East Asian countries feature the highest incidence of moyamoya disease, more particularly Japan and the Republic of Korea. A study conducted in Japan reported the total annual number of moyamoya disease patients at 3,900, with prevalence and annual incidence rates of 3.16 and 0.35 per 100,000, respectively, in 1994. The female-to-male ratio was 1.8 and 10 % of the patients had a family history of the disease. The distribution of the age at onset has two peaks: a dominant peak at 5 years of age and a more modest peak around the late 20s to 30 years of age [4]. A recent review of regional differences shows that incidences per 100,000 patient-years ranged in Japan from 0.35 to 0.94 (95 % CI 0.69–1.19) and in the USA from 0.05 (−0.04–0.12) in Iowa to 0.17 (−0.06–0.40) in Hawaii and were 0.41 (0.28–0.54) in Nanjing, China, and 0.02 (0.003–0.04) in Taiwan. The female-to-male ratio ranged from 1.1 (0.9–1.5) in Nanjing to 2.8 (1.2–6.1) in Iowa. Proportions with cerebral hemorrhage as the initial presentation were 56 % in China, 52 % in Taiwan, 29 % in Hawaii, 21 % in Japan, and 10 % in Iowa. Patients with childhood onset presented most often with ischemia (more than 75 %) in all regions [5].

MMD has two peak ages of onset, initially at 5 years of age (pediatric or juvenile type) and subsequently at 30–50 years of age (adult type). Peak age in male is 10–14 years and 35–49 years, whereas peak in female is 20–24 years and 50–54 years [6]. In 2003, the total number of patients treated in Japan was estimated at 7,700. The female-to-male ratio was 1.8, and a family history was found in 12.1 % of patients. The prevalence rate was calculated at 6.03 per 100,000, and the annual rate of newly diagnosed cases was 0.54 per 100,000. In 2009, an analysis of the regional all-inclusive epidemiological data obtained in Hokkaido, a major island of Japan counting a population of 5.63 million [7], reported a prevalence of 10.5 patients per 100,000 and an annual incidence of 0.94 per 100,000, both of which greatly exceeded the results of the previous surveys. The female-to-male ratio was 2.18 and the age of onset occurred in two peaks with a different trend: the highest peak arose between 45 and 49 years, and the second occurred between 5 and 9 years. A familial history was observed in 15.4 % of patients. These epidemiological features differ significantly from the data obtained in previous studies. However, the higher detection and prevalence reported may not reflect an actual increase in the incidence of moyamoya disease, but may rather be due to the increased availability of noninvasive diagnostic tools, such as MRI/MR angiography.

Moyamoya disease patients’ age distribution shows characteristic bimodal pattern, pediatric and adult patients. The precise mechanism for this bimodal distribution has not been determined. In the pediatric patients, the rapidly progressing maturation of the brain may precipitate deficiency of a balance with cerebral blood flow maturation, and as a consequence, patients progress to develop ischemic attack. However, still many things are unknown about pediatric normal development of cerebral blood flow. This lack of balance between maturation of the brain and development of cerebral blood flow might not be able to explain the full mechanism of the development of ischemic attack in pediatric moyamoya disease patients. In adult moyamoya disease patients, hemorrhagic symptom can occur more commonly than in pediatric patients. In adult moyamoya patients, prevalence of ischemic and hemorrhagic symptom is almost the same.

Another unsolved issue of moyamoya disease is why the number of patients between these pediatric and adult moyamoya patients is small. About this issue, ischemic symptom which commonly occurs in pediatric period may become unlikely to occur because a balance between brain maturation and cerebral blood flow will be achieved. After getting over this dangerous pediatric period, moyamoya disease patient may become symptomatic due to a decrease of cerebral blood flow by arteriosclerosis in the adult period.

Most studies about cytokines in moyamoya disease patients have been performed by the examination of cerebrospinal fluid (CSF) sampled from the subarachnoid space during surgical therapy. Angiogenetic cytokines such as basic fibroblast growth factor (b-FGF), hepatocyte growth factor, and transforming growth factor (TGF) showed increased concentrations in the CSF as well as in other surgical specimens such as the arterial wall specimens and the meningeal specimens. Among these cytokines, angiogenetic cytokine b-FGF has been thought to be related with several findings in moyamoya disease: steno-occlusive lesion in the circle of Willis, the development of moyamoya vessels and dilatation of the cortical small arterioles, and angiogenesis after surgical indirect synangiosis therapy. Reportedly, b-FGF induces the proliferation of vascular endothelial cells, which may precipitate the stenosis of the major arteries. On the contrary, b-FGF has also an angiogenetic and dilatation effect on the small arteries, which may explain the development of moyamoya vessels and the dilated pial arterioles on the cortex in moyamoya disease [10].

The role of cytokine abnormality in moyamoya disease has not yet been totally determined. Elevation of cytokines in the CSF may simply reflect the response of cytokines to hypo-oxygenation status in moyamoya disease. In this scheme, elevated concentrations of cytokines may simply be a consequence of hypo-oxygenation but not a direct pathogenesis of moyamoya disease. Validation study for the elevation mechanism of cytokine levels will be necessary [10].

In cases of familial moyamoya disease, the gene loci 3p24-p26 and 8q23 have been identified using genome-wide analysis, while loci 6q25 and 17q25 were determined using chromosomal search.

Cases of unilateral moyamoya disease progressing to bilateral moyamoya disease have been well known, as well as progression of major artery stenosis on the contralateral side to the initial disease. It has thus been suspected that major artery stenosis, unilateral moyamoya disease, and bilateral moyamoya disease were among a spectrum of relational phenomena, based on genetic susceptibility. In addition, familial moyamoya disease has been known to be an autosomal dominantly inherited disease with incomplete penetrance, and various stages of the disease are thus observed in familial moyamoya disease patients. From these points, a combination of internal genetic factors and external environmental factors has been believed to be relevant for disease occurrence or progression. These mechanisms of moyamoya disease have been reported to be relevant with three heterogeneities, disease heterogeneity, genetic heterogeneity, and locus heterogeneity [11].

Recently, a genome-wide association study identified ring finger protein (RNF)213 (http://​omim.​org/​entry/​613768) as the first moyamoya disease gene [12]. Also, another genome-wide linkage analysis by assuming the inheritance pattern of moyamoya disease as autosomal dominant mode with incomplete penetrance and whole genome-exome analysis provided evidence suggesting the involvement of RNF213 in genetic susceptibility to moyamoya disease [13]. Further studies are ongoing to clarify the biochemical function and pathological role of RNF213 in moyamoya disease [14].

The clinical features of moyamoya disease show substantial difference between pediatric and adult patients. Most pediatric patients with moyamoya disease develop transient ischemic attack (TIA) or cerebral infarction, whereas about half of adult patients develop intracranial bleeding, and half develop TIA or cerebral infarction or both [28]. The symptoms and clinical course may change according to the age and the disease type manifested at the initial attack, and a wide range of severity of symptoms have been noted, such as TIAs and hemorrhagic stroke which resulted in permanent neurological deficits.

According to the recent increase in the availability of MRI/MRA, increasing numbers of patients have been reported, who were incidentally diagnosed as having moyamoya disease during the asymptomatic stage [15] or with only minor complaint such as headache [3]. In pediatric population, acute infantile hemiplegia is one of the most important symptoms of moyamoya disease. Benign familial nocturnal alternating hemiplegia of childhood has been also reported to be a possible symptom of moyamoya disease.

The frequency of each initial symptom in the 1,127 definitive moyamoya disease patients registered until 2000 is presented in Table 1 for the patients with the hemorrhagic type and ischemic type (infarction type, TIA type, and frequent TIA type) of initial attack. For both types, muscle weakness, consciousness disturbance, headache, speech disorder, and sensory disturbance were the most frequent; however, the incidence of consciousness disturbance and headache was higher. Incidence of muscle weakness was lower for patients with the hemorrhagic-type than for the ischemic-type initial attacks (p < 0.01) [3].

Moyamoya disease patients usually show cerebral ischemic change in the anterior territory of the ICA, particularly in the frontal lobe. Therefore, most patients with symptomatic moyamoya disease may present with focal neurological deficits, such as dysarthria, aphasia, or hemiparesis. However, moyamoya disease patients might also occur with other relatively atypical symptoms such as consciousness disturbance, sensory disturbance, visual symptoms, or involuntary movements, particularly in children [29, 30]. Some pediatric patients develop intellectual impairment owing to frontal lobe ischemia, infarction, or both [31]. In adult moyamoya disease patients, cognitive dysfunction, such as short-term memory disturbance, irritability, or agitation, has been reported. Patients who present with these atypical symptoms may be misdiagnosed with psychiatric disorders, such as schizophrenia, depression, or personality disorder.

In pediatric patients, ischemic attacks are typically induced by hyperventilation, for example, when crying or playing with a pinwheel. Electroencephalogram (EEG) findings in pediatric moyamoya patients are characteristic. In healthy children, high-amplitude slow waves are induced during hyperventilation, which will disappear after hyperventilation stops (an event known as build-up phenomenon). However, in pediatric moyamoya disease patients, the slow waves appear again after a recovery of normal ventilation. Pediatric moyamoya disease patients sometimes develop TIA when slow waves appear again during EEG scans. This reappearance of slow waves is pathognomonic for pediatric moyamoya disease patients and is known as rebuild-up phenomenon [32]. Recently, this rebuild-up phenomenon has been reported to be induced by post-hyperventilation hypoxia combined with a hyperventilation-induced reduction in cerebral blood flow and originates in the deep cortical sulci, where the cerebral perfusion reserve is diminished [33]. Rebuild-up phenomenon can completely disappear after effective surgical revascularization [33] (Fig. 5).

About a half of adult moyamoya disease patients develop intracranial hemorrhage, though hemorrhagic symptom is rare in pediatric moyamoya patients [24]. Also, hemorrhagic symptom has been known to be more common in female patients than male patients. Hemorrhagic symptom patients show more severe symptom and deteriorated outcome than ischemic symptom patients.

Two main and one additional causes of intracranial hemorrhage in moyamoya disease have been assumed: (1) rupture of dilated, fragile moyamoya vessels or (2) rupture of saccular aneurysms in the circle of Willis especially in the posterior part. For the first cause, the rupture may be due to persistent hemodynamic stress on the moyamoya vessels and occurs mainly in the basal ganglia, thalamus, or periventricular region, which is common with basal moyamoya vessels. Intraventricular hemorrhage is more frequent in moyamoya disease patients than other origin hemorrhagic patients [34]. Peripheral aneurysms in the collateral vessels or moyamoya vessels might be identified on conventional digital subtraction cerebral angiography [35].

For the second cause, rupture of saccular aneurysms located around the circle of Willis occurs most commonly at the basilar artery bifurcation or at the junction of the basilar artery and the superior cerebellar artery. The vertebrobasilar system has an important role in providing collateral circulation for steno-occlusive change of bilateral internal carotid arteries in moyamoya disease patients. Consequently, hemodynamic stress probably may precipitate the formation of a saccular aneurysm predominantly in the posterior part of the circle of Willis or vertebrobasilar system. Rupture of a saccular aneurysm in the vertebrobasilar system can cause subarachnoid hemorrhage [36]. Therefore, in the imaging diagnosis of moyamoya disease patients, scrutiny for aneurysm especially in the vertebrobasilar system is important. 3-T MRI/MRA examination has superior signal-to-noise ratio, higher spatial resolution, and less invasiveness and, therefore, is suitable for clinical routine follow-up examination for moyamoya disease patients [18].

There is increasing reports that adult moyamoya disease patients might present subarachnoid hemorrhage over the cerebral cortex despite the absence of an intracranial aneurysm [37]. A third cause of intracranial hemorrhage in adult moyamoya disease patients is rupture of the dilated collateral pial superficial arteries on the brain cortical surface, although this is rare [37] (Figs. 6 and 7).

Recently, headache is also considered to be one of the common clinical presentations of pediatric moyamoya disease patients. In many clinical cases, pediatric patients complaining headache may not be considered as having moyamoya disease, and other origins of headache such as meningitis or brain tumor will be looked for. Headache can be seen in about 20–30 % of moyamoya disease patients. Specific type of headache for moyamoya disease patients has not been reported; however, patients can show migraine in the more severely affected side. Also, patients with alternating hemiplegia of childhood showing migraine and hemiplegia have been reported [38]. Moyamoya disease patients may complain of headache before and after revascularization surgery. Preoperative headache in moyamoya disease patients was considered to be related to hypoperfusion or hypo-oxygenation because it has been reported that headaches disappeared after revascularization surgery [39].

Involuntary movements are relatively rare symptoms in moyamoya disease patients, and their frequency is estimated about 5 % [40]. Association of various involuntary movement disorders with moyamoya disease has been reported in the literature. The spectrum of these involuntary movements includes chorea, choreoathetosis, dyskinesia, dystonia, limb shaking, and epilepsia partialis continua. Some of them may occur in a paroxysmal manner, while others can be triggered by the initiation of some movement (“kinesigenic” manner) [41], by some particular form of exercise, or by various types of hyperventilation maneuvers. The involuntary movements are usually transient, ranging in duration from several seconds to a few months, and rarely constant [40].

The main mechanism of onset of these involuntary movements is thought to be cerebral hypoperfusion induced by steno-occlusive change of the internal carotid arteries in the circle of Willis. Limb shaking is typically triggered by diffuse hemispheric hypoperfusion caused by severe stenosis of the ICA. Any activities inducing hyperventilation, such as singing and crying, may precipitate the involuntary movement, because of induced cerebral hypoperfusion. This hypothesis is supported by the fact that revascularization surgery is associated with improvement of the involuntary movements or at least a significant decrease in their frequency [40].

Moyamoya disease should be classified as definitive or probable based on the abovementioned items (1) to (4) [3]. For definitive moyamoya disease, all criteria listed in (1) or (2) and in (3) should be fulfilled. In pediatric patients, however, the criteria in item (1) or (2) (i) and (ii), on one side, and visible stenosis around the terminal portion of the internal carotid arteries, on the other side, are sufficient for a definitive moyamoya disease diagnosis. For probable moyamoya disease, all criteria are fulfilled except item (1) (iii) and/or item (2) (iii) among the criteria of (1) or (2) and (3).

CT scan is one of the primary survey modalities for patients suspected of stroke; however, any definitive diagnostic information of moyamoya disease may not be obtained by this modality. In advanced stages of moyamoya disease, chronic cerebral infarction and unusual cerebral atrophy can be seen on CT scan; however, definitive diagnosis cannot be done [43]. On unenhanced CT scan, the steno-occlusive change and development of moyamoya vessels are not apparent. For the assessment of cerebral vessels, contrast-enhanced CT scan and CT angiography is necessary, and they can precisely show the steno-occlusive change and development of moyamoya vessels. During the diagnosis process of moyamoya disease, findings of unenhanced CT scan of stroke is not enough to exclude moyamoya disease, and further examination such as MRI/MRA or conventional angiography is necessary [43].

Unenhanced CT scan is a reliable imaging modality when the diagnosis of an ischemic or hemorrhagic stroke is suspected. In adult moyamoya disease patients, hemorrhage is common such as intraventricular hemorrhage, cerebral hemorrhage, and subarachnoid hemorrhage due to rupture of moyamoya vessels or aneurysms. In any cases of supratentorial cerebral hemorrhage seen on unenhanced CT scan, hemorrhage due to moyamoya disease must be considered as a differential diagnosis, and further examination such as contrast-enhanced CTA is recommended [43].

The recent advancement of multi-detector row computed tomography (MDCT) scanners has enabled high-resolution three-dimensional reconstruction. CTA and MRA were compared in terms of the steno-occlusive changes exhibited in each vessel. CTA and MRA scores were assigned on the basis of the severity of occlusive changes in the ICA, MCA, ACA, and posterior cerebral artery (PCA). CTA scores were significantly correlated with MRA scores, and their scores were in complete agreement in 39.6 %. The mean CTA score was significantly lower than the mean MRA score. CTA using MDCT is having a higher spatial resolution, therefore, can be a more reliable method than MRA for diagnosing moyamoya disease, particularly in emergency cases [44] (Figs. 9 and 10).

In moyamoya disease patients, anterior circulation (steno-occlusive change of the ICA and collateral moyamoya vessels), posterior circulation (steno-occlusive change of the PCA and leptomeningeal anastomosis collateral vessels from the posterior circulation), and transdural anastomosis collateral vessels such as ethmoidal moyamoya vessels and vault moyamoya vessels should be evaluated to monitor the hemodynamic state of moyamoya disease patients. Time-of-flight (TOF) MRA method is more suitable than phase contrast MRA or other MRA methods because TOF-MRA can show the steno-occlusive change of the major artery and development of moyamoya vessels simultaneously and more precisely. MRI/MRA examination can provide the significant diagnostic information less invasively (without ionizing radiation exposure) compared to conventional angiography.

Cerebral angiography is essential for a definitive diagnosis of moyamoya disease [3]. MRI/MRA can also be used for a definitive diagnosis when the following findings are fulfilled on TOF-MRA imaging conducted using a scanner with a static magnetic field strength of more than 1.5-T (especially 3-T MR scanner is preferable):

Moyamoya disease stage classification has also been reported based on the MR findings (Table 2). In this classification system, the stage is determined by simply assigning scores to the MRA findings and then totaling the scores. The stage classification using this method corresponds well to the conventional classification based on angiography and has been reported to show high sensitivity and specificity [45].

Fluid-attenuated inversion recovery (FLAIR) image has been widely used for the diagnosis of stroke and other cerebral abnormalities with a high capability of lesion detection by nulling the CSF signal with an employment of sophisticated inversion pulse [46]. Characteristic imaging finding on FLAIR has been reported in moyamoya disease patients [46]. On FLAIR image, moyamoya disease patients may show linear or serpentine high signal in the sulci along the cortical surface, which is believed to represent dilated leptomeningeal collateral vessels [46], and this finding is called “FLAIR ivy sign” because of its appearance resembling an ivy on the wall. This sign is frequently observed in distal areas with decreased perfusion caused by vascular stenosis including moyamoya disease. This mechanism of high signal on FLAIR image may at least partly share with the mechanism of findings intra-arterial high signal on FLAIR ivy sign may partly share the mechanism of intra-arterial high signal observed in acute cerebral infarction on FLAIR [47]. The mechanism of FLAIR ivy sign is also applicable to the deep medullary vessel area in moyamoya disease patients, and linear high signal ivy sign was also reported in the deep white matter [48].

FLAIR ivy sign can change its appearance responding to the change of hemodynamic status and, therefore, is useful for the evaluation of hemodynamic status in moyamoya disease patients. Its presence correlates highly with reduced CVR indicating misery perfusion area, and regional arteriocapillary circulation time was elongated [49] but was decreased after bypass surgery, correlated with improved hemodynamic status observed by ¹²³I-IMP-SPECT [50, 51] (Figs. 11, 12, 13 and 14).