Introduction

Moyamoya disease is a chronic progressive disorder that is characterized by bilateral stenosis or occlusion of internal carotid arteries and their proximal branches. “Moyamoya” is a Japanese word representing “puff of smoke” due to the appearance of dilated, fragile collateral vessels at the base of the brain and basal ganglia that looks appear to drift in the air. The diagnostic criteria of moyamoya disease suggested by the Research Committee on Spontaneous Occlusion of the Circle of Willis of the Ministry of Health and Welfare, Japan, are stenosis or occlusion at the terminal portions of the internal carotid arteries or the proximal areas of the anterior or the middle cerebral arteries, abnormal vascular networks in the arterial territories near the occlusive or stenotic lesions, bilateral findings and no other identifiable cause. If lesions appear on a unilateral angiography, patients are diagnosed as probable cases. Moyamoya syndrome can be defined when patients with characteristic moyamoya vasculopathy have well-recognized associated conditions, such as cerebrovascular disease with atherosclerosis, autoimmune disease, meningitis, brain neoplasm, Down’s syndrome, neurofibromatosis, head trauma, or irradiation to the head and neck.

What's new in moyamoya disease

Epidemiology

Japan is known to have the highest worldwide incidence of moyamoya disease. In a recent survey done in Hokkaido, Japan, the annual prevalence and incidence of moyamoya disease were 10.5 and 0.94 per 100,000, respectively and the female to male ratio was 2.18.1) This result differs from that of a previous study, in which the annual prevalence and incidence was estimated at 3.16 and 0.35 per 100,000, respectively and the female to male ratio was shown to be 1.8.45) Likewise, the peak age distribution of patients was 10~14 years old, though a smaller second peak age distribution was seen in patients in their forties in the previous study. However, the recent study showed that the highest peak was between 45-49 years with a second peak from 5-9 years of age. Currently, widespread use of non-invasive diagnostic modalities such as magnetic resonance imaging (MRI) has increased the ability to detect asymptomatic moyamoya disease in adults which might gradually change the epidemiologic features of the disease.

The high incidence of moyamoya disease in East Asia, particularly in Japan, can be explained by genetic rather than environmental factors. Graham and Matoba,7) in their epidemiologic study of moyamoya disease in the USA, found that the incidence and prevalence of moyamoya disease were higher in Hawaii than in the rest of the USA given that there is a larger percentage of people with Asian ethnic origins in Hawaii.

Epidemiologic analyses of familial moyamoya disease, which accounts for about 15% of patients and is inherited in a polygenic or autosomal dominant mode with low penetrance, have shown that the ratio of women to men is 5.0 in familial cases and 1.6 in sporadic cases. The mean age of onset was 11.8 years in familial cases and 30.0 years in sporadic cases.26)30)47) Although no studies have shown a relationship between familial moyamoya disease and the X chromosome, females may be more susceptible to the genetic factors contributing to familial moyamoya disease. Furthermore, these genetic factors may affect the age at onset of familial moyamoya disease.

Pathophysiology

In moyamoya disease, characteristic histopathological findings in the carotid terminations have included fibrocellular thickening of the intima containing proliferated smooth muscle cells, an irregular undulation of the internal elastic lamina and attenuation of the media.5) A recent study on the mechanism of this remodeling in intracranial arterial walls of patients with moyamoya disease suggested that caspase-3-dependent apoptosis might be associated with histopathological changes.41)

Among the various growth factors and cytokines which have been demonstrated to increase in the CSF of patients with moyamoya disease, basic fibroblast growth factor (bFGF) has been detected in the endothelial cells of moyamoya vessels.42) In a so called “bFGF moyamoya disease theory”, a hypothesis was formed to explain most of the specific features of moyamoya disease, whereby bFGF exerts a powerful angiogenic effect and thus induces the proliferation of vascular endothelial cells, smooth muscle cells and fibroblasts.8)48) Further, the presence of bFGF specifically seen in moyamoya disease is supposed to suppress the apoptotic process of smooth muscle cells in the intima.8)

Hepatocyte growth factor, which is highly concentrated in the CSF of patients with moyamoya disease, has been shown to be widely expressed in the media and thickened intima of the carotid terminations in these patients. This finding suggests that intimal thickening and the migration of vascular smooth muscle cells into the intima of the carotid terminations in patients with moyamoya disease are exacerbated by the enhanced expression of hepatocyte growth factor and its receptor.29)

There have also been investigations of the relationship between moyamoya disease and thyroid function.11)44) Furthermore, a recent case control study of pediatric patients with moyamoya disease demonstrated increased thyroid function and elevated thyroid autoantibodies were found more frequently in the patient group than in controls (10.5% vs 0.9%, 13.2% vs 3.5%, respectively).23)

Several studies on the pathogenesis of moyamoya disease have suggested that infection, such as by Pro-pionibacterium acnes, in the head and neck regions may play a role in its pathogenesis.46)

The inheritance pattern of moyamoya disease is known to be autosomal dominant with incomplete penetrance. Two previous genome-wide linkage studies found significant evidence for loci at 3p24.2-p26 and 8q23.10)33) Further, a recent genome-wide parametric linkage analysis for moyamoya disease revealed a major gene locus for autosomal dominant moyamoya disease on chromosome 17q25.3.25)

Clinical presentation

Children and adults display somewhat different features with respect to the clinical manifestations of moyamoya disease. In most children, transient ischemic attack (TIA) or cerebral infarction are the main clinical features of moyamoya disease, whereas about half of affected adults develop spontaneous intracranial hemorrhage, most often in the basal ganglia and thalamus.5) Although the intracranial bleeding in association with increasing hemodynamic stress is mainly caused by the rupture of dilated, fragile moyamoya vessels, dilated collateral arteries on the brain surface also can rupture and cause subarachnoid hemorrhage over the cerebral cortex.32) Because children are generally ineffective at clearly representing TIA symptoms to their family, delays in diagnosis and subsequent treatment have occurred. Thus, the rate of full blown strokes in pediatric patients with moyamoya disease is relatively high.13)

The pathognomonic EEG finding in pediatric patients with moyamoya disease showing high amplitude slow waves which reappear after hyperventilation stops is known as re-build up.18) This specific EEG finding has been suggested to be induced both by reduction in cerebral blood flow and ischemic hypoxia after hyper- ventilation.14)

Headache has been a major presenting symptom in patients with moyamoya disease. In fact, Seol et al. found that preoperative headaches were present in 44 of 204 (21.6%) pediatric patients with moyamoya disease, continuing in 18 even after surgery.38) Decreased cerebral blood flow and progressive recruitment and redistribution of blood flow are known to cause headaches in these patients. Furthermore, cerebral aneurysms and arteriovenous malformations coexisting with moyamoya disease have also been known to provoke headaches by stimulating trigeminal nociceptors due to stretching or by subarachnoid hemorrhage.3) It has been suggested that the typical frontal or migraine-like headache is caused by dilatation of meningeal and leptomeningeal collateral vessels and can occur even after surgery.38)

Diagnosis

The diagnosis of moyamoya disease, particularly in children, should be primarily based on clinical presentations such as neurologic deficits or unexplained symptoms referable to cerebral ischemia.

Angiography has been the gold standard for definitive diagnosis of moyamoya disease. The six-stage classification of cerebral angiographic findings of moyamoya disease, proposed by Suzuki and Takaku,40) has been widely used to classify the disease according to its radiologic severity.

MRI has been a useful tool in detecting both ischemic and hemorrhagic lesions in the brain parenchyma. Asymptomatic microbleeds, which may represent predictors of subsequent hemorrhage in patients with moyamoya disease, can be detected in adult patients on gradient-echo T2-weighted MRI.16) Magnetic resonance angiography (MRA) also has been a powerful non-invasive test for the detection of asymptomatic patients at particularly high risk of developing types of moyamoya disease such as the familial type. If both MRI and MRA show moyamoya-specific radiologic findings, cerebral angiography has been deemed unnecessary for the diagnosis of moyamoya disease, in accordance with the Guidelines of the Research Committee on Spontaneous Occlusion of the Circle of Willis of the Ministry of Health and Welfare, Japan. In a recent study, the “ivy sign”, a leptomeningeal high signal intensity along the cerebral sulci or on the brain surface on fluid-attenuated inversion recovery (FLAIR) MRI in moyamoya disease, showed a significant positive relationship with the severity of ischemic symptoms and negative relationships with the resting cerebral blood flow (CBF) and with the cerebral vascular reserve (CVR).28)

Single photon emission computed tomography (SPECT) or positron emission tomography (PET) have also been used to predict clinical outcomes of moyamoya disease by assessing postoperative basal/acetazolamide stress in patients who have undergone revascularization surgery (Fig. 1).39) Even though measurement of the cerebral oxygen extraction fraction (OEF) with PET can provide information on the hemodynamic status of patients with moyamoya disease, it is not available in Korea because 15O gas for 15O PET, instead of general fluorodeoxyglucose (FDG) PET, has a short half life that is less than 3 minutes. The degree of hemodynamic stress in patients with moyamoya disease can also be quantitatively evaluated through the use of perfusion-weighted MRI (Fig. 2).43)

Treatment

Unlike previous expectations, the incidence of disease progression for moyamoya disease is high even in asymptomatic patients and medical intervention has not been able to stop disease progression.22)

Although few studies have shown the effectiveness of medical therapy for patients with moyamoya disease, two types of medication have been indicated for this disease. Aspirin can be taken to avoid symptoms resulting from emboli from thrombus formation at arterial stenosis sites.35) Further, calcium-channel blockers have been useful in cases of intractable headaches and may be effective in reducing both the frequency and the severity of TIA.36)

Surgery has been the only successful treatment modality to improve cerebral hemodynamics and it can be categorized into direct, indirect and combined revas- cularizations. A direct extracranial-intracranial arterial bypass, typically a STA-MCA bypass, is useful for improving cerebral hemodynamics and resolving ischemic attacks immediately after surgery. Although postoperative hyperperfusion syndrome has been considered to be less common in patients with moyamoya disease, careful monitoring by preoperative and postoperative SPECT and intraoperative blood flow measurement has been required to avoid this rare but serious complication of direct bypass surgery.4) Commonly used indirect procedures have been encephalo-duro-arterio-synangiosis (EDAS), encephalo-myo- synangiosis (EMS) and their various combinations. Indirect bypass has provided effective collateral circulations in pediatric patients, but may take several weeks to months for revascularization to occur and the degree of indirect revascularization has shown declines to poor grades in advanced age groups.2)27)

Combining bypass procedures has advantages of both direct and indirect techniques. In a new combined bypass procedure, patients had single or double STA-MCA anastomosis and concurrent indirect encephaloduromyoarteriopericranial synangiosis through frontotemporal craniotomy covering large areas of the frontal lobe. Postoper- ative studies showed improved cerebral hemodynamics in the operated hemisphere.20)

Perioperative management during revascularization procedures has been important because hemodynamic change can increase the risk of complications. During the procedure, blood pressure is maintained in the normal-to-high range to keep up the cerebral perfusion pressure (CPP) given that cerebral blood flow (CBF) is totally pressure dependent as a result of failure of CBF autoregulation.12) Further, hematocrit greater than 30% has been recommended for normocapnia maintenance. Additionally, during STA-MCA bypass, mild hypothermia and barbiturate-induced burst suppression can be used for neuro- protection.17) This perioperative management is especially important in patients with multiple ischemic attacks before the procedure and a low density area or high signal intensity on the preoperative CT or diffusion-weighted MRI.9) After the procedures, postoperative management, such as use of sedation and non-painful wound-handling techniques designed to ease postoperative wound care, may prevent cerebral ischemic attacks caused by hyperventilation which often results from crying in pediatric moyamoya patients and similarly may reduce the postoperative hospital stay.31)

Prognosis

In adult patients with unilateral moyamoya disease, the incidence of progression to bilateral lesions is higher than previously reported. If mild stenotic changes in the contralateral ACA, MCA and intracranial ICA occur, careful follow-up is crucial, given that the events may be important predictors of increased risk of progression to bilateral disease.15)

The incidence of asymptomatic moyamoya disease is currently higher than previously thought as a consequence of the development of non-invasive radiologic evaluations such as MRI and MRA. Further, a nationwide survey in Japan revealed that asymptomatic moyamoya disease is not a silent disorder but may potentially cause ischemic or hemorrhagic stroke.19)

Several factors in previous studies, such as early onset, completed stroke, cerebral infarction and longer disease duration, have been suggested to have correlations with poor intellectual outcomes in pediatric patients with moyamoya disease.6)24) Subsequently, a recent multivariate analysis revealed that completed stroke and small craniotomy surgery were significantly associated with poor intellectual outcomes.21) Small craniotomy surgery is a technically easy procedure; however, it provides only a limited area for revascularization. If a patient who has had this surgery shows progressive regional cerebral blood flow reduction on SPECT, additional revascularization procedures are recommended.34)

In accordance with a review of clinical and radiologic records of patients with moyamoya disease, a patient’s age as well as functional status at the time of surgery determines the long-term outcome.37)

Conclusions

Several studies have examined the epidemiology, etiology, clinical manifestations and treatment of moyamoya disease since the first case in 1957. However, many characteristics, particularly etiology and pathogenesis, remain poorly understood. Early diagnosis and appropriate treatment are crucial for improving the long-term prognosis of patients with moyamoya disease. As such, further research is necessary to clarify the natural course of moyamoya disease, offer early diagnoses and to give appropriate treatment, thus ensuring the best outcome for patients.

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