Epidemiology

MMD was initially thought to be confined to the Japanese population,³ but cases in other Asian populations were subsequently confirmed.^6,7 Moreover, its presence in non-Asian populations has increasingly been recognized, although at a much lower incidence,^6,8 and ethnicity seems to play a decisive role in the United States.^9–12 In 1992, Goto and Yonekawa reviewed 1063 patients with MMD from countries other than Japan and found 625 patients in Asia, 201 in Europe, 176 in North and South America, 52 in Africa, and 9 in Australia as published in the literature.⁶ The incidence and prevalence of the disease in Europe are believed to be around a 10th that in Japan.¹³

In Japan in 1995, an annual incidence of 0.35 per 100,000 population and a prevalence of 3.16 per 100,000 population were reported. The female-to-male ratio was 1.8. The age at onset had two peaks: a higher peak at 5 years and a lower one around 30 to 49 years.^14–16 These figures, however, seem to have changed (Table 356-1), as indicated by recent surveys.^17,18 The incidence and prevalence are more than twice as high as in the previous surveys. As for the age distribution, the higher incidence was observed in adults 45 to 49 years of age and the second in children 5 to 9 years of age.¹⁷ One of the reasons for the higher annual incidence and prevalence in the recent survey is thought to be the fact that MMD has been diagnosed in asymptomatic patients (up to 18%) on the basis of MRI and MRA findings.¹⁹ This situation is similar to that with cerebral aneurysms, in which unruptured or incidental aneurysms have been detected by MRI and MRA. The tendency for a decrease in the number of children affected in the population might be another reason for these changes. This tendency also affects the incidence of familial MMD. Previously, about 10% of patients had a familial form of the disease, but the recent report indicates an increased incidence of up to 15%. In the United States and Europe, however, familial occurrence has been reported to be less common (less than 6%).^10,20

Pathophysiology and Etiology

Since presumably the first autopsy report by Maki and Nakata in 1965 of a 9-year-old child who died of a subdural hematoma after a 7-year history of relapsing episodes of choreatic movements associated with progressive deterioration of vision and hearing,²¹ postmortem analyses have been performed mostly on adults with intracranial hemorrhage. The characteristic findings of intimal thickening and subsequent stenosis-occlusion at the terminal portion of the ICA along with pathologic changes in neighboring arteries have been enumerated in the guidelines for the diagnosis of MMD^15,22–24; fibrocellular thickening of the intima, irregular disruption of the internal elastic lamina, and attenuation of the media are the main findings. These changes have been observed not only in the carotid fork but also in cortical branches of the middle cerebral artery (MCA). In perforating arteries, microaneurysm formation and fragmented elastic lamina have been detected and are considered to be one of the reasons for intracerebral hemorrhage, as discussed later.

Sometimes, extracranial arteries such as the superficial temporal arteries (STAs) and renal arteries have also been shown to be affected by the same stenotic changes, so MMD can be considered to be a type of systemic disease.^14,23,25,26

Pluripotent peptides and their receptors, such as basic fibroblast growth factor, transforming growth factor-β, and hepatocyte growth factor, have been detected in increased amounts in the STA and the diseased wall of the ICA.^27–29 These growth factors can possibly affect the extent of angiogenesis and intimal hyperplasia in the intracranial and extracranial arteries. In addition, elevated serum levels of soluble vascular cell adhesion molecule type 1, intracellular adhesion molecule type 1, and E-selectin and elevated cerebrospinal fluid levels of nitric oxide metabolites or some specific polypeptides have been reported as well.³⁰ Presumably, endothelial activation by these molecular factors plays a cardinal role in inducing MMD. Recently, apoptosis of smooth muscle cells in the tunica media has been discovered, and elevated levels of caspase-3, an important molecule in the process of apoptosis, have been demonstrated in the tunica media of the MCA, along with elevated expression of hypoxia-inducing factor-1α in its endothelial layer (Fig. 356-2).^31,32 These data confirm that not only the ICA carotid forks but also the neighboring MCAs are affected.

FIGURE 356-2 Molecular biologic findings of the middle cerebral artery (MCA) adjacent to the carotid fork, which is also affected by the occlusive process. Confocal microscopic assessment by double immunofluorescence staining was performed to identify medial cells immunoreactive for single-stranded DNA (ssDNA) and cleaved caspase-3 in moyamoya disease specimens. A-C, Results of double staining for ssDNA (A, green) and actin (B, red). ssDNA-containing cells are also positive for actin (cells with a yellow appearance indicated by the arrows in C, the merged image). D-F, Results of double staining for cleaved caspase-3 (D, green) and actin (E, red). Cleaved caspase-3 is colocalized with actin, as indicated by the arrows in the merged image (F). Hematoxylin-eosin–stained specimens from the MCA (G-J). G and I, Moyamoya disease in the MCA. The intimal hyperplasia is remarkable (G, the arrow indicates the internal elastic lamina). The internal elastic lamina is disrupted (I, the arrow indicates disruption). H and J, The MCA of a control patient (arrows indicate the internal elastic lamina).

(From Takagi Y, Kikuta K, Sadamasa N, et al. Caspase-3-dependent apoptosis in middle cerebral arteries in patients with moyamoya disease. Neurosurg. 2006;59:894-901.)

Since founding of the RCMHWJ in 1977, a genetic approach to investigating cases of familial MMD has been conducted to clarify its pathogenesis. According to recent studies, the mode of inheritance of familial MMD, after having been thought to be multifactorial,^33,34 is presumed to be autosomal dominant with incomplete penetrance.³⁵ In addition, genomic imprinting may be associated with the disease. Furthermore, based on data from genome-wide parametric linkage analysis of MMD in 15 extended Japanese families, significant evidence of linkage has been observed on chromosome 17q25.3, on which a major gene locus for autosomal dominant MMD is considered to lie.^35,36

Clinical Findings

The clinical features of MMD differ considerably between pediatric and adult patients. According to reports from the RCMWHJ, cerebral ischemia, including transient ischemic attacks (TIAs), has been the most common finding (70% to 80%) in children, whereas intracranial bleeding is the typical finding in adults, especially women (up to 66%) (Table 356-2).³⁷ Cerebral ischemia (either TIA or infarction) is the next most common manifestation in adults. In line with our observation and that of other authors, however, cerebral ischemia and not bleeding seems to be the usual manifestation in Europe and the United States.^8–12,38,39 A sudden drop in performance because of low perfusion has been the only clinical finding in about 10% of our adult patients. Infarctions are observed in the cortical and subcortical regions, mainly in the watershed or posterior cerebral artery (PCA) territories, in about 40% of ischemic cases, but the basal ganglia and thalamus are usually spared.^13,40,41

TABLE 356-2 Differences in Clinical Features between Children and Adults with Moyamoya Disease*

* In Europe and the United States, ischemia (and not bleeding) has been reported to be predominant in adults.^8–12,20,38

Data from Handa H, Yonekawa Y. Analysis of filing data bank of 1500 cases of spontaneous occlusion of the circle of Willis and follow-up study of 200 cases for more than 5 years. Stroke (Tokyo). 1985;7:477-480.

The majority of bleeding in adults is intraventricular or periventricular in location and not subarachnoid. Such hemorrhages often recur, with an annual rebleeding rate of 7%, and a third of patients eventually suffer further hemorrhage after a variable interval (days to years)^42–44; the morbidity and mortality associated with these hemorrhages have been reported to be considerable, with only 45% of patients having good neurological recovery and 7% dying. Rebleeding, which often occurs at a location different from the original bleeding site, carries an even graver prognosis: only 20% of patients have a good recovery and nearly 30% die. There are three main causes of intracranial bleeding in patients with MMD^45–49: (1) rupture of dilated and stressed perforating arteries containing microaneurysms, (2) fibrinoid necrosis of the arterial wall in the basal ganglia, and (3) rupture of microaneurysms in the periventricular region, especially around the superolateral wall of the lateral ventricles. These peripheral “false” aneurysms located within moyamoya and peripheral arteries can be identified on cerebral angiography and may be the origin of the bleeding. A special type of subarachnoid hemorrhage over the cerebral cortex without any evidence of aneurysm and a fair prognosis has been sporadically but repeatedly reported in adult patients, although its pathophysiology still remains to be clarified.^50,51

Saccular cerebral aneurysms, a possible cause of a rather rare subarachnoid hemorrhage in this disease, are detected in 4% to 14% of patients, and 16% of these patients have been reported to have multiple aneurysms. These aneurysms occur in three locations^52–56: (1) 60% around the circle of Willis, mainly at the vertebrobasilar territory; (2) 20% in peripheral arteries, such as the posterior and anterior choroidal arteries; and (3) 20% in the abnormal moyamoya vasculature as mentioned earlier. The false aneurysms may disappear spontaneously or after revascularization procedures,⁵² but they might need to be removed surgically because of repeated bleeding.^45,49

Pregnancy and delivery may increase the risk for ischemic or hemorrhagic stroke in female patients.⁵⁷ Hemorrhagic stroke during pregnancy often leads to poor functional outcome.

Mortality in the acute stage has been reported to be low: 2.4% with the infarction type and 16.4% with the hemorrhagic type.²⁰

Incidentally, the terminology moyamoya angiopathy could be of practical use because it can include MMD (idiopathic without basic disease), moyamoya syndrome (with a basic disease such as neurofibromatosis, Down’s syndrome, or sickle cell anemia), or unilateral manifestation of the disease. This can be divided into three different types depending on one’s point of view (e.g., basic disease, unilaterality), but clinically the manifestation is the same, ischemia or bleeding, so that to coin these three under the concept of moyamoya angiopathy would be practical.^11,20

Neuroimaging

Cerebral angiography has been the most common method of diagnosing MMD, as has been emphasized in the diagnostic criteria for MMD by the RCMWHJ.^14,15 Known as the six-stage classification of Suzuki and Takaku,² angiographic progression follows the sequence of (1) narrowing of the carotid fork, (2) initiation of the moyamoya, (3) intensification of the moyamoya, (4) minimization of the moyamoya, (5) reduction of the moyamoya, and (6) disappearance of the moyamoya. Accordingly, narrowing of the ICA proceed to occlusion of the ICA so that finally collateral maintenance of the cerebrum via only the external carotid and vertebrobasilar systems. Progression from stage 1 to stage 6 has been observed in only a limited number of cases. Stage 4 is encountered most frequently. The proximal portion of the PCA is also involved in around half of affected patients,⁴¹ although the posterior circulation has not usually been thought to be affected and contributes as a main source of collateral circulation to the insufficient anterior circulation; steno-occlusive lesions of the posterior circulation were encountered in our European series in 11 patients (16%).²⁰ Attempts at staging on the basis of MRI or cerebral blood flow (CBF) findings or their combination have been made but they still need to be investigated and checked for general acceptance.^38,58 MMD is also characterized by an extensive peculiar development of collateral pathways (see Fig. 356-1)^2,59,60: (1) “basal moyamoya” in the basal ganglia and thalamus, namely abnormally dilated collaterals via the lenticulostriate arteries, the anterior choroidal artery, the posterior choroidal artery, and the posterior communicating artery, (2) “ethmoidal moyamoya” via the anterior and posterior ethmoidal arteries originating from the ophthalmic artery; and (3) “vault moyamoya” via the dural arteries, also called transdural anastomosis.

According to recent guidelines by the RCMWHJ, cerebral angiography is presently not necessary for definitive diagnosis if MRI and MRA (>1 T is desirable) clearly fulfill the criteria.¹⁵ Cerebral angiography still, however, has a solid position in the management of MMD, especially in the planning of surgical treatment and postoperative evaluation, although its inherent risk for ischemic complications should not be underestimated.