Moyamoya disease is a progressive, occlusive disease of the cerebral vasculature with particular involvement of the circle of Willis and the arteries that feed it.[1] The image below is a schematic representation of the circle of Willis, the arteries of the brain, and the brainstem. (See Etiology.)
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Schematic representation of the circle of Willis, arteries of the brain, and brain stem.
The term moyamoya (Japanese for "puff of smoke") refers to the appearance on angiography of abnormal vascular collateral networks that develop adjacent to the stenotic vessels. The steno-occlusive areas are usually bilateral, but unilateral involvement does not exclude the diagnosis. (See Workup.)
Blood vessel walls consist of 3 layers: the intima is the innermost layer; the media is a muscular middle layer; and the adventitia is the outermost layer. Separating the intima and media is the internal elastic lamina, an elastic membrane that is considered the outermost part of the intima. Pathologically, moyamoya disease is characterized by intimal thickening in the walls of the terminal portions of the internal carotid vessels bilaterally. The proliferating intima may contain lipid deposits. The anterior, middle, and posterior cerebral arteries that emanate from the circle of Willis may show varying degrees of stenosis or occlusion. This is associated with fibrocellular thickening of the intima, waving of the internal elastic lamina, and thinning of the media. (See Etiology, Workup, Treatment, and Medication.)
Numerous small vascular channels can be seen around the circle of Willis. These are perforators and anastomotic branches. The pia mater may also have reticular conglomerates of small vessels.
The cause of moyamoya disease is not known. The disease is believed to be genetic. Fukui reported a family history in 10% of patients with the disorder. Moreover, Mineharu suggested that familial moyamoya disease is autosomal dominant with incomplete penetrance that depends on age and genomic imprinting factors.[2] Genetically, susceptibility loci have been found on 3p, 6p, 17q, and band 8q23. Mineharu et al have found a specific gene locus, q25.3, on chromosome 17.[3] A genome-wide association study identified RNF213 as the first gene associated with moyamoya.[4] One meta-analysis demonstrated that there are strong associations between p.R4859K and p.R4810K polymorphisms of the RNF213 gene and moyamoya disease.[5]
People with moyamoya disease have been found to have a higher incidence of elevated thyroid antibodies.[6] While this is an association in some individuals, the significance is not clear. However, it suggests that immune abnormalities may play some role in moyamoya disease.
Associated diseases
Although moyamoya disease may occur by itself in a previously healthy individual, many disease states have been reported in association with moyamoya disease, including the following:
Congenital syndromes - Apert syndrome, Down syndrome, Marfan syndrome, tuberous sclerosis, Turner syndrome, von Recklinghausen disease (Neurofibromatosis Type 1), and Hirschsprung disease
Vascular diseases - Atherosclerotic disease, coarctation of the aorta and fibromuscular dysplasia, cranial trauma, radiation injury, parasellar tumors, and hypertension
These associated conditions may not be causative, but they do warrant consideration due to their impact on treatment. In the presence of these risk factors, the condition is referred to as moyamoya syndrome.
A study indicated that the prevalence of moyamoya disease in California and Washington was 0.086 case per 100,000 people.[8] In this study, the breakdown based on ethnicity as ratio to whites was 4.6 for Asian Americans, 2.2 for African Americans, and 0.5 for Hispanics.
The incidence of moyamoya disease is highest in Japan.[9] The prevalence and incidence of the disorder there has been reported to be 3.16 cases and 0.35 case per 100,000 people, respectively.
Race-, sex-, and age-related demographics
Moyamoya disease occurs primarily in Asians but can also occur (with varying degrees of severity) in whites, blacks, Haitians, and Hispanics.
The female-to-male ratio of moyamoya disease is 1.8:1. Ages for patients with moyamoya disease range from 6 months to 67 years, with the highest peak in the first decade and smaller peaks in the third and fourth decades.[9]
Death from moyamoya disease is usually from hemorrhage. The outcome of the disease depends on the severity and nature of the hemorrhage; the prognosis depends on recurrent attacks.
Mortality rates from moyamoya disease are approximately 10% in adults and 4.3% in children. About 50-60% of affected individuals experience a gradual deterioration of cognitive function, presumably from recurrent strokes.
Patients with moyamoya disease who present for treatment while symptoms are evolving have a better prognosis than do those who present with static symptoms (which probably indicate a completed stroke).
Children and adults with moyamoya disease may have different clinical presentations. The symptoms and clinical course vary widely, with the disease ranging from being asymptomatic to manifesting as transient events to causing severe neurologic deficits. Adults experience hemorrhage more commonly; cerebral ischemic events are more common in children.
Children may have hemiparesis, monoparesis, sensory impairment, involuntary movements, headaches, dizziness, or seizures. Mental retardation or persistent neurologic deficits may be present.
Adults may have symptoms and signs similar to those in children, but intraventricular, subarachnoid, or intracerebral hemorrhage of sudden onset is more common in adults.
Physical examination
Physical examination findings depend on the location and severity of the hemorrhage or ischemic insult. There may be findings that indicate a condition associated with moyamoya syndrome such as skin abnormalities or dysmorphisms.
A meta-analysis published in 2018 showed that approximately 30% of children and adults with moyamoya disease or syndrome have cognitive impairment, even without occurrence of stroke, suggesting that chronic hypoperfusion is a contributing factor.[10]
Misdiagnosis and delayed diagnosis of moyamoya disease are particular pitfalls in the treatment of patients with this disorder. Misdiagnosis can occur easily if the physician does not incorporate moyamoya disease into the differential diagnosis of any patient presenting with stroke. How high moyamoya disease is ranked in the differential depends on presence of atypical features such as young age and absence of obvious risk factors for stroke.
If moyamoya disease is not considered seriously, then appropriate diagnostic tests may not be performed and a delay in diagnosis could result. Because definitive treatment may be surgery, any delay could allow unnecessary progression of disease.
If an ischemic stroke progresses despite preventative treatment with antiplatelet agents or anticoagulants, then moyamoya disease should be considered as a possible etiology. This is especially true if results of a hypercoagulability profile are unremarkable.
Physicians practicing in the community who encounter atypical stroke presentations should not hesitate to seek consultation with a stroke specialist or even to transfer a patient to a facility equipped to care for complex cases.
Several studies may be indicated in patients with moyamoya disease. In a patient with stroke of unclear etiology, a hypercoagulability profile may be helpful. Significant abnormality in any of the following is a risk factor for ischemic stroke:
Protein C
Protein S
Antithrombin III
Homocysteine
Factor V Leiden
The erythrocyte sedimentation rate (ESR) can be obtained as part of the initial workup of possible vasculitis. However, a normal ESR does not rule out vasculitis.
Thyroid function and thyroid autoantibody levels have been shown to be elevated in a significant percentage of pediatric patients with moyamoya disease.[11] Therefore, monitoring these studies is indicated.
Cerebral angiography is the criterion standard for the diagnosis of moyamoya disease. The following findings support the diagnosis:
Stenosis or occlusion at the terminal portion of the internal carotid artery or the proximal portion of the anterior or middle cerebral arteries
Abnormal vascular networks in the vicinity of the occlusive or stenotic areas
Bilaterality of the described findings (although some patients may present with unilateral involvement and then progress)
Magnetic resonance angiography (MRA) or computed tomography angiography (CTA) can be performed. Any of the above findings on MRA or CTA may preclude the need for conventional angiography.
Pharmacologic therapy for moyamoya disease is disappointing. Therapy is primarily directed at complications of the disease. If intracerebral hemorrhage has occurred, then management of hypertension (if present) is imperative. In cases of severe stroke, intensive care unit (ICU) monitoring is indicated until the patient's condition stabilizes. If the patient has had an ischemic stroke, consider anticoagulation or antiplatelet agents.
Activity
Rehabilitation with physical therapy, occupational therapy, and speech therapy should be considered, depending on the neurologic impairment. The extent of therapy can range from bedside treatment to full, comprehensive inpatient rehabilitation. The latter would include physical, occupational, speech, and cognitive therapy. The condition of the patient, including active comorbidities, dictates his or her involvement in rehabilitation therapy.
The rationale behind the administration of anticoagulation and antiplatelet agents is the prevention of further strokes, especially in stenotic vessels (where further infarction can occur if occlusion progresses).
These medications are not approved by the US Food and Drug Administration (FDA) specifically for use in moyamoya disease. Therefore, the decision to treat patients with anticoagulants such as heparin (and, in some cases, warfarin, for long-term anticoagulation) or antiplatelet agents such as aspirin rests on the following: angiogram findings, severity of stroke, and risk/benefit analysis by physicians who are experienced in stroke treatment.
As previously stated, patients with moyamoya disease who present for treatment while symptoms are evolving have a better prognosis than do those who present with static symptoms (which probably indicate a completed stroke).
Various surgical procedures have been used in the treatment of moyamoya disease, with the goal of revascularizing the ischemic hemisphere, including the following[12] :
These procedures can be divided into 2 groups depending on whether they involve direct or indirect anastomosis. The STA-MCA anastomosis is a direct revascularization procedure, whereas indirect procedures depend on the subsequent formation of collateral vessels to increase blood delivery. Which of these procedures is most effective remains controversial. Sufficient evidence suggests that surgical revascularization procedures result in some symptomatic benefits along with demonstration of improved blood flow. Direct and/or combined procedures provide improved vascularization. However, data proving sustained or improved long-term outcomes are insufficient.[14, 15]
STA-MCA anastomosis is very difficult in children younger than 2 years because of the small diameter of the STA. In these cases, EDAS may be more suitable. This procedure sometimes has failed because of poor revascularization. Hoffman suggested that this is due to the presence of atrophy and a layer of spinal fluid between the pia and the arachnoid tissue.[16] Division of the arachnoid membrane and placement of the STA directly on the pial membrane help to avoid the problem. In cases of EDAS failure, EDAMS can be considered.
Initial neurologic consultation is imperative. A neurologist can document neurologic deficits, consider the differential diagnosis, conduct testing to validate suspected etiologies, and commence medical management as indicated.
Neuroradiology consultation is needed to help determine the extent of radiologic testing needed (ie, MRA vs conventional angiography). Based on the results of these tests, a neurosurgeon can decide if surgical intervention will be helpful.
Drug therapy for moyamoya disease depends on the particular manifestations of the disease. For hemorrhage, therapy revolves around the management of hypertension (if present).
For ischemic stroke, anticoagulation with heparin or warfarin may be considered. Safety and efficacy have not been fully established for these drugs, and careful analysis of risk and benefits is needed. These drugs could be useful if thrombosis of vessels is present, but they do not alter the natural history of the disease and they considerably increase the risk of hemorrhage with large strokes.
The same considerations are true for aspirin and other antiplatelet agents. Treatment with anticoagulation or antiplatelet agents should be pursued only after consultation with a neurologist who is experienced in stroke management.
Clinical Context:
Heparin is administered intravenously; it is frequently given with initial bolus in cardiac situations. In stroke, bolus is not recommended. The target dose is aimed at maintaining an activated partial thromboplastin time (aPTT) of 1.5-2 times control. A computed tomography (CT) scan of the brain must be done prior to any anticoagulant use to rule out preexisting intracranial hemorrhage.
Clinical Context:
Warfarin, which is administered orally, is used if long-term anticoagulation is needed. The international normalized ratio (INR) is followed, with a target range of 2-3. A CT scan of the brain must be done prior to any anticoagulant use to rule out preexisting intracranial hemorrhage.
These agents are given for the prevention of further thrombosis and potential infarction of the brain. Caution: Anticoagulation is of unproven benefit in ischemic stroke associated with moyamoya disease. This therapy is therefore considered to be empirical.
Clinical Context:
Aspirin's efficacy in preventing stroke relies on the inhibitory effect of aspirin on platelet function. This presumably helps to prevent thrombus formation and propagation.
These agents can be considered to help prevent future ischemic strokes. As with anticoagulation, aspirin is of unproven benefit in moyamoya disease; its use is considered empirical.
What is moyamoya disease?How is moyamoya disease characterized?What is the etiology of moyamoya disease?What are the risk factors for moyamoya disease?What is the prevalence of moyamoya disease?Which races are at greatest risk for moyamoya disease?How does the prevalence of moyamoya disease vary by sex and age?What is the cause of mortality from moyamoya disease?What is the prognosis of moyamoya disease?What are the signs and symptoms of moyamoya disease?Which physical findings are characteristic of moyamoya disease?Which conditions should be considered in the differential diagnoses of moyamoya disease?What are the differential diagnoses for Moyamoya Disease?What are the risks of delayed or misdiagnosed moyamoya disease?What is the role of lab studies in the evaluation of moyamoya disease?How is moyamoya disease diagnosed?What is the role of pharmacologic therapy in the management of moyamoya disease?What is the role of rehabilitation therapy in the management of moyamoya disease?What is the role of anticoagulation and antiplatelet agents in the treatment of moyamoya disease?Which factors are associated with a better prognosis for moyamoya disease?What is the role of surgery in the treatment of moyamoya disease?Which specialist consultations are required for the management of moyamoya disease?When is drug therapy indicated in the treatment of moyamoya disease?Which medications in the drug class Antiplatelet agents are used in the treatment of Moyamoya Disease?Which medications in the drug class Anticoagulants, Hematologic are used in the treatment of Moyamoya Disease?
Roy Sucholeiki, MD, Director, Comprehensive Seizure and Epilepsy Program, The Neurosciences Institute at Central DuPage Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Jasvinder Chawla, MD, MBA, Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Amy Kao, MD, Attending Neurologist, Children's National Medical Center
Disclosure: Have stock (managed by a financial services company) in healthcare companies including Allergan, Cellectar Biosciences, CVS Health, Danaher Corp, Johnson & Johnson.
Acknowledgements
Robert Stanley Rust Jr, MD, MA Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia; Chair-Elect, Child Neurology Section, American Academy of Neurology
Robert Stanley Rust Jr, MD, MA is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Headache Society, American Neurological Association, Child Neurology Society, International Child Neurology Association, and Society for Pediatric Research
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
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