Research on moyamoya disease has progressed remarkably in the past several decades. Indeed, many new facts concerning the epidemiology of the disease have been revealed and surgical treatments have been drastically improved. However, despite extensive research, the mechanism of moyamoya disease is still unknown. Consequently, the cardinal treatment of this disease has not yet been developed. For further clarification of its etiology, innovative studies are therefore indispensable. The aim of this paper is to review research on the pathogenesis of moyamoya disease to identify milestones in the direction of its true solution. Many hypotheses of the pathogenesis of moyamoya disease have been proposed in the past half century, including infection (viral and bacterial), autoimmune disorders, proteins abnormality, and gene abnormality. Some of these are now considered to be historical achievements. Others, however, can be still subjected to contemporary research. Currently, several genetic abnormalities are considered to offer the most probable hypothesis. In addition, interesting papers have been presented on the role of the endothelial progenitor cell on the pathogenesis of moyamoya disease. Intuitively, however, it appears that a single theory cannot always explain the pathogenesis of this disease adequately. In other words, the complex mechanism of several factors may comprehensively explain the formation of moyamoya disease. The “double hit hypothesis” is probably the best explanation for the complicated pathology and epidemiology of this disease.
Many surgical treatments for moyamoya disease have been developed over the past 40 years. The optimum treatment for ischemic-type moyamoya disease is almost established. The first surgical treatment for the disease was the superficial temporal artery to middle carotid artery (STA-MCA) anastomosis. The discovery of spontaneous collateral formation following the STA-MCA anastomosis surgery led to the development of various indirect bypass procedures. Collateral formation and clinical outcomes from direct and indirect procedures have been compared to assess the merits and limitations of each technique. Experience and a greater understanding of the surgical effects of moyamoya disease have led to the development of surgical procedures combining various direct and indirect bypass techniques for optimal restoration of perfusion. This review of the historical development and efficacy of each procedure will aid surgeons in selecting the most appropriate surgical procedure for patients of different ages with different symptoms and disease severities.
This review describes the basic concepts of surgical revascularization for moyamoya disease, including direct and indirect bypass surgery. Direct bypass surgery can improve cerebral hemodynamics and reduce further ischemic events immediately after surgery, but may be technically challenging in some pediatric patients. Indirect bypass surgery is simple and has widely been used. However, its beneficial effects can be achieved 3 to 4 months after surgery, and surgical design is quite important to determine the extent of surgical collateral pathways. Combined bypass procedure, especially superficial temporal artery (STA) to middle cerebral artery anastomosis and indirect bypass, encephalo-duro-myo-arterio-pericranial synangiosis, is a safe and effective option to improve the short- and long-term outcome in patients with moyamoya disease. Alternative techniques are also described for specific cases with profound cerebral ischemia in the anterior cerebral artery or posterior cerebral artery territory. Special techniques to safely complete bypass surgery and avoid perioperative complications are presented, including methods to prevent delayed wound healing, to avoid facial nerve palsy after surgery, and to preserve the STA and middle meningeal artery during skin incision and craniotomy. Finally, the importance of careful management of patients is emphasized to reduce the incidence of perioperative complications, including ischemic stroke and hyperperfusion syndrome.
To clarify the clinical features of moyamoya disease in Japan, 941 patients with definite moyamoya disease were analyzed from the databases constructed by the Research Committee on Moyamoya Disease, established by the Ministry of Health, Labour and Welfare. Moyamoya disease occurs much more frequently among women than men, with a female-to-male ratio of 1.98. A family history of the disease was observed in 14.9%. The age at onset was characterized by two peaks: one at 5-9 years and another lower peak at around 40 years. Initial clinical features were transient ischemic attack in 46%, infarction in 20%, hemorrhage in 21%, headache in 6%, and epilepsy in 4%. The distribution of the age at onset showed one peak at around 40 years in patients with hemorrhage but two peaks in patients with ischemia.
Moyamoya disease is an idiopathic vascular disorder of the intracranial arteries. Ring finger 213 (RNF213) was previously identified as the strongest susceptibility gene for moyamoya disease in East Asian people by a genome-wide linkage analysis and exome analysis. The coding variant p.R4810K in RNF213 was strongly associated with moyamoya disease in the Japanese (odds ratio: 338.94, p = 1.05 × 10−100) and Korean (odds ratio: 135.63, p = 7.59 × 10−27) populations, and much less strongly associated in the Chinese population (odds ratio: 14.70, p = 2.63 × 10−5). The present study investigated the distribution of variant p.R4810K in RNF213 in 2,508 participants from East and Southeast Asian countries using a TaqMan probe. p.R4810K was detected at an allele frequency of about 1.00% in 4 of 11 investigated locations in China. In contrast, p.R4810K was detected homogeneously at relatively high frequencies of 1.00-1.72% in all investigated locations in Korea and Japan, including Okinawa. p.R4810K was not detected in Southeast Asian populations. The population susceptible to moyamoya disease was estimated to be 16.16 million people in East Asian countries, including 11.41 million Chinese, 1.36 million Korean, and 3.39 million Japanese people. The number of patients with moyamoya disease, which was estimated at approximately one per 300 carriers of p.R4810K, was considered to be 53,800 in East Asian populations.
Stroke during pregnancy associated with moyamoya disease (MMD) has been reported sporadically, but no systematic surveys have been undertaken. To reveal the current clinical situation, the authors conducted Japan's first nationwide survey of pregnancy and delivery associated with MMD. A questionnaire was sent to all 270 perinatal medical centers across Japan to survey their experiences with delivery associated with MMD within the preceding 5 years (Survey I); another questionnaire was sent to 554 adult female patients with MMD regarding their experience with childbirth (Survey II). Survey I included 59 deliveries among patients with previously diagnosed MMD. The incidence of perinatal neurological events and morbidity was 5.1% and 1.7%, respectively. In another five cases, newly diagnosed after perinatal attacks, disability was noted in three cases, including one death from intracranial hemorrhage. Survey II included 278 deliveries. The perinatal attack rate was 6.6% in 76 previously diagnosed cases and 2.0% in 202 cases undiagnosed at pregnancy, but neither group reported permanent morbidity. Caesarean section in previously diagnosed cases accounted for 76.3% of deliveries in Survey I and 69.7% in Survey II, but no significant difference in event rate was found between caesarean section and vaginal delivery in either survey. Although the incidence of perinatal neurological events is low when MMD has been diagnosed, careful monitoring is required in light of the potential for stroke. Serious events, especially intracranial hemorrhage, can occur if MMD has not been diagnosed at pregnancy. Further efforts to establish management guidelines are required to ensure safer childbirth in patients with MMD.
Fifteen years of experience with adult moyamoya disease (MMD) in a single department were analyzed to describe the clinical features and to clarify the existence of the disease entity of adult MMD with special reference to its diagnosis. This study included 348 patients treated between 1996 and 2010. Male to female ratio was 128 to 220 with mean age of 39 years. The presence of neurological symptoms and signs during childhood and mean Suzuki stage according to the age were evaluated. Adult MMD was differentiated from other diseases, such as vasculitis, by comparing the laboratory data including common markers and specific markers for such diseases between 22 adult MMD and 21 atherosclerotic disease (ASD) patients. Conventional angiographic data were analyzed to detect progression in 52 unilateral adult MMD patients over a mean follow-up duration of 4.8 years. Only one of 128 patients (0.8%) aged over 40 years showed childhood symptoms and signs. The distribution of the mean Suzuki stage between patients aged 40 years and under and over 40 years was similar. Laboratory tests differentiating the other diseases with the same phenotype with MMD revealed no difference between adult MMD and ASD. The progression of unilateral MMD to bilateral MMD occurred in 6 of 52 patients (11.5%). Adult MMD is not a syndrome, but a distinct disease entity with significant progression of unilateral MMD to bilateral MMD. Diagnostic and therapeutic strategies should be different from pediatric cases when considering adult MMD.
[123I]iomazenil (IMZ) is a specific radioligand for the central benzodiazepine (BZ) receptor that may be useful as a marker of cortical neuron loss after cerebral ischemia using single photon emission computed tomography (SPECT). This study used statistical imaging analysis for IMZ-SPECT to investigate the relationship between higher brain dysfunction and cortical neuron loss in the medial frontal lobes, to establish a confirmatory diagnosis of higher brain dysfunction in patients with adult moyamoya disease. IMZ-SPECT was estimated by three-dimensional stereotactic surface projections (3D-SSP). Cortical neuron loss was analyzed using the stereotactic extraction estimation (SEE) method (level 3: gyrus level) for 3D-SSP Z-score maps (Z-score >2). Extent of pixels with significant reduction of BZ receptor density within the target gyri (i.e. bilateral medial frontal gyri [MFGs] and anterior cingulate gyri [ACGs]) was calculated. In 6 patients with higher brain dysfunction, significant cortical neuron loss was observed in the bilateral MFGs in 4 patients, unilateral MFG in 1 patient, and bilateral ACGs in 2 patients. In 12 patients without higher brain dysfunction, no significant cortical neuron loss was observed in the bilateral MFGs or ACGs, and mild loss was observed in the bilateral MFGs in 2 patients, unilateral MFG in 4 patients, and unilateral ACG in 2 patients. Long-standing mild hemodynamic ischemia in the anterior circulation of patients with adult moyamoya disease could lead to incomplete brain infarction within the medial frontal lobes. Statistical imaging analysis using 3D-SSP and SEE methods for IMZ-SPECT could demonstrate significant cortical neuron loss in the bilateral frontal medial cortices involving MFG and/or ACG which correlate with higher brain dysfunction in patients with adult moyamoya disease.
Moyamoya disease is a chronic, occlusive cerebrovascular disease with unknown etiology characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Recent advances in molecular biology and genetic research have provided better understanding of the pathophysiology of moyamoya disease, but surgical revascularization still remains the preferred treatment for this entity. The present study investigated the clinical course of 106 consecutive patients with moyamoya disease who underwent superficial temporal artery-middle cerebral artery anastomosis with indirect pial synangiosis in 150 hemispheres. The outcomes of surgery on the operated hemisphere were favorable, with no cerebrovascular event during the outpatient follow-up period (mean 58.4 months) in 89.3% (134/150). Two patients suffered hemorrhagic events on the operated hemisphere during the follow-up period (2/150, 1.33%), one of whom suffered deteriorated neurological status after hemorrhage. Despite the favorable long-term outcome, the incidence of temporary neurological deterioration due to cerebral hyperperfusion was 18.0% (27/150), but no patients suffered permanent neurological deterioration directly caused by hyperperfusion. In conclusion, direct/indirect revascularization surgery is a safe and effective treatment for moyamoya disease, although the issue of bleeding/re-bleeding remains to be solved. Postoperative cerebral hyperperfusion and peri-operative infarction are potential complications of this procedure, so we recommend intensive postoperative care and cerebral blood flow measurement in the acute stage, because the management of hyperperfusion is contradictory to that of ischemia.
Combined superficial temporal artery-middle cerebral artery anastomosis and encephalo-duro-arterio-galeo-synangiosis (EDAGS) were retrospectively compared with indirect bypass, EDAGS with or without inversion, in 134 hemispheres of 96 adult patients with non-hemorrhagic moyamoya disease (MMD) in terms of angiographic findings, perioperative complications, and clinical outcome. Angiographic revascularization seemed to be better in the combined bypass group compared with the EDAGS group (p = 0.045), but perioperative complication tended to be slightly more common in the combined bypass group. No statistical differences were found in clinical outcome. EDAGS is a very reliable alternative to combined bypass in adult MMD. However, randomized clinical trials are needed to assess the long-term efficacy of any bypass surgery in adult patients with MMD.
A 46-year-old woman developed transient ischemic attack (TIA) caused by progressive moyamoya vasculopathy in the right hemisphere. She had presented with minor cerebellar infarction due to left vertebral artery dissection 7 years prior to the onset of TIA. Initial carotid angiography at the onset of vertebral artery dissection demonstrated absence of steno-occlusive changes in the anterior circulation. During the next 7 years, she had been strictly followed up with magnetic resonance angiography every 6 months, which demonstrated the asymptomatic development of steno-occlusive change in the proximal right middle cerebral artery, finally involving the terminal internal carotid artery. Carotid angiography at the onset of TIA showed terminal internal carotid artery stenosis with abnormal vascular network at the right base of the brain, indicating a definitive diagnosis of moyamoya vasculopathy with unilateral involvement. She underwent right superficial temporal artery-middle cerebral artery anastomosis without complication one month later. TIA completely disappeared after surgery, and no cerebrovascular events occurred during the follow-up period of 6 months. De novo formation of moyamoya vasculopathy is extremely rare in adulthood. The present case demonstrated the entire temporal profile of the development of this rare entity in adulthood. The previous presentation of vertebral artery dissection before the development of moyamoya vasculopathy as well as the initiation of steno-occlusive change at the middle cerebral artery is apparently unique.
A 30-year-old female developed moyamoya syndrome after gamma knife surgery (GKS) for cerebral arteriovenous malformation (AVM), and was treated with bypass surgery. She suffered from flittering scotoma, right transient hemianopsia, and headache for 1 year. Cerebral angiography revealed a Spetzler-Martin grade III AVM located in the left occipital lobe. After staged embolization, GKS was performed with a minimum dose of 20 Gy to the periphery of the nidus at the 50% isodose level of the maximum target dose. Gradual nidus regression was achieved, and the clinical symptoms disappeared completely. However, at 30 months after GKS, the patient suffered transient ischemic attack. Cerebral angiography showed left middle cerebral artery occlusion with moyamoya vessels. The patient underwent direct and indirect bypass surgery. After surgery, the patient was free from ischemic symptoms. Chronic inflammation and long-term changes in expression of cytokines and growth factors after GKS may have triggered this case.
A 31-year-old male presenting with intracranial hemorrhage manifesting as deep coma and anisocoria underwent immediate emergency surgery. Three-dimensional computed tomography (CT) angiography revealed stenosis of the right middle cerebral artery (MCA) and perfusion CT immediately after the surgery suggested severe hypoperfusion in the right MCA territory. Postoperative angiography demonstrated right unilateral moyamoya disease. We predicted that brain edema and intracranial pressure (ICP) elevation occurring after the hemorrhage might result in cerebral infarction. Hyperosmotic drugs were contraindicated by dehydration. Therefore, therapeutic hypothermia was induced that controlled the ICP. We considered that the increased ICP, dehydration, vasospasm, and shrinkage of the ruptured vessel comprised the pathogenesis of acute cerebral ischemia after intracranial bleeding. Cerebral hemodynamics should be evaluated during the acute phase of cerebral hemorrhage to prevent subsequent cerebral infarction.
Crossed cerebellar diaschisis (CCD) often occurs after ischemic or hemorrhagic stroke that damages the cortico-ponto-cerebellar pathway. However, CCD due to cerebral hyperperfusion following cerebrovascular reconstruction is rare. A 61-year-old woman presented with transient CCD due to cerebral hyperperfusion following bypass surgery for adult moyamoya disease. She developed transient weakness of the right extremities and was diagnosed with moyamoya disease. First, she underwent superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis with indirect synangiosis on the left. Postoperative course was uneventful. Subsequently, she underwent STA-MCA anastomosis with indirect synangiosis on the right. She complained of mild headache on the right, and single photon emission computed tomography (SPECT) performed on the 7th postoperative day demonstrated hyperperfusion in the right frontal and temporal lobes associated with hypoperfusion in the left cerebellum. Magnetic resonance (MR) imaging demonstrated no new lesions and MR angiography showed patent STA-MCA bypass. Subsequent SPECT showed disappearance of both hyperperfusion and CCD. This case strongly suggests that cerebral hyperperfusion after bypass surgery for moyamoya disease may cause transient CCD. Although the clinical significance is still obscure, this phenomenon indicates the cortico-ponto-cerebellar pathway is interrupted due to hyperperfusion, suggesting the development of hyperperfusion syndrome. Careful observation of cerebral hemodynamics after bypass surgery is warranted to avoid hyperperfusion-related complications.