Understanding and treating moyamoya disease in children

Jodi L. Smith Ph.D., M.D.
View More View Less
  • Division of Pediatric Neurosurgery, Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, Indiana
Full access

Moyamoya disease, a known cause of pediatric stroke, is an unremitting cerebrovascular occlusive disorder of unknown etiology that can lead to devastating, permanent neurological disability if left untreated. It is characterized by progressive stenosis of the intracranial internal carotid arteries and their distal branches and the nearly simultaneous appearance of basal arterial collateral vessels that vascularize hypoperfused brain distal to the occluded vessels. Moyamoya disease may be idiopathic or may occur in association with other syndromes. Most children with moyamoya disease present with recurrent transient ischemic attacks or strokes. Although there is no definitive medical treatment, numerous direct and indirect revascularization procedures have been used to improve the compromised cerebral circulation, with outcomes varying according to procedure type. Such techniques improve the long-term outcome of patients with both idiopathic and syndrome-associated moyamoya disease. This review provides a comprehensive discussion of moyamoya disease in children, with an emphasis on the most effective surgical treatment options.

Abbreviations used in this paper: ACA = anterior cerebral artery; AVM = arteriovenous malformation; bFGF = basic fibroblast growth factor; CBF = cerebral blood flow; ECA = external carotid artery; EDAS = encephaloduroateriosynangiosis; EMS = encephalomyosynangiosis; ICA = internal carotid artery; MCA = middle cerebral artery; OA = occipital artery; STA = superficial temporal artery; TIA = transient ischemic attack.

Moyamoya disease, a known cause of pediatric stroke, is an unremitting cerebrovascular occlusive disorder of unknown etiology that can lead to devastating, permanent neurological disability if left untreated. It is characterized by progressive stenosis of the intracranial internal carotid arteries and their distal branches and the nearly simultaneous appearance of basal arterial collateral vessels that vascularize hypoperfused brain distal to the occluded vessels. Moyamoya disease may be idiopathic or may occur in association with other syndromes. Most children with moyamoya disease present with recurrent transient ischemic attacks or strokes. Although there is no definitive medical treatment, numerous direct and indirect revascularization procedures have been used to improve the compromised cerebral circulation, with outcomes varying according to procedure type. Such techniques improve the long-term outcome of patients with both idiopathic and syndrome-associated moyamoya disease. This review provides a comprehensive discussion of moyamoya disease in children, with an emphasis on the most effective surgical treatment options.

Abbreviations used in this paper: ACA = anterior cerebral artery; AVM = arteriovenous malformation; bFGF = basic fibroblast growth factor; CBF = cerebral blood flow; ECA = external carotid artery; EDAS = encephaloduroateriosynangiosis; EMS = encephalomyosynangiosis; ICA = internal carotid artery; MCA = middle cerebral artery; OA = occipital artery; STA = superficial temporal artery; TIA = transient ischemic attack.

Moyamoya disease is an unremitting cerebrovascular occlusive disorder of unknown etiology that is becoming more widely recognized as a cause of stroke in pediatric and adult patients. In fact, moyamoya disease accounts for ≥ 6% of strokes in children.73,96 If left untreated, it can lead to devastating, permanent neurological disability. It is characterized by progressive narrowing (and, ultimately, occlusion) of the terminal ICA and proximal middle and anterior cerebral arteries and the nearly simultaneous formation of dilated intracranial ICA tributaries at the base of the brain in response to ICA stenosis. These arteries, the so-called moyamoya vessels, traverse the basal ganglia and thalamus, and provide collateral blood flow to areas of hypoperfused brain distal to the narrowed vessels. Takeuchi and Shimizu107 were the first to describe this disease in the Japanese literature in 1957 as a case of “hypoplasia of the bilateral internal carotid arteries.” Kudo50 subsequently introduced it to the English literature in 1968 when he described it as a “spontaneous occlusion of the circle of Willis.” Finally, in 1969, Suzuki and Takaku100 used the term, “moyamoya,” a Japanese expression signifying “something hazy, like a puff of cigarette smoke drifting in the air,” to describe and define this disease process because of the distinctive angiographic appearance of the dilated collateral arteries that develop at the base of the brain in this disorder.

Moyamoya disease may be idiopathic or occur in association with other syndromes. In the literature, moyamoya disease typically refers to the idiopathic form of the arteriopathy,16,52,54 whereas moyamoya syndrome signifies cases in which the characteristic angiographic findings occur in association with other pathological processes such as neurofibromatosis, sickle cell anemia, Down syndrome, and prior cranial irradiation.10,99 These distinctions are important to keep in mind when analyzing outcome data from the literature since most if not all outcome studies are from Japan and other Asian countries. These studies include only those patients with the idiopathic form of moyamoya disease. In contrast, outcome studies from the Western hemisphere include patients with moyamoya disease and those with moyamoya syndrome.91 Despite the distinctions between the idiopathic and syndrome-associated forms, their angiographic and clinical courses are nearly identical.10

Since its initial discovery, moyamoya disease has been studied extensively, and there are now > 1200 publications describing various facets of this disorder and its management.16 Despite this, significant controversy remains regarding its etiology, pathogenesis, diagnosis, and treatment, including indications for treatment.16,82,90,93 Nevertheless, recent advances in research, diagnosis, and operative techniques emphasize the significance of a multidisciplinary approach to the management and further study of this disorder to improve the long-term outcome for patients with moyamoya disease. This review provides a comprehensive discussion of moyamoya disease in children, with an emphasis on the most effective surgical treatment options.

Epidemiology

Moyamoya disease occurs worldwide;20,99 however, the greatest incidence continues to be in East Asia. For instance, in Japan, the idiopathic form of this disease occurs annually in ≥ 0.35–0.54 per 100,000 population (that is, 0.35 in 1994 and 0.54 in 2003).52,114 In contrast, the incidence in Europe is ~ one-tenth the incidence in Japan.123 Moyamoya disease affects both males and females; however, in most series there is a consistent female preponderance, with females being affected nearly twice as often as males.5,73,91 In addition, there is a bimodal age distribution, with patients typically presenting either in the 1st or 4th decade of life.51,99 For those presenting within the 1st decade, ischemic events such as TIAs or strokes are more common. In contrast, adult patients more commonly present with hemorrhage. Because of this, the time to diagnosis is typically longer in pediatric patients.78 Finally, there is a relatively high incidence of familial occurrence, which accounts for ~ 15% of patients.120

Clinical Presentation

Children with moyamoya disease typically present with evidence of cerebral ischemia, and ~ 80% demonstrate TIAs (40%) or cerebral infarction (40%).77 Of these, ~ 80% have extremity weakness or paralysis as the initial finding,68 with or without alternating hemiplegia. Some patients present with ischemic events precipitated by crying, coughing, blowing, or hyperventilation since such activities lead to hypocapnia-induced vasoconstriction of the normal cerebral blood vessels, which in turn causes a transient reduction in CBF in an already compromised cerebral circulation.112 Patients can also present with headaches (likely resulting from dilation of meningeal and leptomeningeal collateral vessels), seizures (including somatosensory focal seizures), involuntary movements of the extremities, and/or a progressive decline in neurocognitive function. Although cerebral hemorrhage can be seen on presentation, it occurs only rarely in children. In contrast, 40–65% of adult patients present with hemorrhage, especially in the basal ganglia (40%), thalamus (15%), or ventricular system (30%).21,77 Symptoms related to posterior circulation ischemia, such as visual field defects, decreased visual acuity, transient blindness, scintillating scotomas, diplopia, ataxia, and vertigo, are uncommon presenting features in both children and adults. However, when they do occur, they are observed more often in children.72

Although most patients present with bilateral involvement, up to 18% of patients have angiographically documented unilateral involvement.40 In children, unilateral involvement typically progresses to bilateral involvement within 1–2 years.38 For example, in 1 study, 33 (14%) of 235 patients presented with unilateral moyamoya disease.94 Of these, 33% progressed to bilateral angiographic disease, on average, within 2.2 years, suggesting that all patients with unilateral disease should be observed closely for disease progression.

Multiple clinical associations have been observed in patients with moyamoya disease.16,91 Such associations may represent significant risk factors for the development of this disorder78 as well as for disease progression in patients with unilateral disease.94 These include prior cranial irradiation; tumors, such as optic gliomas, craniopharyngiomas, and pituitary tumors; genetic disorders, such as Down syndrome, neurofibromatosis (with or without hypothalamic-optic pathway tumors), Fanconi anemia, and sickle cell anemia22 and other hemoglobinopathies; collagen vascular disorders, such as Marfan syndrome, Ehler-Danlos, and homocystinuria; Graves disease;18 congenital cardiac disease; renal artery stenosis; infections, such as tuberculous meningitis and leptospirosis; atherosclerosis; and fibromuscular dysplasia.

Pathology

In moyamoya disease, stenotic changes initially appear in the intracranial ICAs distally at the level of their bifurcation. Later, the stenosis progresses to involve the proximal anterior and MCAs. During subsequent stages, the posterior circulation may also become involved. Histological analyses of the stenotic arteries reveal endothelial hyperplasia and fibrocellular thickening of the intima; tortuosity or undulation and sometimes even duplication of the internal elastic lamina;15,54,63,65,100 and attenuation of the media.101 Affected vessels lack inflammatory changes, suggesting that inflammation does not play a major causative role in vessel pathology.

Concomitant with stenosis, moyamoya vessels (that is, dilated perforating ICA tributaries) develop at the base of the brain in response to chronic ischemia. This intense compensatory recruitment of new vessels provides collateral blood flow to areas of hypoperfused brain distal to the narrowed vessels. These collateral vessels can be categorized as follows70: 1) intracerebral anastomoses, which arise from basal and convexity perforating arteries that penetrate brain parenchyma and anastomose at the external angle of the lateral ventricles; 2) dilated basal collateral networks, which develop directly from circle of Willis vessels and perforating carotid artery–basilar artery anastomoses; 3) cortical-leptomeningeal end-to-end anastomoses, which form over the surface of the brain at watershed areas of the major cerebral artery territories; 4) dural networks, which arise from dural vessels and perfuse ischemic brain through anastomoses with the cortical leptomeningeal system; and 5) extracranial networks, which arise from transdural vessels and connect scalp arteries to the cortical leptomeningeal system. The dural and extracranial arterial networks (vault moyamoya vessels) collateralize the anterior and middle cerebral circulations through vascular connections that form at the sagittal and transverse sinuses, falx, and tentorium.48 These vessels are particularly evident in areas where openings exist between skull, dura, arachnoid, and brain, such as around the venous sinuses or at the skull base where cranial nerves exit the calvaria (for example, at the cribriform plate).

Histologically, moyamoya vessels exhibit thin walls, mural fibrin deposits, fragmentation of the elastic lamina, and microaneurysm formation.99,106,120 Such changes may predispose these vessels to rupture, making them a possible source of hemorrhage,119 especially in adults. In addition, typical saccular aneurysms, many of which are located in posterior circulation vessels (with the basilar tip being the most common),58 are seen more frequently in adults with moyamoya than in the general population.77 Saccular aneurysms1 and pseudoaneurysms, which can develop along peripheral portions of perforating moyamoya vessels and the anterior and posterior choroidal arteries,49,99 also represent potential sources of hemorrhage. The incidence of aneurysms in children with moyamoya disease is ~ 1%, whereas that in adults is ~ 6.2%.77 Finally, AVMs can occur in patients with moyamoya disease, typically in the MCA territory,78 but the relationship between AVMs and moyamoya disease remains unknown.

Pathogenesis and Etiology

Although the pathogenesis and etiology of moyamoya disease remain unknown, genetic and acquired or environmental factors have been implicated in this disease process. The following observations support a role for genetic factors in the pathogenesis of moyamoya disease. The incidence of moyamoya disease is highest in, although not confined to, individuals of Japanese origin.50 Moyamoya disease has a high incidence of familial occurrence, with a familial incidence in Japan of 7–12%.45,95 Moyamoya disease frequently occurs in association with genetically transmitted disorders, including neurofibromatosis, sickle cell anemia, autoimmune disorders, and Down syndrome. Antidouble stranded DNA antibodies and several HLA antigens have also been observed in patients with moyamoya disease.46

Chromosome linkage analyses provide further support for genetic factors in the etiology of moyamoya disease. For example, a linkage study using markers on chromosome 6, where the HLA gene resides, identified an allele that appears to be linked with moyamoya disease.28 In another study, the observation that the characteristic cerebrovascular abnormalities of moyamoya disease are sometimes seen in neurofibromatosis Type 1, of which the causative gene (that is, NF1) has been assigned to 17q11.2, led to microsatellite linkage analyses to ascertain whether a gene related to moyamoya disease is also located on chromosome 17.121 Such analyses detected a gene for familial moyamoya disease on 17q. Besides 17q, microsatellite linkage analyses have shown linkages between moyamoya disease and markers located on 3p, 6q, and 8q.26,28,86,121 Interestingly, a locus for Marfan syndrome, a connective tissue disorder characterized by skeletal and cardiovascular anomalies, maps to 3p9 as does the von Hippel–Lindau disease tumor suppressor gene,59 which is responsible for the vascular tumor, hemangioblastoma. The gene product of the moyamoya gene mapping to 3p, although it has not yet been characterized, likely is fundamental to the formation and maintenance of vascular wall homeostasis. At present the significance of these findings is not entirely certain; however, the eventual molecular characterization of moyamoya disease will likely provide valuable insights into the etiology of this disorder as well as its treatment (for example, gene therapy).

Besides genetic factors, evidence supports a role for acquired or environmental factors in the pathogenesis of moyamoya disease. The observation of moyamoya pathology as a delayed response in patients following irradiation of the skull base for treatment of tumors of the head and neck, especially hypothalamic-optic pathway gliomas and craniopharyngiomas,4,41,79 suggests a role for environmental factors. Infection has also been proposed as a cause based on the observation in some patients of an infectious illness prior to the onset of moya moya disease.19 Moreover, the altered expression of certain mitogens, adhesion molecules, and angiogenic factors64,97,103,118,124 and/or alterations in cellular responses to growth factors and cytokines (small secreted proteins that mediate and regulate immunity, inflammation, and hematopoiesis) in vascular cells117 may play a crucial role in the development of moyamoya pathology (in particular, intimal thickening and media thinning) by affecting vascular endothelial or smooth muscle cell proliferation or migration.65 For example, caspase-3, a cysteine protease essential for programmed cell death, is elevated in MCA specimens from patients with moyamoya disease. This suggests a potential role for caspase-3-dependent apoptosis in attenuation of the media that can be seen in the stenotic vessels in patients with moyamoya disease.101 Furthermore, several studies have shown that bFGF, an angiogenic substance, is elevated in assays of dura and scalp arteries in patients with moyamoya disease24,98 as well as in the CSF of children with moyamoya disease, sampled at the time of revascularization surgery.64 Increased levels of bFGF may play a role in stenosis or in the neovascular response that occurs spontaneously and following cerebral revascularization procedures in patients with moyamoya disease. Although we still do not fully understand the specific mechanisms underlying the pathogenesis and etiology of moyamoya disease, genetic and environmental factors likely play significant roles in the underlying disease process.

Natural History and Prognosis

The natural history of moyamoya disease is still not fully understood; however, it is clear that the rate of disease progression is variable. For example, some patients exhibit a rapidly progressive course with multiple strokes and significant disability within the 1st year of diagnosis. Others demonstrate a more gradual disease progression, with neurological deficits accumulating slowly over many years and often with prolonged symptom-free intervals.78,87 Despite the course, the disease inevitably progresses in untreated patients,53,100 with angiographic and clinical worsening over time. Stability occurs only after the development of sufficient leptomeningeal or transdural collateral vessels. Until then, patients are at risk for developing ischemic symptoms.

A previous study investigated the prognosis of 27 children with moyamoya disease treated conservatively.57 That study revealed that ischemic symptoms, such as TIAs, occurred most often during the first 4 years and then tended to decline over time. In contrast, intellectual deterioration and neurological deficits increased with time; 50–65% of children exhibited a considerable decline in cognitive function. Several factors determine the overall prognosis of patients with moyamoya disease. These include the following: 1) the rapidity and extent of vascular occlusion; 2) the ability to develop effective collateral circulation; 3) the age at onset of symptoms; 4) the severity of presenting neurological deficits and degree of disability; and 5) the extent of infarction seen on CT or MR imaging studies at the time of initial presentation.61 As expected, patients presenting with fixed neurological deficits related to stroke tend to have poorer functional outcomes, with increased difficulty with activities of daily living. Moreover, the extent of disease at the time of diagnosis is a more important prognostic indicator than the age at onset of symptoms.91 For example, children who present with bilateral strokes tend to be developmentally delayed at long-term follow-up, regardless of their age, whereas those with multiple small infarcts or a large nondominant stroke often are educable and capable of leading independent and productive lives.91 Furthermore, if surgical revascularization is performed prior to infarction, the prognosis tends to be excellent even in the face of severe angiographic changes.27,91,113 However, if left untreated, the angiographic process and clinical symptoms invariably progress, leading to clinical deterioration and possible irreversible neurological deficits.27

Diagnosis

Although it is relatively uncommon, moyamoya disease must be considered in any child who presents with symptoms of cerebral ischemia (for example, TIAs manifesting as episodes of hemiparesis, speech disturbance, sensory impairment, involuntary movement, and/or visual disturbance), especially if the symptoms are precipitated by physical exertion, hyperventilation, or crying. Imaging plays a key role in the diagnostic evaluation of these patients. A head CT is typically the first study obtained. In patients with moyamoya disease, the head CT scan frequently shows areas of hypodensity consistent with infarct in cortical watershed zones, basal ganglia, deep white matter, or periventricular regions. The head CT may also reveal hemorrhage, most commonly in the basal ganglia (40%), ventricular system (30%), and thalamus (15%).77,112 Atrophy of the affected hemisphere is frequently seen in patients who have had severe stroke,3 and gyral enhancement can also be observed after contrast administration.104

Magnetic resonance imaging and MR angiography are helpful in the diagnosis of moyamoya disease because they provide greater parenchymal and vascular detail. Magnetic resonance imaging typically reveals diminished flow voids in the ICA, MCA, and ACA and prominent flow voids in the basal ganglia and thalamus from dilated moyamoya vessels that traverse these regions to supply hypoperfused brain distal to the occluded vessels. Such flow voids are virtually diagnostic of moyamoya disease. Magnetic resonance imaging may also demonstrate multiple, small, asymptomatic areas of cerebral infarction, which are typically found in watershed regions between the cortical areas vascularized by the ACA and MCA. Likewise, diffusion weighted, perfusion echo planar, and gradient echo MR imaging techniques are useful for evaluating cerebral ischemia,7,115 with diffusion weighted imaging leading to significantly earlier detection of ischemic lesions in patients with moyamoya disease.7

Magnetic resonance angiography is very useful for diagnosing moyamoya disease, with previous studies showing a sensitivity of 73% and a specificity of 100%.36,116 Sensitivity increases to 92% when MR angiography is combined with MR imaging116 or when MR angiography is performed with selective maximum intensity projection.105 Because of its excellent diagnostic yield and noninvasiveness, some have suggested that MR angiography be used instead of conventional cerebral angiography for the diagnosis of moyamoya disease.8 However, the smaller moyamoya collaterals are visualized more clearly with conventional cerebral angiography,116 which is still the gold standard for diagnosing moyamoya disease. Bilateral selective ECA and ICA injections and a vertebrobasilar artery injection are essential to define the extent of preexisting collaterals from the extracranial circulation, to document areas of cerebral hypoperfusion, and to identify any coexisting aneurysms or AVMs.

Moyamoya disease progresses through the following 6 characteristic angiographic stages:100 1) stenosis of distal intracranial ICAs, often bilaterally; 2) formation of moyamoya collateral vessels at the base of the brain; 3) further prominence of moyamoya vessels as stenosis of the anterior circulation progresses; 4) severe stenosis or occlusion of the entire circle of Willis along with narrowing of the dilated moyamoya vessels and formation of extracranial collateral networks; 5) enlargement of extracranial collateral vessels; and 6) occlusion of the distal ICAs, disappearance of the basal moyamoya vessels, and cerebral vascularization from extracranial sources only. Cerebral angiography allows visualization of extracranial collateral networks and extracranial anastomotic sources such as the anterior branch of the middle meningeal artery, maxillary artery, and ophthalmic artery (for example, through the cribriform plate to supply the undersurface of the frontal lobe and through the falx to supply the ACA distribution).

Electroencephalography can be helpful in the diagnostic workup of pediatric patients with moyamoya disease. In ~ 50% of children with moyamoya disease, electroencephalography will show a hyperventilation-induced diffuse pattern of monophasic slow waves (that is, buildup) followed by a characteristic “re–buildup” phenomenon.47,123 This re–buildup phenomenon occurs after hyperventilation has stopped and involves the appearance of slow waves after disappearance or attenuation of ordinary buildup. This electroencephalography finding, which is characteristic of moyamoya disease, is thought by some to occur as a consequence of decreased arterial CO2 tension, which causes vasoconstriction of previously maximally dilated normal cerebral vessels and leads to cerebral ischemia.39,102 Other investigators have proposed that cerebral hypoxia occurs after the cessation of hyperventilation and that this plays an essential role in the appearance of the re–buildup phenomenon.13,55 In conjunction with this, vasodilation in normal brain areas, which occurs in response to increasing PaCO2 after the cessation of hyperventilation has been hypothesized to induce a possible steal response in cerebral areas suffering from chronic hemodynamic stress. This produces even more profound hypoperfusion in these already ischemic cerebral areas and possibly explains the clinical symptoms initiated by hyperventilation in patients with moyamoya disease.75

Techniques used to evaluate CBF are also very helpful in the diagnosis and management of moyamoya disease. Such techniques, which include Xe-enhanced CT, PET, and SPECT, can identify regional perfusion instability prior to treatment and ascertain the extent of improvement of functional perfusion following therapy.60,62,74,108 Single photon emission CT, with and without acetazolamide/CO2 vasodilatory challenge, is a particularly useful technique that assesses cerebrovascular reserve and helps to predict the likelihood of further disease progression. Occlusion of the major cerebral arteries in patients with moyamoya produces chronic hemodynamic stress. In response to this stress, the cerebral blood vessels supplying ischemic areas vasodilate maximally in an attempt to preserve CBF and compensate for reduced cerebral perfusion. This leads to abnormal vasoreactivity to vasodilatory stimuli, such as hypercapnia or acetazolamide. Consequently, CBF in chronically hypoperfused areas challenged with a vasodilatory stimulus often is paradoxically diminished.75,76 This occurs because the unaffected vessels, which vascularize chronically ischemic areas through leptomeningeal collaterals or poorly developed collaterals from the circle of Willis, promptly dilate in response to vasodilatory stimuli, thereby effectively reducing CBF to areas with an impaired vascular response.

Treatment Options

Some patients with moyamoya disease stabilize clinically without intervention; however, this usually occurs only after they have experienced a significant, debilitating neurological disability. Following a major stroke or hemorrhage, children with moyamoya disease frequently are left with permanent neurological impairment.78,89–91 Consequently, early diagnosis and prompt, appropriate surgical management are of utmost importance.56 Currently, there is no definitive medical treatment to halt the progression or stabilize the course of moyamoya disease. Multiple surgical procedures designed to augment CBF distal to the occluded carotid arteries have been successful in treating moyamoya disease. Although objective evidence from randomized controlled clinical trials suggesting improved function following these procedures is still lacking, several studies examining the long-term outcome in children with moyamoya disease following revascularization surgery strongly suggest that surgical revascularization improves cerebral hemodynamics and reduces the incidence of subsequent ischemic events. In pediatric patients who have undergone surgical revascularization for treatment of symptomatic moyamoya disease, TIAs rapidly decrease or disappear and strokes rarely recur.16,17,29,34,91,113

Because stroke can occur and lead to severe neurological impairment, it is unwise to wait for evidence of ischemic symptoms before recommending surgery.89,90 Moreover, if surgical revascularization is performed before infarction occurs, patients with moyamoya disease who present with TIAs will frequently have excellent outcomes. Patients with angiographic evidence of moyamoya disease are candidates for surgery. Angiographic criteria include the following: 1) stenosis or occlusion of the distal portion of the intracranial ICA and the proximal portions of the ACA and MCA; 2) an abnormal vascular network seen during the arterial phase near the stenosed or occluded vessels; and 3) bilateral involvement.14 If the degree of hypoperfusion on angiography does not appear critical but one suspects symptomatic moyamoya, then a CBF study such as SPECT with acetazolamide challenge should be done to look for reduced cerebral perfusion reserve as an additional indication for surgical treatment. Once the diagnosis has been established, surgery is recommended before further ischemic symptoms and related complications develop. Early diagnosis and prompt surgical revascularization over a wide area are crucial to achieving a good long-term outcome with improved intellectual function.56 If a patient has neurological deficits related to a prior stroke, the decision to operate should be based on the presence of other cortical areas at risk for stroke and on the patient's quality of life if further neurological deficits were to develop.

Options for Medical Treatment

Currently, there is no known medical treatment capable of reversing, halting, or stabilizing the relentless progression of the arteriopathic process in moyamoya disease. Nevertheless, 2 types of medication play a role in the treatment of this disorder: aspirin and calcium channel blockers. Aspirin is taken daily and continued indefinitely to avoid ischemic symptoms owing to possible emboli from microthrombus formation at sites of arterial stenoses.78,89,90 Patients < 6 years of age receive 80 mg/day; the dose is gradually increased up to 300 mg/day in adolescents. Patients are monitored for side effects, such as easy bruising, bleeding, and gastrointestinal irritation, and the aspirin dose is adjusted as needed.

Calcium channel blockers are also effective in treating certain symptoms in patients with moyamoya disease,89 such as persistent postoperative TIAs and intractable headaches. Although the mechanism of action is unknown, calcium channel blockers seem to be effective in reducing the frequency and severity of refractory TIAs in patients with moyamoya disease. Moreover, they can be used to treat headaches in children with moyamoya disease. Headaches can occur before and after revascularization surgery and can be very difficult to treat. Because of their antimigraine pharmacotherapeutic effect, calcium channel blockers are effective in relieving intractable headaches in patients with moyamoya disease.

Although currently there is no evidence that medical management alters the clinical course or outcome of individuals with moyamoya disease, future treatment will likely include the use of medical therapy.89 Plausible examples of potential medical therapies include the use of the following: topical or systemic angiogenic growth factors to induce neovascularization; gene therapy to target genetically determined conditions that occur in association with moyamoya disease; and additional novel therapies that block or alter the arteriopathic disease process.

Options for Surgical Treatment

To date there are no prospective randomized controlled clinical trials to determine the efficacy of surgical revascularization in the treatment of moyamoya disease. Nevertheless, there are a number of studies in the literature that provide strong support for surgical treatment. Revascularization surgery is generally recommended for patients with recurrent or progressive cerebral ischemic events and associated reduced cerebral perfusion reserve. Numerous operative techniques have been described. At the present time, there is no standardized surgical approach for the treatment of moyamoya disease in children, and numerous surgical procedures have been used in a variety of combinations.113 Such techniques aim to prevent further ischemic injury by increasing collateral blood flow to hypoperfused areas of cortex, with most using the external carotid circulation as a donor supply.12,16,17,29,34,48,54,81,91,113

Revascularization procedures can be divided into 3 main groups: indirect (nonanastomotic) bypass techniques, direct (anastomotic) bypass techniques, and indirect and/or direct bypass techniques combined. Indirect bypass techniques include pial synangiosis,2,91 EDAS,67,69 EMS (temporalis muscle with its rich blood supply is sutured to the dura mater),33 encephaloduroateriomyosynangiosis (EDAMS),43 ribbon EDAMS,44 encephalogaleosynangiosis (EGS),110 encephalogaleomyosynangiosis (EGMS),92 omental transplantation,23,31,35 bifrontal encephalogaleoperiosteal synangiosis (EGPS),42,80 and multiple bur hole surgery, with opening of dura and arachnoid over affected areas,11,84 as well as a combination of ≥ 1 of these techniques. One of the biggest criticisms of the indirect techniques has been that the beneficial effects are not immediate because it takes ≥ 3–4 months for collaterals to develop,25,113 and during that time there is a risk of perioperative ischemic stroke.85 The most commonly used direct bypass techniques are the ECA-ICA anastomoses,32 which involve anastomosis of the STA or the OA to the MCA either in isolation or in combination with a variety of indirect bypass techniques.

Numerous studies have reported on the technical aspects, indications, pitfalls, and efficacy of direct and indirect revascularization techniques for the prevention of ischemic symptoms in patients with moyamoya disease. In general, these studies have documented good to excellent angiographic and clinical results, including good collateralization of the MCA territory, reduction in the size of the basal collateral vessels, improved CBF, and partial or complete resolution of ischemic symptoms.12,34,66,109 Increased levels of angiogenic factors, such as bFGF, which is elevated in the CSF in patients with moyamoya disease,64,103,124 likely contribute to the effectiveness of both indirect and direct revascularization techniques by enhancing the formation and in-growth of new blood vessels from extracranial sources.64 Evidence suggests that essentially any surgically created pathway that traverses the skull, dura, and arachnoid will permit formation of cortical collaterals.78,89,90

The STA-MCA Bypass

Direct (anastomotic) bypass techniques, such as the STA-MCA or OA-MCA bypass, which depend on the patency and suitability of the donor vessel, were the first revascularization procedures used in the treatment of moyamoya disease.81 Such procedures provide the greatest amount of immediate collateral blood flow of any of the revascularization procedures, and excellent angiographic and clinical results have been observed.5,17,32,71 With regard to the STA-MCA anastomosis, this technique has been shown to improve the progressive natural history, angiographic appearance, and CBF abnormalities associated with moyamoya disease.17 Moreover, STA-MCA anastomosis is effective in patients in whom prior indirect revascularization procedures have failed. Although this type of direct revascularization procedure has a distinct advantage over indirect revascularization procedures by providing immediate highflow revascularization to ischemic brain regions, there are limitations to its widespread use in children.78,87,91,93 First, the small diameters of the STA and MCA in children make it technically very challenging to accomplish a successful anastomosis that supplies meaningful blood flow to the operated hemisphere. Second, the risk of intraoperative stroke is increased related to the temporary MCA occlusion required for anastomosis and also to the potential damage that can occur to existing transdural anastomoses between the distal STA and cortical arteries. Third, unless the proximal MCA circulation is relatively intact, the amount of blood flow to the entire MCA territory that can be achieved by STA-MCA bypass is severely limited. Based on the fact that published postoperative angiograms have demonstrated collateral circulation derived from scalp and meningeal arteries, which is difficult to distinguish from collateral circulation provided by the surgical anastomosis, the actual role of the anastomosis in the perfusion of the MCA distribution is often tough to determine. Finally, in multiple studies in the literature (especially from Japan), the STA-MCA bypass technique is frequently combined with an indirect technique, such as EMS, in which the inner surface of a partially freed flap of temporalis muscle is applied to the brain surface after creating multiple openings in the arachnoid.17,29,37,67,113 The need to combine techniques suggests that STA-MCA bypass alone does not provide adequate collateral circulation to ischemic brain in at least some patients with moyamoya disease.

The EDAS Procedure

The indirect (nonanastomotic) revascularization technique that is most commonly used to treat moyamoya disease in children is the EDAS procedure.67,69 In this technique, the intact STA (usually parietal STA branch or other scalp donor artery such as the OA or the anterior STA branch) is sutured by its adventitia into a linear opening in the dura subjacent to a small elliptical craniotomy.69 Although early reports in the literature described good to excellent results with this technique,66 subsequent studies have criticized the EDAS technique because of insufficient collateral flow on postoperative angiograms and persistence of ischemic symptoms.6,111 Nevertheless, at least in children, the amount of collateralization that develops and the clinical benefit that can be derived from EDAS alone are roughly the same as those observed from STA-MCA bypass combined with EMS.37

Pial Synangiosis

Another widely used indirect revascularization procedure is pial synangiosis.2,30,87–91,94 This technique, which represents a modification of the EDAS procedure, can be used to treat moyamoya disease in children and adults. Pial synangiosis allows for greater induction of extradural collateral vessels by placing the donor scalp artery in direct contact with the pial vasculature stripped of its meningeal coverings.2,84,88 A retrospective case study evaluating 143 consecutive pediatric patients with moyamoya disease treated with pial synangiosis and followed for an average of 5.1 years (the largest moyamoya revascularization surgery series in the western hemisphere16) showed that patients treated with pial synangiosis stop having strokes and TIAs and have an excellent long-term prognosis.91 This study provided strong evidence that indirect revascularization from pial synangiosis “halts what is normally a relentless clinical deterioration in the untreated patient.”91

The pial synangiosis technique involves the following steps (Fig. 1). A scalp donor artery (most commonly the posterior/parietal branch of the STA) is dissected with a cuff of galea and a large craniotomy bone flap is turned in the region subjacent to the artery (Fig. 1A). The dura is opened in a stellate fashion, making ≥ 6 incisions without disrupting potential meningeal collateral vessels, to increase the surface area of dura exposed to the pial surface and thereby enhance formation of collateral vessels from the dural vascular supply (Fig. 1B). The arachnoid is opened widely over the cortical surface exposed by the dural opening. The intact donor artery is sutured by its galeal cuff directly to the pial surface using several interrupted 10-0 nylon sutures (Fig. 1C).2,88,91 Cerebral angiograms obtained 1 year after pial synangiosis showed excellent MCA collateralization from the donor artery as well as from other meningeal and scalp arteries close to the craniotomy site. In the study by Scott et al.,91 65% of the 195 hemispheres studied showed synangiosis-induced filling of more than two-thirds of the MCA circulation, and 25% showed synangiosis-induced filling of at least one-third of the MCA circulation. More importantly, patients with moyamoya disease who have undergone pial synangiosis have demonstrated an excellent neurological outcome with complete resolution or a significant reduction in the frequency and severity of TIAs during the 1st postoperative year as well as an extremely low incidence of new strokes.2,83,91

Fig. 1.
Fig. 1.

Intraoperative photographs showing a pial synangiosis being performed in a 3-year-old girl. Moyamoya disease had been diagnosed after the patients sustained 2 strokes in the left MCA distribution. She had complete occlusion of the right ICA with associated moyamoya collateral vessels and no antegrade flow in the right MCA and ACA distributions. On the left, moderate stenosis of the left distal ICA was demonstrated, compatible with early moyamoya change. A: Intact STA with a cuff of galea overlying a large area of dura exposed by craniotomy. B: Stellate dural opening. C: Completed pial synangiosis with wide opening of arachnoid and STA sutured by its galeal cuff directly to the pial surface.

Omental Transplantation

Another indirect revascularization technique occasionally used in the treatment of moyamoya disease is intracranial transplantation of the omentum. This involves tunneling an intact omental flap from the abdomen and placing it on the surface of the brain or anastomosing a free flap of omentum via the gastroepiploic artery and vein end-to-end with the superficial temporal artery and vein, respectively.23,31,35 Omental transplantation is typically reserved for treatment of moyamoya disease after a direct or other indirect revascularization procedure has failed to alleviate ischemic symptoms or for revascularization of the frontal pole or medial cortical surface. Omental transplants also provide good collateralization and resolution of ischemic symptoms.23,31,35

Multiple Bur Holes

The multiple cranial bur hole technique is an additional indirect technique that can be used to treat moyamoya disease.11,84 Until recently, this technique has been used in combination with other techniques, such as the STA-MCA bypass, EMS, EDAS, or pial synangiosis, to provide supplemental collateralization, especially to the frontal and occipital lobes, which typically are not well vascularized by these other techniques.95 Unfortunately, the rate of collateral development as determined by postoperative angiography is variable.95 However, a recent study has provided evidence for the use of multiple cranial bur holes bilaterally as the sole treatment for moyamoya disease in children without the use of supplementary revascularization procedures.84 In this study of 14 patients (24 hemispheres), a bilateral retrocoronal scalp incision was made, and the scalp flaps were retracted widely anteriorly and posteriorly to expose the frontal, parietal, temporal, and occipital regions bilaterally. Ten to 24 small triangular flaps of pericranium were then elevated ~ 3 cm apart and bur holes were drilled at each site. The dura, arachnoid, and pia were opened, and the periosteal flap was placed in contact with the cortical surface. Postoperative angiograms obtained 8–12 months after surgery in this small series of patients showed good collateralization of the ischemic brain, and there were no ischemic events postoperatively.

In a recent review of the literature designed to determine the evidence base for the efficacy of surgical revascularization for the treatment of moyamoya disease in children,16 57 of 1260 studies met criteria for review, and all were retrospective case studies. This review included data from 1448 patients, of whom 1322 were pediatric patients (< 21 years of age), with a total of 2218 hemispheres operated either with direct techniques (4%), indirect techniques (73%, all considered as a single group), or a combination of direct and indirect techniques (23%). In this analysis, 51.2% of patients became completely asymptomatic with resolution of TIAs and no neurological signs, 35.5% showed definite clinical improvement, 10.5% showed no change, and 2.7% exhibited deterioration, developing new infarcts. Postoperative angiography showed collateralization of ≥ one-third of the MCA territory (good collateralization) in 83% of indirect procedures (including all types) as well as in 6 of 7 direct procedures and 97 of 101 combined procedures. When the indirect procedure group was compared with pooled data from the direct and combined procedure groups, good collateralization was seen significantly more often in the direct/combined group. However, there was no statistically signifi cant difference in the rate of positive outcomes among the 3 groups of techniques.

Conclusions

Moyamoya disease, although relatively uncommon, is a widely recognized cause of stroke in children and must be considered in the differential diagnosis of any child who presents with symptoms of cerebral ischemia, especially if the symptoms are precipitated by physical exertion, hyperventilation, or crying. If left untreated, moyamoya disease will inevitably progress and can lead to devastating, permanent neurological impairment. Fortunately, excellent long-term prognosis is achievable with prompt diagnosis and appropriate surgical management.

Revascularization surgery is recommended for the treatment of most patients. Currently, there are no randomized controlled trials to determine the efficacy of surgical revascularization; however, numerous studies have provided strong support for surgical intervention. Numerous operative techniques have been described. To date, there is no standardized surgical approach for the treatment of moyamoya disease in children, and numerous surgical procedures have been used in a variety of combinations with variable effectiveness.12,16,17,29,34,48,54,81,91,113 Future investigations are needed to clarify the etiology, pathogenesis, diagnosis, and treatment, including indications for treatment, of this disorder to improve the long-term outcome for patients with moyamoya disease.

Disclaimer

The author reports no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

References

  • 1

    Adams HP Jr, , Kassell NF, , Wisoff HS, & Drake CG: Intracranial saccular aneurysm and moyamoya disease. Stroke 10:174179, 1979

  • 2

    Adelson PD, & Scott RM: Pial synangiosis for moyamoya syndrome in children. Pediatr Neurosurg 23:2633, 1995

  • 3

    Ahmed R, & Ahsan H: Imaging of moyamoya disease. J Pak Med Assoc 47:181185, 1997

  • 4

    Bitzer M, & Topka H: Progressive cerebral occlusive disease after radiation therapy. Stroke 26:131136, 1995

  • 5

    Boone SC, & Samson DS: Observation on moyamoya disease: a case treated with superficial temporal-middle cerebral artery anastomosis. Surg Neurol 9:189193, 1978

    • Search Google Scholar
    • Export Citation
  • 6

    Cahan LD: Failure of encephalo-duro-arterio-synangiosis procedure in moyamoya disease. Pediatr Neurosci 12:5862

  • 7

    Chabbert V, , Ranjeva JP, , Sevely A, , Boetto S, , Berry I, & Manelfe C: Diffusion- and magnetisation transfer-weighted MRI in childhood moya-moya. Neuroradiology 40:267271, 1998

    • Search Google Scholar
    • Export Citation
  • 8

    Chang KH, , Yi JG, , Han MH, & Kim IO: MR imaging findings of moyamoya disease. J Korean Med Sci 5:8590, 1990

  • 9

    Collod G, , Babron MC, , Jondeau G, , Coulon M, , Weissenbach J, & Dubourg O, : A second locus for Marfan syndrome maps to chromosome 3p24.2–p25. Nat Genet 8:264268, 1994

    • Search Google Scholar
    • Export Citation
  • 10

    Cramer SC, , Robertson RL, , Dooling EC, & Scott RM: Moyamoya and Down syndrome. Clinical and radiological features. Stroke 27:21312135, 1996

    • Search Google Scholar
    • Export Citation
  • 11

    Endo M, , Kawano N, , Miyaska Y, & Yada K: Cranial burr hole for revascularization in moyamoya disease. J Neurosurg 71:180185, 1989

  • 12

    Erickson DL, & Koivukangas J: The treatment of Moyamoya disease by superficial temporal-middle cerebral artery (STAMCA) anastomosis. Ann Clin Res 18:47 Suppl 2124, 1986

    • Search Google Scholar
    • Export Citation
  • 13

    Fujiwara J, , Nakahara S, , Enomoto T, , Nakata Y, & Takita H: The effectiveness of O2 administration for transient ischemic attacks in moyamoya disease in children. Childs Nerv Syst 12:6975, 1996

    • Search Google Scholar
    • Export Citation
  • 14

    Fukui M: Current state of study on moyamoya disease in Japan. Surg Neurol 47:138143, 1997

  • 15

    Fukui M, , Kono S, , Sueishi K, & Ikezaki K: Moyamoya disease. Neuropathology 20:Suppl S61S64, 2000

  • 16

    Fung LW, , Thompson D, & Ganesan V: Revascularisation surgery for paediatric moyamoya: a review of the literature. Childs Nerv Syst 21:358364, 2005

    • Search Google Scholar
    • Export Citation
  • 17

    Golby AJ, , Marks MP, , Thompson RC, & Steinberg GK: Direct and combined revascularization in pediatric moyamoya disease. Neurosurgery 45:5058, 1999

    • Search Google Scholar
    • Export Citation
  • 18

    Golomb MR, , Biller J, , Smith JL, , Edwards-Brown M, , Sanchez JC, & Nebesio TD, : A 10-year-old girl with coexistent moyamoya disease and Graves' disease. J Child Neurol 20:620624, 2005

    • Search Google Scholar
    • Export Citation
  • 19

    Gordon N, & Isler W: Childhood moyamoya disease. Dev Med Child Neurol 31:103107, 1989

  • 20

    Goto Y, & Yonekawa Y: Worldwide distribution of moyamoya disease. Neurol Med Chir (Tokyo) 32:883886, 1992

  • 21

    Han DH, , Nam DH, & Oh CW: Moyamoya disease in adults: characteristics of clinical presentation and outcome after encephalo-duro-arterio-synangiosis. Clin Neurol Neurosurg 99:2 Suppl S151S155, 1997

    • Search Google Scholar
    • Export Citation
  • 22

    Hankinson TC, , Bohman LE, , Heyer G, , Licursi M, , Ghatan S, & Feldstein NA, : Surgical treatment of moyamoya syndrome in patients with sickle cell anemia: outcome following encephalodurarteriosynangiosis. J Neurosurg Pediatr 1:211216, 2008

    • Search Google Scholar
    • Export Citation
  • 23

    Havlik RJ, , Fried I, , Chyatte D, & Modlin IM: Encephalo-omental synangiosis in the management of moyamoya disease. Surgery 111:156162, 1992

    • Search Google Scholar
    • Export Citation
  • 24

    Hoshimaru M, , Takahashi JA, , Kikuchi H, , Nagata I, & Hatanaka M: Possible roles of basic fibroblast growth factor in the pathogenesis of moyamoya disease: an immunohistochemical study. J Neurosurg 75:267270, 1991

    • Search Google Scholar
    • Export Citation
  • 25

    Houkin K, , Nakayama N, , Kuroda S, , Ishikawa T, & Nonaka T: How does angiogenesis develop in pediatric moyamoya disease after surgery? A prospective study with MR angiography. Childs Nerv Syst 20:734741, 2004

    • Search Google Scholar
    • Export Citation
  • 26

    Ikeda H, , Sasaki T, , Yoshimoto T, , Fukui M, & Arinami T: Mapping of a familial moyamoya disease gene to chromosome 3p24.2–p26. Am J Hum Genet 64:533537, 1999

    • Search Google Scholar
    • Export Citation
  • 27

    Imaizumi T, , Hayashi K, , Saito K, , Osawa M, & Fukuyama Y: Long-term outcomes of pediatric moyamoya disease monitored to adulthood. Pediatr Neurol 18:321325, 1998

    • Search Google Scholar
    • Export Citation
  • 28

    Inoue TK, , Ikezaki K, , Sasazuki T, , Matsushima T, & Fukui M: Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 15:179182, 2000

    • Search Google Scholar
    • Export Citation
  • 29

    Ishikawa T, , Houkin K, , Kamiyama H, & Abe H: Effects of surgical revascularization on outcome of patients with pediatric moyamoya disease. Stroke 28:11701173, 1997

    • Search Google Scholar
    • Export Citation
  • 30

    Jea A, , Smith ER, , Robertson R, & Scott RM: Moyamoya syndrome associated with down syndrome: outcome after surgical revascularization. Pediatrics 116:e694e701, 2005

    • Search Google Scholar
    • Export Citation
  • 31

    Karasawa J, , Kikuchi H, , Kawamura J, & Sakai T: Intracranial transplantation of the omentum for cerebrovascular moyamoya disease: a two-year follow-up study. Surg Neurol 14:444449, 1980

    • Search Google Scholar
    • Export Citation
  • 32

    Karasawa J, , Kikuchi H, , Furuse S, , Kawamura J, & Sakaki T: Treatment of moyamoya disease with STA-MCA anatomosis. J Neurosurg 49:679688, 1978

    • Search Google Scholar
    • Export Citation
  • 33

    Karasawa J, , Kikuchi H, , Furuse S, , Sakaki T, & Yoshida Y: A surgical treatment of “moyamoya” disease “encephalo-myo synangiosis”. Neurol Med Chir (Tokyo) 17:2937, 1977

    • Search Google Scholar
    • Export Citation
  • 34

    Karasawa J, , Touho H, , Ohnishi H, , Miyamoto S, & Kikuchi H: Long-term follow-up study after extracranial-intracranial bypass surgery for anterior circulation ischemia in childhood moyamoya disease. J Neurosurg 77:8489, 1992

    • Search Google Scholar
    • Export Citation
  • 35

    Karasawa J, , Touho H, , Ohnishi H, , Miyamoto S, & Kikuchi H: Cerebral revascularization using omental transplantation for childhood moyamoya disease. J Neurosurg 79:192196, 1993

    • Search Google Scholar
    • Export Citation
  • 36

    Katz DA, , Marks MP, , Napel SA, , Bracci PM, & Roberts SL: Circle of Willis: evaluation with spiral CT, angiography, MRA and conventional angiography. Radiology 195:445449, 1995

    • Search Google Scholar
    • Export Citation
  • 37

    Kawamura T, , Imaizumi S, , Sakurai Y, , Uenohara H, , Nishino A, & Suzuki S: [Effect of various surgical procedures for moyamoya disease in children and adults.]. No Shinkei Geka 22:933938, 1994. (Jpn)

    • Search Google Scholar
    • Export Citation
  • 38

    Kawano T, , Fukui M, , Hashimoto N, & Yonekawa Y: Follow-up study of patients with “unilateral” moyamoya disease. Neurol Med Chir (Tokyo) 34:744747, 1994

    • Search Google Scholar
    • Export Citation
  • 39

    Kazumata K, , Kuroda S, , Houkin K, , Abe H, & Mitumori K: Regional cerebral hemodynamics during re-build-up phenomenon in childhood moyamoya disease. An analysis using 99mTc-HMPAO SPECT. Childs Nerv Syst 12:161165, 1996

    • Search Google Scholar
    • Export Citation
  • 40

    Kelly ME, , Bell-Stephens TE, , Marks MP, , Do HM, & Steinberg GK: Progression of unilateral moyamoya disease: a clinical series. Cerebrovasc Dis 22:109115, 2006

    • Search Google Scholar
    • Export Citation
  • 41

    Kestle JR, , Hoffman HJ, & Mock AR: Moyamoya phenomenon after radiation for optic glioma. J Neurosurg 79:3235, 1993

  • 42

    Kim S, , Wang K, , Kim I, , Lee DS, & Cho B: Combined encephalo-duroarteriosynangiosis and bifrontal encephalogaleo (periosteal) synangiosis in pediatric moyamoya disease. Neurosurgery 50:8896, 2002

    • Search Google Scholar
    • Export Citation
  • 43

    Kinugasa K, , Mandai S, , Kamata I, , Sugiu K, & Ohmoto T: Surgical treatment of moyamoya disease: operative technique for encephalo-duro-arterio-myo-synangiosis, its follow-up, clinical results, and angiograms. Neurosurgery 32:527531, 1993

    • Search Google Scholar
    • Export Citation
  • 44

    Kinugasa K, , Mandai S, , Tokunaga K, , Kamata I, , Sugiu K, & Handa A, : Ribbon enchephalo-duro-arterio-myo-synangiosis for moyamoya disease. Surg Neurol 41:455461, 1994

    • Search Google Scholar
    • Export Citation
  • 45

    Kitahara T, , Ariga N, , Yamaura A, , Makino H, & Maki Y: Familial occurrence of moyamoya disease: report of 3 Japanese families. J Neurol Neurosurg Psychiatry 42:208214, 1979

    • Search Google Scholar
    • Export Citation
  • 46

    Kitahara T, , Okumura K, , Semba A, , Yamaura A, & Makino H: Genetic and immunologic analysis on moya-moya. J Neurol Neurosurg Psychiatry 45:10481052, 1982

    • Search Google Scholar
    • Export Citation
  • 47

    Kodama N, , Aoki Y, , Hiraga H, , Wada T, & Suzuki J: Electroencephalographic findings in children with moyamoya disease. Arch Neurol 36:1619, 1979

    • Search Google Scholar
    • Export Citation
  • 48

    Kodama N, , Fujiwara S, , Horie Y, , Kayama T, & Suzuki J: [Transdural anastomosis in moyamoya disease–vault moyamoya.]. No Shinkei Geka 8:729737, 1980. (Jpn)

    • Search Google Scholar
    • Export Citation
  • 49

    Kodama N, & Suzuki J: Moyamoya disease associated with aneurysm. J Neurosurg 48:565569, 1978

  • 50

    Kudo T: Spontaneous occlusion of the circle of Willis. A disease apparently confined to the Japanese. Neurology 18:485496, 1968

  • 51

    Kudo T, & Fukuda S: Spontaneous occlusion of the circle of Willis. Shinkei-shimpo 20:750757, 1976

  • 52

    Kuriyama S, , Kusaka Y, , Fujimura M, , Wakai K, , Tamakoshi A, & Hashimoto S, : Prevalence and clinicoepidemiological features of moyamoya disease in Japan: findings from a nationwide epidemiological survey. Stroke 39:4247, 2008

    • Search Google Scholar
    • Export Citation
  • 53

    Kuroda S, , Hashimoto N, , Yoshimoto T, & Iwasaki Y: Research Committee on Moyamoya Disease in Japan: Radiological findings, clinical course, and outcome in asymptomatic moyamoya disease: results of multicenter survey in Japan. Stroke 38:14301435, 2007

    • Search Google Scholar
    • Export Citation
  • 54

    Kuroda S, & Houkin K: Moyamoya disease: current concepts and future perspectives. Lancet Neurol 7:10561066, 2008

  • 55

    Kuroda S, , Houkin K, , Hoshi Y, , Tamura M, , Kazumata K, & Abe H: Cerebral hypoxia after hyperventilation causes “re-buildup” phenomenon and TIA in childhood moyamoya disease. A near-infrared spectroscopy study. Childs Nerv Syst 12:448452, 1996

    • Search Google Scholar
    • Export Citation
  • 56

    Kuroda S, , Houkin K, , Ishikawa T, , Nakayama N, , Ikeda J, & Ishii N, : Determinants of intellectual outcome after surgical revascularization in pediatric moyamoya disease: a multivariate analysis. Childs Nerv Syst 20:302308, 2004

    • Search Google Scholar
    • Export Citation
  • 57

    Kurokawa T, , Tomita S, , Ueda K, , Narazaki O, , Hanai T, & Hasuo K, : Prognosis of occlusive disease of the circle of Willis (moyamoya disease) in children. Pediatr Neurol 1:274277, 1985

    • Search Google Scholar
    • Export Citation
  • 58

    Kwak R, , Ito S, , Yamamoto N, & Kadoya S: [Significance of intracranial aneurysms associated with moyamoya disease: (Part 1). Differences between intracranial aneurysms associated with moyamoya disease and usual saccular aneurysms - review of the literature.]. Neurol Med Chir (Tokyo) 24:97103, 1984. (Jpn)

    • Search Google Scholar
    • Export Citation
  • 59

    Latif F, , Tory K, , Gnarra J, , Yao M, , Duh FM, & Orcutt ML, : Identification of the von Hippel–Lindau disease tumor suppressor gene. Science 260:13171320, 1993

    • Search Google Scholar
    • Export Citation
  • 60

    Liu H, , Peng S, & Li Y: The preoperative and postoperative cerebral blood flow and vasoreactivity in childhood moyamoya disease. Keio J Med 49:1 Suppl A86A89, 2000

    • Search Google Scholar
    • Export Citation
  • 61

    Maki Y, & Enomoto T: Moyamoya disease. Childs Nerv Syst 4:204212, 1988

  • 62

    Maki Y, , Nakada Y, & Nose T: Clinical and radiologic follow-up study of “moyamoya”. Childs Brain 11:155170, 1984

  • 63

    Maki Y, & Nakada Y: [Autopsy of hemangiomatous malformation of the internal carotid artery at the base of the brain.]. No To Shinkei 17:764766, 1965

    • Search Google Scholar
    • Export Citation
  • 64

    Malek AM, , Connors S, , Robertson RL, , Folkman J, & Scott RM: Elevation of cerebrospinal fluid levels of basic fibroblast growth factor in moyamoya and central nervous system disorders. Pediatr Neurosurg 27:182189, 1997

    • Search Google Scholar
    • Export Citation
  • 65

    Masuda J, , Ogata J, & Yutani C: Smooth muscle cell proliferation and localization of macrophages and T-cells in the occlusive intracranial major arteries in moyamoya disease. Stroke 24:19601967, 1993

    • Search Google Scholar
    • Export Citation
  • 66

    Matsushima T, , Fukui M, , Kitamura K, , Hasuo K, , Kuwabara Y, & Kurokawa T: Encephalo-duro-anterior-synangiosis in children with moyamoya disease. Acta Neurochir (Wien) 104:96102, 1990

    • Search Google Scholar
    • Export Citation
  • 67

    Matsushima T, , Inoue T, , Ikezaki K, , Matsukado K, , Natori Y, & Inamura T, : Multiple combined indirect procedure for the surgical treatment of children with moyamoya disease. A comparison with single indirect anastomosis and direct anastomosis. Neurosurg Focus 5:5 E4, 1998

    • Search Google Scholar
    • Export Citation
  • 68

    Matsushima Y, , Aoyagi M, , Niimi Y, , Masaoka H, & Ohno K: Symptoms and their pattern of progression in childhood moya moya disease. Brain Dev 12:784789, 1990

    • Search Google Scholar
    • Export Citation
  • 69

    Matsushima Y, , Fukai N, , Tanaka K, , Tsuruoka S, , Inaba Y, & Aoyagi M, : A new surgical treatment of moyamoya disease in children: a preliminary report. Surg Neurol 15:313320, 1981

    • Search Google Scholar
    • Export Citation
  • 70

    Matsushima Y, & Inaba Y: The specificity of the collaterals to the brain through the study and surgical treatment of moyamoya disease. Stroke 17:117122, 1986

    • Search Google Scholar
    • Export Citation
  • 71

    Mesiwala AH, , Sviri G, , Fatemi N, , Britz GW, & Newell DW: Long-term outcome of superficial temporal artery-middle cerebral artery bypass for patients with moyamoya disease in the US. Neurosurg Focus 24:2 15, 2008

    • Search Google Scholar
    • Export Citation
  • 72

    Miyamoto S, , Kikuchi H, , Karasawa J, , Nagata I, , Ihara I, & Yamagata S: Study of the posterior circulation in moyamoya disease. Part 2: visual disturbances and surgical treatment. J Neurosurg 65:454460, 1986

    • Search Google Scholar
    • Export Citation
  • 73

    Nagaraja D, , Verma A, , Taly AB, , Kumar MV, & Jayakumar PN: Cerebrovascular disease in children. Acta Neurol Scand 90:251255, 1994

  • 74

    Nambu K, , Suzuki R, & Hirakawa K: Cerebral blood flow: measurement with xenon-enhanced dynamic helical CT. Radiology 195:5357, 1995

  • 75

    Nariai T, , Senda M, , Ishii K, , Wakabayashi S, , Yokota T, & Toyama H, : Posthyperventilatory steal response in chronic cerebral hemodynamic stress: a positron emission tomography study. Stroke 29:12811292, 1998

    • Search Google Scholar
    • Export Citation
  • 76

    Nariai T, , Suzuki R, , Matsushima Y, , Ichimura K, , Hirakawa K, & Ishii K, : Surgically induced angiogenesis to compensate for hemodynamic cerebral ischemia. Stroke 25:10141021, 1994

    • Search Google Scholar
    • Export Citation
  • 77

    Nishimoto A, , Ueta K, & Onbe H: Cooperative study on moyamoya disease in Japan. Abstracts of the 10th Meeting on Surgery for Stroke Tokyo, Nyuuron-sha, 1981

    • Search Google Scholar
    • Export Citation
  • 78

    Ohaegbulam C, , Magge S, & Scott RM, Moyamoya syndrome. McLone DG: Pediatric Neurosurgery. Surgery of the Developing Nervous System ed 4 Philadelphia, WB Saunders, 2001. 10771092

    • Search Google Scholar
    • Export Citation
  • 79

    Okuno T, , Prensky AL, & Gado M: The moyamoya syndrome associated with irradiation of an optic glioma in children: report of two cases and review of the literature. Pediatr Neurol 1:311316, 1985

    • Search Google Scholar
    • Export Citation
  • 80

    Park JH, , Yang S, , Chung Y, , Kim JE, , Kim S, & Han DH, : Modified encephalo-duroarteriosynangiosis with bifrontal encephgaleoperiosteal synangiosis for the treatment of pediatric moyamoya disease. Technical note. J Neurosurg 106:3 Suppl 237242, 2007

    • Search Google Scholar
    • Export Citation
  • 81

    Reis CV, , Safavi-Abbasi S, , Zabramski JM, , Gusmao SN, , Spetzler RF, & Preul MC: The history of neurosurgical procedures for moyamoya disease. Neurosurg Focus 20:6 15, 2006

    • Search Google Scholar
    • Export Citation
  • 82

    Roach ES: Immediate surgery for moyamoya syndrome? Not necessarily. Arch Neurol 58:130131, 2001

  • 83

    Robertson RL, , Burrows PE, , Barnes PD, , Robson CD, , Poussaint TY, & Scott RM: Angiographic changes after pial synangiosis in childhood moyamoya disease. AJNR Am J Neuroradiol 18:837845, 1997

    • Search Google Scholar
    • Export Citation
  • 84

    Sainte-Rose C, , Oliveira R, , Puget S, , Beni-Adani L, , Boddaert N, & Thorne J, : Multiple bur hole surgery for the treatment of moyamoya disease in children. J Neurosurg 6 Suppl 105:437443, 2006

    • Search Google Scholar
    • Export Citation
  • 85

    Sakamoto T, , Kawaguchi M, , Kurehara K, , Kitaguchi K, , Furuya H, & Karasawa J: Risk factors for neurologic deterioration after revascularization surgery in patients with moyamoya disease. Anesth Analg 85:10601065, 1997

    • Search Google Scholar
    • Export Citation
  • 86

    Sakurai K, , Horiuchi Y, , Ikeda H, , Ikezaki K, , Yoshimoto T, & Fukui M, : A novel susceptibility locus for moyamoya disease on chromosome 8q23. J Hum Genet 49:278281, 2004

    • Search Google Scholar
    • Export Citation
  • 87

    Scott RM, Surgical treatment of moyamoya syndrome in children. Chapman P: Concepts in Pediatric Neurosurgery New York, S Karger, 1985. 198212

    • Search Google Scholar
    • Export Citation
  • 88

    Scott RM, Pial synangiosis for moyamoya syndrome. Cheek W: Atlas of Pediatric Neurosurgery Philadelphia, WB Saunders, 1996. 157160

  • 89

    Scott RM: Moyamoya syndrome: a surgically treatable cause of stroke in the pediatric patient. Clin Neurosurg 47:378384, 2000

  • 90

    Scott RM: Surgery for moyamoya syndrome? Yes. Arch Neurol 58:128129, 2001

  • 91

    Scott RM, , Smith JL, , Robertson RL, , Madsen JR, , Soriano SG, & Rockoff MA: Long-term outcome in children with moyamoya syndrome after cranial revascularization by pial synangiosis. J Neurosurg 100:2 Suppl 142149, 2004

    • Search Google Scholar
    • Export Citation
  • 92

    Shirane R, , Yoshida Y, , Takahashi T, & Yoshimoto T: Assessment of encephalo-galeo-myo-synangiosis with dural pedicle insertion in childhood moyamoya disease: characteristics of cerebral blood flow and oxygen metabolism. Clin Neurol Neurosurg 99:2 Suppl S79S85, 1997

    • Search Google Scholar
    • Export Citation
  • 93

    Smith JL, & Scott RM: Treatment of moyamoya syndrome in children. Sem Cerebrovasc Dis Stroke 1:225239, 2001

  • 94

    Smith ER, & Scott RM: Progression of disease in unilateral moyamoya syndrome. Neurosurg Focus 24:2 16, 2008

  • 95

    Sogaard I, & Jorgenson J: Familial occurrence of bilateral intracranial occlusion of internal carotid arteries (moyamoya). Acta Neurochir (Wien) 31:245252, 1975

    • Search Google Scholar
    • Export Citation
  • 96

    Soriano SG, , Sethna NF, & Scott RM: Anesthetic management of children with moyamoya syndrome. Anesth Analg 77:10661070, 1993

  • 97

    Soriano SG, , Cowan DB, , Proctor MR, & Scott RM: Levels of soluble adhesion molecules are elevated in the cerebrospinal fluid of children with moyamoya syndrome. Neurosurgery 50:544549, 2002

    • Search Google Scholar
    • Export Citation
  • 98

    Suzui H, , Hoshimaru M, , Takahashi JA, , Kikuchi H, , Fukumoto M, & Ohta M, : Immunohistochemical reactions for fibroblast growth factor receptor in arteries of patients with moyamoya disease. J Neurosurg 35:2025, 1994

    • Search Google Scholar
    • Export Citation
  • 99

    Suzuki J, & Kodama N: Moyamoya disease—a review. Stroke 14:104109, 1983

  • 100

    Suzuki J, & Takaku A: Cerebrovascular “moyamoya” disease: disease showing abnormal net-like vessels in base of brain. Arch Neurol 20:288299, 1969

    • Search Google Scholar
    • Export Citation
  • 101

    Takagi Y, , Kikuta K, , Sadamasa N, , Nozaki K, & Hashimoto N: Caspase-3-dependent apoptosis in middle cerebral arteries in patients with moyamoya disease. Neurosurgery 59:894900, 2006

    • Search Google Scholar
    • Export Citation
  • 102

    Takahashi A, , Fujiwara S, & Suzuki J: [Cerebral angiography following hyperventilation in moyamoya disease–in reference to the “re-build up” phenomenon on EEG.]. No Shinkei Geka 13:255264, 1985. (Jpn)

    • Search Google Scholar
    • Export Citation
  • 103

    Takahashi A, , Sawamura Y, , Houkin K, , Kamiyama H, & Abe H: The CSF in patients with moyamoya disease (spontaneous occlusion of the circle of Willis) contains high level of basic fibroblast growth factor. Neurosci Lett 160:214216, 1993

    • Search Google Scholar
    • Export Citation
  • 104

    Takahashi M, , Miyauchi T, & Kowada M: Computed tomography of moyamoya disease: demonstration of occluded arteries and collateral vessels as important diagnostic signs. Radiology 134:671676, 1980

    • Search Google Scholar
    • Export Citation
  • 105

    Takanashi JI, , Sugita K, & Niimi H: Evaluation of magnetic resonance angiography with selective maximum intensity projection in patients with childhood moyamoya disease. Eur J Paediatr Neurol 2:8389, 1998

    • Search Google Scholar
    • Export Citation
  • 106

    Takeuchi K, , Hara M, , Yokota H, , Okada J, & Akai K: Factors influencing the development of moyamoya phenomenon. Acta Neurochir (Wien) 59:7986, 1981

    • Search Google Scholar
    • Export Citation
  • 107

    Takeuchi K, & Shimizu K: Hypoplasia of the bilateral internal carotid arteries. Brain Nerve 9:3743, 1957

  • 108

    Takeuchi S, , Tanaka R, , Ishii R, , Tsuchida T, , Kobayashi K, & Arai H: Cerebral hemodynamics in patients with moyamoya disease: a study of regional cerebral blood flow by Xe-133 inhalation method. Surg Neurol 23:468474, 1985

    • Search Google Scholar
    • Export Citation
  • 109

    Takeuchi S, , Tsuchida T, , Kobayashi K, , Fukuda M, , Ishii R, & Tanaka R, : Treatment of moyamoya disease by temporal muscle graft “encephalo-myo-synangiosis.”. Childs Brain 10:115, 1983

    • Search Google Scholar
    • Export Citation
  • 110

    Takikawa S, , Kamiyama H, , Abe H, , Mitsumori K, & Tsuru M: Hemodynamic evaluation of vascular reconstructive surgery for childhood moyamoya disease using single photon emission computed tomography. Neurol Med Chir (Tokyo) 30:389395, 1990

    • Search Google Scholar
    • Export Citation
  • 111

    Touho H, , Karasawa J, , Ohnishi H, , Yamada K, & Shibamoto K: Surgical reconstruction of failed indirect anastomosis in childhood moyamoya disease. Neurosurgery 32:935940, 1993

    • Search Google Scholar
    • Export Citation
  • 112

    Ueki K, , Meyer FB, & Mellinger JF: Moyamoya disease: the disorder and surgical treatment. Mayo Clin Proc 69:749757, 1994

  • 113

    Veeravagu A, , Guzman R, , Path CG, , Hou LC, , Lee M, & Steinberg GK: Moyamoya disease in pediatric patients: outcomes of neurosurgical interventions. Neurosurg Focus 24:2 19, 2008

    • Search Google Scholar
    • Export Citation
  • 114

    Wakai K, , Tamakoshi A, , Ikezaki K, , Fukui M, , Kawamura T, & Aoki R, : Epidemiological features of moyamoya disease in Japan: findings from a nationwide survey. Clin Neurol Neurosurg 99:2 Suppl S1S5, 1997

    • Search Google Scholar
    • Export Citation
  • 115

    Yamada I, , Himeno Y, , Nagaoka T, , Akimoto H, , Matsushima Y, & Kuroiwa T, : Moyamoya disease: evaluation with diffusionweighted and perfusion echo-planar MR imaging. Radiology 212:340347, 1999

    • Search Google Scholar
    • Export Citation
  • 116

    Yamada I, , Suzuki S, & Matsushima Y: Moyamoya disease: comparison of assessment with MR angiography and MR imaging versus conventional angiography. Radiology 196:211218, 1995

    • Search Google Scholar
    • Export Citation
  • 117

    Yamamoto M, , Aoyagi M, , Fukai N, , Matsushima Y, & Yamamoto K: Differences in cellular responses to mitogens in arterial smooth muscle cells derived from patients with moyamoya disease. Stroke 29:11881193, 1998

    • Search Google Scholar
    • Export Citation
  • 118

    Yamamoto M, , Aoyagi M, , Tajima S, , Wachi H, , Fukai N, & Matsushima Y, : Increase in elastin gene expression and protein synthesis in arterial smooth muscle cells derived from patients with moyamoya disease. Stroke 28:17331738, 1997

    • Search Google Scholar
    • Export Citation
  • 119

    Yamashita M, , Oka K, & Tanaka K: Histopathology of the brain vascular network in moyamoya disease. Stroke 14:5058, 1983

  • 120

    Yamauchi T, , Houkin K, , Tada M, & Abe H: Familial occurrence of moyamoya disease. Clin Neurol Neurosurg 99:2 Suppl S162S167, 1997

  • 121

    Yamauchi T, , Tada M, , Houkin K, , Tanaka T, , Nakamura Y, & Kuroda S, : Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 31:930935, 2000

    • Search Google Scholar
    • Export Citation
  • 122

    Yonekawa Y, , Ogata N, , Kaku Y, , Taub E, & Imhof HG: Moyamoya disease in Europe, past and present status. Clin Neurol Neurosurg 99:2 Suppl S58S60, 1997

    • Search Google Scholar
    • Export Citation
  • 123

    Yoshii N, & Kudo T: EEG study on occlusion of the Willis arterial ring. Clin Neurol (Tokyo) 8:301309, 1968. (Jpn)

  • 124

    Yoshimoto T, , Houkin K, , Takahashi A, & Abe H: Angiogenic factors in moyamoya disease. Stroke 27:21602165, 1996

If the inline PDF is not rendering correctly, you can download the PDF file here.

Contributor Notes

Address correspondence to: Jodi L. Smith, Ph.D., M.D., Division of Pediatric Neurosurgery, Riley Hospital for Children, 702 Barnhill Drive, Suite 1134, Indianapolis, Indiana 46202. email: jodlsmit@iupui.edu.
  • View in gallery

    Intraoperative photographs showing a pial synangiosis being performed in a 3-year-old girl. Moyamoya disease had been diagnosed after the patients sustained 2 strokes in the left MCA distribution. She had complete occlusion of the right ICA with associated moyamoya collateral vessels and no antegrade flow in the right MCA and ACA distributions. On the left, moderate stenosis of the left distal ICA was demonstrated, compatible with early moyamoya change. A: Intact STA with a cuff of galea overlying a large area of dura exposed by craniotomy. B: Stellate dural opening. C: Completed pial synangiosis with wide opening of arachnoid and STA sutured by its galeal cuff directly to the pial surface.

  • 1

    Adams HP Jr, , Kassell NF, , Wisoff HS, & Drake CG: Intracranial saccular aneurysm and moyamoya disease. Stroke 10:174179, 1979

  • 2

    Adelson PD, & Scott RM: Pial synangiosis for moyamoya syndrome in children. Pediatr Neurosurg 23:2633, 1995

  • 3

    Ahmed R, & Ahsan H: Imaging of moyamoya disease. J Pak Med Assoc 47:181185, 1997

  • 4

    Bitzer M, & Topka H: Progressive cerebral occlusive disease after radiation therapy. Stroke 26:131136, 1995

  • 5

    Boone SC, & Samson DS: Observation on moyamoya disease: a case treated with superficial temporal-middle cerebral artery anastomosis. Surg Neurol 9:189193, 1978

    • Search Google Scholar
    • Export Citation
  • 6

    Cahan LD: Failure of encephalo-duro-arterio-synangiosis procedure in moyamoya disease. Pediatr Neurosci 12:5862

  • 7

    Chabbert V, , Ranjeva JP, , Sevely A, , Boetto S, , Berry I, & Manelfe C: Diffusion- and magnetisation transfer-weighted MRI in childhood moya-moya. Neuroradiology 40:267271, 1998

    • Search Google Scholar
    • Export Citation
  • 8

    Chang KH, , Yi JG, , Han MH, & Kim IO: MR imaging findings of moyamoya disease. J Korean Med Sci 5:8590, 1990

  • 9

    Collod G, , Babron MC, , Jondeau G, , Coulon M, , Weissenbach J, & Dubourg O, : A second locus for Marfan syndrome maps to chromosome 3p24.2–p25. Nat Genet 8:264268, 1994

    • Search Google Scholar
    • Export Citation
  • 10

    Cramer SC, , Robertson RL, , Dooling EC, & Scott RM: Moyamoya and Down syndrome. Clinical and radiological features. Stroke 27:21312135, 1996

    • Search Google Scholar
    • Export Citation
  • 11

    Endo M, , Kawano N, , Miyaska Y, & Yada K: Cranial burr hole for revascularization in moyamoya disease. J Neurosurg 71:180185, 1989

  • 12

    Erickson DL, & Koivukangas J: The treatment of Moyamoya disease by superficial temporal-middle cerebral artery (STAMCA) anastomosis. Ann Clin Res 18:47 Suppl 2124, 1986

    • Search Google Scholar
    • Export Citation
  • 13

    Fujiwara J, , Nakahara S, , Enomoto T, , Nakata Y, & Takita H: The effectiveness of O2 administration for transient ischemic attacks in moyamoya disease in children. Childs Nerv Syst 12:6975, 1996

    • Search Google Scholar
    • Export Citation
  • 14

    Fukui M: Current state of study on moyamoya disease in Japan. Surg Neurol 47:138143, 1997

  • 15

    Fukui M, , Kono S, , Sueishi K, & Ikezaki K: Moyamoya disease. Neuropathology 20:Suppl S61S64, 2000

  • 16

    Fung LW, , Thompson D, & Ganesan V: Revascularisation surgery for paediatric moyamoya: a review of the literature. Childs Nerv Syst 21:358364, 2005

    • Search Google Scholar
    • Export Citation
  • 17

    Golby AJ, , Marks MP, , Thompson RC, & Steinberg GK: Direct and combined revascularization in pediatric moyamoya disease. Neurosurgery 45:5058, 1999

    • Search Google Scholar
    • Export Citation
  • 18

    Golomb MR, , Biller J, , Smith JL, , Edwards-Brown M, , Sanchez JC, & Nebesio TD, : A 10-year-old girl with coexistent moyamoya disease and Graves' disease. J Child Neurol 20:620624, 2005

    • Search Google Scholar
    • Export Citation
  • 19

    Gordon N, & Isler W: Childhood moyamoya disease. Dev Med Child Neurol 31:103107, 1989

  • 20

    Goto Y, & Yonekawa Y: Worldwide distribution of moyamoya disease. Neurol Med Chir (Tokyo) 32:883886, 1992

  • 21

    Han DH, , Nam DH, & Oh CW: Moyamoya disease in adults: characteristics of clinical presentation and outcome after encephalo-duro-arterio-synangiosis. Clin Neurol Neurosurg 99:2 Suppl S151S155, 1997

    • Search Google Scholar
    • Export Citation
  • 22

    Hankinson TC, , Bohman LE, , Heyer G, , Licursi M, , Ghatan S, & Feldstein NA, : Surgical treatment of moyamoya syndrome in patients with sickle cell anemia: outcome following encephalodurarteriosynangiosis. J Neurosurg Pediatr 1:211216, 2008

    • Search Google Scholar
    • Export Citation
  • 23

    Havlik RJ, , Fried I, , Chyatte D, & Modlin IM: Encephalo-omental synangiosis in the management of moyamoya disease. Surgery 111:156162, 1992

    • Search Google Scholar
    • Export Citation
  • 24

    Hoshimaru M, , Takahashi JA, , Kikuchi H, , Nagata I, & Hatanaka M: Possible roles of basic fibroblast growth factor in the pathogenesis of moyamoya disease: an immunohistochemical study. J Neurosurg 75:267270, 1991

    • Search Google Scholar
    • Export Citation
  • 25

    Houkin K, , Nakayama N, , Kuroda S, , Ishikawa T, & Nonaka T: How does angiogenesis develop in pediatric moyamoya disease after surgery? A prospective study with MR angiography. Childs Nerv Syst 20:734741, 2004

    • Search Google Scholar
    • Export Citation
  • 26

    Ikeda H, , Sasaki T, , Yoshimoto T, , Fukui M, & Arinami T: Mapping of a familial moyamoya disease gene to chromosome 3p24.2–p26. Am J Hum Genet 64:533537, 1999

    • Search Google Scholar
    • Export Citation
  • 27

    Imaizumi T, , Hayashi K, , Saito K, , Osawa M, & Fukuyama Y: Long-term outcomes of pediatric moyamoya disease monitored to adulthood. Pediatr Neurol 18:321325, 1998

    • Search Google Scholar
    • Export Citation
  • 28

    Inoue TK, , Ikezaki K, , Sasazuki T, , Matsushima T, & Fukui M: Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 15:179182, 2000

    • Search Google Scholar
    • Export Citation
  • 29

    Ishikawa T, , Houkin K, , Kamiyama H, & Abe H: Effects of surgical revascularization on outcome of patients with pediatric moyamoya disease. Stroke 28:11701173, 1997

    • Search Google Scholar
    • Export Citation
  • 30

    Jea A, , Smith ER, , Robertson R, & Scott RM: Moyamoya syndrome associated with down syndrome: outcome after surgical revascularization. Pediatrics 116:e694e701, 2005

    • Search Google Scholar
    • Export Citation
  • 31

    Karasawa J, , Kikuchi H, , Kawamura J, & Sakai T: Intracranial transplantation of the omentum for cerebrovascular moyamoya disease: a two-year follow-up study. Surg Neurol 14:444449, 1980

    • Search Google Scholar
    • Export Citation
  • 32

    Karasawa J, , Kikuchi H, , Furuse S, , Kawamura J, & Sakaki T: Treatment of moyamoya disease with STA-MCA anatomosis. J Neurosurg 49:679688, 1978

    • Search Google Scholar
    • Export Citation
  • 33

    Karasawa J, , Kikuchi H, , Furuse S, , Sakaki T, & Yoshida Y: A surgical treatment of “moyamoya” disease “encephalo-myo synangiosis”. Neurol Med Chir (Tokyo) 17:2937, 1977

    • Search Google Scholar
    • Export Citation
  • 34

    Karasawa J, , Touho H, , Ohnishi H, , Miyamoto S, & Kikuchi H: Long-term follow-up study after extracranial-intracranial bypass surgery for anterior circulation ischemia in childhood moyamoya disease. J Neurosurg 77:8489, 1992

    • Search Google Scholar
    • Export Citation
  • 35

    Karasawa J, , Touho H, , Ohnishi H, , Miyamoto S, & Kikuchi H: Cerebral revascularization using omental transplantation for childhood moyamoya disease. J Neurosurg 79:192196, 1993

    • Search Google Scholar
    • Export Citation
  • 36

    Katz DA, , Marks MP, , Napel SA, , Bracci PM, & Roberts SL: Circle of Willis: evaluation with spiral CT, angiography, MRA and conventional angiography. Radiology 195:445449, 1995

    • Search Google Scholar
    • Export Citation
  • 37

    Kawamura T, , Imaizumi S, , Sakurai Y, , Uenohara H, , Nishino A, & Suzuki S: [Effect of various surgical procedures for moyamoya disease in children and adults.]. No Shinkei Geka 22:933938, 1994. (Jpn)

    • Search Google Scholar
    • Export Citation
  • 38

    Kawano T, , Fukui M, , Hashimoto N, & Yonekawa Y: Follow-up study of patients with “unilateral” moyamoya disease. Neurol Med Chir (Tokyo) 34:744747, 1994

    • Search Google Scholar
    • Export Citation
  • 39

    Kazumata K, , Kuroda S, , Houkin K, , Abe H, & Mitumori K: Regional cerebral hemodynamics during re-build-up phenomenon in childhood moyamoya disease. An analysis using 99mTc-HMPAO SPECT. Childs Nerv Syst 12:161165, 1996

    • Search Google Scholar
    • Export Citation
  • 40

    Kelly ME, , Bell-Stephens TE, , Marks MP, , Do HM, & Steinberg GK: Progression of unilateral moyamoya disease: a clinical series. Cerebrovasc Dis 22:109115, 2006

    • Search Google Scholar
    • Export Citation
  • 41

    Kestle JR, , Hoffman HJ, & Mock AR: Moyamoya phenomenon after radiation for optic glioma. J Neurosurg 79:3235, 1993

  • 42

    Kim S, , Wang K, , Kim I, , Lee DS, & Cho B: Combined encephalo-duroarteriosynangiosis and bifrontal encephalogaleo (periosteal) synangiosis in pediatric moyamoya disease. Neurosurgery 50:8896, 2002

    • Search Google Scholar
    • Export Citation
  • 43

    Kinugasa K, , Mandai S, , Kamata I, , Sugiu K, & Ohmoto T: Surgical treatment of moyamoya disease: operative technique for encephalo-duro-arterio-myo-synangiosis, its follow-up, clinical results, and angiograms. Neurosurgery 32:527531, 1993

    • Search Google Scholar
    • Export Citation
  • 44

    Kinugasa K, , Mandai S, , Tokunaga K, , Kamata I, , Sugiu K, & Handa A, : Ribbon enchephalo-duro-arterio-myo-synangiosis for moyamoya disease. Surg Neurol 41:455461, 1994

    • Search Google Scholar
    • Export Citation
  • 45

    Kitahara T, , Ariga N, , Yamaura A, , Makino H, & Maki Y: Familial occurrence of moyamoya disease: report of 3 Japanese families. J Neurol Neurosurg Psychiatry 42:208214, 1979

    • Search Google Scholar
    • Export Citation
  • 46

    Kitahara T, , Okumura K, , Semba A, , Yamaura A, & Makino H: Genetic and immunologic analysis on moya-moya. J Neurol Neurosurg Psychiatry 45:10481052, 1982

    • Search Google Scholar
    • Export Citation
  • 47

    Kodama N, , Aoki Y, , Hiraga H, , Wada T, & Suzuki J: Electroencephalographic findings in children with moyamoya disease. Arch Neurol 36:1619, 1979

    • Search Google Scholar
    • Export Citation
  • 48

    Kodama N, , Fujiwara S, , Horie Y, , Kayama T, & Suzuki J: [Transdural anastomosis in moyamoya disease–vault moyamoya.]. No Shinkei Geka 8:729737, 1980. (Jpn)

    • Search Google Scholar
    • Export Citation
  • 49

    Kodama N, & Suzuki J: Moyamoya disease associated with aneurysm. J Neurosurg 48:565569, 1978

  • 50

    Kudo T: Spontaneous occlusion of the circle of Willis. A disease apparently confined to the Japanese. Neurology 18:485496, 1968

  • 51

    Kudo T, & Fukuda S: Spontaneous occlusion of the circle of Willis. Shinkei-shimpo 20:750757, 1976

  • 52

    Kuriyama S, , Kusaka Y, , Fujimura M, , Wakai K, , Tamakoshi A, & Hashimoto S, : Prevalence and clinicoepidemiological features of moyamoya disease in Japan: findings from a nationwide epidemiological survey. Stroke 39:4247, 2008

    • Search Google Scholar
    • Export Citation
  • 53

    Kuroda S, , Hashimoto N, , Yoshimoto T, & Iwasaki Y: Research Committee on Moyamoya Disease in Japan: Radiological findings, clinical course, and outcome in asymptomatic moyamoya disease: results of multicenter survey in Japan. Stroke 38:14301435, 2007

    • Search Google Scholar
    • Export Citation
  • 54

    Kuroda S, & Houkin K: Moyamoya disease: current concepts and future perspectives. Lancet Neurol 7:10561066, 2008

  • 55

    Kuroda S, , Houkin K, , Hoshi Y, , Tamura M, , Kazumata K, & Abe H: Cerebral hypoxia after hyperventilation causes “re-buildup” phenomenon and TIA in childhood moyamoya disease. A near-infrared spectroscopy study. Childs Nerv Syst 12:448452, 1996

    • Search Google Scholar
    • Export Citation
  • 56

    Kuroda S, , Houkin K, , Ishikawa T, , Nakayama N, , Ikeda J, & Ishii N, : Determinants of intellectual outcome after surgical revascularization in pediatric moyamoya disease: a multivariate analysis. Childs Nerv Syst 20:302308, 2004

    • Search Google Scholar
    • Export Citation
  • 57

    Kurokawa T, , Tomita S, , Ueda K, , Narazaki O, , Hanai T, & Hasuo K, : Prognosis of occlusive disease of the circle of Willis (moyamoya disease) in children. Pediatr Neurol 1:274277, 1985

    • Search Google Scholar
    • Export Citation
  • 58

    Kwak R, , Ito S, , Yamamoto N, & Kadoya S: [Significance of intracranial aneurysms associated with moyamoya disease: (Part 1). Differences between intracranial aneurysms associated with moyamoya disease and usual saccular aneurysms - review of the literature.]. Neurol Med Chir (Tokyo) 24:97103, 1984. (Jpn)

    • Search Google Scholar
    • Export Citation
  • 59

    Latif F, , Tory K, , Gnarra J, , Yao M, , Duh FM, & Orcutt ML, : Identification of the von Hippel–Lindau disease tumor suppressor gene. Science 260:13171320, 1993

    • Search Google Scholar
    • Export Citation
  • 60

    Liu H, , Peng S, & Li Y: The preoperative and postoperative cerebral blood flow and vasoreactivity in childhood moyamoya disease. Keio J Med 49:1 Suppl A86A89, 2000

    • Search Google Scholar
    • Export Citation
  • 61

    Maki Y, & Enomoto T: Moyamoya disease. Childs Nerv Syst 4:204212, 1988

  • 62

    Maki Y, , Nakada Y, & Nose T: Clinical and radiologic follow-up study of “moyamoya”. Childs Brain 11:155170, 1984

  • 63

    Maki Y, & Nakada Y: [Autopsy of hemangiomatous malformation of the internal carotid artery at the base of the brain.]. No To Shinkei 17:764766, 1965

    • Search Google Scholar
    • Export Citation
  • 64

    Malek AM, , Connors S, , Robertson RL, , Folkman J, & Scott RM: Elevation of cerebrospinal fluid levels of basic fibroblast growth factor in moyamoya and central nervous system disorders. Pediatr Neurosurg 27:182189, 1997

    • Search Google Scholar
    • Export Citation
  • 65

    Masuda J, , Ogata J, & Yutani C: Smooth muscle cell proliferation and localization of macrophages and T-cells in the occlusive intracranial major arteries in moyamoya disease. Stroke 24:19601967, 1993

    • Search Google Scholar
    • Export Citation
  • 66

    Matsushima T, , Fukui M, , Kitamura K, , Hasuo K, , Kuwabara Y, & Kurokawa T: Encephalo-duro-anterior-synangiosis in children with moyamoya disease. Acta Neurochir (Wien) 104:96102, 1990

    • Search Google Scholar
    • Export Citation
  • 67

    Matsushima T, , Inoue T, , Ikezaki K, , Matsukado K, , Natori Y, & Inamura T, : Multiple combined indirect procedure for the surgical treatment of children with moyamoya disease. A comparison with single indirect anastomosis and direct anastomosis. Neurosurg Focus 5:5 E4, 1998

    • Search Google Scholar
    • Export Citation
  • 68

    Matsushima Y, , Aoyagi M, , Niimi Y, , Masaoka H, & Ohno K: Symptoms and their pattern of progression in childhood moya moya disease. Brain Dev 12:784789, 1990

    • Search Google Scholar
    • Export Citation
  • 69

    Matsushima Y, , Fukai N, , Tanaka K, , Tsuruoka S, , Inaba Y, & Aoyagi M, : A new surgical treatment of moyamoya disease in children: a preliminary report. Surg Neurol 15:313320, 1981