7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis : Nijasri Charnnarong Suwanwela, MD : Jos Biller, MD, FACP, FAAN, FAHA, Douglas R Nordli, Jr, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 08, 2022. INTRODUCTION Moyamoya is an uncommon cerebrovascular condition characterized by progressive narrowing of large intracranial arteries and the secondary development of prominent small-vessel collaterals. These collateral vessels produce a characteristic smoky appearance on angiography, which was first called "moyamoya," a Japanese word meaning puffy, obscure, or hazy like a puff of smoke in the air. Moyamoya is a progressive disorder that may lead to ischemic stroke or intracranial hemorrhage in children and adults. This topic will review the etiologies, clinical features, and diagnosis of moyamoya. The prognosis and treatment of moyamoya are discussed separately. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis".) CLASSIFICATION AND TERMINOLOGY The term "moyamoya" describes the specific angiographic findings of unilateral or bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation ( image 1). https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 1/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no associated conditions. This may also be called primary or idiopathic moyamoya disease as well as the descriptive "spontaneous occlusion of the circle of Willis" [1,2]. Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition as described below. (See 'Associated conditions' below.) These secondary forms of the condition have been termed "moyamoya phenomenon," "angiographic moyamoya," or "quasi-moyamoya disease" [1,3-5]. ETIOLOGY AND PATHOGENESIS The etiology of MMD is unknown, but genetic associations have been identified. MMS has been associated with multiple conditions, which may implicate diverse pathophysiologic processes leading to the characteristic vascular abnormalities. Genetic associations The high incidence among the Japanese population, together with a familial occurrence of approximately 10 to 15 percent of cases, strongly suggests a genetic etiology. Accumulating evidence suggests that the RNF213 gene on chromosome 17q25.3 is an important susceptibility factor for MMD in populations in several East Asian countries [6-14]. Several reports have also linked familial MMD to chromosomes 3p24.2, p26, 6q25, 8q23, and 12p12 [15-17]. Although the mode of inheritance is not established, one study suggested that familial moyamoya is an autosomal dominant disease with incomplete penetrance [18]. The authors proposed that genomic imprinting and epigenetic modification may account for the predominantly maternal transmission and elevated female-to-male incidence ratio. (See 'Epidemiology' below and "Inheritance patterns of monogenic disorders (Mendelian and non- Mendelian)", section on 'Parent-of-origin effects (imprinting)'.) A later genome-wide association study confirmed the relationship of MMD and a previously reported locus on chromosome 17q25 [19]. The study also identified 10 novel risk loci, including the genes regulating homocysteine metabolism, loci related to large vessel disease, and loci that are highly expressed in the immune system. Associated conditions There are many conditions associated with MMS. They may be causative or syndromic. Some of the conditions reported to be associated with MMS include: Disease affecting arteries around the circle of Willis https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 2/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Atherosclerosis [20] Radiation therapy to the base of the brain [21] (see "Delayed complications of cranial irradiation", section on 'Cerebrovascular effects') Cranial trauma [22] Brain tumors [23-25] Meningitis [26] Other viral or bacterial infection (eg, Cutibacterium acnes, leptospirosis, human immunodeficiency virus [HIV]) [27-29] Hematologic conditions Sickle cell disease [30-32] Beta thalassemia [33] Fanconi anemia [34] Hereditary spherocytosis [35] Homocystinuria and hyperhomocysteinemia [36] Factor XII deficiency [37] Essential thrombocythemia [38] Protein S deficiency [39-41] Pyruvate kinase deficiency [42] Vasculitis and autoimmune and multisystem diseases Systemic lupus erythematosus [43] Polyarteritis nodosa and postinfectious vasculopathy [44] Graves disease and thyroiditis [45-48] Sneddon syndrome and the antiphospholipid antibody syndrome [49,50] Anti-Ro and anti-La antibodies [51] Type 1 diabetes mellitus [48] Pulmonary sarcoidosis [52,53] Genetic and developmental disorders Alagille syndrome [54,55] Down syndrome [56,57] Hypomelanosis of Ito [58] Marfan syndrome [59] Microcephalic osteodysplastic primordial dwarfism type 2 [60] Multisystem disorder with short stature, hypergonadotropic hypogonadism, and dysmorphism [61,62] https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 3/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Neurofibromatosis type 1 [63-66] Noonan syndrome [67-69] Phakomatosis pigmentovascularis type IIIb [70] Prader-Willi syndrome [71] Pseudoxanthoma elasticum [72] Sturge-Weber syndrome [73] Tuberous sclerosis [74] Turner syndrome [75] Williams syndrome [76] Morning glory optic disc anomaly ( image 2), usually in conjunction with other craniofacial abnormalities [77-79] (see "Congenital and acquired abnormalities of the optic nerve", section on 'Morning glory disc') Other vasculopathies and extracranial cardiovascular diseases Coarctation of the aorta [80] Congenital heart disease [81] Fibromuscular dysplasia [82] Renal artery stenosis [83] Metabolic diseases Type I glycogenosis [84,85] Hyperphosphatasia [86] Primary oxalosis [87] Renal disorders Polycystic kidney disease [88-90] Wilms tumor [83,91-103] Pathogenesis The pathophysiologic processes leading to arterial stenosis and small vessel collateralization involve vessel wall thickening and angiogenesis. A genetic susceptibility may be implicated in MMD, while underlying associated conditions trigger the development of MMS. Vascular changes in moyamoya may be related to impaired response to inflammation or defects in cellular repair mechanisms [104]. Such changes have been associated with evidence of increased angiogenesis-related factors, including endothelial colony-forming cells, various cytokines, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) [105-107]. High levels of fibroblast growth factor, which may stimulate arterial growth, have been found in the vascular intima, media, and smooth muscle as well as cerebrospinal fluid https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 4/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate among patients with moyamoya [108,109]. Transforming growth factor beta-1 (TGFB1), which mediates neovascularization, may also contribute to the pathogenesis [110,111]. High levels of hepatocyte growth factor (a strong inducer of angiogenesis) have been detected in the carotid fork and cerebrospinal fluid in patients with moyamoya [112]. Pathologic findings Tissue analysis in patients with moyamoya shows evidence of arterial vessel narrowing and secondary vascular proliferation characteristic of the disease as well as tissue damage related to the vascular abnormalities. Stroke Brain tissue of patients with moyamoya usually reveals evidence of prior ischemic or hemorrhagic stroke. Multiple areas of cerebral infarction and focal cortical atrophy are commonly found. Although large-vessel stenosis and occlusion are the hallmark of this disease, extensive territorial infarction is uncommon. The brain infarcts are generally small and located in the basal ganglia, internal capsule, thalamus, and subcortical regions [113]. However, the cause of death in most autopsy cases is intracerebral hemorrhage [93]. The hemorrhage is commonly found in the basal ganglia, thalamus, hypothalamus, midbrain, and/or periventricular region. Bleeding into the intraventricular space is frequently observed. Vascular stenosis Pathologic vascular lesions appear in the large vessels of the circle of Willis and in the small collateral vessels [94]. The terminal portions of the internal carotid arteries as well as the proximal middle and anterior cerebral arteries are most commonly involved [114]. Some patients may have unilateral stenosis at presentation, although progression to bilateral involvement may occur [115,116]. Less frequently, the posterior circulation is affected, especially the posterior cerebral artery. In the affected large arteries, variable stenosis or occlusion is associated with intimal fibrocellular thickening, tortuosity or duplication of the internal elastic lamina, and attenuation of the media [91,117-119]. Collateral vessels One of the hallmarks of moyamoya is the presence of a collateral meshwork of overgrown and dilated small arteries, the moyamoya vessels, that branch from the circle of Willis ( image 3). The pathology of the smaller perforating vessels in moyamoya is variable. Morphometric analysis suggests that some are dilated with relatively thin walls, while others are stenotic with thick walls [117]. Dilated vessels, more common in younger patients than in adults, tend to show fibrosis with attenuation of the media and microaneurysm formation. Histologic study from autopsy specimens of aneurysms showed disappearance of internal https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 5/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate elastic lamina and media [92]. These findings are similar to those of the berry aneurysms commonly observed in primary subarachnoid hemorrhage. Leptomeningeal vessels are another source of collaterals in moyamoya. As a result of intracranial internal carotid artery stenosis, leptomeningeal anastomoses may develop from the three main cerebral arteries (middle, anterior, and posterior). These collaterals result from dilatation of preexisting arteries and veins. In addition, transdural anastomoses, termed vault moyamoya, may develop from extracranial arteries such as the middle meningeal and superficial temporal arteries [95]. Aneurysms Cerebral aneurysms have been associated with moyamoya in a number of reports [96-100]. Aneurysms can develop at vessel branching points in the circle of Willis or along collateral vessels [101,120]. In a review of 111 moyamoya patients with cerebral aneurysm, most presented with intracranial hemorrhage and were found to have a single aneurysm in 86 percent of cases. Aneurysms along the circle of Willis were found in 56 percent, of which almost 60 percent were in the posterior circulation [120]. Aneurysms can also arise from the small collateral moyamoya vessels, choroidal arteries, or other peripheral collateral arteries [101]. These small-vessel aneurysms are the major cause of parenchymal (intracerebral) hemorrhage in moyamoya. Extracranial involvement In patients with moyamoya, stenosis due to fibrocellular intimal thickening may also affect the extracranial and systemic arteries, including the cervical carotid, renal, pulmonary, and coronary vessels [91,102]. Involvement of the renal arteries has been most frequently reported. In one study of 86 patients with MMD, six had renal artery stenosis, two had associated renovascular hypertension, and one had a renal artery aneurysm [83]. Similarly, in a later study of 73 consecutive patients with MMD, four had renal artery stenosis [121]. EPIDEMIOLOGY Incidence and prevalence The relative prevalence of MMD and MMS vary geographically. MMD is more common in East Asian countries than elsewhere, with the highest prevalence found in Japan, China, and Korea [114,122,123]. In epidemiologic surveys conducted in Japan, the following observations have been made [124- 127]: The annual incidence of moyamoya is 0.35 to 0.94 per 100,000 population. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 6/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate The prevalence of moyamoya is 3.2 to 10.5 per 100,000 population. There is a female predominance, with a female-to-male ratio of 1.9. A family history of MMD is present in 10 to 12 percent of patients. Using hospital admissions data, a United States study found an incidence of 0.57 per 100,000 persons/year [128]. Among ethnic groups in California, the moyamoya incidence rate for Asian Americans was 0.28 per 100,000, similar to that in Japan. The incidence rates were lower for African American, White American, and Hispanic populations (0.13, 0.06, and 0.03 per 100,000, respectively). The incidence of MMS in Japan is approximately 10 times lower than MMD [129,130]. Age distribution MMD and MMS both occur in children and adults; presentation in infancy is uncommon [131,132]. Data from a nationwide registry in Japan, with 2545 cases of MMD, showed a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second broader peak at approximately 40 years of age [127]. A cohort study of 802 patients with MMD from China also demonstrated a bimodal age distribution, with a major peak at five to nine years of age and another peak at 35 to 39 years of age [133]. CLINICAL PRESENTATIONS Moyamoya has varying clinical presentations; the expression of disease and the age at presentation are influenced by regional and ethnic differences. Ischemic stroke and transient ischemic attack The most common initial presentation of moyamoya is ischemic stroke [134-138]. Transient ischemic attack (TIA) is also a frequent initial presentation and may be recurrent [134,138]. In one retrospective series from the United States, 61 percent of 31 adults with MMD or MMS presented with ischemic symptoms; in those with stroke, the predominant pattern was a border- zone pattern of infarction [137]. In another retrospective study, 21 German patients with MMD all presented with ischemic events, including 16 who were adults at symptom onset [136]. In children, symptomatic episodes of ischemia in the anterior and middle cerebral artery vascular territories may commonly be triggered by exercise, crying, coughing, straining, fever, or hyperventilation [104,139,140]. In the International Pediatric Stroke Study involving 174 children with moyamoya, ischemic stroke was the initial presentation in 90 percent of children and TIA in 7.5 percent [134]. Ischemic symptoms of hemiparesis or speech impairment predominated, reflecting the predilection for stenosis of the anterior cerebral circulation (anterior and middle https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 7/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate cerebral artery territories). In this series, 20 percent of children had recurrent symptoms in the median 13-month follow-up interval. Multiple recurrent events are common in other studies as well, likely reflecting the fixed stenosis susceptible to recurrent hypoperfusion. In one study from Korea of 88 children and adults who were followed for 6 to 216 months, multiple cerebrovascular events occurred in 55 percent [141]. Recurrences were most commonly ischemic. Intracerebral, intraventricular, and subarachnoid hemorrhage While ischemic symptoms may be more common at presentation, hemorrhagic complications of moyamoya, mainly intracerebral hemorrhage (ICH), represent a significant clinical burden. ICH is more common in adults than children [138,142]. In the International Pediatric Stroke Study, ICH was the presenting syndrome in 2.5 percent [134], while, in a series of adult patients, 10 percent of patients presented with intracranial hematoma [137]. In a systematic review, intracerebral hemorrhage at initial presentation was more frequent for patients in China and Taiwan than in the United States [135]. Intraventricular hemorrhage with or without ICH was a common presentation of MMD, according to one report from Korea [143]. In adults who presented with ICH or intraventricular hemorrhage, small aneurysms in the periventricular area have been reported ( image 4). Patients may also present with subarachnoid hemorrhage [144]. Seizures Patients with moyamoya present infrequently with seizures, often secondary to ischemic damage [145]. The rate of epilepsy may be more frequent in children than in adults [142]. Other manifestations Headache Headache is common in patients with moyamoya [146]. Migraine is the most common headache phenotype, but tension-type headache and cluster headache have also been reported [147,148]. Other neurologic symptoms There are case reports of patients with moyamoya who develop dystonia, chorea, or dyskinesia, but these appear to be uncommon manifestations [149-151]. Asymptomatic disease Moyamoya can be found incidentally in asymptomatic patients undergoing screening imaging for other conditions or because of family history [152,153]. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 8/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate A nationwide study in Japan using a questionnaire in 1994 identified 33 asymptomatic cases (1.5 percent) out of a total of 2193 patients [154]. INITIAL TEST FINDINGS Because patients with MMD or MMS may present with signs and symptoms of acute cerebrovascular disease, initial testing typically includes neuroimaging. Electroencephalography is often performed in patients with seizures and sometimes in those with transient ischemic attack (TIA). Specific findings on these tests may suggest moyamoya. Neuroimaging Cerebral infarction may involve cortical and subcortical regions ( image 5). Ischemic injury distal to the stenotic or occluded moyamoya vessel is common in superficial and deep border-zone regions most susceptible to hypoperfusion [155]. Patterns of infarction may be suggestive of moyamoya, but these features are not specific for this condition. In a retrospective series of 32 adults with first-ever ischemic stroke, patients with early-stage MMD had ischemic lesions involving only deep subcortical structures, while those with advanced stage had predominantly cortical lesions [156]. In patients with intracerebral hemorrhage (ICH), bleeding occurs in deep structures such as the basal ganglia, thalamus, and/or ventricular system. Bleeding in the cortical and subcortical regions has been reported with lower frequency [157,158]. Asymptomatic cerebral microbleeds were present on T2*-weighted gradient-echo magnetic resonance imaging (MRI) in 30 percent or more of adult patients with MMD [159-161]. One study of 50 patients with moyamoya found that the presence of multiple microbleeds was an independent risk factor for subsequent intracerebral hemorrhage (hazard ratio [HR] 2.89, 95% CI 1.001-13.24) [160]. Additional MRI findings have been implicated in identifying vascular changes consistent with moyamoya: Dilated collateral vessels in the basal ganglia or thalamus can be demonstrated as multiple punctate flow voids, a finding that is considered virtually diagnostic of moyamoya ( image 6) [162]. The "ivy sign" refers to focal, tubular, or serpentine hyperintensities on fluid-attenuated inversion recovery (FLAIR) or contrast-enhanced T1 images in the subarachnoid spaces that represent slow, retrograde collateral flow through engorged pial vessels via leptomeningeal anastomoses ( image 7) [163-165]. Observational data of 48 patients with ischemic symptoms and MMD showed the extent of the ivy sign was associated with a reduction in cerebral vascular reserve assessed by single-photon emission computed https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 9/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate tomography (SPECT) [166]. This sign is not specific for MMS/MMD and has been reported in association with large-vessel stenosis or occlusions, where it is referred to as FLAIR vascular hyperintensities or the hyperintense vessel sign [167]. The "brush sign" refers to prominent hypointensity in medullary veins draining areas of impaired cerebral perfusion on susceptibility-weighted imaging (SWI), a high-spatial- resolution 3D gradient-echo MRI technique that accentuates paramagnetic properties of blood products such as deoxyhemoglobin. In a group of 33 patients, the brush sign was identified more often in moyamoya patients with TIA and infarction than in asymptomatic patients. This sign was also more prominent in those with impaired cerebrovascular reserve ( image 8) [168]. Like the ivy sign, the "brush sign" is not specific for moyamoya and has been identified in patients with subacute stroke from many causes [169]. Post-contrast enhancement within the arterial wall may be seen using high-resolution MRI [170]. One study of 24 patients with moyamoya who underwent high-resolution vessel wall imaging protocol with 3-tesla MRI showed that patients with MMD demonstrated concentric enhancement of the distal internal carotid arteries, whereas patients with intracranial atherosclerotic disease generally had focal and eccentric enhancement of the symptomatic arterial segment [171]. In addition, at six-month follow-up, vessel wall enhancement was found in eight of the nine patients (odds ratio [OR] 36.2, 95% CI 2.8- 475.0), while absence of enhancement was associated with nonprogressive stenosis. This technique may be helpful if angiographic findings on other more routine testing are not diagnostic but may not be readily available in many centers. Electroencephalographic findings Children with MMD often exhibit abnormalities on electroencephalography (EEG). Hyperventilation, performed as a part of EEG protocol, induces generalized high-voltage slow waves (the "build-up" phenomenon) that resolve after hyperventilation stops. The reappearance of generalized or localized high-voltage slow waves on EEG 20 to 60 seconds after the end of hyperventilation (the "rebuild-up" phenomenon) is considered pathognomonic for moyamoya and occurs in approximately two-thirds of affected children [172,173]. Asymmetric posterior alpha activity and centrotemporal slowing have also been described in children with moyamoya. Background abnormalities in children and adults with MMD include nonspecific generalized, asymmetric, or localized slow-wave activity [173,174]. Of note, hyperventilation should be minimized in patients with a diagnosis of moyamoya since it may induce reflex cerebral vasoconstriction [175]. While EEG with hyperventilation was reported https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 10/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate to be safe in one series of 127 children [173], rare reports link hyperventilation to limb-shaking TIA and episodes of chorea and dystonia [176-178]. DIAGNOSIS The diagnosis of moyamoya is made by identifying the characteristic angiographic appearance of bilateral stenoses affecting the distal internal carotid arteries (or other proximal circle of Willis vessels) along with the presence of prominent collateral vessels ( image 5). MMS is diagnosed by identifying characteristic angiographic features in the setting of an associated condition. MMD is diagnosed in patients with a genetic susceptibility or family history of moyamoya after associated conditions have been excluded. (See 'Associated conditions' above.) Indications for vascular imaging The possibility of MMD disease should be considered in: Children or young adults with repeated symptoms of ischemic attacks resulting from low perfusion in the same arterial territory. Patients who lack common factors for primary intracerebral hemorrhage (ICH) but present with intracerebral hemorrhage in brain regions supplied by small vessels that branch from the circle of Willis (eg, caudate, thalamus, or intraventricular hemorrhage within the lateral ventricles) ( image 9). Children or young adults with ischemic or hemorrhagic stroke who may lack common cerebrovascular risk factors. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Differential diagnosis'.) Patients who undergo MRI, particularly in the context of evaluation for cerebral ischemia, that shows associated findings such as dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," the "brush sign," or enhancement of the arterial wall. (See 'Neuroimaging' above.) Diagnostic criteria Definitive diagnosis of moyamoya requires neurovascular imaging. Diagnostic criteria proposed by a Japanese research committee include the following major requirements [4]: Stenosis or occlusion at the terminal portion of the internal carotid artery and at the proximal portion of the anterior and middle cerebral arteries. Abnormal vascular networks in the basal ganglia; these networks can also be diagnosed by the presence of multiple flow voids on brain MRI. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 11/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Angiographic findings are present bilaterally; cases with unilateral angiographic findings are considered probable. For the diagnosis of MMD, underlying associated conditions (suggestive instead of MMS) are excluded. (See 'Further evaluation' below.) Angiography Stenotic distal internal carotid or proximal circle of Willis arteries and prominent collateral vessels can be identified by angiogram, computed tomography angiogram (CTA), or magnetic resonance angiography (MRA). Conventional digital subtraction angiography (DSA) is the gold standard for the diagnosis of MMD. Additionally, DSA is typically required for treatment planning. Characteristic angiographic findings include stenosis or occlusion at the distal internal carotid artery and the origin of the anterior cerebral and middle cerebral arteries on both sides, as well as abnormal vascular networks at the basal ganglia or moyamoya vessels ( image 1). Noninvasive imaging (CTA and MRA) can demonstrate stenotic or occlusive lesions in the distal internal carotid arteries ( image 10) and the arteries around the circle of Willis [179-181]. Although less sensitive than DSA for smaller vessels, noninvasive testing can also visualize the collateral "moyamoya vessels" in the basal ganglia ( image 11). Nevertheless, due to its high diagnostic yield and noninvasive nature, CTA and MRA have supplanted conventional DSA in many centers as the initial imaging modality to evaluate moyamoya [162,181]. Because the vascular changes and associated risks of ischemia or hemorrhage sequelae in MMD and MMS are often progressive, characterizing the degree of vascular abnormality is important. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis", section on 'Neuroimaging'.) Angiographic severity staging systems can provide insight and guidance. Suzuki followed patients with MMD and classified the angiographic progression [182,183]. Further evaluation In the absence of a known genetic predisposition to MMD or known diagnosis associated with MMS (eg, sickle cell anemia), patients should be further evaluated for underlying conditions in order to institute the most appropriate secondary prevention strategy. Evaluation for vasculitis and other metabolic conditions may be indicated when suggestive features of clinical presentation are present. In general, work-up for atherosclerotic risk factors such as diabetes, dyslipidemia, hyperhomocysteinemia, and alternative sources to large-vessel vasculopathy should be performed. (See "Primary angiitis of the central nervous system in adults", section on 'When to suspect the diagnosis' and "Intracranial large artery atherosclerosis: https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 12/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Epidemiology, clinical manifestations, and diagnosis", section on 'Identifying other causes of intracranial stenosis'.) Hemodynamic studies are useful both pre- and postoperatively to help determine cerebrovascular reserve and to assess disease severity and risk of ischemic morbidity. These topics are discussed elsewhere. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis", section on 'Neuroimaging'.) SCREENING IMAGING In general, we do not screen asymptomatic individuals for moyamoya; however, screening with a noninvasive angiographic modality may be reasonable in those with a family history of MMD, particularly individuals from or with families from Eastern Asia. The 2008 American Heart Association Stroke Council guidelines state that there is insufficient evidence to justify screening studies in asymptomatic individuals or in relatives of patients with MMS in the absence of a strong family history of MMD or medical conditions that predispose to MMS [162]. Even in individuals with a strong family history of MMD or those with medical conditions that predispose to MMS, the utility of angiographic screening is unclear, particularly since available medical and surgical treatment of asymptomatic MMD is of uncertain benefit. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Classification and terminology Moyamoya describes chronic progressive cerebrovascular diseases typically characterized by bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation. (See 'Classification and terminology' above.) Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no underlying risk factors. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 13/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition. (See 'Classification and terminology' above and 'Associated conditions' above.) Epidemiology MMD and MMS are rare. MMD is more common in East Asian countries than elsewhere. There is a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second, broader peak at approximately 40 years of age. (See 'Incidence and prevalence' above.) Clinical presentations Ischemic stroke and transient ischemic attack (TIA) affecting the anterior circulation are the most common clinical presentations. (See 'Ischemic stroke and transient ischemic attack' above and 'Neuroimaging' above.) Intracranial hemorrhage is less common and is rare in children. Hemorrhage usually affects deep structures such as the basal ganglia or thalamus but may also be intraventricular or subarachnoid. (See 'Intracerebral, intraventricular, and subarachnoid hemorrhage' above and 'Neuroimaging' above.) Clinical and imaging findings suggestive of underlying moyamoya pathology MRI findings that suggest the diagnosis of moyamoya include dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," or the "brush sign." (See 'Neuroimaging' above.) The diagnosis of moyamoya is most often considered in those with suggestive MRI findings in the context of evaluation for ischemic stroke. Other settings in which the diagnosis should be considered include repeated episodes of ischemia in the same arterial territory, deep intracerebral hemorrhage in the absence of hypertension or other known cause, and ischemic or hemorrhagic stroke in children or young adults who lack cerebrovascular risk factors. (See 'Indications for vascular imaging' above.) Diagnosis The diagnosis of moyamoya is made by angiographic demonstration of bilateral stenoses affecting the distal internal carotid arteries or proximal circle of Willis vessels along with the presence of prominent basal collateral vessels. (See 'Diagnosis' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Smith ER, Scott RM. Spontaneous occlusion of the circle of Willis in children: pediatric moyamoya summary with proposed evidence-based practice guidelines. A review. J https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 14/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Neurosurg Pediatr 2012; 9:353. 2. Fukui M. Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis ('moyamoya' disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan. Clin Neurol Neurosurg 1997; 99 Suppl 2:S238. 3. Arias EJ, Derdeyn CP, Dacey RG Jr, Zipfel GJ. Advances and surgical considerations in the treatment of moyamoya disease. Neurosurgery 2014; 74 Suppl 1:S116. 4. Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis, Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo) 2012; 52:245. 5. Kim JS, Bang OY, Oh CW. Moyamoya disease. In: Uncommon Causes of Stroke, 3rd ed, Capla n L, Biller J (Eds), Cambridge University Press, New York, NY 2018. p.545. 6. Kamada F, Aoki Y, Narisawa A, et al. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet 2011; 56:34. 7. Liu W, Morito D, Takashima S, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One 2011; 6:e22542. 8. Miyatake S, Miyake N, Touho H, et al. Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology 2012; 78:803. 9. Yamauchi T, Tada M, Houkin K, et al. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 2000; 31:930. 10. Mineharu Y, Liu W, Inoue K, et al. Autosomal dominant moyamoya disease maps to chromosome 17q25.3. Neurology 2008; 70:2357. 11. Miyawaki S, Imai H, Takayanagi S, et al. Identification of a genetic variant common to moyamoya disease and intracranial major artery stenosis/occlusion. Stroke 2012; 43:3371. 12. Wu Z, Jiang H, Zhang L, et al. Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population. PLoS One 2012; 7:e48179. 13. Bang OY, Ryoo S, Kim SJ, et al. Adult Moyamoya Disease: A Burden of Intracranial Stenosis in East Asians? PLoS One 2015; 10:e0130663. 14. Wang Y, Zhang Z, Wei L, et al. Predictive role of heterozygous p.R4810K of RNF213 in the phenotype of Chinese moyamoya disease. Neurology 2020; 94:e678. 15. Ikeda H, Sasaki T, Yoshimoto T, et al. Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet 1999; 64:533. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 15/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 16. Inoue TK, Ikezaki K, Sasazuki T, et al. Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 2000; 15:179. 17. Sakurai K, Horiuchi Y, Ikeda H, et al. A novel susceptibility locus for moyamoya disease on chromosome 8q23. J Hum Genet 2004; 49:278. 18. Mineharu Y, Takenaka K, Yamakawa H, et al. Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting. J Neurol Neurosurg Psychiatry 2006; 77:1025. 19. Duan L, Wei L, Tian Y, et al. Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study. Stroke 2018; 49:11. 20. Lee SJ, Ahn JY. Stenosis of the proximal external carotid artery in an adult with moyamoya disease: moyamoya or atherosclerotic change? Neurol Med Chir (Tokyo) 2007; 47:356. 21. Ullrich NJ, Robertson R, Kinnamon DD, et al. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology 2007; 68:932. 22. Fernandez-Alvarez E, Pineda M, Royo C, Manzanares R. "Moya-moya' disease caused by cranial trauma. Brain Dev 1979; 1:133. 23. Kitano S, Sakamoto H, Fujitani K, Kobayashi Y. Moyamoya disease associated with a brain stem glioma. Childs Nerv Syst 2000; 16:251. 24. Arita K, Uozumi T, Oki S, et al. Moyamoya disease associated with pituitary adenoma report of two cases. Neurol Med Chir (Tokyo) 1992; 32:753. 25. Tsuji N, Kuriyama T, Iwamoto M, Shizuki K. Moyamoya disease associated with craniopharyngioma. Surg Neurol 1984; 21:588. 26. Czartoski T, Hallam D, Lacy JM, et al. Postinfectious vasculopathy with evolution to moyamoya syndrome. J Neurol Neurosurg Psychiatry 2005; 76:256. 27. Yamada H, Deguchi K, Tanigawara T, et al. The relationship between moyamoya disease and bacterial infection. Clin Neurol Neurosurg 1997; 99 Suppl 2:S221. 28. Sharfstein SR, Ahmed S, Islam MQ, et al. Case of moyamoya disease in a patient with advanced acquired immunodeficiency syndrome. J Stroke Cerebrovasc Dis 2007; 16:268.