Recent Advances for Global Perspectives on Etiology, Pathophysiology, Clinical Presentations, and Management of Moyamoya Disease

Maiko Charles Mkwambe, Dongchi Zhao^*, Youping Deng^*

Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, China.

DOI: 10.4236/wjns.2024.141002                

Abstract

Moyamoya disease (MMD) is a condition characterized by the gradual narrowing and blockage of blood vessels in the brain, specifically those in the circle of Willis and the arteries that supply it. This results in reduced blood flow and oxygen to the brain, leading to progressive symptoms and potential complications. The underlying pathophysiological mechanism remains elucidated. However, recent studies have highlighted numerous etiologic factors: abnormal immune complex responses, susceptibility genes, branched-chain amino acids, antibodies, heritable diseases, and acquired diseases, which may be the great potential triggers for the development of moyamoya disease. Its clinical presentation has varying degrees from transient asymptomatic events to significant neurological deficits. Moyamoya disease (MMD) shows different patterns in children and adults. Children with MMD are more susceptible to ischemic events due to decreased blood flow to the brain. Conversely, adults with MMD are more prone to hemorrhagic events involving brain bleeding. Children with MMD may experience a range of symptoms including motor impairments, sensory issues, seizures, headaches, dizziness, cognitive delays, or ongoing neurological problems. Although adults may present with similar clinical symptoms as children, they are more prone to experiencing sudden onset intraventricular, subarachnoid, or intracerebral hemorrhages. One of the challenges in moyamoya disease is the potential for misdiagnosis or delayed diagnosis, particularly when physicians fail to consider MMD as a possible cause in stroke patients. This review aims to provide a comprehensive overview of recent global studies on the pathophysiology of MMD, along with advancements in its management. Additionally, the review will delve into various surgical treatment options for MMD, as well as its rare occurrence alongside atrioventricular malformations. Exciting prospects include the use of autologous bone marrow transplant and the potential role of Connexin 43 protein treatment in the development of moyamoya disease.

Keywords

Moyamoya Disease (MMD), Etiology, Pathophysiology, Clinical Presentations, Management, Future Promising Avenues

1. Introduction

Moyamoya disease (MMD) is a condition marked by the progressive narrowing of the internal carotid artery and circle of Willis, leading to chronic bilateral vasculopathy. The exact cause of MMD is unknown. In contrast, moyamoya syndrome (MMS) is characterized by the occurrence of the same phenomenon in conjunction with other neurological or extra-neurological conditions, which can be either inherited or acquired [1] [2] . People diagnosed with Moyamoya disease (MMD) have a higher likelihood of experiencing stroke, cognitive difficulties, and delays in their development. Collateral vessels, known as moyamoya vessels, develop in response to chronic brain ischemia. Recent research has identified several susceptibility genes, including individuals diagnosed with familial moyamoya disease, that have the 95% p. R4810K variant in the RNF213 gene [3] . Studies have found that Moyamoya disease is more common in individuals of Asian descent, with a higher prevalence observed in Japan where the condition was first discovered [4] . Interestingly, MMD is linked to have an association with mutations in human RNF213 and ACTA2 genes. MMD has a bimodal distribution, with peaks between the ages of 5 to 10 years in children and then between ages 30 - 50 years in adults; the population of patients from the second peak is smaller than the first. MMD has a family history, which is positive in 10% - 15% of patients with initial onset followed by slow progression [4] [5] . According to a prospective study involving 23 patients diagnosed with ischemic MMD using DSA, it was discovered that TGFβ1 is crucial in facilitating the development of collateral blood vessels by increasing the expression of VEGF in ischemic MMD. Comparatively higher levels of TGFβ1 were observed in the plasma of ischemic MMD patients when compared to individuals with aneurysms and those who are in good health. This finding led to the conclusion that TGFβ1 plays a significant role in promoting collateral formation in ischemic MMD [6] . Cerebral angiography has played a critical role in the diagnosis and grading of MMD. The presence of “a puff of smoke” or moyamoya vessels, observed through catheter angiography at the base of the brain, is considered the characteristic feature that is specific to MMD [7] . Cerebral angiography carries the risk of complications, including brain ischemia and vascular damage, with reported incidences of 2.9% - 9.3%. This risk is particularly higher in pediatric patients and those with MMD who have significant hemodynamic compromise [8] . A case-control study conducted between September 2020 and December 2021 found that elevated levels of circulating BCAAs were linked to a higher risk of MMD and its various clinical subtypes in a group of 360 adults with MMD and 89 healthy controls [9] . But, advancements in high-throughput multi-omics technologies have provided new insights into the origins of diseases [10] . MMD encompasses both ischemic and hemorrhagic blood types, with ischemic MMD being more common in children and cerebral hemorrhage being predominantly observed in adults. The mortality rate of hemorrhagic MMD is reported to be higher compared to ischemic MMD [11] . Henceforth, objective of this review is to explore the lesser-known causes of moyamoya disease, focusing on recent advancements in understanding its pathophysiology, available treatment options, and potential future directions in this era of significant scientific breakthroughs.

2. Etiology of Moyamoya Disease

2.1. Genetic Predisposition

Moyamoya disease has been widely accepted that it has a genetic component, with specific gene mutations with approximately 10% of patients identified in familial cases. Mineharu proposed that familial moyamoya disease follows an autosomal dominant inheritance pattern, characterized by incomplete penetrance that is influenced by factors such as age and genomic imprinting [12] . Through a comprehensive analysis of the entire genome, a study on moyamoya disease (MMD) successfully identified RNF213 as the initial gene linked to this condition [13] . On the other hand, another study found that, mutations in RNF213 may disrupt normal vascular development and lead to abnormal angiogenesis, resulting in the characteristic narrowing of blood vessels in moyamoya disease [14] . In a notable genome-wide association study conducted by Duan et al. in China, they discovered ten previously unidentified risk loci, alongside RNF213, that have significant genetic implications for moyamoya disease (MMD). Two of these newly identified risk genes, MTHFR and TCN2, play a role in the metabolism of homocysteine, which is a recognized risk factor for coronary heart disease and stroke. These genes have an impact on endothelial function and angiogenesis, further highlighting their relevance in MMD [14] . However, individuals who carry the RNF213 p. (R4810K) gene mutation, both in homozygous and heterozygous states, have been found to have arteriopathies in various arteries such as the coronary, renal, celiac, mesenteric, and iliac arteries. This discovery suggests the importance of conducting systematic screenings for extracranial vasculopathy in both adult and pediatric patients with moyamoya disease (MMD) [15] .

2.2. The Role of Inflammatory Cytokines

The presence of extracranial vasculopathy in individuals with moyamoya disease (MMD) is not limited to the R4810K gene variant. This is evidenced by the recent discovery of a new clinical syndrome characterized by childhood-onset MMD with diffuse occlusive vasculopathy [16] . A recent discovery has linked a specific genetic mutation to the development of urticarial lesions, which are accompanied by elevated levels of inflammatory cytokines. These cytokines, such as IL-1β, tumor necrosis factor alpha, and IL-6, mimic the symptoms of an acute cytokine storm. This finding emphasizes the importance of RNF213 as a key inflammatory mediator and a significant factor in the development of moyamoya disease (MMD) [17] . Moyamoya disease (MMD) is linked to Down syndrome, sickle cell disease, cancer, and exposure to radiation.

2.3. Autoimmune Conditions

Autoimmune conditions, such as systemic lupus erythematosus (SLE) and thyroid disease, have been associated with moyamoya disease. Autoimmune mechanisms may contribute to the vascular inflammation and narrowing observed in moyamoya disease. Autoimmune responses targeting vascular endothelial cells or components of the blood-brain barrier may lead to vascular dysfunction and the development of moyamoya disease [18] [19] .

Additionally, studies suggest that autoimmune conditions and infection may also contribute to the development of MMD [20] . Graves’ disease, a thyroid disorder, has been found to progress more rapidly in patients with moyamoya disease (MMD). These patients also have a higher incidence of stroke. This suggests that Graves’ disease is an independent factor in the progression of MMD in adult patients, indicating shared underlying mechanisms between the two conditions and other autoimmune diseases [21] .

2.4. The Role of Bacterial Infections

Additionally, complications of progressive arterial occlusive disease have been observed in patients following purulent meningitis. This condition can be caused by various pathogens such as Hemophilus influenzae, Streptococcus pneumoniae, Mycobacterium tuberculosis, and Leptospira. These complications typically develop around two weeks after the onset of the disease and are characterized by a progressive nature. Late-onset morphologic changes in the circle of Willis are also observed [22] . Moyamoya disease (MMD) can occur following viral infections associated with certain arteriopathies like transient cerebral arteriopathy (TIA) and progressive arteriopathies. These infections can contribute to the development of moyamoya angiopathy (MMA) [23] . Post-infectious vasculopathy may be due to an autoimmune response triggered by infection, involving β2-GP1 and post-infectious antiphospholipid syndrome. This could explain an abnormal immune response to viral infection, leading to an increased vulnerability to moyamoya disease [24] .

2.5. Viral Infections

Viral infections have been implicated in the development of moyamoya disease. Emerging evidence suggests a link between viral-associated Moyamoya disease (MMD) and COVID-19 caused by SARS-CoV-2. COVID-19 patients with increased blood clotting may also have effects on RNF213 and caveolin-1 due to the cytokine storm associated with the virus [25] [26] . Other studies have found that, viruses such as human herpesvirus 6 (HHV-6) and varicella-zoster virus (VZV) have been detected in the blood vessels of moyamoya disease patients. It is hypothesized that viral infections may trigger an immune response and subsequent inflammation in the blood vessels, leading to stenosis and the development of moyamoya disease [27] [28] .

3. Pathophysiology of Moyamoya Disease

Moyamoya disease (MMD) is a condition where the inner layer of the walls of the internal carotid vessels, especially in their end segments, becomes thickened. This thickening may contain lipid deposits. The arteries branching from the circle of Willis, like the anterior, middle, and posterior cerebral arteries, can become narrowed or blocked to varying degrees. This narrowing is associated with the thickening of the inner artery walls, the waving of a specific elastic layer, and the thinning of the middle layer. Within the circle of Willis, there are small channels known as perforators and anastomotic branches that facilitate vascular connections. The pia mater, a thin membrane covering the brain, may also have clusters of small vessels.

Figure 1 illustrates the continuous blockage of major brain arteries, specifically the internal carotid arteries and their branches. This blockage is caused by the increased presence of growth factors such as VEGF (Vascular endothelial growth factor), TGF (transforming growth factor), HGF (Hepatocyte growth factor), MMPs (Matrix metallopeptidases), and bFGF (basic fibroblast growth factor) in the brain tissue. These growth factors promote the formation of new blood vessels, known as collateral vessels, which serve as a compensatory mechanism to bypass the narrowed or blocked arteries. However, these collateral vessels are fragile and susceptible to rupture, resulting in brain hemorrhage and an elevated risk of stroke.

Although the exact cause of MMD is not fully understood, several studies have identified various factors that may contribute to its development. Specific gene mutations can contribute to the development of Moyamoya disease (MMD), Moyamoya syndrome (MMS), and cerebral arteriopathies. For instance, autosomal recessive MMD with achalasia is associated with mutations in the GUCY1A3 gene, which plays a role in nitric oxide signaling. Mutations in the ACTA2 gene, specifically heterozygous missense mutations, can cause a condition that exhibits similarities to Moyamoya disease. These mutations affect the production of smooth muscle actin. Mutations in the SAMHD1 gene can cause an inflammatory syndrome accompanied by moyamoya-like vasculopathy. X-linked MMS with short stature and facial dysmorphism is linked to deletions in the BRCC3 gene on the X chromosome. Additionally, de novo mutations in the CBL gene, involved in protein degradation, can result in severe early-onset pediatric moyamoya arteriopathy [28] - [33] . The narrowing of blood vessels in Moyamoya disease is thought to lead to chronic brain ischemia, causing an

Figure 1. Pathophysiology of Moyamoya disease.

increase in the production of proangiogenic factors such as fibroblast growth factor and hepatocyte growth factor. This overexpression of proangiogenic factors is believed to stimulate the formation of a delicate network of collateral vessels [1] [34] . A study by Junsheng Li et al. found that Methionine sulfoxide (MetO) is linked to a higher risk of Moyamoya disease (MMD) and its subtypes. However, betaine has shown promise in reducing inflammation and oxidative stress following brain ischemia and reperfusion injury. This is achieved by increasing the levels of MetO reductase. The study also noted that MetO can inhibit the cleavage of ADAMTS-13, which can contribute to thrombosis in oxidative stress-related diseases [35] . Hemoglobin (Hb) and triglycerides (TG) have been found to play a role in the development of Moyamoya disease (MMD). Higher levels of Hb are linked to inflammation and increased risk of stroke and poor prognosis. Elevated TG levels also contribute to the risk of cerebrovascular diseases, such as artery stenosis. Early prevention of hyperuricemia and lipid abnormalities has been shown to decrease the occurrence of MMD. However, the exact connection between Hb and TG in the pathology of MMD is not fully understood [36] . Shifu Li et al.’s study revealed that molecular biology and next-generation sequencing technologies have improved our understanding of disease mechanisms at the genetic and mRNA levels. This includes identifying differentially expressed genes (DEGs) and immune complexes. The study also found that gene-miRNA interactions play a role in modifying protein expression during disease progression by targeting specific factors [37] .

4. Clinical Presentation of Moyamoya Disease

Moyamoya disease (MMD) presents differently in children and adults. Children typically exhibit symptoms such as hemiparesis, sensory impairments, seizures, headaches, and mental deficits. In contrast, adults with MMD often experience sudden intraventricular or subarachnoid hemorrhage, along with similar symptoms to children.

5. Diagnostic Evaluations of Moyamoya Disease

5.1. Laboratory Evaluation

Evaluating hypercoagulability profiles is important for both pediatric and adult patients with Moyamoya disease. These profiles consist of various markers, including protein C, protein S, antithrombin III, homocysteine, factor V Leiden, erythrocyte sedimentation rate (ESR), thyroid function, and thyroid antibody levels. Studies have indicated that these markers are frequently elevated in individuals with moyamoya disease. One possible explanation is that the elevation of proinflammatory and angiogenic cytokines stimulates the production of growth factor-β and basic fibroblast growth factor. This ultimately leads to the formation of new blood vessels and angiogenesis. Additionally, both microangiopathic and macroangiopathic changes contribute to the development of ischemic symptoms in Moya-Moya syndrome [38] .

5.2. Imaging Evaluations

Various imaging techniques have been investigated, but brain angiogram remains the gold standard for diagnosing Moyamoya disease [1] [39] .

5.3. Conventional Cerebral Angiography

Study found blockages in the internal carotid artery or the anterior/middle cerebral arteries, accompanied by abnormal blood vessel networks. The condition is usually bilateral, but unilateral involvement can occur in some patients [39] . Studies have found that most patients had moderate to severe grades of disease, with only a small percentage having milder grades. Among the patients with atypical symptoms, the majority had moderate to severe disease. In a small percentage of patients, angiography showed a small superficial temporal artery, resulting in changes to surgical plans and the use of indirect bypass alone [40] [41] . Angiographic findings in moyamoya disease include:

Basal Collateral Vessels: Moyamoya disease is often associated with the development of basal collateral vessels, also known as moyamoya vessels, at the base of the brain. These vessels arise from the external carotid artery system and provide compensatory blood flow to the affected areas.

String of Beads Sign: On angiography, a characteristic finding in moyamoya disease is the “string of beads” appearance of collateral vessels. This sign refers to the alternating areas of stenosis and dilation along the course of the basal collateral vessels.

Moyamoya Phenomenon: In addition to the characteristic angiographic findings in moyamoya disease, a similar pattern of collateral vessel formation can also be observed in other conditions, known as the moyamoya phenomenon. The moyamoya phenomenon can occur secondary to various underlying conditions, such as sickle cell disease, neurofibromatosis type 1, and radiation therapy [40] [41] .

5.4. Magnetic Resonance Imaging (MRI)

MRI scans are valuable for identifying hemorrhages and strokes in the brain. When using FLAIR and T2 weighted sequences, old ischemic lesions appear as bright areas in the white matter, typically found in the distal vasculature or border zone areas. The FLAIR sequence can also reveal linear bright areas that indicate slowed blood flow and follow the brain’s grooves, referred to as the “ivy” sign [42] .

5.5. Cerebral Perfusion Measurement

Various imaging techniques, such as CTP, SPECT, MRI, xenon-enhanced CT, PET scan, and arterial spin labeling, are used in these evaluations. These methods typically show increased oxygen extraction, decreased overall blood flow in the brain with a focus on the posterior cerebral region, and impaired blood vessel response to carbon dioxide and acetazolamide in the area supplied by the internal carotid artery. These findings suggest a limited ability to regulate blood flow in the brain, known as low cerebrovascular reserve [43] [44] [45] [46] .

5.6. Transcranial Doppler (TCD)

TCD has shown clinical utility in assessing disease progression and treatment response in patients with Moyamoya disease.

Disease Progression: TCD can provide valuable information about the progression of Moyamoya disease by measuring blood flow velocities in the affected vessels. Progressive stenosis or occlusion of the internal carotid arteries and their branches can be detected by increased blood flow velocities in the collateral vessels. TCD can monitor changes in blood flow velocities over time, helping to identify disease progression and guide treatment decisions.

Treatment Response: TCD can be used to evaluate the hemodynamic changes following surgical or endovascular revascularization procedures in Moyamoya disease. Postoperative TCD can assess the improvement in blood flow velocities and the establishment of collateral circulation. TCD findings can help determine the effectiveness of revascularization procedures and guide further management.

Monitoring Collateral Circulation: TCD can assess the development and function of collateral circulation in patients with Moyamoya disease. By measuring blood flow velocities in the collateral vessels, TCD can provide information about the adequacy of collateral circulation and its contribution to cerebral perfusion [47] [48] .

5.7. Electroencephalography (EEG)

Seizures and their abnormal patterns are frequently observed in pediatric patients with MMD. EEG can help differentiate between different transient neurological events in MMD. The ‘Rebuild-up’ phenomenon, seen in about half of moyamoya patients, involves the reappearance of slow waves with higher amplitudes following hyperventilation and is not found in other conditions. This phenomenon indicates reduced blood flow. In a study by Jia Lu et al., abnormal EEG patterns were found in 93.3% of cases, with focal slowing being the most common (80.0%), followed by epileptiform discharge (66.7%) and diffuse slowing (60.0%) [49] .

5.8. Magnetic Resonance Angiography (MRA)

This is a reliable examination for assessing cerebral arteries and determining the degree of narrowing and collateral circulation around steno-occlusive lesions. In adults, the existence of a one-sided obstructive condition is classified as “Probable moyamoya”, while bilateral occlusion in adults or unilateral occlusion in children is classified as “Definite moyamoya”. This classification is due to the high likelihood of unilateral occlusion progressing to bilateral occlusion in children. It is worth noting that posterior circulation is usually unaffected in MMD, but it can be involved in Moyamoya syndrome [50] [51] .

6. Clinical Staging of Moyamoya Disease

Currently, Suzuki staging is the preferred clinical guide for staging MMD. The stages of MMD according to Suzuki staging are as follows:

Stage 1: Stenosis or constriction occurring solely at the end segment of the internal carotid artery, as observed through angiography.

Stage 2: The occurrence of stenosis in the smaller branches at the end of the internal carotid artery, accompanied by the presence of deep moyamoya vessels, as observed through angiography.

Stage 3: The increased visibility and prominence of deep moyamoya vessels observed during angiographic examination. At this stage, MRA imaging may show a distinct “puff of smoke” appearance. Additionally, the bending or deviation of the anterior cerebral artery (ACA) and middle cerebral arteries (MCA) can also be observed.

Stage 4: Is the decrease of moyamoya syndrome describing the decrease in visibility and prominence of deep moyamoya vessels seen during angiographic examination. This stage is characterized by the emergence of transdural collaterals and the bending or deviation of the posterior cerebral artery (PCA).

Stage 5: “Diminishment of moyamoya”, the continuous decline in the visibility and significance of deep moyamoya vessels seen during angiographic exams. As these progress, there is a further decrease in the presence of these vessels, while transdural collateral vessels continue to develop and become more prominent.

Stage 6: “The fading away of moyamoya”, the absence of profound moyamoya vessels seen in angiographic exams, along with complete blockage of the internal carotid artery (ICA). Consequently, the external carotid artery primarily supplies blood to the regions of the anterior cerebral artery (ACA) and middle cerebral artery (MCA) [1] .

7. Treatment Options for Moyamoya Disease

7.1. Conservative Management

The primary objective in managing Moyamoya disease is to maintain cerebral blood flow and prevent additional strokes resulting from the gradual formation of blood clots. Aspirin is often prescribed to prevent strokes in moyamoya patients, despite limited evidence of its direct benefits. Many neurologists still recommend its use due to its potential to reduce the risk of future strokes, considering other risk factors. Aspirin is also used as a long-term therapy to prevent blood clot formation. The recommended dosage generally falls between 50 and 100 mg [52] [53] . Yuki Hamada et al. found ivy signs on imaging scans of a 67-year-old patient with moyamoya disease which were associated with an increase in the size of cerebral infarction but disappeared once the ischemia resolved, suggesting changes in blood flow. Interestingly, the patient had a favorable outcome without the need for antithrombotic therapy. This emphasizes the significance of considering multiple factors, including the patient’s anatomical background and the severity of ischemia, when managing moyamoya disease during the acute phase [54] . However, in a study by Jae Youn Kim et al., it was found that cilostazol led to larger outer diameters and less severe narrowing compared to other treatment groups. When considering clinical and genetic factors, it was determined that only the use of cilostazol was independently linked to negative remodeling after treatment [55] .

7.2. Surgical Management

The most effective treatment for Moyamoya disease (MMD) is recommended when there is a decline in cerebral hemodynamics. Surgery is especially beneficial for children due to the rapid progression typically seen in the pediatric form of MMD [56] . There are multiple bypass techniques available for revascularization in Moyamoya disease (MMD). The choice of technique depends on factors like the patient’s age, preoperative hemodynamics, neurological condition, and the specific areas in need of revascularization and at higher risk [57] . Encephalomyo spongiosis (EMS) and encephalo-duro-arterio spongiosis (EDAS) are procedures that use different arteries as blood supply sources. Various techniques, such as EMAS, EDAMS, and EGS, are used for different cases of Moyamoya disease. In situations where the posterior circulation is affected, the occipital artery can be employed as an indirect bypass [58] . Yixuan et al. found that indirect revascularization surgery using the superficial temporal artery (STA) as the bypass vessel resulted in a rapid and short mean transit time (MTT) before and after the procedure. Although there was no statistical difference between subgroups, the study suggests that this surgery can effectively decrease the risk of recurrent stroke in patients with both Moyamoya disease (MMD) and Moyamoya syndrome (MMS) [59] . Sanjeev A Sreenivasan et al’s study found a minimal occurrence of perioperative stroke and reversible transient ischemic attack (TIA). Additionally, it was interesting to note that 87% of patients experienced symptomatic improvement after undergoing the procedure [60] . Ultimately, Xiang-Yang Bao et al’s study found that indirect reconstruction is a better approach for improving blood supply in ischemic areas of the brain compared to direct revascularization. Indirect reconstruction provides more stable and long-lasting benefits, while direct revascularization only offers temporary relief. The blood supply formed through indirect reconstruction is based on the severity of ischemia, allowing for a natural and balanced distribution of blood to different areas. It typically takes several weeks or even months for new collateral circulation to develop after indirect revascularization [61] .

7.3. Direct Revascularization

In this surgical approach, the external temporal artery is used as the primary vascular circulation for arterial bypass surgery. It leads to immediate improvement in cerebral blood flow but requires a skilled surgeon. A study by Feng Gao et al. found similar Glasgow Coma Scale (GCS) scores after surgery in both groups. However, there were notable differences in clinical effectiveness and overall success rate. Both groups showed improvement in modified Rankin Scale (mRS) scores and Karnofsky Performance Scale (KPS) scores on the seventh-day post-surgery. Therefore, combining superficial temporal artery-middle cerebral artery bypass grafting surgery with a temporal muscle patch can result in better clinical outcomes for patients with Moyamoya disease, leading to a reduction in coma symptoms [62] .

7.4. Combined Bypass

This surgical approach combines direct and indirect bypass techniques using the superficial temporal artery (STA) to the middle cerebral artery (MCA) anastomosis and encephaloduroarteriosynangiosis (EDAMS). The parietal branch is used for direct bypass, while the remaining STA branch is used for pial synangiosis. A study by Siang Lee et al. found that the rates of perioperative adverse events were similar between the direct/combined bypass (DB/CB) and indirect bypass (IB) groups, except for slightly higher wound complications in the DB/CB group. However, the rates of post-surgical revascularization favored DB/CB over IB. Therefore, combined bypass is a Reliable and efficient option for pediatric patients with moyamoya disease/moyamoya syndrome. However, there is insufficient evidence to conclusively support the notion that direct bypass or collateral bypass may yield superior long-term angiographic revascularization results in comparison to indirect bypass [63] .

7.5. Palliative Embolization Where Radiosurgery Is Not Suitable

Very rarely reported in recent studies, where surgical management is very challenging and even controversial, when there is incidental existence of Arteriovenous malformation with MMD (1.7 per 1000 persons), where the vascular circular to the affected area comes from the branches of the external carotid artery (ECA) that pass through the protective membrane surrounding the brain called the dura mater [64] [65] . The symptoms of neurodegenerative diseases, such as progressive focal deficits, seizures, cognitive decline, and other neurological symptoms, can make it difficult to recognize and diagnose these conditions [66] . De Leacy R et al. highlighted that treating arteriovenous malformation in patients who have non-hemorrhagic neurological deficits can be a difficult and debated task [67] . Interestingly, imperial embolization is the best for arteriovenous malformation and arteriovenous fistula patients. Nevertheless, still controversial exists, since there is no justifiable evidence that it is necessary to fully treat arteriovenous malformation (AVM) and arteriovenous fistula (AVF), as it is important to consider that the blood supply to the anterior cerebral artery (ACA) and middle cerebral artery (MCA) might be dependent on the AVM [68] .

7.6. Future Promising Avenues: Role of Protein Connexin 43 on Moyamoya Disease

New and promising treatment options for Moyamoya disease have been discovered. A study by Liming Zhao et al. examined the effects of autologous bone marrow stem cell therapy (ABMSCT) on inflammatory factors and Conexin43 (Cx43) protein levels in patients with Moyamoya disease. The results showed that the experimental group had lower percentages of patients in higher disease grades (IV, III, and II) compared to the control group. Conversely, the experimental group had a higher percentage of patients in the lowest disease grade (I) compared to the control group. Additionally, the experimental group experienced reduced incidences of intracranial infection, hydrocephalus, hemiplegia, and transient neurological dysfunction [69] . These positive outcomes were attributed to the ABMSCT treatment’s ability to decrease inflammatory response, remove damaged vascular tissues, and promote tissue repair, surpassing the benefits of surgical interventions.

8. Conclusion

The specific cause of Moyamoya disease (MMD) is still unknown, but research suggests that genetic factors and complex immune and inflammatory responses contribute to its development. While MMD can present with different clinical symptoms, surgical treatment remains the primary approach for achieving meaningful clinical improvements. The main challenge that remains is recognizing Moyamoya disease as a potential diagnosis in all patients who exhibit signs of a stroke. It is crucial to promptly evaluate these patients and provide appropriate treatment options based on their specific conditions.

Availability of Data and Materials

The data used to support the findings in this review article are incorporated in the article.

Authors’ Contributions

The authors M. C. M conceived the idea; D. Y and M. C. M drafted and wrote the manuscript; D. Y and D. Z provided the cornerstone intellectual contents in writing up the manuscript. All authors have read and agreed to publish the article.

NOTES

*Corresponding authors.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

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