosures
None.
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