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.

Noninvasive imaging techniques can now be effectively used for the diagnosis of MMD. In particular, MRI and MRA demonstrate the characteristic findings of stenotic-occlusive carotid lesions and basal moyamoya, especially with the use of high-tesla settings (Fig. 356-3). T1-weighted MRI is sensitive in detecting basal moyamoya.^58,61 According to recent reports, microbleeding has been detected in about 15% to 44% of adult patients on T2-weighted images (Fig. 356-4). Microbleeding has been proposed as a predictor of subsequent hemorrhagic stroke.⁶²

FIGURE 356-3 Comparison of 1.5- and 3-T magnetic resonance angiography (MRA). A and C, 1.5-T MRA. B and D, 3-T MRA. Arrows indicate better visualization of moyamoya vasculature on the 3-T images.

FIGURE 356-4 Examples of microbleeding (arrows) seen on T2-weighted magnetic resonance imaging. A, Microbleeding at the ventricular wall in an adult patient with ischemia. B, Multiple microbleeding (along with a trace of past macrohemorrhage on the right side), especially in the left paraventricular region.

(Courtesy of Dr. K. Kikuta, Department of Neurosurgery, University of Kyoto.)

Once the diagnosis is made, other imaging modalities can provide additional decisive information for management of this disease. Xenon-enhanced computed tomography, single-photon emission computed tomography, and positron emission tomography (PET) can be used to measure regional CBF and metabolic distribution. Reduced CBF and cerebrovascular reactivity to CO₂ or acetazolamide (or to both) are characteristically detected in the ICA territory (Fig. 356-5).^63–67 Such reduction in cerebral perfusion pressure (cerebral blood volume [CBV]/CBF) is compensated by an increase in CBV and the oxygen extraction fraction. Perfusion instability detected by measurement of these parameters is supposed to forecast progression of the disease. These parameters can also be used to confirm the effectiveness of surgical revascularization.

FIGURE 356-5 Compromised hemodynamic reserve verified by H₂¹⁵O positron emission tomography and postoperative improvement in a patient with transient ischemic attacks. A, Impaired hemodynamic reserve on loading with acetazolamide (Diamox), especially in the left hemisphere. B, Postoperatively improved reserve in the left hemisphere at the territory of the anterior cerebral artery (ACA) and middle cerebral artery (MCA). The patient had been treated with a standard superior temporal artery (STA)-MCA bypass plus an STA-ACA bypass 3 months previously. A, anterior; L, left; P, posterior; R, right.

(Courtesy of Dr. A. Buck, Nuclear Medicine, University of Zürich.)

Treatment

Because of its unknown etiology, no specific treatment of MMD is available. Acetylsalicylic acid or other antiplatelet drugs are given because studies have revealed that they may have an influence on the progression of vascular stenosis. Relatively fresh thrombus has been seen at the stenotic site of the ICA on autopsy.^22,23 These agents might also be effective in the presence of atherosclerosis in adult MMD. Calcium antagonists have been administered empirically for headache and steroids for involuntary movement or at the time of frequent TIAs.¹⁴

Surgical Treatment

Surgical revascularization procedures are used to augment CBF and improve impaired hemodynamic situations that cannot be resolved by nonsurgical treatment. Neurosurgical techniques for the treatment of MMD have been grouped into two main categories: direct revascularization with microvascular extracranial-to-intracranial (EC-IC) bypass and indirect revascularization without microvascular anastomotic procedures. Currently, there are no clear data indicating definite superiority of either of the methods. The indirect revascularization method is aimed at stimulating the development of new vascular networks and is thought to lead to delayed collateralization, but the extent of revascularization is considered unpredictable, whereas direct revascularization can selectively perfuse ischemic areas immediately but, in so doing, may cause hyperperfusion syndrome as a complication.^68,69 Many surgeons are combining STA-MCA bypass and indirect revascularization, although the latter is done inadvertently more or less at the time of the STA-MCA bypass procedure and during closure of the craniotomy.

Direct Revascularization Procedure Using a Microvascular Technique for Superior Temporal Artery–Middle Cerebral Artery Bypass

The STA-MCA bypass technique pioneered in 1967 by Donaghy and Yasargil^70,71 was applied several years later by Reichman and colleagues, Karasawa and associates, and Yonekawa and Yasargil to the treatment of MMD.^72–74 The parietal or, less often, the frontal branch of the STA (donor vessels; ≈1 mm in diameter) is first located by Doppler sonography and then dissected along its course via a linear incision (8 to 10 cm of dissection and free preparation). This is followed by a small craniotomy (2.5 to 3 cm in diameter) with its center about 6 cm cranial to the external acoustic meatus, which corresponds to the end of the sylvian fissure. After locating a suitable branch of the MCA, direct anastomosis between the STA branch and the cortical MCA branch is achieved with 8 to 10 interrupted stitches of 10-0 or 11-0 suture. Common branches used in this technique are the angular, posterior temporal, and posterior parietal arteries. The rolandic or prerolandic arteries (or both) and in some cases the operculofrontal or candelabra group of branches can also be used by placing the craniotomy at another location according to findings on angiography or PET. Direct revascularization thus has the advantage of selectively supplying territories of ischemia detected by PET or other methods (STA–anterior cerebral artery [ACA] or STA-PCA bypass) (Fig. 356-6). As with mental retardation in children, adults with a remarkable drop in performance because of low perfusion in the ACA territory could benefit from an STA-ACA bypass in combination with a standard STA-MCA bypass (see Fig. 356-5).^8,75,76 The frontal branch of the STA is anastomosed to the medial internal frontal artery, a branch of the ACA (approximately 1 mm in diameter) at the medial convexity of the frontal lobe. It can usually be found a few centimeters anterior to the coronal suture. When the entire extent of the frontal branch is dissected, its length is long enough to reach the midline for completion of the anastomotic procedure.⁷⁵ Otherwise, an interposition graft in which either a portion of the parietal branch of the STA or a portion of the saphenous vein is placed between the frontal branch and the medial internal frontal artery will also make the procedure possible.⁷⁷ In patients with low perfusion of the PCA territory and corresponding symptomatology of visual disturbances, an STA-PCA or occipital artery–PCA bypass may be considered. Performance of the latter bypass via the supracerebellar transtentorial approach in the sitting position has the advantage that the trunk of the PCA does not need to be temporarily occluded for the anastomotic procedure; the posterior temporal artery, which courses over the parahippocampal gyrus at its posterior portion, is used as a recipient artery.⁷⁶

FIGURE 356-6 Artist’s drawing of a superior temporal artery–middle cerebral artery (STA-MCA) bypass along with an STA–anterior cerebral artery (ACA) bypass and an occipital artery–posterior cerebral artery (OA-PCA) bypass. A, Standard combination of an STA-MCA bypass with an STA-ACA bypass. The latter can be done by stretching the dissected frontal branch of the STA (as illustrated) or by an interposition graft with the use of a portion of the STA parietal branch or a portion of the saphenous vein. B, Lateral view of a postoperative angiogram indicating (arrows) the stretched frontal branch anastomosed to a branch of the distal ACA. The MCA branches are filled by the standard STA-MCA bypass, which was combined with aforementioned STA-MCA bypass. C, Operative sequence for an OA-PCA bypass via the paramedian supracerebellar transtentorial approach.⁷⁵

Indirect Bypass Techniques

Encephalomyosynangiosis (EMS), reported by Henschen in 1950,⁷⁸ was first applied to the treatment of MMD by Karasawa and colleagues in the late 1970s⁷⁹ and has now been widely used as a surgical intervention. One reason for its current use may be the infrequent existence of an appropriate cortical branch of the MCA on the surface of the brain in patients with MMD, especially children, which makes direct revascularization difficult or impossible. Another reason is to facilitate gradual revascularization according to the needs of the ischemic brain so that hyperperfusion secondary to direct revascularization^68,69 does not need to be taken into account. This technique involves implanting the temporalis muscle on the lateral brain surface and securing it to the dural edges. The temporalis muscle is considered to be a potential source of collateral circulation over the ischemic brain, and it is appropriately situated anatomically.

Encephaloduroarteriosynangiosis (EDAS) was developed by Matsushima and coworkers⁸⁰ in 1979 and is now the preferred technique for indirect revascularization. This technique requires exposure and dissection of the parietal branch of the STA with preservation of vascular flow. After a craniotomy over the sylvian fissure, the dissected STA is laid onto the cortical surface after having opened the arachnoidea extensively beforehand.

There are many other variations of procedures consisting of the use of pedicled muscles, galea, periosteum, and the dura mater, combinations of which can be used as novel indirect revascularization methods. These variations are not discussed in detail here because they are more or less modifications of EMS in which the blood supply of the external carotid artery is introduced into the ICA territory.

For the indirect revascularization method, a rather large craniotomy is recommended in anticipation of a good revascularization. However, extensive exposure of ischemic brain might have the disadvantage of an additional temporary intraoperative reduction in CBF, which could result in ischemic complications.

Invasive free graft transplantation of the autogenic omentum majus on the ischemic brain surface^81,82 might have only historical value as an indirect revascularization method, although selective application of this method for ischemia in the ACA or PCA territory could be kept in mind.

Selection of these surgical procedures is now dependent on the surgeon’s personal experience. Direct revascularization techniques or combining them with an indirect procedure is considered to be the therapy of choice in adults because indirect methods alone have been reported to be unpredictable or ineffective in achieving good revascularization.^14,38

Prognosis

The natural history of MMD must still be clarified. Seventy-five percent to 80% of cases are thought to have a benign course in terms of life expectancy, with or without surgical treatment.¹⁴ These patients perform well in independently carrying out activities of daily life. However, limited adaptability to social and school life or impairment of neurological soft signs has been reported.

After revascularization procedures, the majority of adult patients with MMD have been reported to be free of TIAs and ischemic strokes.^{9,10,14,38,86} Rebleeding has been reported to occur in about 30% to 65% of patients during follow-up.^42,44 The effectiveness of revascularization procedures in preventing rebleeding must still be settled, although a 12.5% to 20% reduction in rebleeding risk^14,43 has been reported. At present, the Japanese Adult Moyamoya (JAM) trial, a multicenter randomized clinical trial, is now in progress to evaluate whether direct or combined bypass surgery can reduce the risk for rebleeding in adult patients with MMD.⁸⁷

Patients with unilateral MMD should be monitored carefully because 7% to 27% of such patients, including children, have been reported to progress to bilateral disease within a few years of follow-up.⁸⁸ Recently, 15 of 63 adult patients were reported to have shown progression during a follow-up period of approximately 6 years.⁸⁹ A patient may have more than one manifestation, first ischemia and then bleeding, or vice versa. In a group of adult patients with MMD since childhood, about 44% are expected to have experienced bleeding.⁴²

MRI and MRA can now detect asymptomatic patients with MMD more often than before, but their natural course is still unclear. The annual risk for any stroke in these patients has been reported to be 3.2%.¹⁹

Conclusion

MMD is a rare disease of unknown etiology, although recent studies in Japan have shown some increase in the annual incidence and prevalence that is presumably due mostly to the inclusion of asymptomatic patients in whom MMD was diagnosed with MRI and MRA. The two ages at which the incidence is greatest seem to have changed accordingly: the previous higher peak at 5 years of age and the second lower peak at 40 years of age have recently changed to a lower peak at 5 to 9 years and a higher peak at 45 to 49 years. The clinical findings seem to not have changed: mostly ischemia in children and bleeding in adults. However, ischemia and not bleeding seems to be the predominant manifestation in white adults, in whom the incidence and prevalence are presumed to be far less and around a 10th (in Europe) that in Japanese reports. To augment CBF for treatment of the ischemic type, direct surgical revascularization by means of microsurgical EC-IC bypass with or without indirect revascularization via EMS or EDAS is currently performed. Although the effectiveness of such revascularization procedures in treating ischemia has been established, their effectiveness in preventing or reducing episodes of rebleeding in the hemorrhagic type of MMD by diminishing hemodynamic stress on the abnormal moyamoya vasculature must still be determined.

Acknowledgment

Most of the information in this chapter originated from annual reports of the research committee on MMD sponsored by the Ministry of Health, Labor, and Welfare, Japan, founded in 1977 (the first principal investigator was Prof. Fumio Goto). The previous achievements were reported in 1992.¹⁴ The authors are indebted to the committee members. We thank Mr. Peter Roth for his artistic illustrations in this chapter.