Stroke & Vascular Disorders
Jun. 30, 2022
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This article includes discussion of Moyamoya disease, cerebral arterial rete, cerebral basal rete mirabile, cerebral juxtabasilar telangiectasia, hypoplasia of the internal carotid artery, idiopathic progressive occlusive disease of the circle of Willis, Nishimoto disease, rete mirabile, spontaneous occlusion of the circle of Willis, and Moyamoya phenomenon. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
In this article, the authors provide a comprehensive overview of moyamoya disease, including advances in the genetics and molecular biology of moyamoya disease, the role of newer imaging techniques, and the surgical management of moyamoya disease.
• Moyamoya disease is an idiopathic non-atherosclerotic vasculopathy with characteristic angiographic abnormalities involving the terminal internal carotid artery and its branches.
• Similar angiographic changes have been associated with diverse conditions, including neurofibromatosis, craniopharyngioma, Down syndrome, sickle cell disease, Graves disease, and the use of vasoconstrictive drugs such as cocaine.
• Patients can be asymptomatic or present with ischemic or hemorrhagic strokes. Other manifestations include intellectual dysfunction, seizures, and movement disorders.
• Early surgical intervention (eg, encephalo-duro-arterio-synangiosis) before the establishment of irreversible hemodynamic change appears to be effective in preventing complications from progressive arterial stenosis and collateral formation.
Moyamoya disease is a nonatherosclerotic and noninflammatory condition characterized by progressive stenosis of the terminal internal carotid artery and the proximal portions of the anterior cerebral and middle cerebral arteries (89; 143). The disease is usually bilateral but can be unilateral. It may begin as an asymptomatic isolated stenosis of the middle cerebral artery stem, progressing to symptomatic moyamoya disease over a few years (19). The term "moyamoya disease" is used when the internal carotid artery stenoses and associated collaterals are observed and when no associated diseases are identified. "Moyamoya phenomenon" is used to describe the extensive collateralization of the circle of Willis arteries associated with severe unilateral or bilateral internal carotid artery stenosis or occlusion in the presence of conditions such as sickle cell disease, atherosclerosis, cranial irradiation, and neurofibromatosis. Synonyms include "idiopathic progressive occlusive disease of the circle of Willis," "spontaneous occlusion of the circle of Willis" (85) "cerebral basal rete mirabile," and "cerebral juxtabasilar telangiectasia."
The history of moyamoya disease is fascinating. Shimizu and Takeuchi published the first case of moyamoya disease in 1957(146). Suzuki was the first to use the Japanese term "moyamoya" to describe the hazy, cloudy “puff of smoke” appearance of the network of dilated, abnormal microvasculature occurring in the region of the circle of Willis (151). These authors also described the six stages of angiographic progression, from stage 1 (narrowing of the carotid artery) to stage 6 when moyamoya vessels disappear and the external carotid arteries supply collateral flow. In 1964, Nishimoto published a series of 24 cases, including three new cases and 21 cases from the literature. The first autopsy report by Maki in 1965 demonstrated a narrowing of the lumen of the internal carotid artery, with intimal thickening but no abnormality of the media or adventitia and no inflammatory changes (104). In 1967, the proceedings of the Japan Neurosurgical Society were published and included a discussion of moyamoya disease (84). In 1968, Kudo published 12 cases and proposed that the dilated penetrating arteries represented an attempt to form collaterals in response to progressive occlusion of the main affected arteries (85). The same year, Nishimoto published a collection of 96 cases (124); therefore, the disease is sometimes referred to as “Nishimoto disease” or “Nishimoto-Takeuchi-Kudo disease.”
In 1977 the Research Committee on Moyamoya Disease organized by the Japanese Ministry of Health and Welfare proposed the following features in the angiographic definition of moyamoya disease: (1) stenosis or occlusion of the terminal portions of both internal carotid arteries and the proximal portions of the anterior cerebral and middle cerebral arteries; (2) visualization of abnormal vascular networks during the arterial phase in the vicinity of the occlusions; and (3) the absence of diseases that may be associated with the development of the moyamoya phenomenon, including meningitis, atherosclerosis, radiation, neurofibromatosis, Down syndrome, sickle cell disease, and neoplasms. In the case of unilateral typical angiographic changes and in the absence of the previously mentioned associated conditions, the case may be classified as probable (33).
Tavares reported the first non-Japanese cases in 1969 (161). He described 10 cases and discussed the three major collateral pathways: (1) the circle of Willis, (2) leptomeningeal arteries, and (3) transdural vessels. Since Tavares' report, cases have been reported from all over the world. Large single and multicenter co-operative studies have described the clinical features of patient populations from various countries, including the United States, and have highlighted differences between Caucasians and Eastern populations (16; 175; 82; 35; 110; 13; 38).
Epidemiological studies have shown that nearly 18% of individuals with moyamoya disease are asymptomatic (08; 87). However, asymptomatic disease is not benign, imparting an annual stroke risk exceeding 3% (88). The disease may begin as an asymptomatic isolated stenosis of the middle cerebral artery stem, progressing to symptomatic moyamoya disease over a few years (19).
The Ministry of Health and Welfare of Japan has defined four types of moyamoya disease: ischemic, hemorrhagic, epileptic, and “other.” Symptoms typically result from cerebral ischemia, infarction, or hemorrhage, depending on the adequacy or the rupture of the delicate developing collateral vessels. There appears to be an “unsteady state” during collateral development, with higher susceptibility for transient ischemic attacks or stroke at younger ages. Patients who develop adequate collaterals can remain asymptomatic until, or if, they have a hemorrhage. The risk of hemorrhage increases with age. In the Japanese population, the most common age of presentation is five to 10 years. A bimodal age of presentation occurs with the first peak in the first decade of life and the second during the fourth decade. There is a slight female predominance (female to male ratio of 1.8:1). The western population presents at a later age. The mean age was 17 years in the Indiana series (175) and 32 years in the Houston series (16), and the median age was 42 years in the St. Louis series (36).
Ischemic symptoms predominate in the young, with transient ischemic attacks occurring in approximately 40% and ischemic stroke in approximately 30%. Those with unilateral moyamoya appear to have a lower risk for infarction (125). The transient ischemic attacks are usually motor related and may remain unilateral or may alternate sides. Transient ischemic attacks may be precipitated by fever, crying, coughing, or hyperventilation during exercise or while playing wind instruments. Cerebral hypoperfusion can result in movement disorders such as hemidystonia, hemichoreoathetosis, paroxysmal exercise-induced dyskinesia, and “limb-shaking TIAs” (103; 102; 20). However, clinical presentation with a movement disorder is rare, particularly in the pediatric population. In the Stanford series, four children out of 118 presented with movement disorders, and in all four patients the movement disorder resolved after surgical revascularization (129). Progressive pseudobulbar palsy has also been described. It is not uncommon in pediatric patients to experience signs of orthostatic intolerance, such as headache, vertigo/dizziness on standing, fatigue, and difficulty with getting out of bed (162).
Other symptoms include intellectual dysfunction ranging from mental slowness to profound retardation from underlying strokes, transient sensory deficits, dysarthria, headaches, and seizures (151; 16). In Karasawa's series of 104 patients who were treated surgically, 36% of patients diagnosed before three years of age had subnormal IQs (below 82); all patients had underlying strokes. Subnormal IQs were noted in 18% of patients between three and seven years of age. Those who developed symptoms after seven years of age had a normal or borderline IQ (59). In adults, executive functioning appears to be more impaired than memory and perception; however, their overall level of cognitive dysfunction is less severe than in children (Karzmark et al 2008). Epilepsy is reported in about 25% of pediatric cases and in 5% of adult cases. Gelastic attacks have been reported in a child with Moyamoya disease (150). Patients with moyamoya phenomenon might manifest signs and symptoms of the associated condition, for example neurofibromatosis, sickle cell anemia, and Down syndrome. Ocular abnormalities such as morning glory disc anomaly and choroidal coloboma have been associated with Moyamoya disease (106; 09; 83; 97; 15).
Hemorrhagic symptoms (typically an altered level of consciousness) predominate in older patients, with a frequency of approximately 60% (Han et al 2000). However, in the Western literature, the incidence of hemorrhage appears to be lower, approximately 12% to 14% (16; 175). As compared to primary intracerebral hemorrhage, moyamoya disease patients have higher rates of rebleeding and infarction, and hemorrhages are often intraventricular in location (121). Microbleeds on susceptibility weighted MRI are found in over 40% of patients, can accumulate over time, and higher numbers of microbleeds appear to predict future symptomatic brain hemorrhage (65; 66; 117; 92).
There are at least three different sources for hemorrhages in moyamoya disease. A major source is weakened dilated moyamoya vessels. In addition, a number of cases of angiographically identified aneurysms forming on collateral vessels have been reported, including aneurysms on the anterior choroidal, posterior choroidal, and penetrating arteries (155). Some might be pseudoaneurysms, as follow-up angiograms have documented the disappearance of aneurysms (77; 165; 37). Another source of hemorrhage is the rupture of aneurysms that have formed on those vessels that are providing collateral flow. The basilar artery is an important source for the leptomeningeal collateral flow and is subject to increased hemodynamic stress, which is assumed to contribute to the formation of the basilar aneurysms (77; 52; 80). Furuse noted that of 44 cases of aneurysms found with moyamoya, there were 24 adults and three children with aneurysms of the moyamoya vessels (31). Seventeen patients had aneurysms independent of the moyamoya vessels; the locations were basilar artery (8), anterior communicating artery (3), middle cerebral arteries (2), internal carotid artery (3), and posterior communicating artery (1). Aneurysms can form on the transdural collateral vessels; rupture of one of these lesions can produce an acute subdural hematoma (94; 128). Morioka and colleagues analyzed angiographic findings in a series of 107 patients and concluded that angiographic dilatation and branch extension of the anterior choroidal and posterior communicating arteries are predictors of hemorrhage (119). Abnormal periventricular collaterals have been associated with hemorrhagic presentations (30).
The risk of recurrent hemorrhage is high, and rebleeding can occur as late as 20 years after the initial bleed. Aoki reported that rebleeding occurred in 17% to 33% of cases during a follow-up period of up to 18 years (07). Morioka and colleagues reported a rebleeding rate of 61% during a mean follow-up period of 12.7 years in a series of 36 patients who were not surgically treated (119). Kobayashi and colleagues reported similarly high rates of rebleeding and emphasized that the type and side of hemorrhage can vary (75).
Limited data on prognosis are available. Prognosis appears to be related to the age of onset and the type of symptoms. Patients who present at less than five years of age appear to have a worse outcome. Patients who have repetitive transient ischemic attacks, without stroke have a benign outcome. Patients who present with hemorrhage have a high mortality and high risk of recurrent hemorrhages and infarctions (121).
The pathophysiology of cerebral arterial narrowing in patients with moyamoya disease and moyamoya phenomenon is not known. Moyamoya disease appears to be distinct from moyamoya phenomenon on the basis of the absence of associated diseases such as neurofibromatosis, craniopharyngioma, optic glioma, distal internal carotid artery compression by tumor, Down syndrome, chronic meningitis, leptospiral infections, atherosclerosis, sickle cell disease, antiphospholipid syndrome or lupus anticoagulant, Alagille syndrome, osteogenesis imperfecta, Costello syndrome, Graves disease, use of vasoconstrictive drugs such as cocaine, use of birth control pills (possibly in combination with cigarettes), essential thrombocythemia, and thrombotic thrombocytopenic purpura (143).
Although most cases of moyamoya disease appear to be sporadic, 7% to 15% occur as familial cases where the mode of inheritance is probably autosomal dominant with incomplete penetrance (113) or X-linked recessive (41). A number of possible triggering events have been proposed, including infectious and inflammatory processes and mechanical trauma (159; 169). Histological, genetic, proteomic, and molecular studies have started providing insights into the pathogenesis of moyamoya disease (02).
A role for angiogenesis and vascular remodeling is suggested by studies showing a higher number of circulating endothelial progenitor cells, higher levels of growth factors, and increased matrix metalloproteinase (MMP) expression (25; 132; 58; 99). Studies have examined the role of growth factors, including vascular endothelial growth factor, angiopoietins, platelet-derived growth factor, integrins, basic fibroblast growth factor, transforming growth factor-beta1, and hepatocyte growth factor (179; 43; 123; 100). Several groups have evaluated the possible role of basic fibroblast growth factor, a potent mitogen of smooth muscle cells and vascular endothelial cells. High levels of this growth factor have been found in endothelial and smooth muscle cells of superficial temporal arteries of patients with moyamoya disease (45). Cerebrospinal fluid samples from patients with moyamoya disease demonstrate significantly elevated levels of basic fibroblast growth factor over controls but not over other abnormal vascular disorders of the central nervous system (105). The dura of the moyamoya patients also demonstrated strong staining for basic fibroblast growth factor of the meningeal and vascular cells. Basic fibroblast growth factor is required for the movement of vascular cells during neovascularization, suggesting this may be the messenger involved in the neovascularity that occurs in moyamoya disease.
Genome-wide association studies have identified the c.14576G>A variant in the ring finger protein 213 (RNF213) as the first susceptibility gene for moyamoya disease with high risk for various phenotypes of moyamoya disease (56; 116). The homozygous variant is associated with early onset and more severe phenotype (67). A study found a high frequency of this genetic marker in Asian patients with presumed atherosclerotic intracranial disease, suggesting that may actually have moyamoya disease (10). A Chinese study has showed a higher carrying rate of RNF213 p.R4810K in patients with moyamoya disease, associated with earlier onset age and more severe posterior cerebral artery involvement (166). Genetic linkage studies of moyamoya disease have shown that susceptibility loci are located on chromosome 3p (47), 6q (50), 17q (174), 17q25.3 (112), 8q, and 12p (140). Interestingly, genes encoding tissue inhibitor of metalloproteinase [TIMP] 2 and TIMP 4 span chromosomes 3p and 17q, and a study of familial moyamoya disease found single nucleotide polymorphisms of these genes (57). An X-linked moyamoya syndrome characterized by moyamoya angiopathy, short stature, facial dysmorphism, hypogonadism, hypertension, and dilated cardiomyopathy has been shown to result from Xq28 deletions (114). Genetic studies have found an association between moyamoya disease and mutations in the NF-1 gene and the smooth muscle alpha-actin gene ACTA-2, which promotes smooth muscle proliferation, suggesting a role for hyperplastic vasculopathy (34; 111).
Sera from patients with moyamoya disease have a higher incidence of anti-alpha-fodrin autoantibodies, suggesting a role for chronic endothelial cell apoptosis (126). Immunohistochemistry studies on middle cerebral artery specimens from moyamoya patients have shown evidence for caspase-3-dependent apoptosis (154). Finally, case-control studies have found a higher prevalence of elevated thyroid autoantibodies and other autoantibody mediated conditions in patients with moyamoya disease (69; 98; 13), which extends previous observations of moyamoya disease in patients with Graves disease (49; 46; 145).
Moyamoya disease results from slowly progressive occlusion of the distal internal carotid artery, which permits the development of the unique small anastomotic collateral pathways. Factors that trigger the opening of these collateral pathways or the development of new collateral pathways are not well defined but may be related to chronic hypoperfusion and release of angiogenic growth factors. Pathological examination of the distal internal carotid artery reveals intimal thickening from smooth muscle cell proliferation and reduplication of the elastic lamina. The medial fibrosis and attenuation of the wall thickness with occasional regions of discontinuity of the elastic lamina of the penetrating vessels predispose to rupture from the hemodynamic stress of increased volume flow (127). Lipid deposition is minimal or absent (107). Intimal thickening may be the result of smooth muscle cell proliferation and conversion from a contractile state to a secretory state. Some authors have suggested local thrombosis contributes to both progressive stenosis and ischemic events (172; 173). A prospective study found evidence for prothrombotic disorders such as protein S deficiency and lupus anticoagulant and anticardiolipin antibodies in four of 10 consecutive children with moyamoya disease (12).
Although most prevalent in Japan, Korea, China, Taiwan, India, and other Asian countries, moyamoya disease has been reported in various races and countries including the United States, Greece, and Turkey. It is the most common pediatric cerebrovascular disease in Japan, with a prevalence of approximately three in 100,000 and girls twice as commonly affected as boys (134). In Europe, the incidence is much lower (0.3 patients per center per year), as it is in the United States (0.086 per 100,000 persons) (163; 134). An epidemiological survey from Japan found that moyamoya disease peaked earlier in men (10 to 14 years) as compared to women (20 to 24 years) (86). There is a 7% to 12% incidence of familial cases (47; 86). Epidemiological studies have shown that nearly 18% of individuals with moyamoya disease are asymptomatic (08). The annual risk for stroke is 3%. However, nearly one third of children can develop recurrent stroke within one year (29).
There are no known preventive strategies.
Moyamoya is an angiographic diagnosis. Numerous conditions have been associated with moyamoya “phenomenon” and should be investigated with appropriate tests. The differential diagnosis is determined by the mode of onset. In young patients with transient ischemic attacks, alternative diagnoses include hypoglycemia, cardiac source emboli, hypercoagulable states, or seizures. Moyamoya disease is progressive, and serial vascular imaging can help distinguish it from reversible arteriopathies such as childhood transient cerebral arteriopathy (14). Primary CNS angiitis rarely manifests with similar angiographic changes and can be distinguished with examination of the cerebrospinal fluid and MRI findings, (eg, infarct topography) (81). Another important differential in the acute setting, especially if the initial presentation includes headaches, and hemorrhagic and ischemic lesions, is reversible cerebral vasoconstriction syndrome (22). The RCVS2 score and clinical approach can be a tool to help differentiate these patients in the acute setting (136). Moyamoya disease should be considered in children with alternating hemiparesis or transient ischemic attacks induced by hyperventilation. Seizures may be a manifestation of the cerebral ischemia in 25% of pediatric cases, and moyamoya should be in the differential for young patients, especially in cases of focal seizures.
In the older patients who present with intracerebral hemorrhage or intraventricular hemorrhage, moyamoya should be included in the list of potential causes.
The diagnosis rests on the identification of the angiographic changes. Abnormalities detected by CT or MRI depend on the stage of development of the moyamoya, as well as the adequacy of collateral flow.
Noncontrast CT performed in patients with ischemic syndromes can be normal or show nonspecific abnormalities such as sulcal or ventricular dilatation. Infarctions in the borderzone territories between the anterior cerebral, middle cerebral, and posterior cerebral arteries are common. Infarctions may be located in the cerebral cortex or the centrum semiovale, which is supplied by medullary arteries arising from the cortical branches. Deep infarctions in regions of the penetrating arteries are also common. The actual distribution of the infarction is dependent on the collateral vessels and the pattern of supply. In general, infarctions in the posterior cerebral artery territory are rare. Patients with cortical infarctions, and those with posteriorly distributed lesions, tend to have more advanced stages of disease (70). In patients with brain hemorrhage, the location of the bleed can be intraparenchymal (basal ganglia), with or without intraventricular extension, or primarily intraventricular. Subdural hematomas and subarachnoid hemorrhages are not uncommon.
MRI detects the same pattern of infarctions as seen with CT. In addition, MRI may detect the presence of moyamoya vessels (dilated, tortuous signal void regions in the basal ganglia) or the severe stenosis and occlusion of the distal internal carotid artery. Asymptomatic microbleeds can be identified using T2*-weighted gradient-echo MRI or susceptibility-weighted MRI in over 40% of patients, accumulate over time, and higher numbers predict a higher risk for symptomatic brain hemorrhage (65; 66; 117; 92). Leptomeningeal contrast enhancement (the "ivy sign"), believed to represent the fine vascular network over the pial surface, can be seen in up to one third of patients on contrast-enhanced T1-weighted images and FLAIR images (78; 176). The ivy sign indicates severe hypoperfusion and reduced cerebrovascular reserve (63; 118; 164) and can improve after bypass surgery (62). Following contrast administration, there may be a diffuse enhancement of the basal ganglia in the region of the moyamoya vessels. Medullary streaks, believed to represent dilated medullary vessels due to chronic hypoperfusion, can be seen on high-resolution T2 images (40). Ongoing research is investigating the utility of 3T MRI in distinguishing the various intracranial arteriopathies, such as moyamoya, atherosclerosis, and vasculitis (153; 137; 04). Preliminary high-resolution MRI studies show that the cerebral arteries in patients with moyamoya disease rarely enhance and show smaller, concentric occlusion as compared to patients with symptomatic intracranial atherosclerosis (73).
Transcranial Doppler ultrasound imaging may be a useful noninvasive test to follow the progression of intracranial vascular stenosis over time (131). In addition, transcranial Doppler ultrasound findings could be used in conjunction with invasive and noninvasive angiographic tests to determine the severity or stage of moyamoya (95). Relatively noninvasive angiographic techniques are gaining favor in diagnosing moyamoya. 3-D CT angiography might have value in the evaluation of surgical bypass patency and in following the disease progression (64). Magnetic resonance angiography appears sensitive to detect the local cerebral arterial stenoses and collateral circulation (26; 156; 138; 170). However, transfemoral contrast cerebral angiography remains the gold standard for diagnosis. The complication rate of cerebral angiography is not higher in the moyamoya population (135).
Suzuki's 1969 description remains the best overall reference for the six sequential stages of angiographic progression of the disease (151). In stage 1, the distal internal carotid artery narrows, virtually always distal to the origin of the ophthalmic artery and usually distal to the posterior communicating artery (both potential anastomotic sources). In stage 2, the moyamoya begins, accompanied by resistance-lowering dilation of the large intracerebral arteries. There is slight moyamoya formation from dilation of the penetrating arteries, primarily in the basal ganglia. Although no external carotid to intracranial vessel anastomoses are present at this stage, vertebral angiography can demonstrate leptomeningeal collaterals. In stage 3, the moyamoya formation intensifies, and filling of the middle cerebral and anterior cerebral artery trunks and branches is progressively lost although maintaining the posterior communicating artery. In stage 4, the moyamoya abates, the terminal internal carotid artery is occluded, and the posterior communicating artery usually becomes occluded. The middle cerebral and anterior cerebral artery branches are filled via the moyamoya vessels, and collateral flow comes from the external carotid artery to the intracranial internal carotid artery territory through transdural collaterals via the orbit into the infraorbital branches and via the meningeal branches to the cortical branches. In stage 5, the moyamoya continues to abate, and the moyamoya vessels begin to involute. There is a progressive increase in the extracranial carotid artery collaterals. In stage 6, the moyamoya disappears; the siphon of the internal carotid artery is occluded. Only the extracranial carotid artery collaterals are visualized on carotid arteriography. The cerebral circulation is maintained only by the route of the external carotid or the vertebral artery. Yamashita, reporting on 22 autopsied cases, noted that both the density and extent of the vascular network were conspicuous in children and adolescents (171). In the older patients, the network was usually restricted to a small area of the base of the brain, whereas transdural collaterals were more conspicuous. These findings support the sequence of changes proposed by Suzuki.
Because the internal carotid artery stenosis occurs distal to the origin of the posterior communicating and ophthalmic arteries and often involves the proximal anterior cerebral artery, the circle of Willis is unable to provide collateral flow. Matsushima and Inaba have described three collateral pathways: (1) leptomeningeal collaterals from the posterior cerebral artery to the distal middle cerebral and anterior cerebral artery; (2) dilated penetrating arteries between the distal internal carotid artery, the proximal anterior cerebral artery, the middle cerebral artery, and the choroidal system; and (3) transdural collateral from the external carotid system to the intracranial carotid system (108).
Cerebral blood flow may be normal or decreased depending on the adequacy of collaterals. Patients with symptomatic moyamoya have decreased vasoreactivity in response to hypercarbia or acetazolamide consistent with exhausted reserve or maximal dilation of the autoregulatory arterioles (160; 51; 152). PET and SPECT scanning have demonstrated similar findings (157; 48; 120).
Electroencephalography may be useful in the evaluation of these patients. Typically, there is a normal to slow background. Focal slow activity may be noted. With hyperventilation there may be bursts of high-amplitude delta. Following cessation of hyperventilation, the delta activity can resolve and spontaneously recur. Suzuki has referred to this as the "re-build up phenomenon." This appears to be much more frequent in advanced cases and in children (76; 90). The utility of EEG as an adjunctive diagnostic and follow-up modality to assess hemodynamic status was shown in a study of 127 patients where 80% showed abnormal EEG findings before revascularization surgery. The typical rebuild-up phenomenon was observed in 65%, and localized build-up in 25%, without any significant clinical ischemic events during and after hyperventilation. Rebuild-up was more frequent in individuals younger than 13 years or with advanced disease, and its location correlated with SPECT and perfusion-MRI abnormalities. Persistent rebuild-up in postoperative follow-up was associated with poorer clinical outcomes (17).
Guidelines on the management of moyamoya disease have been published (27; 147). Because ischemic stroke is common and can occur from emboli as well as thrombus formation, antiplatelet (aspirin) therapy is considered beneficial (142; 134). Warfarin is contraindicated because of the risk for spontaneous bleeding from abnormal moyamoya vessels. Indeed, multicenter data from the International Pediatric Stroke Study Group show that patients with moyamoya disease are typically treated with antiplatelet agents rather than warfarin (32). However, some patients with associated hypercoagulable states such as factor V Leiden mutation can be treated with warfarin to prevent arterial thrombosis (53). Steroids have been successfully used in a few cases of movement disorders (130). Anecdotal reports have suggested benefit with calcium channel blockers (109; 44). However, none of the medications can reverse or slow disease progression.
Historically, there has been ambiguity about the choice of surgical procedure, its timing, and long-term benefit (133; 142; 167). Literature accumulated over the past few years indicates that early surgical revascularization procedures result in improved intellectual outcome (93) and a significantly lower risk for recurrent subsequent strokes and transient ischemic attacks (71; 144). Analysis of surgical revascularization procedures in 329 consecutive patients (233 adults, 96 children) from Stanford University, showed that the cumulative risk for perioperative or subsequent stroke or death over five years was low (5.5%), and the cohort had a significant improvement in the quality of life (35). Similarly encouraging results have been documented in a study of 43 adult patients treated with the EDAS procedure at Columbia University (148). Careful patient selection using techniques, such as positron emission tomography (182), perfusion-CT with acetazolamide challenge (05), or BOLD-MRI (42), which help to assess the risk for cerebral ischemia, may further improve outcomes after surgery. Acute stroke in the preoperative period and reduced cerebrovascular reserve are associated with poor surgical outcome (06). Whether surgical intervention decreases the risk of rebleeding remains unclear (178).
A number of surgical interventions have been designed to improve collateral flow to the cortical surface using the external carotid circulation as a donor supply, including extracranial to intracranial anastomoses and superficial temporal artery to middle cerebral artery bypass. Several techniques that do not require direct anastomoses have been developed and involve placement of the extracranial arteries on the cortical brain surface (pial synangiosis). These techniques rely on the spontaneous development of collateral connections due to the particularly high levels of endogenous growth factors in patients with moyamoya. Encephalomyosynangiosis (EMS) involves placement of the temporalis muscle directly onto the brain surface. Encephalo-duro-angio-synangiosis (EDAS) involves the attachment of scalp artery in a strip of galea that is freed from the pericranium and fascia. A linear dural slit is made to allow suturing of the galea to the dura, and the artery and galea are laid on the arachnid membrane. In encephalo-arterio-synangiosis, the superficial temporal artery is stripped along its course, and the artery with the strip of galea is laid on the arachnoid membrane. Encephalo-duro-arterio-myo-synangiosis involves a combination of the above techniques (74; 177). These procedures are sometimes done in combination with a superficial temporal artery to middle cerebral artery bypass. Angiography following these indirect revascularization procedures demonstrates anastomoses that can be detected as early as two weeks after surgery but are usually seen by three months postoperatively. Perfusion MRI and arterial spin-labeled MRI have been used to evaluate the adequacy of collateral development (11). Guidelines issued by the American Heart Association Stroke Council recommend indirect revascularization techniques for younger children, whose small caliber vessels make direct anastomosis difficult, and direct bypass techniques in older individuals (134). Indications for surgery include progressive ischemic symptoms or evidence for tissue "at risk" for ischemia, eg, poor cerebrovascular reserve (05; 21). Early surgical intervention (eg, encephalo-duro-arterio-synangiosis) before the establishment of irreversible hemodynamic change has shown benefit in preventing stroke in children and adults, as well as in delaying cognitive decline and improving performance in activities of daily living (36; 35; 68; 180). In adults, surgical revascularization procedures have been shown to improve cerebral metabolism and hemodynamics, clinical function, cognition, and prevent strokes (18; 23; 91; 115; 11; 96; 139). A metanalysis indicated a superiority of direct bypass on future stroke risk as compared to indirect bypass (OR 0.494, p = 0.028) (54). Another metanalysis showed a lower rate of long-term hemorrhages in patients with direct bypass as compared to indirect bypass, despite a higher rate of perioperative hemorrhage (149). Clinical trials are needed to indicate which method is superior.
Kashiwazaki and colleagues have suggested a score entitled the Berlin Grading System based on MRI, DSA, and SPECT imaging for stratification of clinical severity and prediction of postoperative neurologic morbidity (61). Aspirin may be indicated after revascularization, as it showed a trend to less mid- and long-term strokes postoperatively (181).
Several case reports describe the occurrence of strokes (usually hemorrhagic strokes) around the time of pregnancy (79; 168; 122; 72). At least three studies have shown a relatively low risk of complications (mostly transient ischemic attacks or seizures with full recovery) during pregnancy and delivery (28; 55; 24). Vaginal delivery appears safe (158). In a Chinese study, the risk of hemorrhagic stroke was approximately three percent during pregnancy or puerperium, which was not significantly different from the risk in nonpregnant women (101). Care should be taken to avoid hypocapnia, hypotension, or hypertension. Whether cesarean section lowers the risk for complications is unknown (79). A combined spinal and epidural technique has been advocated because it allows better analgesia than epidural anesthesia and more hemodynamic stability than either general or spinal anesthesia (01).
Anesthetic risks for moyamoya are particularly high for any surgical procedure, and anesthesia can precipitate symptoms for the first time. Hyperventilation should be avoided because this may decrease cerebral blood flow secondary to cerebral vasoconstriction. Carbon dioxide levels should be normal to slightly elevated during anesthesia. Normovolemia should be maintained and blood pressure controlled carefully so as to avoid hypotension and hypertension. Intraoperative EEG may be helpful. Intravenous anesthesia may be superior to inhalational anesthesia secondary to decreased intracerebral steal (141). However, a retrospective analysis of 72 moyamoya patients undergoing surgical revascularization showed that there was no significant difference in the incidence of postoperative complications occurring within two weeks with use of either intravenous or inhalation anesthesia (03).
Steven R Levine MD
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