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Bang and Fujimura: Medical Management of Adult Moyamoya Disease: A Review and Relevant Cases With Ischemic Events

Abstract

Moyamoya disease (MMD) is a rare and progressive cerebrovascular disorder characterized by stenosis or occlusion of the internal carotid arteries resulting in the development of fragile collateral vessels at the base of the brain. Surgical revascularization is the primary treatment option for preventing ischemic and hemorrhagic events; however, the role of medical management has become increasingly recognized, particularly in cases involving asymptomatic patients or those at a high risk for surgical complications. In this review, we aimed to investigate the current guidelines and evidence supporting various medical management strategies for MMD, including the importance of controlling risk factors and judicious use of antithrombotic therapy. Given the considerable variability in patient presentation, such as age of onset, symptomatology, and comorbid conditions, it is crucial to adopt tailored therapeutic approaches that address each patient’s unique characteristics. The existing literature on medical management is limited. However, individualized strategies may effectively mitigate the risk of ischemic events and improve the overall patient outcomes. Further research is essential to develop comprehensive and standardized treatment protocols for medical management of adult patients with MMD. In addition, ongoing trials and efforts to develop disease-modifying agents are discussed.

Introduction

Moyamoya disease (MMD) is a rare progressive cerebrovascular disorder characterized by stenosis or occlusion of the internal carotid arteries and development of fragile collateral vessels at the base of the brain. Surgical revascularization is the primary treatment for preventing ischemic and hemorrhagic events; however, the role of medical management in adult patients with MMD is being increasingly recognized, particularly in specific clinical situations. For MMD, the efficacy of medical management is not as well established as that of surgical interventions. Evidence regarding long-term outcomes of patients treated with medical therapy alone is limited. Recent guidelines for MMD from Japan (Research Committee on Moyamoya Disease, 2022), Europe (European Stroke Organization [ESO] guidelines, 2023), and the United States (American Heart Association/American Stroke Association [AHA/ASA] scientific statement, 2023) have been published [1-3]. However, there are some differences in medical management that have not been covered in detail. The guidelines or scientific statements for the medical management of MMD provide only brief descriptions of the recommendations regarding the use of antithrombotic agents and blood pressure control, with the level of evidence (LOE) for each recommendation being weak.
MMD presents with substantial variability among patients in terms of the age of onset, symptoms (asymptomatic, acute unstable course, remote symptomatic), comorbidities (vascular risk factors, autoimmune disease), and types and mechanisms of stroke (ischemic [hemodynamic or embolic] or hemorrhagic), which may necessitate tailored therapy. Therefore, it may be more beneficial to carefully assess and administer treatment based on the individual characteristics of each patient, rather than strictly adhering to uniform medical management based on guidelines. This paper explores scenarios in which medical management plays a crucial role, discusses the evidence supporting its efficacy in relevant cases, and reviews key strategies, such as risk factor control and antithrombotic use in the spectrum of MMD treatment.
For this review, we searched PubMed and ClinicalTrials.gov for relevant references to studies published in English up to August 2024. We used the search terms “moyamoya disease,” “medical management,” “antithrombotic agents,” and “risk factor management.” In addition, we identified references in relevant articles and reviews. The final reference list was generated based on the originality and relevance of the article to the topic. We did not discuss the genetic variants related to MMD, and surgical or hemorrhagic MMD treatments in depth, as these topics have been reviewed elsewhere [3,4].

The role of medical management in MMD

Surgical treatments such as bypass surgery are recommended for symptomatic patients with occlusion, reduced vascular reservoirs, or fragile choroidal collateral networks [1-3,5]. Medical management of MMD is essential, especially for patients who may not be immediate candidates for surgical treatment, such as (1) hemodynamically stable, asymptomatic, or mildly symptomatic patients; (2) patients at a high risk of perioperative complications; (3) progression after surgical revascularization; or (4) those with systematic vasculopathy related to ring finger protein 213 (RNF213) variants.

Asymptomatic or non-vascular symptomatic patients

Notably, some adult patients with MMD are asymptomatic or have non-vascular symptoms such as headaches, seizures, and anxiety/depression. Often, these symptoms are not directly associated with hypoperfusion. Epidemiological studies in Japan suggest that the prevalence of asymptomatic MMD or MMD with a mild presentation is steadily increasing in adults and children, likely due to the increasing number of patients undergoing neuroimaging for headaches and dizziness [6,7].
Unlike childhood-onset MMD, the progression of asymptomatic MMD in adults has previously been considered less likely because the disease advances in the angiographic stage between childhood and adolescence and often stabilizes afterward [8,9]. Therefore, adults with asymptomatic MMD may have a lower risk of stroke than those with symptomatic MMD, and medical management alone could be considered in such cases. A recent multicenter, prospective cohort study (Asymptomatic Moyamoya Registry [AMORE]) in Japan showed that the annual stroke risk was 1.0% in asymptomatic adults with MMD, the majority of which had hemorrhagic stroke [10]. The AMORE study further indicated that hemorrhagic stroke in asymptomatic adults with MMD was closely associated with choroidal anastomosis development, which is the characteristic collateral prominent in hemorrhagic MMD [11]. However, asymptomatic MMD does not necessarily indicate a stable condition, as the disease is dynamic and can progress unpredictably (Figure 1). Stenosis progression in adult patients with asymptomatic or hemodynamically stable, non-vascular symptomatic MMD varies and may be related to stroke [12-14]. MMD has a bimodal peak; hence, it is necessary to confirm whether the stenosis detected in the adult is a case of de novo development of MMD [15]. Stenosis progression or choroidal anastomosis development that may carry a risk of stroke is typically detected using serial luminal imaging [10,12]. Notably, high-resolution vessel wall magnetic resonance imaging (HR-MRI) can demonstrate circular vascular enhancement associated with progressive and symptomatic MMD [16-18]. A recent study of adult patients with MMD showed that decreased cerebral blood volume and circular enhancement of arterial wall were associated with increased incidence of stroke in patients receiving medical management alone [19]. In contrast, patients with asymptomatic stable MMD often showed typical shrinkage of the involved segments without an enhancement on HR-MRI.
Therefore, in adult patients, it is essential to confirm that any existing symptoms are not related to hemodynamic compromise. In cases of asymptomatic MMD, periodic vascular assessments or recent techniques such as HR-MRI should be employed to verify that the condition is stable, indicating that surgical intervention may not be necessary. This reassurance can help alleviate patient concerns, and conservative management for any symptoms should be implemented accordingly.

Non-surgical candidates or high risk of perioperative complications

Suzuki stage and hemodynamic compromise may be less severe in cases of ischemic MMD than in hemorrhagic MMD. Embolic stroke may occur in some cases because of stenosis rather than occlusion, and such cases may be unsuitable for surgical treatment (Figure 2). Medical management alone, with regular imaging and clinical follow-up, is required to monitor the disease progression.
In addition, some patients with symptomatic MMD may require medical management while awaiting surgical evaluation for bypass surgery. Patients awaiting surgical intervention and those deemed unsuitable for surgery owing to advanced age, comorbidities, or patient preference can benefit from medical management to control their symptoms and reduce the risk of stroke.
Surgery may be contraindicated in the following situations: (1) severe systemic illness or advanced age, (2) high risk of intraoperative ischemia, (3) pre-existing extensive brain damage owing to cerebral infarction or hemorrhage, and (4) unclear surgical indications (such as sufficient collateral circulation). Medical management is typically prioritized in these situations.
Furthermore, revascularization surgery is complicated by either perioperative ischemic or hemorrhagic events because of cerebral hyperperfusion syndrome, which is related to the patient’s age or comorbidities, such as hypertension, unstable clinical presentation (such as fluctuation of symptoms), pre-existing neurological deficits resulting from infarction, and advanced stage with poor collaterals [20-23]. Kim et al. [22] recommended delaying revascularization surgery for at least 6 weeks after the most recent cerebral infarction in these high risk patients. Medical management, including antiplatelet use and control of risk factors, such as strict control of blood pressure, could be important to optimize outcomes in this setting. Single antiplatelet therapy is preferred because of the substantial risk of hemorrhagic stroke in patients with asymptomatic or ischemic MMD. Dual antiplatelet therapy is generally not considered in adults with MMD, especially in cases with prominent periventricular anastomosis, such as choroidal channels [24].

MMD spectral diseases

Aside from the aforementioned MMD spectrum, in terms of clinical phenotypes, the RNF213 variant was recently reported to be associated with non-MMD disorders such as intracranial atherosclerosis and systemic vasculopathy (for example, pulmonary and renal artery stenosis) [25].
Notably, intracranial atherosclerosis and MMD are prevalent in Asian populations. RNF213 R4810K was present in 21.9%-24.3% of patients with non-MMD intracranial atherosclerosis [26-28]. As such, patients with RNF213 variation may be prone to atherosclerosis. A large Japanese population study evaluated R4810K in various stroke subtypes and confirmed that this variant was only associated with large artery disease [29]. Patients with this variant and large artery disease showed a lower age of stroke onset, female predominance, and anterior circulation distribution, compared with non-carriers. In addition, R4810K is associated with smaller-sized intracranial arteries, suggesting impaired vasculogenesis [30,31]. HR-MRI studies showed that negative remodeling involved all the intracranial arteries, and tandem lesions were more common in R4810K carriers, which were associated with a higher risk of recurrent events and progression of stenosis [31-33]. Hemodynamic studies have shown that the R4810K variant predisposes the smaller intracranial arteries to hemodynamic compromise in the presence of intracranial atherosclerosis [31]. In this RNF213 variant associated with intracranial atherosclerosis, aggressive medical management, including using high-dose statins, should be considered because high-dose statin treatment effectively stabilized patients with intracranial atherosclerotic plaques as documented by HR-MRI (Figure 3) [33,34].
The etiology of the specific site of vascular system involvement in MMD remains unknown. Nevertheless, extracranial involvement of MMD has been described in case reports of coronary, pulmonary, and renal artery stenosis (Figure 4) [35-38]. The R4810K variant causes classical MMD in a gene-dose-dependent manner when present in a heterozygous state, but the same variant can result in MMD and systemic vascular diseases when present in the homozygous state [35,36]. A prospective coronary and aortic computed tomography angiography study in adult patients with MMD revealed that 17% had significant (>50%) stenosis on systemic arteries, and RNF213 variants, especially the R4810K homozygous variant, were associated with extracranial vasculopathy [39]. The penetrance rate of MMD in this variant’s homozygote is much higher than that in the heterozygote carrier [40,41]. Therefore, early recognition and appropriate intervention for homozygote carriers is needed because extracranial arterial manifestations could be fatal compared to MMD.

Key components of medical management

Risk factor control

Controlling vascular risk factors is crucial for the medical management of MMD. The RNF213 genetic variant may be associated with vascular risk factors such as hypertension [42]. Vascular risk factors can exacerbate MMD progression and increase the risk of ischemic and hemorrhagic strokes in patients with adult MMD. In addition, vascular risk factors such as diabetes were associated with recurrent stroke in non-surgically treated adult patients with MMD [43]. Hypertension and dyslipidemia increase the risk of stroke in asymptomatic patients with MMD [44]. A prospective study comparing the modifiable risk factors for MMD with age-matched healthy control subjects showed that MMD is associated with modifiable risk factors [45]. In this study, obesity and homocysteine were associated with a high risk of MMD, while increased high-density lipoprotein cholesterol and albumin lower the risk of MMD. Antihypertensives are recommended for MMD, particularly during the early phase of intracerebral hemorrhage. In addition, appropriate hypertension management could reduce the risk of stroke events, perioperative complications such as cerebral infarction or hyperperfusion syndrome, and poor functional outcomes [46,47]. These findings suggest that aggressive management of these conditions is essential. Patients should be counseled on lifestyle modifications, such as dietary changes, smoking cessation, and regular physical activity, to reduce the overall vascular risk.
Statins, which are commonly used to treat hyperlipidemia, possess pleiotropic effects, including anti-inflammatory and endothelial-stabilizing properties. Limited preclinical and human data suggests that statins may slow disease progression and induce collateral development. In unilateral MMD cases, hyperlipidemia was associated with radiographic progression, suggesting possible synergistic effects of elevated lipid on the underlying moyamoya vasculopathy and that statin may attenuate MMD progression [48]. A preclinical study showed that statins inhibit neointimal formation through a combined inhibition of smooth muscle cell proliferation and invasion by inhibiting matrix metalloproteinase-9 (MMP-9) [49]. A prospective study evaluating the angiographic collateral circulation flow after encephaloduroarteriosynangiosis in MMD showed that atorvastatin at 20 mg increased circulating endothelial progenitor cells and is effective for forming postoperative collateral circulation [50].
Prospective cohort studies have shown that hyperhomocysteinemia was associated with adult MMD and poor angiogenesis after surgery [45,51]. An in vitro study showed that hyperhomocysteinemia inhibited angiogenesis [51]. Patients with MMD had increased MMP-9 expression, and hyperhomocysteinemia was associated with inflammation and increased MMP-9 expression in the vascular wall [52,53]. These findings suggest that efforts to lower the homocysteine level (for example, the use of folate) may be beneficial for patients with MMD and hyperhomocysteinemia.

Antithrombotic therapy

Current guidelines for using antiplatelet agents in patients with MMD state that antiplatelet therapy may be reasonable for patients with a history of ischemic stroke or transient ischemic attack (TIA) to reduce the risk of embolic stroke, although with a low supporting quality of evidence [1-3,5].
• 2021 Japanese guidelines [1]: Oral administration of antiplatelet agents may be considered as a medical treatment for ischemic MMD (grade C, LOE low).
• 2021 AHA/ASA guidelines [5]: The use of antiplatelet therapy, typically aspirin monotherapy, for preventing ischemic stroke or TIA may be reasonable (grade 2b; low LOE) in patients with MMD and a history of ischemic stroke or TIA.
• 2023 AHA/ASA scientific statement [3]: Antiplatelet use for preventing ischemic events in surgical and non-surgical patients with ischemic moyamoya vasculopathy may be reasonable. Cilostazol, a vasodilator, may improve survival, cerebral blood flow (CBF), and cognition to a greater extent than other antiplatelet drugs. However, these findings require further validation.
• 2023 ESO guidelines [2]: Uncertainty persists over the benefits and risks of long-term antiplatelet therapy (LOE very low) in patients with MMD; however, expert consensus suggests using long-term antiplatelet therapy to reduce the risk of embolic stroke without increasing hemorrhagic stroke. In addition, they suggested that continuing antiplatelet treatment as monotherapy (aspirin) during bypass surgery is safe. They recommended discontinuation of clopidogrel or another antiplatelet therapy for 7 days before surgery in cases of dual antiplatelet therapy (aspirin + clopidogrel or other antiplatelets).
To date, no randomized clinical trials have investigated the use of antiplatelet agents to prevent stroke in patients with MMD. Notably, most reports were retrospective observational studies or prospective, but small cohorts, often including only Asian patients (Table 1). In addition, many studies did not consider vascular risk factors or whether surgical revascularization was performed, and few studies directly compared different antiplatelet regimens. Nevertheless, antiplatelet therapy is commonly prescribed for adult patients with MMD. An international survey showed that antiplatelet therapy is recommended in the majority of non-Asian responders and in only minor Asian experts [54]. Perhaps this could be caused by differences in disease presentation between Asians and non-Asians; hemorrhagic presentation is more common in Asians [55,56], and hemorrhagic stroke risk is higher in patients with hemorrhagic MMD than in ischemic MMD [57]. A nationwide Japanese survey showed that antiplatelet use (aspirin, followed by cilostazol and clopidogrel) is the most popular option after surgery for ischemic MMD (two-thirds of the departments), while the majority departments reported no antiplatelet use “in principle” for asymptomatic MMD [58]. A recent population-based cohort study using a large national Korean database showed that antiplatelet agents were prescribed for most patients with MMD, and recently, cilostazol was increasingly being prescribed compared to the other antiplatelet agents [59].
Aspirin, clopidogrel, and cilostazol are the most frequently studied antiplatelet agents; however, only few studies have directly compared their efficacy and safety (Table 1). MMD is not a single condition, and the efficacy and choice of antiplatelet therapy may vary depending on factors such as age of onset (childhood vs. adult-onset), initial presentation (asymptomatic, ischemic, or hemorrhagic), and clinical setting (e.g., acute ischemic stroke, perioperative stage, or hemodynamically stable MMD). Guidelines for MMD do not recommend specific antiplatelet agents. However, the patient characteristics should be carefully considered when selecting antiplatelet agents.
• Antiplatelet therapy (aspirin monotherapy) is recommended for patients with ischemic symptoms or those at a high risk of recurrence, but not for those with hemorrhagic manifestations or those at risk of bleeding. A meta-analysis of nine studies involving 16,186 patients with MMD revealed that antiplatelet therapy reduced the risk of hemorrhagic stroke, but was not associated with ischemic stroke or functional outcomes. However, the study included only Asian patients with follow-up periods ranging from 6 to 218 months, and only a few studies have reported on specific antiplatelet regimens. In addition, the MMD subtypes (ischemic and hemorrhagic) and differences in whether patients underwent revascularization surgery varied depending on the study [60].
• Impaired washout of emboli is an important mechanism of brain infarction in patients with cerebral hypoperfusion; however, cerebral infarction/TIA is not exclusively a consequence of hemodynamic impairment in patients with MMD. Intraluminal thrombi is a principal pathological vascular change in patients with MMD, along with stenosis or occlusion associated with fibrocellular thickening of the intima [61]. Ischemic stroke in intracranial large disease that occurs through one of these four mechanisms: (1) in situ thrombosis, causing arterial territory infarction; (2) thromboembolism, causing embolic infarction; (3) hypoperfusion, causing a watershed or borderzone infarction; or (4) branch occlusive disease occluding the perforator’s orifice, causing deep infarction. An analysis of infarct pattern and collateral status using multimodal magnetic resonance imaging (MRI) of a prospective cohort of adult patients with MMD and acute ischemic stroke showed that most patients (83.7%) showed embolic pattern and rarely deep (9.3%) or hemodynamic infarct pattern (7%), and most cases showed good collateral status [62]. In addition, in line with other studies, one-third of patients showed microembolic signals on transcranial Doppler monitoring [62-65]. These findings suggest that embolic phenomenon plays an important role in acute ischemic stroke (Figure 2). Reportedly, the short-term use of dual antiplatelet agents (a combination of aspirin and clopidogrel) reduces microembolism in atherosclerotic, occlusive, and cerebrovascular diseases [66,67], but evidence supporting the use of a dual antiplatelet regimen in adult patients with MMD and acute ischemic stroke is absent. Therefore, therapeutic strategies against thromboembolism, particularly antiplatelet regimens and the duration of antiplatelet use in these patients, require clinical trials.
• After the acute phase of ischemic MMD, it is beneficial to use maintenance antiplatelet agents with pleiotropic effects and low risk of bleeding. Cilostazol is a reversible, selective phosphodiesterase 3 inhibitor, and an attractive option for MMD because it has a combination of antiplatelet and pleiotropic effects. Patients on cilostazol have a lower risk of hemorrhagic stroke compared with those on aspirin [68]. Cilostazol has vasodilatory properties, inhibits smooth muscle cell proliferation [69], and activates endothelial progenitor cells for angiogenesis [70], which would theoretically mitigate the angiographic progression of MMD. Small prospective observational studies showed that cilostazol improves cerebral perfusion and cognition more than clopidogrel in adult non-surgical patients with MMD [71-73]. In addition, a serial HR-MRI study of adult MMD showed that progressive shrinkage of large intracranial arteries is common, and this can be prevented by using cilostazol and no other antiplatelet agent (Figure 5) [74]. A large Korean population cohort study evaluated the use of antiplatelet regimens and found that antiplatelet use reduced mortality in patients with MMD by 23%, and cilostazol is associated with greater survival benefit compared with other antiplatelet regimens [59].

Management of hemodynamics

Maintaining adequate cerebral perfusion is critical in patients with MMD. Liming et al. [75] evaluated the impact of blood pressure changes on cerebral blood perfusion using single-photon emission computed tomography. They showed that CBF in patients with MMD is susceptible to small blood pressure changes, and cerebral autoregulation might be affected by short dynamic blood pressure modifications. Hypotension can reduce cerebral perfusion, whereas hypertension may increase the risk of hemorrhage in patients with fragile collateral vessels. Therefore, blood pressure should be carefully managed to prevent ischemic and hemorrhagic events.
Hypervolemia and induced hypertension are treatment strategies for patients with transient neurological deterioration or events related to local hypoperfusion. A randomized controlled trial of therapeutically induced hypertension in patients with non-cardioembolic stroke who were ineligible for revascularization therapy and those with progressive stroke showed that induced hypertension increased the occurrence of early neurological improvement without increasing the risk of intracranial hemorrhage/edema [76]. For patients with MMD, inducing hypertension and hypervolemia was safe and prevented perioperative transient neurological decline [77]. No patients in the induced hypertension and hypervolemia therapy group experienced recurrent transient neurological events or readmission after discharge, suggesting that flow augmentation may be clinically useful in reducing the incidence of transient neurological events after surgery for MMD. Hypertension can also be induced in patients with MMD who experience neurological deterioration, but cannot undergo surgery or are awaiting surgical intervention. However, close monitoring and individualized blood pressure targets are essential components of medical management, and randomized controlled trials in patients with MMD are needed.

Thyroid disorders and autoimmune disease

The 2021 Japanese diagnostic criteria for MMD state that patients with autoimmune diseases should be excluded from moyamoya syndrome, but cases with hyperthyroidism can be diagnosed with MMD [78]. Thyroid dysfunction and elevated levels of thyroid autoantibodies are associated with an increased risk of MMD. Thyroid function tests and thyroid autoantibody screening may identify environmental factors related to immune responses, such as anti-thyroperoxidase and anti-thyroglobulin levels, which are elevated in patients with MMD [79-81]. Thyroid autoantibodies may play a role in autoimmune mechanisms and may potentially contribute to vascular changes in patients with MMD lacking the susceptibility RNF213 p.R4810K variant. The prevalence of elevated thyroid autoantibodies was 31.5% in patients with MMD without the RNF213 variant, 15.5% in those with the RNF213 variant, and 12.8% in healthy controls [82]. Moreover, the simultaneous presence of the RNF213 variant and thyroid autoantibodies was associated with advanced MMD (posterior cerebral artery involvement). These findings suggest that thyroid autoantibody tests should be considered in patients with MMD, especially in adult female patients with terminal internal carotid artery involvement.
The optimal treatment strategy for this condition remains to be established. A single-center study showed excellent revascularization with intracranial stenting and bypass surgery [83]. However, thyroid autoantibody tests are required before considering surgical intervention. Further studies are needed to test whether stenotic lesions associated with thyroid autoantibodies can be reversed by controlling the underlying autoimmune activity (such as glucocorticoid use) [84].
Revascularization surgery for patients with MMD in the thyrotoxic state is considered a contraindication because of the potentially high risk of perioperative ischemic complications. Therefore, an accurate diagnosis of hyperthyroidism through prompt evaluation of thyroid function is essential in suspected cases. Medical management, including antithyroid therapy, should be used in ischemic MMD associated with hyperthyroidism, and revascularization surgery should be attempted after confirming the euthyroid state to avoid surgical complications (Figure 6).
The algorithm for managing ischemic MMD associated with Graves’ disease includes the following: First, patients should be managed with antithyroid and antiplatelet therapies in the acute stages of cerebral infarction. Second, the persistent (irreversible) angioarchitecture of MMD should be confirmed using repeated magnetic resonance angiography (MRA) and catheter angiography in the euthyroid state. Finally, surgical revascularization by superficial temporal artery-middle cerebral artery bypass was attempted after confirming hemodynamic compromise in the euthyroid state. A case series of adult patients with MMD and Graves’ disease managed using a similar algorithm showed the favorable outcome of revascularization surgery after strict antithyroid therapy [85].

Acute thrombolysis and endovascular therapy

The use of intravenous thrombolysis with caution in the hyperactive phase of ischemic MMD and the differential role of endovascular treatment between the subtypes are mentioned in several guidelines, including the following:
• 2021 Japanese guideline [1]: Intravenous thrombolysis with recombinant tissue plasminogen activator should be considered after careful evaluation of the risk of hemorrhagic complications in the hyperacute phase of cerebral ischemia in MMD (grade C, LOE low).
• 2023 AHA/ASA scientific statement [3]: Endovascular treatment with stents or angioplasty is not advisable for ischemic MMD. Hemorrhagic aneurysms of the moyamoya vessels can be treated endovascularly or through revascularization surgery.
However, the efficacy and safety of endovascular treatment with stents or angioplasty for MMD have rarely been investigated. A recent analysis of 19 patients from 10 studies showed that endovascular treatment plays a limited role in managing symptomatic ischemic MMD [86]. Angiographic restenosis was observed in 68.8% of the patients, and the periprocedural complication rate was 9.5%. MMD is primarily a proliferative disease of the intima that may be associated with a high rate of in-stent restenosis and poor long-term stent durability.

Conclusions and perspectives

Through this review and relevant cases, it was observed that MMD treatment varies greatly across cases, depending on the acuteness, presenting symptoms, hemodynamic status, as well as the vascular system involved (systemic vasculopathy), and stroke mechanisms. In addition, the heterogeneity of MMD in terms of genetic and environmental factors complicates the development of a one-size-fits-all treatment strategy. Medical management may involve precision medicine using genetic, molecular, and imaging biomarkers to identify patients most likely to benefit from specific treatments. Personalized approaches based on each patient’s underlying characteristics can help optimize patient outcomes more effectively. The dynamic nature of MMD necessitates close monitoring and individualized treatment plans.
Surgical revascularization remains the mainstay treatment for MMD. However, medical management plays a critical role in specific clinical situations, particularly in asymptomatic or mildly symptomatic patients and in those ineligible for surgery. Most available literature comprises observational studies and case series, and the lack of large-scale randomized controlled trials limits our ability to draw definitive conclusions regarding the efficacy of medical management of patients with MMD. Evidence supporting medical management is limited; however, controlling the risk factors and judicious use of antiplatelet agents may help mitigate the risk of ischemic events and improve patient outcomes. Further research is needed to efficiently define the role of medical therapy and develop standardized treatment protocols for managing adult patients with MMD.
Table 2 presents the ongoing trials regarding the emerging medical management of MMD, including remote ischemic conditioning, a proposed angio-/neuroprotective technique, transcranial stimulation, and erythropoietin, an essential growth factor with angiogenic effects. A randomized controlled trial of remote ischemic conditioning twice daily for 1 year showed improved CBF measured by multiple delay pseudo-continuous arterial spin labeling at 1 year [87]. A prospective single-arm study of combination therapy of multiple burr holes and intravenous erythropoietin pretreatment in adult patients with acute ischemic MMD showed that this combination therapy allows safe and effective revascularization [88].
Finally, disease-modifying agents are very important in the medical management of MMD. MMD is a progressive cerebrovascular disease. A serial HR-MRI study with a mean interval of 2.5 years showed a progressive shrinkage of large intracranial arteries, although patients showed stable clinical courses without recurrent events [74]. Similarly, a serial MRA and perfusion MRI study at 1 year showed progressive stenosis and deterioration of CBF [87]. In addition, after bypass surgery, de novo development of MMD on the contralateral side or posterior cerebral artery is common (up to one-third), and this is associated with recurrent stroke on the contralateral side and compromise of collateral flow, respectively [48,89-92]. Moreover, as mentioned above, the RNF213 variant with the genetic susceptibility factor for MMD is associated with this system [25]. These findings call for disease-modifying treatment aimed at halting or slowing disease progression, but at present, no disease-modifying treatment has been established for patients with MMD.
MMD is thought to result from abnormal remodeling of blood vessels related to impaired endothelial progenitor cells and cytokines/growth factors [93-95], chronic inflammation [96], endothelial dysfunction, and a genetic predisposition to impaired vascular pruning and adaptive remodeling [40]. However, its exact pathophysiology remains incompletely understood. Despite its unclear etiology, recent studies and experimental treatments have targeted various aspects of MMD pathophysiology to modify disease progression. For example, a preclinical study showed that local transplantation of bone marrow mesenchymal stem cells in the temporal muscle with encephalomyosyn angiosis in an MMD-mimicking mouse model promoted angiogenesis and cognitive behavior [97]. Zhao et al. [98] applied autologous bone marrow stem cell therapy in patients with MMD. In this trial bypass surgery (the control group) or autologous stem cells (the experimental group) were applied after craniectomy to patients with MMD, and the levels of conexin43 protein and proinflammatory cytokines were measured. They found that treatment with autologous bone marrow stem cells reduced vascular tissue damage and inflammation, with lower local complication rates than those in the control group. However, stem cells from patients with MMD also carry the RNF213 variant, and allogeneic transplantation of stem cells from healthy subjects may be advantageous. In addition, the therapeutic effects of stem cells are probably because of stem cell-derived exosomes rather than stem cells [99]. Recently, we reported that clinical-scale stem cell-derived exosome therapeutics are feasible, cost-effective, and have improved functional recovery following experimental stroke [100]. Therefore, preclinical studies for early phase clinical trials on allogeneic mesenchymal stem cell-derived exosome therapy (SNE-101M) for patients with MMD are currently underway. Emerging disease-targeting therapies are promising; however, many remain in experimental or early clinical trial stages. The next step will be to conduct large-scale studies to evaluate the long-term efficacy and safety of these treatments, with the ultimate goal of preventing disease progression and improving outcomes in patients with MMD.

Notes

Funding statement
This study was supported by the Korean Fund for Regenerative Medicine (KFRM) grant by Korean government (no. RS-2022-00070517) and JSPS KAKENHI grant number 23H03015 (Miki Fujimura).
Conflicts of interest
The authors have no financial conflicts of interest.
Author contribution
Conceptualization: OYB. Study design: OYB. Methodology: OYB. Data collection: OYB, MF. Investigation: OYB, MF. Writing—original draft: OYB, MF. Writing—review & editing: OYB, MF. Funding acquisition: OYB, MF. Approval of final manuscript: all authors.

Acknowledgments

O.Y.B. is the CEO of the S&E bio, Inc.

Figure 1.
De novo development of moyamoya disease in a 51-year-old male who experienced recurrent left hemiparesis. (A) Digital subtraction angiography (DSA) image at the initial presentation showing right middle cerebral artery (MCA) stenosis without evident moyamoya vessels. (B) High-resolution vessel wall magnetic resonance imaging (HR-MRI) demonstrated no evidence of atherosclerotic plaque or arterial dissection in the right MCA but showed luminal narrowing (outer diameter, 2 mm) and circular enhancement (arrowhead). (C) The patient experienced recurrent cerebral infarction 3 months later, and repeat DSA revealed newly developed moyamoya vessels (arrowhead). (D) Perfusion MRI, including arterial spin labeling (ASL) and time-to-peak (TTP) maps, indicated reduced cerebral blood flow and delayed cerebral perfusion, leading to a decision to perform direct bypass surgery.
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Figure 2.
Stroke occurrence in the stenotic segment stabilizes over time. A 42-year-old female with an RNF213 heterozygote carrier, who underwent bypass surgery for a right hemispheric infarct, presented with transient right hemiparesis. Initial transfemoral cerebral angiography (TFCA) showed stenosis only in the right middle cerebral artery (MCA), and transcranial Doppler monitoring detected microembolic signals (TCD MESs). High-resolution vessel wall magnetic resonance imaging (HR-MRI) revealed a circular enhancement in the stenotic segment of the left MCA (arrowhead). The patient was treated with antiplatelet therapy and no further symptoms recurred. Follow-up time-of-flight magnetic resonance angiography (TOF-MRA) showed improvement in stenosis and resolution of the vessel wall enhancement (arrowhead).
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Figure 3.
Intracranial plaque associated with RNF213 variant. A 61-year-old female with an RNF213 variant heterozygous carrier with a family history of moyamoya disease presented with recurrent right hemiparesis. Transfemoral cerebral angiography (TFCA) revealed diffuse stenosis from the left distal internal carotid artery to the proximal middle cerebral artery (MCA) without moyamoya vessels. High-resolution vessel wall magnetic resonance imaging (HR-MRI) of the stenotic segment shows negative remodeling (outer diameter, 1.9 mm) and a plaque with intraplaque hemorrhage (yellow arrow) on the non-enhanced T1-weighted image. The affected area exhibits eccentric enhancement (arrowhead). After treatment with aspirin and high-dose statins, follow-up HR-MRI at 1 year showed improvement in the enhancing plaque and a slight reduction in stenosis (arrowhead).
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Figure 4.
Systemic vasculopathy associated with RNF213 variant. A 39-year-old female with an RNF213 variant heterozygote carrier was diagnosed with asymptomatic moyamoya disease (MMD) after transfemoral cerebral angiography (TFCA) revealed characteristic features of the disease. She had a family history of MMD and premature myocardial infarction, and a relative who died young from the latter. The patient presented with chest pain and was diagnosed with unstable angina. Coronary angiography (CAG) revealed diffuse spastic stenosis suggesting RNF213 variant-related systemic vasculopathy.
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Figure 5.
A substantial improvement in vascular remodeling in patients with moyamoya disease prescribed cilostazol. A 24-year-old female presented with transient sensory changes on the right side. Genetic testing reveals RNF213 heterozygosity, and HR-MRI revealed negative remodeling and circular enhancement. She was prescribed cilostazol (100 mg) twice daily during the study period and underwent serial HR-MRI three times. (A) Time-of-flight magnetic resonance angiography (TOF-MRA) showed improvement in bilateral stenosis of the middle cerebral arteries (MCAs) during the follow-up. Baseline TOF-MRA indicated severe stenosis in the bilateral MCAs; however, only mild stenosis was observed in the left MCA at the last follow-up TOF-MRA. (B) HR-MRI indicated left MCA shrinkage, which improved in follow-up imaging (outer diameter of MCA: 1.10 mm at baseline, 1.55 mm at the intermediate follow-up, and 1.70 mm at the last follow-up). Vascular enhancement was persistently observed in the follow-up images. Reproduced from Kim et al. J Clin Neurol 2022;18:610-618,74 under the terms of Creative Commons (CC-BY-NC) License.
jos-2024-04273f5.jpg
Figure 6.
Adult moyamoya disease associated with Graves’ disease. A 40-year-old female with ischemic-onset moyamoya disease (MMD) was diagnosed with Graves’ disease and presented with left homonymous hemianopsia. Magnetic resonance images of (A) diffusion-weighted images (DWI), (B) fluid-attenuated inversion recovery (FLAIR), and (C) magnetic resonance angiography (MRA) at onset demonstrate acute cerebral infarction in the right occipital lobe and bilateral internal carotid artery (ICA) terminal stenosis with decreased signal intensity in the bilateral middle and anterior cerebral arteries (MCA and ACA). In light of her previous history of weight loss and hand tremors, she was diagnosed with hyperthyroidism (free T3 8.69 pg/mL, free T4 3.27 ng/dL, undetectable thyroid stimulating hormone [TSH]; and positive anti-TSH receptor antibody and anti-thyroglobulin antibody); thus, she was managed medically with antithyroid therapy with 15 mg/day of methimazole and 15 mg/day of potassium iodide for 2 weeks. (D) MRA after antithyroid therapy (euthyroid state) demonstrated no change in bilateral ICA terminal stenosis. (E and F) Catheter angiography in the euthyroid state confirmed the definitive diagnosis of MMD (carotid angiograms) when (G) iodine-123 metaiodobenzylguanidine single-photon emission computed tomography (IMP SPECT) delineated a marked hemodynamic compromise in the affected hemisphere, suggesting surgical revascularization in the right hemisphere. The patient then underwent revascularization surgery in a euthyroid state, without complications. (H-J) Intraoperative view of the right superficial temporal artery (STA)-MCA bypass. (H and I) The M4 segment of the right MCA is explored, and the stump of the right STA is anastomosed. (J) Indocyanine green videoangiography demonstrating an apparent patent STA-MCA bypass. (K) MRA performed 2 days after revascularization demonstrated patent STA-MCA bypass with thick high signal intensity (arrow). (L) IMP SPECT performed 1 day after revascularization indicated hemodynamic improvement in the right hemisphere.
jos-2024-04273f6.jpg
Table 1.
Antiplatelet therapy in patients with moyamoya disease
Reference Study design Population Outcome Results
Ogasawara et al. (2022) [101] Prospective observational (n=57) Nonsurgical, ischemic adult MMD with misery perfusion on PET Recurrence of ischemic events and functional outcome Medical management alone is associated with poor patient outcome; three patients declined undergoing bypass surgery and developed recurrent strokes (ischemic 2, hemorrhagic 1).
Miyoshi et al. (2019) [102] Prospective observational (n=102) Nonsurgical, ischemic adult MMD without misery perfusion on PET Recurrence of ischemic stroke and PET FU at 2 years In patients with medication alone, incidence of recurrent ischemic events was 3% per 2 years. In patients without recurrent events, PET perfusion and cognitive function had not deteriorated.
Chiba et al. (2018) [71] Prospective observational (n=68) Nonsurgical, ischemic adult MMD without misery perfusion on PET CBF on PET at 2 years Cilostazol improves cerebral perfusion better than clopidogrel.
Ando et al. (2019) [73] Prospective observational (n=66) Nonsurgical, ischemic adult MMD without misery perfusion on PET Cognition at 2 years Cilostazol may improve cognition better than clopidogrel.
Kitakami et al. (2022) [72] Prospective observational (n=68) Nonsurgical, ischemic adult MMD without misery perfusion on PET and without recurrence events during 2-year FU Recurrence of ischemic events and changes in CBF during another 3-year FU Low incidence (6% per 5 years) of further ischemic events with medical management alone.
Relative increase in relative CBF with cilostazol but not with clopidogrel.
Oomori et al. (2022) [103] Prospective observational (n=68) Nonsurgical, ischemic adult MMD without misery perfusion on PET MRA and SPECT at 5-year FU Angiographic disease progression was observed in 12% for 5 years in medically treated adult ischemic MMD. CBF was reduced in patients with angiographic disease progression even when ischemic events did not occur.
Pang et al. (2021) [104] Retrospective observation (n=243) Adult MMD with stable hemodynamic status Ischemic or hemorrhagic stroke during FU (mean 5 years) AP medication failed to prevent ischemic stroke, but did not increase the risk of hemorrhagic stroke.
Kim et al. (2022) [74] Retrospective observation (n=66) Adult MMD undergoing serial HR-MRI (mean interval 2.5 years) Negative remodeling as measured by outer diameter of involved segment Progressive shrinkage of large intracranial arteries is common, which can be prevented by using cilostazol but not any other AP.
Xiang et al. (2022) [105] Retrospective observation (n=95) Adult MMD undergoing bypass surgery Bypass patency, ischemic events, and bleeding risk Postoperative aspirin use improves patency and reduces ischemic complication without elevated bleeding risk compared with non-users.
Lu et al. (2021) [106] Retrospective observation (n=217) Adult ischemic MMD undergoing bypass surgery Bypass patency, ischemic events, and bleeding risk Immediate postoperative aspirin use improves patency without increasing the bleeding risk.
Zhao et al. (2017) [107] Retrospective observation (n=184) Adult ischemic MMD undergoing bypass surgery Bypass patency, ischemic events, and bleeding risk Postoperative aspirin use did not improve patency or decrease the incidence of ischemic or bleeding events.
Yamada et al. (2016) [108] Prospective registry study of Research Committee on MMD in Japan (n=1,146) Adult and childhood MMD Ischemic and hemorrhagic stroke for up to 10 years In adult ischemic MMD, recurrent ischemic stroke was lower in the surgery group than in the non-surgery group, and the rate of cerebral infarction did not differ between AP users and non-users, but hemorrhagic stroke was lower with AP use.
Onozuka et al. (2016) [109] Retrospective observation (n=1,925) Adult non-hemorrhagic MMD Disability on hospital admission (mRS 0 or 1) Prehospital AP use was associated with good functional status on hospital admission.
Ye et al. (2020) [110] Retrospective data of nationwide registry data in Japan (n=159) Adult ischemic MMD of conservative care vs. AP vs. bypass surgery Ischemic stroke, functional independence during FU (mean 2.75 years) Risk of ischemic stroke was lowest with surgical revascularization, while AP was better than conservative care. No difference in functional status and bleeding events among the groups
Seo et al. (2021) [59] Retrospective, population-based, cohort study (n=163,347) Korean health insurance data on newly diagnosed adult MMD with 14-year FU Survival Reduced mortality with cilostazol compared to other AP or none user
Liu et al. (2023) [60] Meta-analysis of nine studies (n=16,186) Adult and childhood MMD All cause of mortality AP was associated with reduced risk of hemorrhagic stroke but not ischemic stroke or an independent outcome.
Ischemic or hemorrhagic stroke
MMD, moyamoya disease; PET, positron-emission tomography; FU, follow-up; CBF, cerebral blood flow; MRA, magnetic resonance angiography; SPECT, singlephoton emission computed tomography; AP, antiplatelet agent; HR-MRI, high-resolution vessel wall magnetic resonance imaging; mRS, modified Rankin Scale score.
Table 2.
Current ongoing clinical trials
Study name (clinicaltrial.gov) Objectives Study arm Primary outcome
Remote ischemic conditioning (RIC)
 The Safety and Efficacy of RIC on Adult MMD (RIC-AMD) (NCT04012268) [87] To explore the safety and efficacy of RIC on adult patients with MMD Temporal bilateral arm cuffing 5 cycles for 5 min alternatively twice daily for 1 year Improvement ratio of mean CBF as measured by arterial spin labeling
 Effects of Remote Ischemic Preconditioning with Postconditioning (RIPC with RIPostC) on Neurologic Outcome (NCT03072914) To evaluate whether RIPC with RIPostC reduces the major neurocomplication in adult patients with MMD undergoing STA-MCA anastomosis Temporal lower limb cuffing for 5 min 4 cycles, preoperatively and postoperatively Number of major adverse events (hyperperfusion syndrome, hypoperfusion, brain hemorrhage, acute infarction)
Conservative management
 Long-term Outcomes of Conservative Management in Patients with MMD and Their First-degree Relatives (LAMORA) (NCT05332756) To investigate the long-term outcomes of conservative management in childhood and adult patients with MMD and their first-degree relatives Medical management of antiplatelets, antiepileptics, antihypertensives, and vasodilators, depending on the presentation Cerebrovascular events
Transcranial stimulation
 Efficacy and Safety of rTMS for Cognitive Rehabilitation in MMD (NCT03543748) To evaluate the safety and effectiveness of transcranial magnetic stimulation (TMS) in adult patients with MMD who received surgical revascularization TMS of a total of 2,000 trains will be delivered successively. The pulses will be delivered at 80% of motor thresholds. Neurocognitive outcomes at 3-month follow-up after TMS
 A Study of Cerebral Perfusion with tDCS in Chronic Hypoperfusion (NCT06477107) To examine whether transcranial direct current stimulation (tDCS) increases CBF and improves cognitive impairment in adult MMD Soterix® 4×1 HD-tDCS for inducing cortical neuromodulation Changes in CBF at days 0, 14, 44, and 58
Erythropoietin (EPO)
 Multiple Burrhole Therapy with Erythropoietin for Unstable Moyamoya (NCT03162588) [88] To evaluate the indirect revascularization outcomes of combination of multiple burr holes with IV EPO pretreatment on adult patients with MMD and acute neurological presentation Epokine® 40,000 units mixed in IV saline 100 mL over 1 h for three consecutive days Functional status of the participants after 6 months of procedure assessed by modified Rankin Scale.
The multiple burr holes procedure in area of hypoperfusion Transdural arteriogenesis
 Effect of Recombinant Human EPO on the Postoperative Neurologic Outcome in Pediatric MMD Patients (NCT03882060) To evaluate the effect of EPO on the neovascularization of pediatric patients with MMD To evaluate effect of postoperative IV Recombinant human EPO (500 U/kg IV)×3 times; preoperative (12-24 h before), during surgery, and postoperative (12-24 h after) Postoperative <12 months angiogenesis
dl-3-n-butylphthalide (NBP)
 NBP in Patients with MMD of High Risk for Ischemic Cerebrovascular Events (NICE-MMD) (NCT04205578) NBP in adult patients with MMD at a high risk for ischemic events after revascularization surgery dl-3-n-butylphthalide Perioperative ischemic stroke rate
Perioperative death rate
Rate of transient neurological deficit
MMD, moyamoya disease; CBF, cerebral blood flow; STA-MCA, superficial temporal artery-middle cerebral artery; IV, intravenous.

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