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Moyamoya disease is a unique cerebrovascular disease that is characterized by progressive bilateral stenotic alteration at the terminal portion of the internal carotid arteries. These changes induce the formation of an abnormal vascular network composed of collateral pathways known as moyamoya vessels. In quasi-moyamoya disease, a similar stenotic vascular abnormality is associated with an underlying disease, which is sometimes an inflammatory disease. Recent advances in moyamoya disease research implicate genetic background and immunological mediators, and postulate an association with inflammatory disease as a cause of, or progressive factor in, quasi-moyamoya disease. Although this disease has well-defined clinical and radiological characteristics, the role of inflammation has not been rigorously explored. Herein, we focused on reviewing two main themes: (1) molecular biology of inflammation in moyamoya disease, and (2) clinical significance of inflammation in quasi-moyamoya disease. We have summarized the findings of the former theme according to the following topics: (1) inflammatory biomarkers, (2) genetic background of inflammatory response, (3) endothelial progenitor cells, and (4) noncoding ribonucleic acids. Under the latter theme, we summarized the findings according to the following topics: (1) influence of inflammatory disease, (2) vascular remodeling, and (3) mechanisms gleaned from clinical cases. This review includes articles published up to February 2019 and provides novel insights for the treatment of the moyamoya disease and quasi-moyamoya disease.

Moyamoya disease (MMD) is a unique progressive steno-occlusive disease of the distal ends of bilateral internal arteries and their proximal branches. The difference in clinical symptoms between adult and children MMD patients has been well recognized. In this study, we sought to investigate the phenomenon through histopathological study. Fifty-one patients underwent surgical procedures for treatment of standard indications of MMD at Kyoto University Hospital. Fifty-nine specimens of MCA were obtained from MMD patients during the surgical procedures. Five MCA samples were also obtained in the same way from control patients. The samples were analyzed by histopathological methods. In this study, MCA specimens from MMD patients had significantly thinner media and thicker intima than control specimens. In subsequent analysis, adult (≥ 20 years) patients had thicker intima of MCA compared to pediatric (< 20 years) patients. There is no difference in internal elastic lamina pathology between adult and pediatric patients. Our results indicated that the pathological feature of MMD in tunica media occurs in both adult and pediatric patients. However, the MMD feature in tunica intima of MCA is more prominent in adult patients. Further analysis from MCA specimens and other researches are necessary to elucidate the pathophysiology of MMD.

This review describes the basic concepts of surgical revascularization for moyamoya disease, including direct and indirect bypass surgery. Direct bypass surgery can improve cerebral hemodynamics and reduce further ischemic events immediately after surgery, but may be technically challenging in some pediatric patients. Indirect bypass surgery is simple and has widely been used. However, its beneficial effects can be achieved 3 to 4 months after surgery, and surgical design is quite important to determine the extent of surgical collateral pathways. Combined bypass procedure, especially superficial temporal artery (STA) to middle cerebral artery anastomosis and indirect bypass, encephalo-duro-myo-arterio-pericranial synangiosis, is a safe and effective option to improve the short- and long-term outcome in patients with moyamoya disease. Alternative techniques are also described for specific cases with profound cerebral ischemia in the anterior cerebral artery or posterior cerebral artery territory. Special techniques to safely complete bypass surgery and avoid perioperative complications are presented, including methods to prevent delayed wound healing, to avoid facial nerve palsy after surgery, and to preserve the STA and middle meningeal artery during skin incision and craniotomy. Finally, the importance of careful management of patients is emphasized to reduce the incidence of perioperative complications, including ischemic stroke and hyperperfusion syndrome.

The mechanisms through which moyamoya disease occurs and progresses remain unknown. Recent studies have indicated the involvement of circulating endothelial progenitor cells (EPCs) in the development of moyamoya disease. This study directly investigated the participation of EPCs in moyamoya disease, using specimens of the supraclinoid internal carotid artery collected from two adult patients. The specimens were stained with primary antibodies against CD34, CD133, and vascular endothelial growth factor receptor-2 (VEGFR2) to localize the circulating EPCs in the thickened intima of occlusive arterial lesion. The CD34- and VEGFR2-positive cells were densely found in the thickened intima of occlusive arterial lesion, particularly clustered in the superficial layer of thickened intima. However, the number of CD34- and CD133-positive cells was very small. The CD34-positive cells also expressed von Willebrand factor on the surface of thickened intima and were also positive for α-smooth muscle actin in the deeper layer. These findings suggest that circulating EPCs may be involved in the development of occlusive arterial lesion in moyamoya disease.

Three cases of ruptured intracranial aneurysm associated with moyamoya disease are presented. Endovascular treatments were performed successfully in two patients with major artery aneurysms. One patient with a collateral aneurysm was managed conservatively and follow-up angiography 1 year later demonstrated spontaneous disappearance of the aneurysm. Our experience suggests that although aneurysms associated with moyamoya disease show differences in evolution and location, endovascular treatment of major artery aneurysms is safe and effective, and peripheral aneurysms which cannot be directly accessed for surgery or endovascular embolization may be treated conservatively.

A 69-year-old woman was admitted to our hospital because of fluctuating dysarthria during the past 2 months. Magnetic resonance imaging revealed old cerebral infarction of the left cerebral hemisphere with acute subarachnoid hemorrhage in the left sylvian fissure. Cerebral angiography showed a large saccular aneurysm, 14 mm in diameter, at the bifurcation of the left middle cerebral artery (MCA) in association with moyamoya vasculopathy with atherosclerosis, including steno-occlusive changes at the bilateral terminal internal carotid arteries and abnormal net-like vessels at the base of the brain. She underwent microsurgical neck clipping of the large aneurysm followed by superficial temporal artery-MCA anastomosis without complication. Intraoperative findings showed no evidence of aneurysm rupture, suggesting that the subarachnoid hemorrhage was due to the intrinsic pathology of moyamoya vasculopathy. The postoperative course was uneventful, and the patient was discharged without neurological deficit. Association of moyamoya syndrome with large MCA aneurysm is extremely rare, and formation of large aneurysm at the vascular territory of an occluded vessel is apparently unique.

A 32-year-old man presented with malignant craniopharyngioma associated with moyamoya syndrome manifesting as right visual disturbance. Magnetic resonance (MR) imaging revealed a parasellar mass lesion diagnosed as adamantinomatous craniopharyngioma. He underwent three surgical procedures and repeated courses of radiotherapy, and was able to resume his daily life. MR imaging demonstrated tumor regrowth and bilateral occlusions of the internal carotid arteries (ICAs) with basal moyamoya phenomenon, which might have been induced by irradiation and/or tumor compression, 10 years after the initial manifestations. Sufficient debulking was safely achieved via the transsphenoidal route and histological examination revealed squamous cell carcinoma, indicating malignant transformation of craniopharyngioma. The tumor relapsed after only one month, so transsphenoidal tumor debulking was tried again. However, the postoperative course was unfavorable because of intraoperative bleeding from the right ICA. Malignant transformation of craniopharyngioma may be included in moyamoya syndrome. The treatment strategy should be carefully considered in such a complicated situation.

Moyamoya disease is characterized by progressive occlusion of the internal carotid artery or its terminal branches, associated with formation of extensive collateral vessels (moyamoya vessels) at the base of the brain. Whether unilateral moyamoya disease, confirmed by typical angiographic evidence of moyamoya disease unilaterally and normal or equivocal findings contralaterally, is an early form of definite (bilateral) moyamoya disease remains controversial. The present study investigated the incidence and clinical features of unilateral moyamoya disease in a series of patients treated for moyamoya disease. Fifty-two patients were diagnosed with definite moyamoya disease and nine patients with unilateral moyamoya disease. Sex, age, signs at onset, neuroimaging findings, treatment, course of the disease, and family history of unilateral moyamoya disease were reviewed. Among the nine patients with unilateral moyamoya disease, there were twice as many females as males, and mean age at onset was 39.0 years. The clinical presentation was ischemic in three patients, bleeding in one, and asymptomatic in five. Two had familial moyamoya disease. Progression to bilateral lesions is known to occur in pediatric patients and patients with stenotic changes of the contralateral internal carotid artery bifurcation. Some unilateral cases are caused by the same genetic defects as definite cases, and others seem to be an unusual form of stenoocclusive process of cerebral arteries. Surgical treatment on the symptomatic side followed by close observation for bilateral involvement is recommended.

A 55-year-old woman presented with moyamoya disease manifesting as recurrent transient ischemic attacks despite taking aspirin and antihypertensive agent. Angiography showed the characteristic angiographic appearance with bilateral internal carotid artery occlusion and abnormal collateral vessels. Left external carotid angiography demonstrated moderate stenosis of the proximal external carotid artery (ECA). A self-expandable stent was successfully placed in the left ECA to improve ipsilateral cerebral perfusion. The patient had an uneventful outcome after a 1-year follow up. Involvement of the proximal ECA is very unusual in moyamoya disease, and might result from hemodynamic stress or degenerative atherosclerosis. Revascularization procedures for stenoses of proximal ECA may improve cerebral perfusion in patients with moyamoya disease.

Moyamoya disease (MMD) is a cerebrovascular occlusive disease characterized by progressive stenosis or occlusion at the distal ends of the bilateral internal carotid arteries. Vascular structural changes were previously detected using postmortem specimens. This study investigated 35 specimens of the middle cerebral artery (MCA) from 25 patients undergoing surgical treatment for MMD. Six MCA samples were also obtained from six control subjects. Histological examination showed that MCA specimens from patients with MMD had significantly thinner media and thicker intima than control specimens. In addition, abnormal findings of the internal elastic lamina and eosin-positive deposits in the intima were detected. Medial thinness and intimal hyperplasia occurred in the MCA of patients with MMD.

Some patients with moyamoya disease treated by conventional surgical procedures may develop postoperative refractory ischemia and perioperative cerebral infarction in the anterior cerebral artery (ACA) territory. We present a novel operative procedure for moyamoya disease to avoid the risk of ischemia in the ACA territory, which consists of simultaneous superficial temporal artery (STA) to middle cerebral artery (MCA) or ACA bypass with pan-synangiosis, encephalo-duro-arterio-myo-synangiosis for the lateral frontal and temporal areas, and encephalo-galeo-arterio-synangiosis for the medial frontal area. This procedure can establish direct bypass to the ACA territory at the first intervention. Simultaneous STA-MCA and STA-ACA bypasses with pan-synangiosis is suitable for patients with moyamoya disease associated with severely impaired perfusion of the ACA territory requiring direct bypass surgery.

A 40-year-old female presented with growth hormone (GH)-secreting pituitary adenoma associated with primary moyamoya disease manifesting as amenorrhea, acromegaly, and transient ischemic attack. Magnetic resonance (MR) imaging revealed a tumor mass extending from the sella turcica to the suprasellar cistern, and MR angiography demonstrated stenoses in the bilateral internal carotid arteries with basal moyamoya vessels. Her blood GH and insulin-like growth factor (IGF-1) levels were elevated to 78.94 and 923.0 ng/ml, respectively. The patient underwent removal of the pituitary adenoma because her ischemic symptoms disappeared after oral aspirin medication. Subtotal resection resulted in persistence of the high blood GH and IGF-1 levels. Postoperative MR angiography showed progression of the stenoses in the bilateral internal carotid arteries. Excess systemic GH and IGF-1 may participate in the progression of vascular disease and so could have caused the deterioration of the moyamoya disease.

The diagnostic accuracy of three-dimensional constructive interference in steady state (CISS) magnetic resonance (MR) imaging was evaluated for the assessment of idiopathic moyamoya disease. Six consecutive patients underwent MR angiography, CISS imaging, and digital subtraction angiography. MR angiography and CISS imaging visualization of the steno-occlusive changes in the distal internal carotid arteries and the development of moyamoya vessels in the basal cistern were compared to the results obtained by digital subtraction angiography. MR angiography revealed the steno-occlusive changes correctly in nine and overestimated the changes in three of 12 hemispheres examined. CISS imaging showed the steno-occlusive changes defined as decreased caliber of the internal carotid artery correctly in two, underestimated the changes in nine, and overestimated the changes in one of the 12 hemispheres. MR angiography detected moyamoya vessels correctly in five and underestimated the vessels in seven of the 12 hemispheres. CISS imaging revealed the moyamoya vessels correctly in 10, underestimated the vessels in one, and overestimated the vessels in one of the 12 hemispheres. CISS imaging can supplement MR angiography in the non-invasive diagnosis of moyamoya disease, especially for the evaluation of moyamoya vessels.

A 61-year-old female presented with a unique case of moyamoya disease associated with pulmonary sarcoidosis. She was admitted for sudden onset of left temporalgia with episode of numbness on face, tongue, and upper extremity on the right side. The next morning, she had symptoms of Gerstmann syndrome and her ability to speak was disturbed. Her medical history included radical resection of lung cancer on the right side. She had no symptoms of pulmonary sarcoidosis. Neuroimaging showed an infarction in the left occipital lobe. Angiography showed occlusions of the bilateral internal carotid arteries at the supraclinoid portions. Subsequently, a left superficial temporal artery-middle cerebral artery anastomosis with encephalo-myo-synangiosis was performed. Ninety-three days after admission, she suddenly developed dyspnea which resulted in death 3 hours later. Autopsy findings showed typical epithelioid granulomas of sarcoid type in the lymph nodes of the peribronchus, lung, and liver. Thrombotic emboli were found in the bilateral pulmonary arteries, and marked fibrous intimal thickening in the bilateral internal carotid arteries. Immunological reaction with inflammatory events may cause pathological changes in patients with moyamoya disease or sarcoidosis. The co-incidence in this case suggests that some common inflammatory events may be involved in the pathogenesis of these diseases.

A 19-year-old male presented with intraventricular hemorrhage manifesting as sudden onset of headache. Angiography showed mild stenotic changes in the distal internal carotid artery and proximal anterior cerebral artery only on the right. The anterior choroidal artery and lenticulostriate arteries appeared dilated, and an aneurysm-like shadow was seen in the distal right anterior choroidal artery. He was discharged without treatment. Eighteen months later, he presented with a second intraventricular hemorrhage manifesting as sudden occipitalgia, vomiting, and nausea. He had hyperreflexia of the left extremities and paresthesia of the left upper extremity. Angiography showed marked progression of the vascular abnormalities bilaterally. Moyamoya vessels were also present. He received bilateral encephalo-duro-arterio-myo-synangiosis with good results. Moyamoya disease may cause hemorrhage even at an early stage.

The authors examined 31 patients with moyamoya disease in Yugoslavia. Among them four intracranial aneurysms were disclosed, two in males and two others in females. The aneurysms, which were present in adult patients only, were diagnosed angiographically. Three of four patients died several days or weeks after onset of hemorrhage. The aneurysms were located within the basal abnormal vascular network, on a distal branch of the posterior cerebral artery, on the top of the basilar artery, and on the posterior branch of the middle meningeal artery. The moyamoya disease on the side of the individual aneurysms was most often stage III or IV.

A 30-year-old female and a 38-year-old male developed "definite" moyamoya disease after presenting with "probable" moyamoya disease manifesting as ischemic stroke. Angiography at first presentation demonstrated unilateral involvement with normal contralateral findings. The cases were classified as adult type "probable" moyamoya disease according to the diagnostic criteria. Follow-up angiography demonstrated the occlusive lesions had become bilateral, satisfying the criteria for "definite" cases. Serial angiography is required in adults presenting with "probable" moyamoya disease manifesting as ischemic stroke.

The authors report a case of unilateral moyamoya disease which developed into moyamoya disease 3 years later. Unilateral moyamoya disease is generally defined as moyamoya disease, but the exact relationship is unknown. In this case, occlusive changes developed in the stenotic carotid fork, and in a similar portion contralaterally which was intact. Follow-up 4-vessel angiography is strongly recommended even for unilateral moyamoya disease.