Moyamoya Disease

Pathophysiology, diagnosis, and treatment

Background: Moyamoya disease is a cerebrovascular angiopathy that can lead to ischemic and hemorrhagic stroke in both children and adults. Approximately 6 – 10% of all strokes and transient ischemic attacks in childhood are attributable to Moyamoya disease. It is characterized by bilateral stenosis of the intracranial internal carotid arteries, with the formation of collateral vessels. Recent advances in the understanding of genetic causes, pathophysiological mechanisms, and imaging techniques have substantially changed the management of the disease over the past decades.

Methods: This narrative review is based on a literature search in PubMed and Embase on the pathophysiology, diagnosis, clinical course, and treatment of Moyamoya disease. In addition, clinical and experimental data were included from the authors’ institution, a specialized center in which more than 500 Moyamoya patients have been treated surgically.

Results: The pathogenesis of Moyamoya disease is based on a multifactorial interaction of genetic predisposition (particularly, RNF213-mutations) and vascular remodeling processes, with endothelial dysfunction playing a key role. The diagnostic evaluation includes modern imaging techniques (DSA, MRI, PET) and novel classification systems. Surgical revascularization—notably, combined bypass surgery—is currently the most effective therapeutic approach. Long-term postoperative follow-up data from our center show a low complication rate (6.3%) after combined bypass surgery as well as a low postoperative stroke rate. In children, interdisciplinary management is essential, as early diagnosis and timely surgery are crucial for prognosis.

Conclusion: Moyamoya disease requires specialized diagnosis and treatment. Surgical revascularization is the key therapeutic approach to reduce the risk of stroke. Future research should aim to elucidate the causal mechanisms of the disease and identify strategies for earlier diagnosis.

Cite this as: Mertens R, Siebert E, Endres M, Nikolaus M, Danyel M, Vajkoczy P: Moyamoya disease: Pathophysiology, diagnosis, and treatment. Dtsch Arztebl Int 2025; 122: 722–8. DOI: 10.3238/arztebl.m2025.0185

Moyamoya disease is a cerebrovascular disorder that was first described in Japan in 1957 (1). It is characterized by progressive stenosis of the intracranial internal carotid artery (ICA) and its main branches (middle cerebral artery, MCA, and anterior cerebral artery, ACA). More rarely, the posterior cerebral artery (PCA) may also be affected. This leads to the formation of compensatory vascular collaterals as a result of pathologically increased arteriogenic activity; on cerebral angiography, these collaterals resemble a “puff of smoke” (Japanese: moyamoya). A distinction is made between primary Moyamoya disease and the secondary form, Moyamoya syndrome. In the latter, the typical angiographic changes occur in association with well-defined associated disorders, such as genetic syndromes (for example, trisomy 21, neurofibromatosis type 1, and sickle cell anemia) or following radiotherapy to the skull base region. In the absence of known risk factors or associated disorders, the condition is, by definition, classified as idiopathic Moyamoya disease. Moyamoya disease typically develops bilaterally, whereas Moyamoya syndrome more commonly presents with a unilateral manifestation. The vascular changes in both subtypes are collectively referred to as Moyamoya angiopathy (MMA) and lead to similar symptoms, caused both by stenosis of the ICA (ischemic stroke) and by the fragility of the collateral vessels (hemorrhagic stroke). In addition to these two principal manifestations, rarer symptoms include headaches, epileptic seizures, as well as cognitive and psychological impairments (2, 3). Moyamoya disease occurs most frequently in the East Asian countries of Japan, Korea, and China, with an incidence of 1 per 100 000 population. In western countries, its incidence is approximately one-tenth of that rate, and cerebral hemorrhages occur less frequently than in Asia (4, 5). The highest incidence is seen in two age groups: children around 5 years of age and adults around 40 years of age. Women are twice as likely to be affected as men. Despite its rarity, Moyamoya disease is responsible for 6–10% of all childhood strokes (out of a total of approximately 300–500 strokes per year, estimated on the basis of Anglo-American data) and transient ischemic attacks (TIA) in Germany (2, 6, 7, 8), and is increasingly considered to be a cause of stroke in both children and young adults. Our 2001 article published in Deutsches Ärzteblatt already provided a comprehensive description of Moyamoya disease (9). More than twenty years after that publication and the treatment of over 500 patients at our center, this review aims to provide an up-to-date insight into the progress made since then. To this end, a literature search covering the years up to 2024 was conducted in PubMed and Embase. In addition, data from our own patient cohort were taken into consideration (eBox).

Box

Moyamoya Disease: Data on Frequency in Germany

eBox

Description of Our Patient Cohort

New insights into pathophysiology and genetics

Histopathologically, the stenosed arteries are characterized by the following abnormalities:

• Fibrocellular thickening of the tunica intima as a result of smooth muscle cell proliferation,
• irregular undulation (waviness) of the lamina elastica interna, and
• atrophy of the tunica media (2).

The pathophysiological role of individual vascular wall cell types has not yet been fully elucidated. Comparative transcriptome analysis of endothelial cells and smooth muscle cells differentiated from induced pluripotent stem cells (iPSCs) revealed statistically significant differences in the profiles of endothelial cells between patients with Moyamoya disease and healthy subjects, but not in the profiles of smooth muscle cells. This observation suggests that Moyamoya angiopathy is predominantly mediated by endothelial processes (10). It is also unclear whether the formation of vascular collaterals represents an adaptive reaction to vascular occlusion, or whether these are two separate processes that can be attributed to the same pathophysiological mechanism (Figure 1). Our own experimental studies showed increased matrix metalloproteinase-9 (MMP-9) activity (11), as well as significant upregulation of angiopoietin-2 (Ang2) in the affected vascular segments (12), providing evidence of the complex interplay between vascular remodeling and arteriogenesis. Furthermore, the young age at disease onset, the presence of familial cases, and the clustering in East Asia led to the assumption of a genetic cause early on. In 2011, the RNF213 gene, which encodes ring finger protein 213, was identified as a risk gene for Moyamoya disease. The p.R4810K gene variant was described as the strongest predisposing factor in the East Asian population. An autosomal dominant pattern of inheritance with incomplete penetrance (< 1% occurrence of the disease in heterozygous mutation carriers) is assumed, with homozygous carriers of this variant being more severely affected. This variant has not been detected in Western countries, but other rare RNF213 gene variants have been described (13, 14, e1, e2, e3). RNF213 serves as a ubiquitin ligase that marks target proteins, thereby regulating their degradation or function in cellular signaling pathways, and plays a role in angiogenesis and vascular remodeling (14, e4). Furthermore, as an antimicrobial protein, RNF213 carries out important functions in the immune system (15, e5). However, RNF213 knockout mice did not exhibit a Moyamoya-like phenotype (16). Thus, Moyamoya disease is considered a multifactorial disorder in which genetic predisposition and suspected environmental influences (for example, radiation, infections, and autoimmune processes) both contribute to the development of the disease (14, 17, 18). In the case of young age at onset, increased familial incidence, or atypical disease manifestation, the cause may be monogenic, in which case genetic testing may be beneficial. Extensive genetic studies, multi-transgenic animal models, and translational organoid models will be required in the future to further elucidate the underlying pathomechanisms.

Figure 1

Pathophysiology of Moyamoya disease

Advances in imaging and functional diagnostics

Early diagnosis is crucial for reducing the risk of serious neurological complications. Suspected Moyamoya angiopathy should be considered in young patients with stroke, TIA, or intracerebral hemorrhage of unknown etiology, as well as in those with a positive family history or associated disorders. These patients should receive prompt referral to a specialized center for further diagnostic evaluation. Digital subtraction angiography (DSA) and magnetic resonance imaging (MRI) are considered the gold standard (19) (Figure 2 a, b). A fundamental distinction is made between quantitative and non-quantitative imaging methods.

Figure 2

a) Moyamoya disease on cerebral angiography. Upper row: digital subtraction angiography (DSA) of the left internal carotid artery (ICA) in Moyamoya disease. Visualization of terminal ICA stenosis (arrowhead) with multiple compensatory Moyamoya collaterals (asterisk) that resemble a cloud of smoke (Japanese: moyamoya). For comparison, the lower row shows a DSA of the left ICA in a healthy control. b) Magnetic resonance imaging findings: The axial FLAIR sequences show multiple ischemic lesions in the right border zone (white arrowheads), in the subcortical white matter—and thus in the watershed zones on both sides (black arrowheads)—and in the left basal ganglia (lacunar infarction, blue arrowhead). The “ivy sign” appears as a branching hyperintense signal along the brain surface and reflects leptomeningeal collateral formation (yellow arrowheads). Mild atrophy of the right hemisphere is also visible.

Non-quantitative techniques include MRI and various angiography methods such as DSA and MR angiography (MR-A). These techniques enable visualization of structural lesions in the brain as well as vascular stenosis and collaterals. Historical classification systems such as the Suzuki classification (1969) are used to characterize disease stage based on vascular morphology (20). However, a significant drawback of the Suzuki classification is that it does not correlate either with the hemodynamic status of the brain parenchyma or with clinical symptoms (21). Newer approaches to refining diagnosis include direct vascular wall imaging on MRI. Typical findings include absent or only minimal vessel wall thickening, low to absent contrast enhancement, and smoothly delineated, circumferentially symmetric vessel narrowing (22). These features distinguish Moyamoya angiopathy from atherosclerotic or inflammatory vascular disorders, and particularly in equivocal cases, vessel wall imaging can support early and more precise diagnosis. The “ivy sign” on MRI can also point to impaired cerebral perfusion. It appears as a hyperintense signal with a branching pattern along the brain surface and reflects leptomeningeal collateral formation (23).

Quantitative methods are used to assess cerebral hemodynamic status and cerebrovascular reserve capacity (CVRC), that is, the ability of cerebral vessels to respond to vasodilatory stimuli with increased blood flow. These include techniques such as positron emission tomography (PET) (eFigure a), which measures regional cerebral perfusion using radioactive tracers. The CVRC is determined by perfusion measurements before and after administration of a vasodilatory stimulus (for example, acetazolamide) and allows an assessment of hemodynamic compensatory capacity in the setting of impending ischemia (23). This serves to assess stroke risk and supports decision-making with regard to surgical revascularization (24, e3).

eFigure

a) The [15O]H2O PET-MRI of the brain at rest, during acetazolamide-induced vasodilation, and after calculation of the relative reserve capacity (%) shows bilateral impairment of the cerebrovascular reserve capacity (CVRC) in the perfusion territories of the middle cerebral artery (ACM, white arrowheads). b) Schematic representation of an STA–MCA bypass. Here, the superficial temporal artery (STA) is microsurgically anastomosed to a cortical branch of the middle cerebral artery (MCA) (black circle). ACA, anterior cerebral artery; ICA, internal carotid artery. c) Illustration of the STA–MCA anastomosis. The microsurgical anastomosis between the STA as the donor vessel and a cortical branch of the MCA as the recipient vessel, performed through a standardized, approximately 3-cm craniotomy, is shown. Illustration modified from Lucia et al., Neurosurgical Review 2022; license: CC BY 4.0 (e6).

Another crucial advance in the assessment of Moyamoya angiopathy was the introduction of the Berlin Grading System—an additive score that combines quantitative (functional) and non-quantitative (morphological) imaging techniques (Table). Here, a risk assessment is carried out based on MRI, CVRC, and the collateral pattern on DSA. The score was developed at our clinic on the basis of a cohort of 40 patients with bilateral Moyamoya disease and has proven suitable for stratifying clinical symptoms. An ROC analysis showed an area under the curve (AUC) of 0.80 for the Berlin Grading System with regard to the presence of clinical symptoms. This represents good discriminatory power and means that in 80% of cases, the score assigns a higher grade to a symptomatic hemisphere than to an asymptomatic one (25). Furthermore, it has been shown that the score is also suitable for the stratification of postoperative ischemia risk following bypass surgery (26). External validation was carried out by Moyamoya centers in Stanford (USA) (27) and Toyama (Japan) (Japan) (28).

Table

The “Berlin Grading System” of Moyamoya disease

Natural course of the disease

Data on the natural history of Moyamoya disease are derived primarily from retrospective analyses, demonstrating a marked difference in the risk of cerebrovascular events between symptomatic and asymptomatic patients.

Among patients of European descent with ischemic stroke or intracerebral hemorrhage, the annual rate of recurrent stroke was 13.3%, while the rate of recurrent hemorrhage was 1.7% (29). A Korean cohort study found a stroke risk of 40% for the hemorrhagic subtype and 33% for the ischemic subtype over a period of 10 years (30). In Japan, morphological disease progression was observed in 23.8% of patients over a period of 6 years. A total of 53.3% of patients developed new clinical symptoms in conjunction with the progression (31). Due to this high risk of stroke recurrence, patients with symptomatic Moyamoya disease should be referred to specialized centers for further diagnostic evaluation and surgical treatment (24, e3).

The optimal management of asymptomatic patients, in contrast, is controversial and the subject of ongoing research. The AMORE study (Asymptomatic Moyamoya Registry)—a multicenter prospective cohort study conducted in Japan—observed 103 asymptomatic patients over a period of 5 years. The annual rate of stroke was 1.4% per person (32). In view of this low risk, it is unclear whether surgical treatment confers a benefit for asymptomatic patients. Therefore, the European guidelines recommend hemodynamic assessment in order to identify hemispheres at greater risk of stroke. In asymptomatic patients with impaired hemodynamic status and silent ischemic lesions in the hypoperfused cerebral region, surgical treatment should be considered. Independent of this, close follow-up is recommended (24).

Pharmacological and surgical management

The aim of pharmacological treatment in Moyamoya disease is to reduce the risk of stroke. The use of antiplatelet agents such as acetylsalicylic acid (ASA) may be helpful in the prevention of ischemic events, although the level of evidence is low (24, e3). Caution is advised when treating headache syndromes, particularly with migraine medications that cause vasoconstriction (e.g., triptans) or lower blood pressure (e.g., beta-blockers, flunarizine), as these may worsen cerebrovascular hemodynamics (33). It is also essential to treat other stroke risk factors (such as arterial hypertension, diabetes mellitus, obesity, and dyslipidemia).

Since no causal treatment is available as yet, surgical revascularization represents the only established method for restoring cerebral blood flow. Indications include previous ischemic strokes and intracerebral hemorrhages, corresponding morphologic lesions, reduced regional cerebral blood flow, and impaired CVRC (24, e3). With regard to the timing of surgery following an acute cerebrovascular event, the guidelines recommend waiting 6–12 weeks (24). Three surgical techniques are used: direct, indirect, and combined revascularization (34). Direct revascularization typically involves a bypass between the superficial temporal artery (STA), which runs outside the skull, and a branch of the middle cerebral artery (MCA) on the surface of the brain. This STA–MCA bypass is performed through a small craniotomy (eFigure b, c). Indirect revascularization consists of transposing tissue supplied by the extracranial external carotid artery (ECA) onto the surface of the brain to promote the ingrowth of new vessels. These techniques include encephaloduro-synangiosis (EDS) and encephalo-myo-synangiosis (EMS), in which, for example, the temporal muscle is placed on the surface of the brain (35). In combined surgery, direct and indirect techniques are used simultaneously. There are no randomized controlled trials (RCTs) to date that directly compare the efficacy of the individual techniques. An exception is the „Japan Adult Moyamoya“ study (JAM trial), which investigated the benefit of bilateral direct bypass surgery compared with medical therapy in patients with Moyamoya disease presenting with intracerebral hemorrhage. The study showed a statistically significant reduction in future hemorrhage risk with surgery (2.7%/year versus 7.6%/year; p = 0.04) (36). More recent meta-analyses, based on retrospective studies and one RCT, support the benefit of surgical revascularization in both hemorrhagic and ischemic Moyamoya disease (37). Direct and combined bypass techniques are superior to indirect bypass in terms of recurrent strokes and hemorrhage, with combined bypass achieving the best outcomes (38). Therefore, the 2023 European Moyamoya guideline of the European Stroke Organisation (ESO) recommends the preferential use of direct or combined techniques over indirect revascularization (24). Accordingly, our interdisciplinary team treated 502 patients between 1998 and 2023 (eBox). Our department is among the largest specialized Moyamoya disease centers in Europe, treating patients from across Germany as well as from other European countries and internationally. Surgical treatment was performed in a standardized manner using a combined procedure (STA–MCA bypass + EDS) via a small craniotomy measuring 3 cm in diameter. Long-term data for 276 patients showed a perioperative complication rate of 6.3%. In a sub-cohort of 44 patients with a follow-up period of ≥ 5 years (mean 7.4 ± 1.8 [range: 5.1–10.9] years), the bypass patency rate was 95.7%, with a stroke risk of 0.3% per patient-year. In another sub-cohort of 107 patients with ≥ 5 years follow-up (mean 10.3 ± 4.0 [range: 5.0–24.4] years), 87.9% achieved a good functional outcome (mRS 0–2), and 90.7% were independent in daily life. No cases of severe disability or death (mRS ≥ 5) were observed. These data from the largest European cohort to date demonstrate the safety and efficacy of this form of surgical revascularization, which reduces the risk of stroke to a minimum.

Special considerations in the care of children

The diagnosis and treatment of Moyamoya disease in childhood present specific challenges. Young children in particular can develop severe symptoms and require timely care in specialized centers in order to prevent cognitive and physical sequelae. Symptoms in children are less specific than in adults. Children under 2 years of age are at high risk for recurrent strokes that may be associated with functional deficits and epilepsy. Children over 5 years of age often present with TIA episodes, headaches, and migraine. In addition, Moyamoya angiopathy often occurs in childhood in the context of Moyamoya syndrome, and developmental delay may be a nonspecific early symptom (3, 39). Imaging in infants and young children is considerably more challenging, since the use of radiation and radioactive tracers is restricted, and general anesthesia with endotracheal intubation is often required due to limited patient cooperation. Surgical revascularization is likewise recommended in children with hemodynamic impairment and recurrent symptoms. Here again, a direct or combined bypass should be preferred over indirect revascularization. If a direct bypass is technically not feasible, indirect revascularization alone is recommended in children (24). However, randomized controlled trials comparing surgical and conservative treatment strategies are lacking. In a retrospective multicenter study conducted in China, 214 children underwent surgical revascularization, while 68 received conservative treatment. The mean follow-up period was 41 months (range: 9–145 months). The results showed a significant reduction in stroke risk among operated children (2.8% versus 13.2%), with a relative risk of 0.21 (95% confidence interval: [0.08; 0.57]). Moreover, a markedly lower rate of functional impairment was observed in the surgical group (2.8% versus 20.6%), with a relative risk of 0.14 [0.05; 0.34]. These results support the recommendation for affected children to undergo early bypass surgery in order to minimize disease progression and reduce the risk of stroke and permanent sequelae (24, 40). Given the multifaceted clinical and diagnostic challenges, interdisciplinary care involving pediatric neurology, genetics, neuroradiology, and neurosurgery is required, as established at the Charité.

Summary

Moyamoya angiopathy is a vascular disease of the brain that can cause both ischemic and hemorrhagic strokes in young patients. It is characterized by steno-occlusive changes in the intracranial arteries and the formation of vascular collaterals. Genetic factors—most notably mutations in the RNF213 gene—combined with environmental factors play a central role, with endothelial cells contributing significantly to the pathogenesis. Diagnosis is based on MRI, DSA, and perfusion imaging. Early diagnosis is particularly crucial in children. Surgical revascularization by means of combined bypass surgery is considered the most effective treatment option. Further experimental research using transgenic animal and organoid models is needed to better understand the pathophysiology of the disease, identify biomarkers for early detection, and develop causal therapeutic approaches.

Conflict of interest statement
The authors declare that no conflict of interests exists.

Manuscript submitted on 8 April 2025, revised version accepted on
14 October 2025.

Translated from the original German by Christine Rye.

Corresponding author
Prof. Dr. med. Peter Vajkoczy

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