World Neurosurgery

Angiographic Collateralization Patterns of Moyamoya Angiopathy in Patients with

Down Syndrome: A Comparison with Idiopathic Moyamoya Disease
--Manuscript Draft--

Manuscript Number: WNS-21-973

Article Type: Original Articles

Keywords: moyamoya; down syndrome; trisomy 21; angiopathy; stroke

Abstract: Background

Down syndrome (DS) is known to be associated with Moyamoya syndrome (MMS).

However, it remains unclear whether cerebral collateralization features of patients with
DS/MMS carry any distinction from patients with idiopathic Moyamoya disease (MMD).
We sought to compare angiographic collateralization patterns between patients with
DS/MMS and idiopathic MMD using a quantitative grading system.

Methods

This was a retrospective case-control study. The medical records of patients who
presented to our institution between 1990 and 2019 who were diagnosed with either
idiopathic MMD or MMS were retrospectively reviewed. Patients diagnosed with MMS
with a concomitant diagnosis of DS with available angiograms were included.
Angiographic data was considered on a per-hemisphere basis. Age-matched control
hemispheres from the idiopathic MMD cohort were selected. Baseline demographic
and clinical variables were compared between cohorts. Angiographic collateralization
patterns were compared between cohorts based on a previously-described grading
system ranging from 1 (poor collateralization) to 12 (excellent collateralization). Follow-
up data including interval ischemic events were collected and compared between
groups.

Results

Fifteen total hemispheres belonged to patients with DS/MMS (8 total patients);15 age-
matched control hemispheres were selected from 10 total patients with idiopathic
MMD. There were no statistically significant differences between groups in terms of
cardiovascular comorbidities. DS/MMS hemispheres had higher total mean
collateralization scores compared to control hemispheres (6.9 ± 1.5 versus 5.4 ± 1.2,
respectively, P = 0.004).

Conclusions

Patients with DS/MMS may have more robust collateralization patterns compared to
patients with idiopathic MMD. The current data are limited due to small sample sizes.

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Anthony S. Larson, B.S.

Mayo Clinic Department of Neurosurgery
200 First Street SW
Rochester, MN USA 55905
612-210-6084
Lars4689@umn.edu

Edward C. Benzel, MD
Editor-in-chief
World Neurosurgery

26th of February 2021

Dear Dr. Benzel,

We are pleased to submit our original manuscript entitled “Angiographic Collateralization

Patterns of Moyamoya Angiopathy in Patients with Down Syndrome: A Comparison with
Idiopathic Moyamoya Disease” for consideration for publication in World Neurosurgery

All authors certify that they have no affiliations with or involvement in any organization or entity
with any financial interest (such as honoraria; educational grants; participation in speakers’
bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and
expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or
professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials
discussed in this manuscript.

I, Anthony Larson, certify that this manuscript is a unique submission and is not being
considered for publication in part or in full, with any other source in any medium.

All authors report no relevant financial disclosures or conflicts of interest. I confirm that the
manuscript has been read and approved for submission by all of the named authors.

We thank you for your consideration.

Sincerely,

Anthony S. Larson, B.S.

Mayo Clinic
Department of Neurosurgery
Title Page

Title: Angiographic Collateralization Patterns of Moyamoya Angiopathy in Patients with Down

Syndrome: A Comparison with Idiopathic Moyamoya Disease

Authors: Anthony Larson, B.S.1,2, Lorenzo Rinaldo, M.D., Ph.D.2, Giuseppe Lanzino, M.D.1,2,
James Klaas, M.D.3

Author Information:
1
Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA, 55905
2
Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN, USA, 55905
3
Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA, 55905

Corresponding Author:
Anthony Larson
200 First Street SW
Rochester, MN, USA, 55905
Email: lars4689@umn.edu
Ph: 612-210-6084

Author emails:
James Klaas: Klaas.James@mayo.edu
Lorenzo Rinaldo: Rinaldo.Lorenzo@mayo.edu
Giuseppe Lanzino: Lanzino.Giuseppe@mayo.edu

Key words: moyamoya; down syndrome; trisomy 21; angiopathy; stroke

Running head: Angiographic features of Down syndrome with Moyamoya Syndrome

Abstract word count: 250

Manuscript word count: 3,011
Number of figures: 1
Number of Tables: 3
Number of Supplementary Tables: 1

Sources of funding: No funding was obtained to carry out this study

Ethics approval statement: All patients included in this study provided written informed
consent for participation in research activities at our institution. This study was approved by
Mayo Clinic Institutional Review Board.

Competing Interests: All authors declare no competing interests

Disclosure-Conflict of Interest [authors to provide own statement,
.doc(x) format preferred]

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Abbreviations

Abbreviations:
ACA = anterior cerebral artery
atPCA = Anterior temporal branch of the PCA
DS = Down syndrome
EC-IC = extracranial to intracranial bypass
ICA = internal carotid artery
MCA = Middle cerebral artery
MMD = moyamoya disease
MMS = moyamoya syndrome
PCA = posterior cerebral artery
pPCA= Parieto-occipital branch of the PCA
SD = standard deviation
TIA = transient ischemic attack
Manuscript (Must be in .doc or .docx format) Click here to access/download;Manuscript (Must be in .doc or
.docx format);MMS and Down Syndrome Final World Nsgy.docx
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Title: Angiographic Collateralization Patterns of Moyamoya Angiopathy in Patients with Down

Syndrome: A Comparison with Idiopathic Moyamoya Disease

Authors: Anthony Larson, B.S.1,2, Lorenzo Rinaldo, M.D., Ph.D.2, Giuseppe Lanzino, M.D.1,2,
James Klaas, M.D.3

Author Information:
1
Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA, 55905
2
Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN, USA, 55905
3
Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA, 55905

Corresponding Author:
Anthony Larson
200 First Street SW
Rochester, MN, USA, 55905
Email: lars4689@umn.edu
Ph: 612-210-6084

Author emails:
James Klaas: Klaas.James@mayo.edu
Lorenzo Rinaldo: Rinaldo.Lorenzo@mayo.edu
Giuseppe Lanzino: Lanzino.Giuseppe@mayo.edu

Key words: moyamoya; down syndrome; trisomy 21; angiopathy; stroke

Running head: Angiographic features of Down syndrome with Moyamoya Syndrome

Abstract word count: 250

Manuscript word count: 3,011
Number of figures: 1
Number of Tables: 3
Number of Supplementary Tables: 1

Sources of funding: No funding was obtained to carry out this study

Ethics approval statement: All patients included in this study provided written informed
consent for participation in research activities at our institution. This study was approved by
Mayo Clinic Institutional Review Board.

Competing Interests: All authors declare no competing interests

Abbreviations:
ACA = anterior cerebral artery
atPCA = Anterior temporal branch of the PCA
DS = Down syndrome
EC-IC = extracranial to intracranial bypass
ICA = internal carotid artery
MCA = Middle cerebral artery
MMD = moyamoya disease
MMS = moyamoya syndrome
PCA = posterior cerebral artery
pPCA= Parieto-occipital branch of the PCA
SD = standard deviation
TIA = transient ischemic attack
Abstract

Background:

Down syndrome (DS) is known to be associated with Moyamoya syndrome (MMS). However, it

remains unclear whether cerebral collateralization features of patients with DS/MMS carry any

distinction from patients with idiopathic Moyamoya disease (MMD). We sought to compare

angiographic collateralization patterns between patients with DS/MMS and idiopathic MMD

using a quantitative grading system.

Methods:

This was a retrospective case-control study. The medical records of patients who presented to

our institution between 1990 and 2019 who were diagnosed with either idiopathic MMD or

MMS were retrospectively reviewed. Patients diagnosed with MMS with a concomitant

diagnosis of DS with available angiograms were included. Angiographic data was considered on

a per-hemisphere basis. Age-matched control hemispheres from the idiopathic MMD cohort

were selected. Baseline demographic and clinical variables were compared between cohorts.

Angiographic collateralization patterns were compared between cohorts based on a previously-

described grading system ranging from 1 (poor collateralization) to 12 (excellent

collateralization). Follow-up data including interval ischemic events were collected and

compared between groups.

Results:

Fifteen total hemispheres belonged to patients with DS/MMS (8 total patients);15 age-matched

control hemispheres were selected from 10 total patients with idiopathic MMD. There were no
statistically significant differences between groups in terms of cardiovascular comorbidities.

DS/MMS hemispheres had higher total mean collateralization scores compared to control

hemispheres (6.9 ± 1.5 versus 5.4 ± 1.2, respectively, P = 0.004).

Conclusions:

Patients with DS/MMS may have more robust collateralization patterns compared to patients

with idiopathic MMD. The current data are limited due to small sample sizes.
Introduction

Moyamoya angiopathy is a chronic disease involving progressive occlusion of the

supraclinoid internal carotid artery (ICA) and its proximal branches with concomitant formation

of enlarged basal collateral and leptomeningeal vessels. When Moyamoya angiopathy occurs

without a known underlying condition, it is termed Moyamoya Disease (MMD), whereas the

presence of an associated condition implies a diagnosis of Moyamoya Syndrome (MMS).1 There

are several, heterogeneous conditions and/or exposures that have been associated with MMS.

One such condition is trisomy 21, or Down syndrome (DS).2 The prevalence of DS

among Moyamoya patients has been estimated at 3,760 patients per 100,000.3 Despite this

relatively high prevalence, few studies have outlined the various clinical, radiographic and

surgical features associated with DS patients diagnosed with MMS (DS/MMS). In this regard,

reporting of such information remains important in order to better understand the disease process

of MMS in context of DS, and for clinicians to be aware of effective management options.

Because MMS/DS remains poorly understood, it is largely unknown whether or not a

distinction in cerebrovascular phenotype exists between idiopathic MMD and MMS/DS. Prior

reports have opined that no radiographic distinctions are readily apparent between DS/MMS and

MMD.2, 4, 5 However, it is important to note that these prior studies did not include direct

angiographic comparisons between patients with DS/MMS and MMD and, therefore, did not

address whether specific patterns of collateralization may differ between the two groups. Such

knowledge may inform clinicians and surgeons as to whether or not DS/MMS may have distinct

collateralization patterns from idiopathic MMD patients, potentially influencing treatment

considerations.
 Existing grading systems that are utilized to classify the extent of disease progression in

MMD are largely based on qualitative interpretations of collateralization patterns. Recently, Liu

et al.6 described a grading system that quantified the degree of collateralization based on the

angiographic distribution of collateral contributions to the anterior circulation. This grading

system was found to correlate well with the severity of clinical symptoms of MMD patients, as

well as the therapeutic prognosis, indicating that this system may be useful in prognostication

and surgical risk stratification. Furthermore, this system is likely useful in providing a

quantitative evaluation of collateralization patterns in MMD patients: This system may therefore

be utilized in comparing the angiographic collateralization patterns between two subpopulations

of patients with moyamoya angiopathy.

The aim of the current study is two-fold: First, we sought to compare angiographic

collateralization patterns found in patients with DS/MMS and idiopathic MMD using a recently-

described quantitative grading system. Second, we hoped to aid in further understanding DS in

the context of MMS by describing our own institutional case series.

Methods

Study Population and Patient Grouping

Institutional review board approval was obtained prior to the initiation of this study. All

patients who were included provided written informed consent for involvement in research

activities. The medical records of patients who presented to our institution between 1990 and

2019 who were diagnosed with either idiopathic MMD or MMS by a staff neurologist or

neurosurgeon according to previously described criteria7 were retrospectively reviewed. Each

patient with MMD or MMS underwent a clinical evaluation that consisted of a thorough history
and physical exam with an experienced staff neurologist at our institution. In most cases, this

also included additional laboratory evaluations for potential underlying causes of intracranial

vessel stenosis including autoimmune and thrombophilia/coagulation studies as previously

described,8 and genetic testing in select cases. Furthermore, each patient’s medical records were

reviewed for documentation of underlying autoimmune disease (systemic lupus erythematosus,

Grave’s disease, autoimmune hepatitis, type-1 diabetes mellitus, Sjogren’s syndrome,

inflammatory bowel disease, Hashimoto’s thyroiditis, rheumatoid arthritis, Takayasu’s arteritis)

connective tissue diseases (fibromuscular dysplasia, Marfan syndrome), prior cranial irradiation,

intracranial neoplasm, documentation of prior intracranial infections (vasculitis, encephalitis or

meningitis) or genetic syndromes (Sickle cell disease, Trisomy 21, Noonan syndrome, Turner’s

syndrome, Sturge-Weber syndrome, Tuberous Sclerosis, myotonic dystrophy or

neurofibromatosis).

Radiographically, patients were diagnosed with idiopathic MMD based on the presence

of collateral vessel proliferation at the skull base with concomitant intracranial stenosis of the

proximal anterior cerebral (ACA), middle cerebral (MCA) and/or distal internal carotid artery

(ICA) either unilaterally or bilaterally on digital subtraction angiography (DSA) performed at our

own or outside institution. Patients found to have these angiographic findings in the setting of

one or more of the above disease processes were classified as having MMS.

In order to compare patients with idiopathic MMD to those with DS/MMS, patients with

an underlying diagnosis of DS were selected from the group of patients with MMS. All

angiographic data was considered on a per-hemisphere basis. Patients without DSA studies

available for review were excluded. Patients that did not have available angiograms prior to

undergoing any form of extracranial to intracranial bypass (EC-IC) were also excluded. For a
case-control study, age-matched hemispheres from the idiopathic MMD cohort were selected as

a control group in a 1:1 fashion. Due to a limited number of hemispheres of each age, MMD

hemispheres within 2 years of age relative to DS/MMS hemispheres were considered as

acceptable controls. Therefore, the final patient/hemisphere cohort consisted of two groups:

idiopathic MMD controls and DS/MMS, all of whom had initial DSA imaging available for

review.

Demographic and Baseline Clinical Characteristics

Relevant demographic and baseline clinical characteristics were abstracted from the

charts of all patients included. Demographic information that was collected included age at

initial diagnosis of MMD or MMS, ethnicity and sex. Clinical characteristics that were collected

included relevant vascular comorbidities as well as the clinical presentation of MMD or MMS in

each population (ischemic, hemorrhagic or other). Ischemic presentations were classified as

ischemic stroke or transient ischemic attack (TIA).

Imaging Analysis

Digital subtraction angiograms from each included patient were reviewed by a

neurosurgeon with endovascular subspecialty training who was blinded to patient clinical

information at the time of angiographic review. Modified Suzuki grades were assigned to each

patient based on a scale of 1 to 6 as previously-described.9 Angiographic characteristics were

determined on a per-affected hemisphere basis.

 In order to quantify collateralization patterns, the grading system as described by Liu et

al.6 was utilized. Briefly, scores were quantified by assessing the degree of collateralization

between the following leptomeningeal vascular territories:

1. Parieto-occipital branch of the PCA (pPCA) anastomoses with the posterior peri-callosal

artery of the ACA. These anastomoses were scored from 0 to 2.

2. Anterior temporal branch of the PCA (atPCA) anastomoses to the temporal branch of the

MCA. These anastomoses were scored from 0 to 1.

3. pPCA anastomoses to the MCA. These anastomoses were scored from 0 to 3.

In addition to the leptomeningeal vascular territories, basal perforators were also assessed

by determining the “collateralization Suzuki score”, which was based on modified Suzuki scores,

where modified Suzuki scores of 6 to 1 corresponded to collateralization Suzuki scores of 1 to 6.

The leptomeningeal scores and collateralization Suzuki scores were summed to create a

total collateralization score for each patient. Scores of 1 to 4 corresponded to poor collateral

status (grade 1), scores of 5 to 8 to fair collateral status (grade 2), and scores of 9 to 12 to good

collateral status (grade 3).6 The following mean values of angiographic features were compared

between DS/MMS and MMD patients: leptomeningeal scores (for each individual vascular

territory and total leptomeningeal scores), collateralization Suzuki scores, and total

collateralization scores. The proportion of each cohort belonging to each collateral status grade

(i.e. grade 1, 2 or 3) were also compared between groups.

Follow-up and Surgical Data

 From each patient record, data was collected on follow-up findings and surgical

revascularization procedures performed (if any). Follow-up data included the length of follow-up

and presence of any interval intracranial events including stroke (either hemorrhagic or ischemic)

as diagnosed on imaging studies (including either MRI or CT) or TIA as diagnosed by a

neurologist from our institution. Surgical data that was collected included whether or not a

revascularization procedure was performed (either direct or indirect extracranial-intracranial

bypass). The presence of any interval intracranial ischemic events was determined for all patients

in each cohort, and specifically for those who underwent a revascularization procedure.

Institutional Cohort

In order to further describe the features of DS/MMS, we sought to review our own

institutional cohort of patients with Down Syndrome also diagnosed with MMS. All DS/MMS

patients were included regardless of whether or not they had DSA studies or follow-up available.

Relevant data abstracted from each patient’s medical record included age, sex, clinical

presentation, comorbidities, imaging characteristics, surgical characteristics (if any) and follow-

up data.

Statistical Analysis

The primary objective of this study was to compare the angiographic features of

hemispheres belonging to patients with idiopathic MMD to those belonging to patients with

DS/MMS. Secondary objectives included comparing baseline clinical/demographic

characteristics between groups, comparing outcome and revascularization status between

cohorts, and providing a description of our institutional cohort of patients with DS/MMS.
 Means and standard deviations (SD) were calculated for continuous variables. Student’s

two-tailed t-test was used to compare mean values of continuous variables between cohorts.

Percentages were calculated for binary variables. Fisher’s Exact Probability Test was used to

determine significance between binary data. P-values below 0.05 were considered statistically

significant. All calculations were performed in Microsoft Excel and STATA 14.1 (StataCorp,

College Station, Texas, USA).

Results

Study Population, Baseline Clinical and Demographic Characteristics

Our patient selection process is outlined in Figure 1. Baseline clinical and demographic

data for each patient cohort are summarized in Table 1. Fifteen total hemispheres belonged to

patients with DS/MMS (8 total patients). Four patients with DS/MMS from our institutional

cohort were excluded because they did not have a DSA available to review for this study. There

were a total of 177 hemispheres belonging to 90 patients with idiopathic MMD from which 15

age-matched control hemispheres were selected (10 total patients). The mean age at MMS

diagnosis of patients with DS was 20.6 years (SD ± 11.6 years) compared to a mean age of 19.1

(± 11.3) in MMD controls (P = 0.78), indicating acceptable age matching between cohorts. There

was no difference in the distribution of ethnicities between cohorts, with most patients being of

Caucasian ethnicity (P = 0.67). There were no statistically significant differences between groups

in terms of cardiovascular comorbidities. There was no difference in the distribution of

presenting symptoms between cohorts (P = 0.97), with ischemic presentations being the most

common in both groups

 We also compared baseline clinical and demographic characteristics between our entire

DS/MMS (all 12 patients) and all patients with MMD (90 patients). Patients with DS/MMS had a

mean age at MM diagnosis of 23.1 years (± 12.5) compared to a mean age of 33.5 (± 14.9) in

patients with idiopathic MMD (P = 0.007). These data are summarized in Table 2. Our complete

institutional cohort of DS/MMS patient-level data is provided in Supplementary Table 1.

Angiographic Comparison

Angiographic data are summarized in Table 3. In regards to leptomeningeal

collateralization, DS/MMS hemispheres tended to have higher mean collateralization scores

relative to control MMD hemispheres, although the only area in which there was a statistically

significant difference between DS/MMS and MMD hemispheres was the pPCA to MCA score

(1.4 ± 1.1 versus 0.67 ± 0.81, respectively, P = 0.04). The mean total leptomeningeal score in

DS/MMS hemispheres was 2.8 ± 1.9, compared to 2.0 ± 1.2 in control MMD hemispheres (P =

0.21). DS/MMS hemispheres had a higher mean Suzuki collateralization score (4.1 ± 1.2)

compared to MMD hemispheres (3.3 ± 1.2), although this did not reach statistical significance (P

= 0.09). DS/MMS hemispheres had higher total mean collateralization scores compared to

control hemispheres (6.9 ± 1.5 versus 5.4 ± 1.2, respectively, P = 0.004). In regards to

collateralization grades, DS/MMS hemispheres had a higher proportion of grade 3

collateralization (13.3% versus 0.0%) whereas control MMD hemispheres had a higher

proportion of grade 1 collateralization (20.0% versus 6.7%), although these distributions were

not statistically significant (P = 0.44)

Revascularization and Follow-up

 Regarding follow-up, nine MMD patients had available follow-up data (90.0% of

included MMD control patients); six (75.0%) DS/MMS patients had available follow-up. Three

patients with DS/MMS underwent revascularization procedures compared to nine idiopathic

MMD patients (P = 0.04). At a mean follow-up interval of 49.1 months, no MMD patients had a

recurrent ischemic event (TIA or stroke). This was compared to two patients with DS/MMS

(33.3%) at a mean follow-up of 40.1 months (P = 0.27). Of all patients in both cohorts, none who

underwent revascularization procedures had interval ischemic events. Revascularization and

follow-up data is summarized in Table 4.

Discussion

In the current study, we compared the angiographic features of collateralization between

hemispheres belonging to patients with idiopathic MMD and those belonging to patients with

Down Syndrome-associated MMS based on a novel quantitative grading system.6 The primary

finding of this study is that DS/MMS hemispheres had higher total collateralization scores

compared to idiopathic MMD controls. However, this increase in collateralization scores did not

seem to be associated with a better outcome at follow-up. Although it is challenging to make

robust conclusions from our data given the small sample sizes, these findings may suggest that

angiographic collateralization patterns may differ between DS/MMS and idiopathic MMD.

Intriguingly, we also found that a high percentage of DS/MMS patients presented with

ischemic symptoms (stroke or TIA) which is consistent with prior reports.4 When comparing

patients with DS/MMS to the overall MMD cohort, DS/MMS patients were also found to be, on

average, younger compared to MMD patients, implying that this cohort is more likely to present

with a pediatric picture of MMD, which includes a higher prevalence of ischemic events in
contrast to hemorrhage.10 This finding is important and implies that clinicians who are caring for

a DS patient with symptoms concerning for cerebral ischemia should strongly consider

evaluating for underlying moyamoya angiopathy.

Moyamoya syndrome in the context of Down syndrome remains incompletely

understood, as relatively few cases have been reported.2, 4, 5, 11-17 To date the largest series was

reported by See et al.4 who reported on a total of 32 patients (51 affected hemispheres) with DS/

MMS. Interestingly, when compared to patients under 21 years old with a diagnosis of MMS but

without DS, patients with DS/MMS were found to have an older mean age of diagnosis (8.4

versus 6.5 years). This is in contrast to our findings here, which indicate that patients with DS

had a younger age at diagnosis (21.9 versus 33.9 years), although our study population consisted

of patients of all ages. These findings suggest that patients with DS/MMS are likely to present at

a later timepoint when compared to pediatric MMS patients without DS, (likely due to

developmental delay and difficulty in recognizing neurological symptoms) but are more likely to

be diagnosed at an earlier age relative to idiopathic MMD patients overall.

In addition to the study by See et al.4 other reports that have analyzed the radiographic

features of DS/MMS have indicated that the cerebrovascular phenotype of DS/MMS is

comparable to those with idiopathic MMD.2, 5 However, these studies are limited in that no direct

comparison between DS/MMS and MMD angiograms were made. In this regard, and in addition

to a quantitative assessment of collateralization patterns in each case, our study is unique.

Moreover, the conclusion drawn from the present data is also in contrast to predicate studies,

namely that DS/MMS patients may have better collateralization patterns compared to age-

matched MMD controls.

 Moyamoya syndrome consists of a moyamoya-like cerebrovascular phenotype in the

context of several distinct underlying disease entities. Besides DS, other entities/exposures

implicated in MMS include sickle cell anemia,18 neurofibromatosis,19 prior cranial irradiation,20

and autoimmune disorders.8 The underlying pathogenetics of idiopathic MMD continue to be

elucidated, and multiple important genetic and cytological discoveries have been made in recent

years.21 Similarly, certain genetic susceptibilities have also been implicated in MMS in the

context of underlying syndromes.22, 23 Despite this, it remains largely unclear how the

aforementioned disease entities contribute to a moyamoya-like phenotype. In the case of DS and

MMS in particular, one hypothesis is that overexpression of several important genes related to

cerebral arterial regulation and remodeling are located on chromosome 21.2 Given that

angiographic phenotypes are similar in many regards between DS/MMS and idiopathic MMD, it

may be hypothesized that the two entities share many commonalities in their respective

pathogenetic mechanisms. However, our finding that DS/MMS may have more robust

collateralization patterns suggests the possibility of subtle distinctions in the underlying

pathomechanics between DS/MMS and idiopathic MMD. As to what these distinctions may be,

nevertheless, remains unclear and further study is required.

Our study consists of several important limitations that require consideration. First and

foremost, our sample sizes were small, which may have prevented statistical significance from

being reached in many comparisons. Second, our study was retrospective in nature, and thus we

could not completely account for the disease course of patients prior to presenting to our

institution, which is a tertiary referral center specializing in MMD. This fact may have affected

the results of demographic comparisons between groups. Third, the scoring system utilized in the

current study has not been validated in additional moyamoya populations, specifically, western
populations. Finally, our study did not fully assess potential differences in MRI/CT-based

features (e.g. presence and distribution of infarctions) between DS/MMS and MMD patients.

Based on previous studies, however, it is unlikely that any significant difference would be found

between groups. 2, 4 Future reports will, ideally, include larger sample sizes and improve upon

the aforementioned limitations.

Conclusions

Patients with DS and MMS may have more robust collateralization patterns compared to

patients with idiopathic MMD, although our data are limited due to small sample sizes. Patients

with DS who present with symptoms concerning for cerebral ischemia should be strongly

considered for evaluation of MMS. Further study is required in order to more fully understand

MMS in the context of Trisomy 21.

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Down syndrome. Pediatric neurology. 1985;1(3): 174-179.

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moya moya disease: report of a case in a child with Down's syndrome. Pediatrics. 1977;60(1):
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Figure Legend

Figure 1. Patient selection strategy.

Abbreviations: DSA = digital subtraction angiography; MMD = moyamoya disease; MMS =

moyamoya syndrome
Table 1 Click here to access/download;Table(s);Table 1.docx

Table 1. Baseline demographic and clinical features of Down Syndrome and MMD patients

Down Syndrome (N = 8) MMD Controls (N = 10) P-value

Mean age at MM diagnosis (SD) 20.6 (11.6) 19.1 (11.3) 0.78
No. female (%) 4 (50.0) 6 (75.0) 0.99
Ethnicity, no. (%)
Caucasian 5 (62.5) 7 (70.0) 0.67
Asian 1 (12.5) 2 (20.0)
African-American 1 (12.5) 0 (0.0)
Other 1 (12.5) 1 (10.0)
Comorbidities
Hypertension 1 (12.5) 3 (37.5) 0.59
Hyperlipidemia 2 (25.0) 1 (12.5) 0.54
Coronary artery disease 0 (0.0) 0 (0.0) 0.99
Diabetes mellitus 1 (12.5) 0 (0.0) 0.59
Smoker 0 (0.0) 0 (0.0) 0.99
Presentation of MM, no. (%)
Ischemic 7 (87.5) 9 (90.0) 0.97
Hemorrhagic 0 (0.0) 0 (0.0)
Other 1 (12.5) 1 (10.0)
Table 2 Click here to access/download;Table(s);Table 2.docx

Table 2. Analysis of demographic and clinical features between all Down syndrome patients and all MMD patients from our
institutional cohort.

Down Syndrome (N = 12) MMD (N = 90) P-value

Mean age at MM diagnosis (SD) 23.1 (12.5) 33.5 (14.9) 0.007
No. female (%) 7 (58.3) 62 (68.9) 0.52
Ethnicity, no. (%)
Caucasian 9 (75.0) 69 (67.0) 0.39
Asian 1 (8.3) 9 (8.7)
African-American 1 (8.3) 1 (1.0)
Other 1 (8.3) 11 (12.2)
Comorbidities
Hypertension 1 (8.3) 39 (43.3) 0.03
Hyperlipidemia 2 (16.7) 37 (41.1) 0.12
Coronary artery disease 0 (0.0) 2 (2.2) 0.99
Diabetes mellitus 1 (8.3) 13 (14.4) 0.70
Smoker 0 (0.0) 41 (45.6) 0.003
Presentation of MM, no. (%)
Ischemic 10 (83.3) 71 (78.9) 0.91
Hemorrhagic 0 (0.0) 7 (5.6)
Other 2 (16.7) 14 (15.6)
Abbreviations: MM = moyamoya; MMD = moyamoya disease; SD = standard deviation
Table 3 Click here to access/download;Table(s);Table 3.docx

Table 3. Angiographic characteristics of Down Syndrome associated MMS and MMD

Down Syndrome (N = 8 patients) MMD (N = 10 patients) P-value
No. of affected hemispheres 15 15
Collateral Circulation Grading a

pPCA to ACA 1.1 (0.96) 1.2 (0.86) 0.69

atPCA to MCA 0.33 (0.49) 0.20 (0.41) 0.43
pPCA to MCA 1.4 (1.1) 0.67 (0.81) 0.04
Total leptomeningeal score 2.8 (1.9) 2.0 (1.2) 0.21
Suzuki Collateral Score 4.1 (1.2) 3.3 (1.2) 0.09
Mean total collateral score 6.9 (1.5) 5.4 (1.2) 0.004
Grades
1 1 (6.7) 3 (20.0)
2 12 (80.0) 12 (80.0) 0.44
3 2 (13.3) 0 (0.0)
aBased off of the grading system described by Liu et al.6

Abbreviations: ACA = anterior cerebral artery; atPCA = anterior temporal branch of the PCA; EC = extracranial; IC = intracranial;
ipsi = ipsilateral; MCA = middle cerebral artery; PCA = posterior cerebral artery
Table 4 Click here to access/download;Table(s);Table 4.docx

Table 4. Revascularization and follow-up

Down Syndrome (N = 8) MMD Controls (N = 10) P-value
No. patients with revascularization (%) 3 (37.5) 9 (90.0) 0.04
No. of patients with available follow-up (%) 6 (75.0) 9 (90.0) 0.56
Mean follow-up interval, mo. (SD) 40.1 (23.9) 49.1 (54.9) 0.69
No. total patients with interval ischemic events (%) 2 (33.3) 0 (0.0) 0.27
No. patients with revascularization with interval ischemic events (%) 0 (0.0) 0 (0.0) 0.99
Abbreviations: SD = standard deviation
Figure 1 Click here to access/download;Figure(s);Fig 1..tiff
Supplementary Table 1

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Supplementary Material (Video/Media Files)
Supplementary Table 1.docx