Western Moyamoya Phenotype: A Scoping Review

Moyamoya, a rare angiographic finding, is characterized by chronic and progressive stenosis at the terminal end of the internal carotid artery, followed by collateralization of the cerebral vasculature at the base of the skull. Coined by Suzuki and Takaku in 1969, the term “moyamoya” means a “puff of smoke” in Japanese, a reference to the angiographic appearance of moyamoya collateralization. Moyamoya is most commonly found in East Asian countries, where much governmental and civilian effort has been expended to characterize this unique disease process. However, despite its rarity, the occurrence of moyamoya in Western countries is associated with significant divergence regarding incidence, gender, sex, age at diagnosis, clinical presentation, and outcomes. Here, we attempted to review the Western literature on moyamoya presentation using the PubMed database to characterize the Western phenotype of moyamoya. We were guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR). We reviewed papers generated from a search with keywords “moyamoya case report,” those reported from a Western institution, and those reported on a relevant association. Our scoping review demonstrated various clinical associations with moyamoya. Moreover, we summarized the demographic profile and clinical symptomatology, as well as reported disease associations to better elucidate the Western phenotype of moyamoya.

moyamoya for greater appreciation of this wide-ranging condition.
MMD and MMS occur mostly in East Asian populations where much governmental and civilian effort has been expended to characterize this unique disease process, which has highlighted important features of the moyamoya phenotype in a broad and robust collection of literature. However, the rarity with which MMS afflicts the Western world presents a unique challenge in the study of its Western phenotype, known to present as a distinct clinical entity [12]. Moreover, various studies in the United States have found rates of MMD increasing over time [13,14], making characterization of associated conditions especially critical. Table  1 references several national in-patient studies reported in the last several decades that are representative of roughly 20% of all US hospital admissions for those years; it demonstrates rising moyamoya rates.

Study
Reference  To our knowledge, this is the first attempt to date to collect all known case reports in the literature of Western-type moyamoya for a comprehensive analysis of the unique features with which Western moyamoya can be encountered. Guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) (Appendices, Figures 2, 3), we aim to answer the research question: what is known about the demographic profiles and clinical symptomatology of Western moyamoya and the diseases that are associated with it?

Protocol and Registration
Our scoping review protocol was not registered.

Eligibility Criteria
We included English-language papers identified by their titles as etiology of moyamoya or moyamoya symptoms. We excluded papers for which the first author's address was located in Asia (if the first author's address was unavailable, then the first available address of any author thereafter was used).

Information Sources and Search
A literature search of PubMed was performed to collate case reports on moyamoya. Duplicates were removed manually by the authors. The following search term was used to screen for relevant papers on PubMed published in the preceding 10 years on August 9, 2020: "moyamoya case report."

Selection of Sources of Evidence
Papers were initially screened by their titles only. However, to better define their status according to the inclusion criteria, the abstract and/or paper were read to clarify ambiguities. Further, for the purpose of the review, relevant papers were read and mined for relevant content. Finally, the association between moyamoya and each symptom and associated pathology was explored in relevant additional literature.

Data Charting Process and Data Items
Data were manually extracted as profiles of patients with major findings relevant to the review and were added to an excel spreadsheet. Unique findings were further reviewed outside of the search criteria for the Discussion section.

Synthesis of Results
Results were grouped based on the association reported by the paper. Additionally, they were classified by the country of the first author's address according to the inclusion/exclusion criteria.

Results
Primary search on PubMed using keywords "moyamoya case report" for primary sources, filtered to only include papers published in the last 10 years, yielded 725 papers. A total of 368 papers were removed on applying exclusion criteria, leaving 357 papers. From these papers, 153 were selected for further analysis using our inclusion criteria. See Figure 1 for a flowchart schematic of literature search results.   We categorized the 153 papers into two categories that will be discussed separately. Overall, 44 papers reported a symptom associated with moyamoya, and 109 reported a condition associated with moyamoya. Table 3 tabulates symptoms reported in 44 papers describing a moyamoya symptom association.  None of the previously mentioned large database studies reported aneurysms as a primary reported endpoint, possibly because of its rarity in Western patients. One study in Germany published in 2016 of 55 moyamoya patients showed that 37 (67.3%) had suffered from a headache in the last year, with 47.9% having migraine-like headaches, of which 58.8% of the cases described migraine aura [109,172]. The rates of hemorrhage reported in several large studies are presented in Table 4.
A case of central deafness in a Caucasian child with moyamoya was reported. The child was a three-year-old male with no known Asian ancestry and was presumed to have suffered developmental retardation because of his cerebrovascular stenosis [176].
Regarding ophthalmologic symptoms, studies have been reported of a moyamoya patient with acute cortical blindness [115] and another with ocular ischemic syndrome [116].
The most commonly reported stroke type was ischemic infarction. In National Inpatient Sample (NIS) studies of disease profiles of moyamoya patients in the United States, ischemic stroke was the most common co-occurring symptom, with an incidence of 20.7% in the 1988-2004 study and 11.6% in the 2005-2008 study. In the 2013 Nationwide Readmission Database (NRD) study, 5% of moyamoya patients presenting for revascularization surgery were coded for ischemic stroke.
In the United States, symptomatic moyamoya patients have lower rates of hemorrhagic stroke than their Japanese and Korean counterparts (33.6% vs. 61% and 59%). This supports the notion that moyamoya outside of the West is pathophysiologically distinct from its presentation in East Asia. Additionally, hemorrhagic stroke was more frequent in adults than in children (18.1% vs. 1.5%, p < 0.05) [14]. Further, 20.7% of patients in the NIS study from 1988 to 2004 were diagnosed with ischemic stroke, 7.4% with intracerebral hemorrhage, 3.1% subarachnoid hemorrhage, 3.4% transient ischemic attack (TIA), 13.5% anemia, and 13.6% with sickle cell disease or trait [17]. A higher percentage of moyamoya patients in the West have an identifiable underlying condition than their East Asian counterparts [177].
Additionally, the 2018 study of moyamoya patients who underwent revascularization surgery found that vascular risk factors were common, with one out of four having diabetes, half having hypertension, and 40% each having hypocholesteremia or a history of smoking. Further, moyamoya has also been reported in patients with fibromuscular dysplasia [178]. Renovascular hypertension has also been reported in association with moyamoya [179].  We found 10 (9%) papers describing an association between moyamoya and an autoimmune condition. This finding is consistent with previous reports of associations between MMS and autoimmune diseases in Eastern cohorts [180,181]. In 2012, one research group at the Mayo Clinic in Rochester reported an unusually high prevalence of autoimmune diseases among their cohort of mostly white, mid-Western patients. Later, in 2016, another group in Washington reported four cases of MMS with pre-existing type 1 diabetes mellitus. Two of the patients also had Graves' disease, and another had systemic lupus erythematosus [52]. Then, in 2017, researchers analyzed 2,633 patients in the NIS dataset from 2009 to 2012 and reported a strong (p < 0.05) association between adult-onset autoimmune diseases and moyamoya (NIS lacks distinction between MMS and MMD) in the pediatric population (but not the adult population). The adult-onset autoimmune diseases included Addison's disease, dermatomyositis, granulomatosis with polyangiitis, Graves' disease, multiple sclerosis, myasthenia gravis, polymyositis, primary systemic vasculitis, rheumatoid arthritis, Sjogren's disease, systemic lupus erythematosus, systemic sclerosis, and thyroiditis. By contrast, juvenileonset autoimmune diseases, including diabetes mellitus type 1 and juvenile rheumatoid arthritis, were associated with moyamoya in both the pediatric and adult populations [15]. Finally, in 2018, 26% of 31 mostly Caucasian MMD patients in Kentucky were reported to have a co-existing autoimmune condition, including rheumatoid arthritis, lupus, hypothyroidism, psoriasis, polyglandular autoimmune type 1, autoimmune hepatitis, Addison's disease, immune thrombocytopenic purpura, Crohn's disease, multiple sclerosis, celiac sprue, and dermatitis herpetiformis [182]. Other reports have shown an association between moyamoya and febrile infection-related epilepsy syndrome (FIRES) [101], Graves' disease [182], and collagenous colitis [183]. Of note, not a single case of co-existing moyamoya and Sjogren's syndrome could be found for a Western patient.

Disease Associations
The association between autoimmunity and moyamoya has been thoroughly demonstrated using animal models. Half a century ago, researchers noticed that moyamoya patients were experiencing leptospirosis complications, in which 81.4% of their cerebral spine fluid had a positive immune response. Later, in 1983, Japanese researchers observed that moyamoya patients were at a greater risk for tonsillitis, otitis media, maxillary sinusitis, and fever and infection of unknown origin. However, more recent research has called into question the proposed autoimmune etiology of the moyamoya phenotype [184].
Moyamoya has been reported in association with glycogen storage disease type 1a in France [191] and the United States [192]. Additionally, it has been reported in association with Alagille syndrome [93,193], a rare, autosomal dominant hepatic disorder. A few cases of moyamoya have been reported in patients with Turner's syndrome [94,193]. In our literature search, we found one case of moyamoya with Aicardi Goutieres syndrome [194].
We found three (3%) papers describing an association between moyamoya and drugs. Oral contraceptives have been recognized as a potential risk factor for moyamoya in the West since at least 1984 [195]. A small cohort study conducted in Canada and the United States consisting of 39 patients with moyamoya [196] and another literature review of moyamoya cases in the United States [183], both in 1997, showed that oral contraceptive use was associated with moyamoya. We found one report of cocaine abuse associated with moyamoya [21]. Another two articles reported an association with nilotinib, a second-generation tyrosine kinase inhibitor [23], and bevacizumab [22].
Sickle cell anemia predisposes patients to internal carotid artery stenosis, leading to moyamoya [198]. A 2019 study identified 61 studies in the literature on sickle cell-associated moyamoya revascularization surgery outcomes, presumably a significant number of which occurred in the Western population [199]. A 2011 NIS study of moyamoya admissions from 1988 to 2004 showed that 13.6% of all moyamoya patients had sickle cell disease or trait at admission [17].
To our knowledge, five cases of MMS with hereditary spherocytosis have been reported [75], of which at least three were Western patients.
Additionally, East Asian researchers have reported at least five cases of moyamoya associated with paroxysmal nocturnal hemoglobinuria [200], although to our knowledge, none have been reported to date in Western patients. Additional hematological conditions not identified by our search criteria included hemoglobin Fairfax-beta-thalassemia in 2008 in Indiana [201] and hemoglobin E/beta-thalassemia in 2009 in Cambodia [202].
We found 12 (11%) papers describing an association between moyamoya and Neurocutaneous disorders, including one case of tuberous sclerosis [35] and the rest of neurofibromatosis type 1 (NF1) [24][25][26][27][28][29][30][31][32][33][34]. One study found approximately 250 children with NF1 in the literature since 1976 [12], and another NIS study found 51 of 2,247 moyamoya patients with NF between 1988 and 2004 [17]. NF1 is an autosomal dominant genetic neurocutaneous disorder caused by a mutation in the NF1 gene, located on chromosome 17 (17q11.2). The disorder leads to a large spectrum of central nervous system manifestations, including learning disabilities, mental retardation, seizures, attention deficit with hyperkinesia disorder, neurofibromas, and optic nerve glioma. While the mechanism by which NF1 leads to moyamoya is unknown, it is probably related to the function of the protein encoded by the NF1 gene, a negative regulator of Ras. This is especially plausible because moyamoya is known to be associated with RASopathies, including Noonan syndrome and Costello syndrome.
Associations between tumors and moyamoya have been reported in East Asian literature, but they are very rare [203]. Furthermore, we found two (2%) papers that described an association between moyamoya and a post-infection state, including meningitis secondary to Aspergillus fumigatus and Escherichia coli [114] and pneumococcal meningitis [113].
On further analysis, we found several other reports of post-infectious moyamoya, including quaternary neurosyphilis in 1989 [204] and Haemophilus influenaze type C meningitis in Texas in 2003 [205]. Moreover, one national multicenter study identified five South African children (four girls of indigenous African ancestry) with human immunodeficiency virus-associated vasculopathy and MMS [206], and a Canadian and US cohort demonstrated an association between moyamoya and tuberculosis in 1997 [196]. Finally, a patient with acquired immunodeficiency syndrome was reported as presenting concurrently with moyamoya [207].
We found six (6%) papers describing an association between moyamoya and radiation therapy. Radiation therapy is a known risk factor for the development of cerebrovascular pathologies. A recent 2019 PubMed analysis of case reports of radiation-induced moyamoya found 54 reported cases [208]. Proton beam therapy, a safer alternative to traditional radiation therapy, has also been associated with moyamoya [55].
One of the first reported cases of moyamoya associated with radiation therapy in the United States was published in 1978 [209], followed by what was probably the first cohort study of the association in Western patients in Toronto, Ontario in 1993 with five patients treated for optic gliomas [210]. All patients were Caucasian, and four received 5,000 rad of radiation or more and one received 2,500 rad. In four cases, the presentation was ischemic and two patients presented with TIAs. While there have been several recent meta-analyses of the literature regarding the association between radiation therapy and moyamoya in the global population, there have been none published to date specifically for Western populations to our knowledge.
Specifically, the association between Down syndrome and moyamoya has been known for some time [211,212], with as many as 80 distinct cases, excluding large population analyses, being reported in the literature [213]. Although the pathophysiology of this association is not well understood, it might be related to developmental vascular anomalies [212], especially regarding proteins involved in vascular physiology that are encoded in chromosome 21, such as cystathionine B-synthetase, interferon-gamma receptor, superoxide dismutase, and chains of collagen type VI. Antiphospholipid antibodies have also been found in both moyamoya and Down syndrome and may reflect a possible link between these two pathologic entities [90]. Moreover, patients with Down syndrome have a higher prevalence of autoimmune disorders and autoantibodies, similar to moyamoya, which has been noted for its association with autoimmune disorders, and prevalence of antiphospholipid antibodies [16].
However, less is known about the particular Western expression and prevalence of moyamoya in association with Down syndrome [90,213,214]. In probably the first large analysis in Western cohorts, Kainth [215], moyamoya patients are estimated to have a 26-fold increased prevalence of Down syndrome relative to the general population. Moreover, the prevalence of Down syndrome among patients admitted with moyamoya who were <15 years of age was found to be 9.5% or 9,540 per 100,000 live births. Finally, the incidence of moyamoya among Down syndrome patients was approximately three times higher than the general population [214].
There appears to be a nuanced difference between the demographic presentation of moyamoya in Down syndrome and the typical presentation. First, the percentage prevalence of Down syndrome among moyamoya patients appears to be the highest in white (65.4% vs. 47.4%) and Hispanic patients (14.6% vs. 10.4%) and especially low among blacks (10.7% vs. 25.9%). The percentage prevalence among females with Down syndrome-associated moyamoya is lower than non-Down syndrome-associated moyamoya (58.4% vs. 70.5%). Moreover, patients with moyamoya who have Down syndrome are at a greater risk for ischemic symptoms and at a lesser risk for hemorrhagic strokes (p < 0.05). On average, they experience a hospital admission at a younger age (16.2 vs. 33) [16], despite the fact that their moyamoya initially presents at an older age (8.4 vs. 6.5) [213]. These patients more often achieve better neurologic outcomes after surgical revascularization than non-Down syndrome-associated moyamoya (as reflected in improved modified Rankin scale scores in 97% of cases and lack of post-discharge strokes), despite more often being symptomatic (100% vs. 75%) and experiencing surgical complications (perioperative stroke rate per hemisphere 5.9% vs. 4%, and perioperative seizure high at 16%). Down syndrome-associated moyamoya patients are reported to have strokes more often than non-Down syndrome moyamoya patients (87% vs 68%) and more often experience seizures before diagnosis (26% vs. 6%) [90].

Demographics
The results of three studies using the NIS, the largest publicly available, all-payer inpatient database in the United States that represents 20% of all annual US hospital admissions, are presented in Table 5.  Estimates for relative rates of moyamoya between biological sexes range from 61.9% to 75% among females. However, an NIS study found that moyamoya patients younger than 18 from 1988 to 2004 displayed a male predominance before 1998 and that the rates of moyamoya among females significantly increased after 1994 for ages 36-55. Interestingly, the study also found that among African Americans, there was no significant female predominance [17].

Discussion
This paper presents the first attempt at a scoping review of the Western presentation of MMS. Moyamoya is a unique angiographic finding, characterized by stenosis of the supraclinoid internal carotid artery, middle carotid artery, anterior carotid artery, or their branches, followed by extensive collateralization of the cerebral vasculature at the base of the skull. It has historically been considered endemic to Asian populations, especially Japananese and Korean, where most cases have been found. However, a significant minority of patients in the West have presented with moyamoya findings lacking an obvious Asian heritage. Motivations for compiling this report include: (1) prevalence rate of moyamoya has been rising in recent years [14] (although possibly due to improved diagnostics and awareness [13] rather than increased prevalence of pathophysiologic mechanisms); (2) the western phenotype has been known for some time to diverge from its Asian counterpart; and (3) moyamoya has been associated with significant risk for cerebrovascular accidents. Elucidating the disease profile can provide insights into the unique pathophysiology of moyamoya and provide the groundwork for therapeutics.
We searched PubMed for case reports on moyamoya published in the last 10 years, which resulted in 725 papers. From these, we selected 357 English-language papers that reported a moyamoya association (with moyamoya as either etiology or symptom). We then selected 153 papers by excluding those reporting on patients from Asian populations. This selection was not straightforward as patients' heritage and location of presentation were often not available. At the risk of misidentifying a few reports and in the interest of consistency, simplicity, and efficiency, we chose to categorize the patients' East-West localization based on the location of the lead institution from which the paper was published.
Symptoms of note were, in order of prevalence in reports, neurological, stroke, hemorrhage, headache, aneurysm, dental, and ophthalmologic. Further review of the literature revealed that neurological symptoms associated with moyamoya include laryngomalacia, hypotension encephalopathy, behavioral changes, language deficits, transient psychosis, hemiplegia and movement disorders, hearing loss, and cognitive difficulties. Vascular symptoms (excluding specific markers of moyamoya, for example, occlusion of anterior, middle cerebral, and internal carotid arteries) included vertebral artery, carotid artery, ophthalmic artery, retinal artery and vein, pulmonary artery occlusions, retinal artery tortuosity, arteriovenous fistula, and vascular smooth muscle proliferation. Ophthalmologic symptoms included acute cortical blindess, ocular ischemic syndrome, and ocular malformations.
In several large analyses of multi-year NIS data, ischemic stroke was the most common symptom occurring in association with moyamoya, followed by hemorrhage, subarachnoid hemorrhage, TIA, anemia, and sickle cell disease.
Roughly two-thirds of western moyamoya patients were females, with numbers from NIS studies of moyamoya patients ranging from 62% to 72%, and a slightly higher ratio for moyamoya patients presenting for revascularization surgery (74%). The female-to-male ratio appears to be rising, with 61 Common disease profiles of moyamoya patients include, in order of prevalence in reports, syndromes, vascular, congenital, hematologic, neurocutaneous, autoimmune, radiation therapy, metabolic, physical trauma, drugs, and post-infectious pathologies. Vascular comorbidities were especially common, with one 2018 study of revascularization moyamoya patients reporting that one of four presented with diabetes, half with hypertension, and 40% for both hypercholesterolemia and smoking.
Of note, Down syndrome, a common condition associated with moyamoya, is more prevalent in Caucasian and Hispanic populations, and less common in women relative to the non-Down syndrome moyamoya population. Down syndrome patients with moyamoya are diagnosed with moyamoya at an older age but present at a hospital at a younger age and are more symptomatic (especially strokes and seizures), although they have better neurologic outcomes after revascularization surgery than non-Down syndrome moyamoya patients. Additionally, tumor-associated moyamoa appears to be a rare occurrence.
Autoimmune conditions commonly occur in association with moyamoya, and we found nine reports in our literature serac (10%). This is not surprising given that moyamoya has long been thought to have a pathophysiologic relationship with autoimmunity. This has been supported by half a century of research, although more recent findings have called this paradigm into question [184].
Limitations to our review include the inconsistency of reports included in our analysis, such that some reports may have been inappropriately excluded and that those included might not be representative of the overall prevalence of Western patients. Additionally, using the location of the first author as a surrogate for the patient's heritage has obvious limitations as an immigrant or descendent of immigrants would not freely share ethnicity. Moreover, generalized disease and symptom profiles serve as only a guide for future research but cannot provide specific extrapolations for individual presentations.

Conclusions
Our scoping review of the relevant Western literature on moyamoya has revealed an interesting panoply of demographic data, symptomatology, and associated diseases. Moyamoya is part of a complex web of interconnected disease processes that culminate in a unique radiographic finding. Moreover, while moyamoya is often thought of as native to East Asia, it presents often enough in the West that it can be understood as a unique moyamoya phenotype. Here, we aimed to collate literature reports on moyamoya presentation in the West to better appreciate and understand the unique Western moyamoya phenotype. We hope that this information guides treatment planning as moyamoya findings can herald the advent or concurrence of potentially fatal disease processes. Additionally, highlighting the unique characteristics of the Western moyamoya presentation can help further guide researchers to important discoveries in moyamoya pathophysiologic pathways and sequelae. This could, in turn, translate into discoveries of more effective treatment targets and therapeutic developments. Further research is warranted in the form of rigorously conducted systematic reviews to better contrast the Eastern and Western moyamoya phenotypes to stratify treatment planning with a greater degree of granularity.