Moyamoya Disease - Clinical Tree

Key Points

Moyamoya disease is an unusual form of chronic cerebrovascular occlusive disease that is characterized by angiographic findings of bilateral stenosis or occlusion at the terminal portion of the internal carotid artery together with an abnormal vascular network at the base of the brain.
The major cellular components of the thickened intima formed in arteries of the circle of Willis and the major branches are smooth muscle cells. Migration and proliferation of smooth muscle cells in the intima, induced by unknown mechanisms, may lead to the intimal thickening in association with morphologic and biochemical alteration of extracellular matrix components including elastin, collagen, and other proteoglycans.
Clinical symptoms and signs are the manifestations of cerebrovascular events secondary to the intracranial vascular lesions, including hemorrhagic stroke, ischemic stroke, transient ischemic attacks (TIAs), and seizure.
The largest peak in age distribution is observed in 10–14-year-old patients, with a smaller peak in their 40s. Ischemic events are common in childhood, whereas hemorrhagic strokes are frequently seen in adulthood.
Remarkable regional differences in the frequency have been reported. Incidence is high in Japan, and large numbers of patients were also reported in Korea and China. The female-to-male ratio is 1.8:1.
Although genetic linkage analysis demonstrated that hereditary factors may be involved in susceptibility to moyamoya disease, etiology has not been fully elucidated yet.
Ischemic and hemorrhagic lesions can be detected by magnetic resonance imaging (MRI) and computed tomography. Stenotic or occlusive lesions at the distal ends of the internal carotid arteries are demonstrated by angiography and MR angiography (MRA). Apparent moyamoya vessels can be visualized as fine unusual vessels on angiogram, MRA, and also as a signal void on the MRI.
Carotid ultrasonography is useful to evaluate diameter greatly reduced at the proximal portion of the internal carotid artery above the bulbus, like a Champagne bottle neck.
Antiplatelet agents are prescribed to prevent recurrent ischemic attacks, although they have never been tested thoroughly in clinical trials.
Surgical revascularization, including direct bypass surgery, indirect bypass surgery, and a combination of the two, has been performed to give additional collateral flow to the ischemic brain. A recent multicenter randomized controlled study supported preventative effect of direct bypass against rebleeding in adult-onset hemorrhagic moyamoya disease.

Moyamoya disease is an unusual form of chronic cerebrovascular occlusive disease that is characterized by angiographic findings of bilateral stenosis or occlusion at the terminal portion of the internal carotid artery together with an abnormal vascular network at the base of the brain ( Fig. 40.1 ). The first report of a patient with this disease was published in 1957 by Takeuchi and Shimizu with the diagnosis of “bilateral hypoplasia of the internal carotid arteries.” This patient was a 29-year-old man who had been suffering from visual disturbance and hemiconvulsive seizures since the age of 10 years. Takeuchi and Shimizu considered this arterial occlusion to be congenital hypoplasia that differed from atherosclerosis on the basis of the histologic examination of a branch of the external carotid artery. Since then, similar cases have been reported, mainly among the Japanese, and a variety of names have been applied to the condition—“cerebral juxta-basal telangiectasia” by Sano, “cerebral arterial rete” by Handa and colleagues, “rete mirabile” by Weidner and associates, and “cerebral basal rete mirabile” by Nishimoto and Takeuchi. The terms “spontaneous occlusion of the circle of Willis,” used by Kudo, and “moyamoya disease” are now commonly used in the literature. The term moyamoya disease was proposed by Suzuki and Takaku, taken from the characteristic angiographic findings of an abnormal vascular network at the base of the brain; the Japanese word moyamoya , meaning “vague or hazy puff of smoke,” describes its appearance.

Extensive investigations of patients with this characteristic angiographic finding have been conducted over the past 60 years. It is now well known that progression of stenosis or occlusion of the intracranial major arteries, including the distal ends of the internal carotid arteries, is the primary lesion of this disease and that the abnormal vascular network (moyamoya vessels) at the base of the brain is their collateral supply, developed secondary to brain ischemia (see Fig. 40.1 ). ^, ^, ^, A guideline for the diagnosis of moyamoya disease was established by the Research Committee on Spontaneous Occlusion of the Circle of Willis, organized by the Ministry of Health and Welfare, Japan (MHWJ), and the latest version (1997) was published in Japanese and English, ^, but continued research has added new insights into this disease.

Guideline for Diagnosis

The guideline for the diagnosis of moyamoya disease developed by the MHWJ’s Research Committee on Spontaneous Occlusion of the Circle of Willis ( Box 40.1 ) has been used not only for patient diagnosis but also for follow-up and further investigation into the etiology and pathogenesis of this unique and mysterious disorder.

BOX 40.1

Diagnostic Guidelines for Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease)

From Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis; Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo) . 2012;52:245.

1.
Cerebral angiography is considered essential for the diagnosis and must show at least the following findings:
- i.
  Stenosis or occlusion at the terminal portion of the internal carotid artery or proximal portions of the anterior and/or middle cerebral artery
- ii.
  Abnormal vascular networks in the vicinity of the occlusive or stenotic lesions in the arterial phase
- iii.
  Bilaterality of findings a and b.
2.
However, when magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) findings meet all of the following criteria, cerebral angiography can be omitted:
- i.
  MRA shows stenosis or occlusion at the terminal portion of the internal carotid artery or proximal portion of the anterior and/or the middle cerebral artery.
- ii.
  MRA shows abnormal vascular networks in the basal ganglia. Note: When 2 or more visible flow voids are present in the basal ganglia on MRI, at least unilaterally, they can be deemed as representing an abnormal vascular network.
- iii.
  Bilaterality of findings i and ii.
3.
Moyamoya disease is an illness of unknown etiology. The differential diagnosis of this disease includes similar cerebrovascular lesions associated with the following underlying diseases, which should, therefore, be excluded: (i) atherosclerosis, (ii) autoimmune disease, (iii) meningitis, (iv) brain neoplasm, (v) Down syndrome, (vi) von Recklinghausen disease, (vii) head injury, (viii) cerebrovascular lesions after head irradiation, and (ix) others.
4.
Pathologic findings that can be used as references for the diagnosis:
- i.
  Thickening of the arterial intima, mainly in the terminal portion of the internal carotid arteries, and narrowing or blockage of the lumen caused by this change, usually bilateral. Occasionally, lipid deposits are also present in the thickened intima.
- ii.
  Arteries such as the anterior, middle, and posterior cerebral arteries forming the circle of Willis occasionally show varying degrees of stenosis or occlusion associated with fibrocellular thickening of the intima, waviness of the internal elastic lamina, and thinning of the media.
- iii.
  Numerous small vascular channels (perforating and anastomotic branches) can be seen around the circle of Willis
- iv.
  Pia mater may also show reticular conglomerates of small vessels.

Diagnostic Assessment

Moyamoya disease should be classified as definitive or probable based on the above-mentioned items i–iv. When autopsy is performed in the absence of cerebral angiography, the condition should be diagnosed based on the criteria in item iv.

Definitive moyamoya disease: All criteria listed in 1 or 2 and in 3 should be met. In children, however, the criteria in item 1 or 2.i and 2.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 diagnosis.

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.

Prior to 1995, the guideline stated that cerebral angiography is indispensable to diagnosis in all but the autopsied cases. Because the quality of the images of magnetic resonance imaging (MRI) and MR angiography (MRA) has improved, the Research Committee concluded in 1995 that the diagnosis can be made without conventional cerebral angiography if MRI and MRA clearly demonstrate all the findings that indicate moyamoya disease. The substitution of noninvasive imaging methods for angiography is helpful for patients, especially children.

This revision also contains the addition of autoimmune disorders to the list of disorders that should be considered in any patient being evaluated for moyamoya disease, to avoid confusing this disease with other disorders in which vascular lesions resembling those of moyamoya disease can form. A correct diagnosis is essential for selecting the optimal plan of treatment.

Epidemiology

The incidence and prevalence of moyamoya disease in the Japanese have been surveyed by collaborative studies in 1984, 1989, and 1994. The prevalence and annual incidence are calculated to be 3.16 and 0.35 per 100,000 population, respectively. Female preponderance has been reported with a female-to-male ratio of 1.8:1. The largest peak in age distribution was observed in patients 10–14 years old, with a smaller peak in patients in their 40s. The age at onset was younger than 10 years in 47.8% of the patients (childhood moyamoya), although the disease had developed in some patients between the ages of 25 and 49 years (adult-type moyamoya) ( Fig. 40.2 ).

Fig. 40.2, Distribution of age at onset and sex of patients with moyamoya disease.

Evidence of familial moyamoya disease has been accumulating in the medical literature. ^, Family histories of moyamoya disease were found in 10% of patients, and 13 pairs of homozygous twins were reported as having the disease. The contribution of hereditary factors to the occurrence of moyamoya disease is discussed later, in the section on etiology and pathogenesis.

Although regional predilection has never been reported within Japan, there are remarkable regional differences in the frequency of reported moyamoya worldwide. ^, After the report by Taveras in 1969, reports of moyamoya disease have been growing among non-Japanese people, including white and black people, although it is rare in white patients. ^, None of the races has as high an incidence as the Japanese, but relatively large numbers of patients have been found in Korea ^, and China. ^,

Korean neurosurgeons performed the first nationwide cooperative survey of moyamoya disease in their country in 1988, and 289 patients were registered. The reported clinical features of these patients were different from those of Japanese patients, raising questions about whether this heterogeneity suggests racial and regional differences or differences between the criteria used for diagnosis in the two countries. Further analysis by Japanese investigators reclassified the Korean cases into definite, probable, and unlikely cases. The definite cases had similar clinical features and age at onset in both populations. There was a slight female predominance (ratio 1.3:1), and the incidence of hemorrhage was higher in females than in males. The incidence of brain infarction and hemorrhage was significantly higher, whereas the rates of transient ischemic attacks (TIAs) and seizures were lower in Korean than in Japanese subjects. The incidence of infarction in children and that of hemorrhage in both children and adults were also statistically higher in Koreans.

Such studies should be undertaken in Western and other Asian countries for clarification of the racial significance and genetic background of this disease.

Pathology

Pathologic observations of approximately 100 autopsy cases of moyamoya disease revealed various forms of cerebrovascular lesions in the brain, and their macroscopic and microscopic findings have been accumulated. ^, The lesion observed most commonly at autopsy is intracranial hemorrhage, which is a major cause of death for patients with moyamoya disease. Massive parenchymatous hemorrhage (intracerebral hemorrhage) occurs frequently in the basal ganglia, thalamus, hypothalamus, cerebral peduncle, and midbrain, and often extends and ruptures to the intraventricular spaces. Subarachnoid hemorrhage (SAH) also occurs, but primary SAH caused by rupture of aneurysms seems to be not so frequent as described previously, and many cases appear to be secondary extensions of parenchymatous hemorrhage. In addition, old brain infarction and focal cortical atrophy of the brain are not uncommon findings and are often found in multiples. ^, Furthermore, the infarcts are mostly small and localized in the basal ganglia, internal capsule, thalamus, and subcortex. Large arterial territorial infarcts are rare in moyamoya disease, although occlusion of the intracranial major arteries is present. This finding may suggest the function of moyamoya vessels as collateral pathways after arterial occlusion. The frequency and distribution of intracranial hemorrhage and infarction found at autopsy may not be typical of moyamoya disease, as such specimens obtained from the circle of Willis and moyamoya vessels are biased by the unavoidable clinical circumstances related to their deaths. Nevertheless, the histologic and immunohistochemical analyses of the postmortem materials have provided valuable information relating to the pathogenesis of lesion formation in this disease.

The Circle of Willis and the Major Branches

In the guideline for the diagnosis of moyamoya disease, the pathologic findings in the intracranial arteries are included to allow for diagnosis in patients who did not undergo angiography during life (see Box 40.1 ). ^, The histologic appearance of the circle of Willis and the major branches of the patients with moyamoya disease is characteristic, but not specific for this disease. ^, ^, Therefore, it is not always possible to diagnose moyamoya disease solely on the basis of pathologic findings.

On macroscopic observation, the circle of Willis and the major branches are tapered and narrowed entirely or partially with overgrown and dilated arteries branching from the circle of Willis ( Fig. 40.3 ). The degree of tapering of arteries as well as the network formation of dilated arteries (moyamoya vessels) and their distributions vary from case to case. The distal ends of the internal carotid arteries are affected by severe narrowing or occlusion.

Fig. 40.3, Macroscopic appearance of the circle of Willis in a 66-year-old woman with moyamoya disease at autopsy. Tapering of anterior and middle cerebral arteries can be seen bilaterally with network formation of dilated arteries (basal moyamoya vessels).

In conventional staining of specimens obtained from the circle of Willis or its major branches with lesion involvement, the arterial lumen is severely narrowed or occluded by fibrocellular intimal thickening ( Figs. 40.4A and 40.5A ). ^, ^, ^, The thickened intima appears to be in a laminated structure, with duplication or triplication of internal elastic lamina and a wavy appearance. These features closely resemble the structure noted focally at arterial branching portions in normal controls, the so-called intimal cushion. The outer diameter of the affected artery usually becomes smaller, and the underlying media are markedly attenuated. These histologic features are common to lesions at any site, although the extent of intimal thickening and the distribution in the circle of Willis are variable.

Fig. 40.4, Microscopic appearance of the circle of Willis in patients with moyamoya disease at autopsy. (A) Intracranial portion of right internal carotid artery of a 60-year-old woman (elastica van Gieson stain). (B) Main trunk of the right middle cerebral artery of a 36-year-old man. Arrows indicate mural fibrin thrombi with its organization (Mallory phosphotungstic acid-hematoxylin [PTAH] stain).

Fig. 40.5, Microscopic appearance of the basilar artery of a 14-year-old girl with moyamoya disease at autopsy. (A) H&E stain; (B) immunohistochemical stain for muscle actin; (C) staining for proliferating cell nuclear antigen (PCNA). Arrows in C indicate the nuclei stained positively for PCNA.

Immunohistochemical staining demonstrated that the thickened intima is composed mainly of smooth muscle cells (SMCs) (see Fig. 40.5B ) that are phenotypically modulated from the contractile type to the synthetic. Some SMCs in the intima were stained positively with the antibody for proliferating cell nuclear antigen (see Fig. 40.5C ), which strongly suggests that active SMC proliferation and phenotypic modulation contribute to the formation of fibrocellular intimal thickening of the arteries. Lipid deposition and lipid-containing macrophages (foam cells) have been found in some autopsy cases but are now considered features of atherosclerosis.

Mural thrombi are often found in the stenotic arteries (see Fig. 40.4B ), but their frequency varies. ^, ^, ^, Judging from their histologic features, the organization of such thrombi appears to contribute to the pathogenesis of fibrocellular intimal thickening.

Aneurysm formation, a relatively common finding in the circle of Willis in patients with moyamoya disease, and its pathology are summarized later.

Perforating Arteries (Moyamoya Vessels)

The vascular network at the base of the brain consists of dilated medium-sized or small muscular arteries branching off the circle of Willis, anterior choroidal arteries, intracranial portions of internal carotid arteries, and posterior cerebral arteries. These arteries form complex channels that usually connect to the distal portion of the anterior and middle cerebral arteries. Numerous small dilated and tortuous vessels originating from these channels enter into the base of the brain, corresponding to lenticulostriate and thalamoperforate arteries.

In microscopic observations, these perforating arteries in the brain parenchyma show two patterns of histologic changes: (1) a dilated artery with a relatively thin wall and (2) a thick-walled artery showing luminal stenosis. Dilatation of the arteries is more prominent in young patients. The majority of dilated arteries show fibrosis and marked attenuation of the media with occasional segmentation of the elastic lamina. With hemodynamic stress or aging, the dilated arteries with attenuated walls may predispose to focal protrusion (microaneurysm formation) of the arterial wall, and its rupture is considered one of the mechanisms leading to parenchymatous hemorrhage in patients with moyamoya disease ( Fig. 40.6 ). Fibrinoid necrosis of the perforating arteries in the process of aneurysm formation has been shown in hypertensive parenchymatous hemorrhage, but has never been confirmed pathologically in patients with moyamoya disease.

Fig. 40.6, Microscopic appearance of the perforating arteries of patients with moyamoya disease at autopsy. (A) The artery in the right caudate nucleus of a 60-year-old woman with parenchymatous hemorrhage shows marked dilatation with rupture (elastica van Gieson stain). (B) Some of the arteries in the left thalamus of a 39-year-old woman show luminal stenosis due to fibrous and edematous intimal thickening (hematoxylin & eosin stain).

In contrast, stenotic vessels are less common in young patients. These vessels show concentric thickening of the intima with duplication of the elastic lamina and fibrosis of the tunica media (see Fig. 40.6 ). Partial dilatation with discontinuity of the elastic lamina and occluding thrombus formation with its organization and recanalization are occasionally found. These histologic changes in the perforating arteries indicate that the arterial obstructive changes in patients with moyamoya disease are not limited to the circle of Willis and its major branches.

Leptomeningeal Vessels

The leptomeningeal anastomoses among the three main cerebral arteries and transdural anastomoses from the external carotid arteries are commonly observed as an abnormal vascular network on cerebral angiograms in patients with moyamoya disease (so-called vault moyamoya). ^, ^, A histopathologic and morphometric study of the leptomeningeal vessels in autopsied brains with moyamoya disease clarified that such anastomoses are not newly formed vessels, but merely dilated preexisting vessels. Attenuation or disruption of the internal elastic lamina is remarkable in patients with a short history of moyamoya disease, and fibrous intimal thickening is more prominent in patients with a longer history of the disease. These structural adaptations in the vascular walls of the leptomeningeal vessels suggest their participation in the collateral circulation at the cerebral cortical surfaces.

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