Last updated:
02/09/2023
Years published: 1989, 1996, 2003, 2004, 2007, 2009, 2012, 2015, 2018, 2023
NORD gratefully acknowledges Edward R. Smith, MD, Department of Neurosurgery, Children’s Hospital Boston/Harvard Medical School, and R. Michael Scott, MD, Neurosurgeon-in-Chief-emeritus, Children’s Hospital Boston, for assistance in the preparation of this report.
Moyamoya disease is a progressive disorder that affects the blood vessels in the brain (cerebrovascular). It is characterized by the narrowing (stenosis) and/or closing (occlusion) of the carotid artery inside the skull, a major artery that delivers blood to the brain. At the same time, tiny blood vessels at the base of the brain open up in an apparent attempt to supply blood to the brain distal to the blockage. These tiny vessels are the “moyamoya” vessels for which the disease was named. Inadequate blood supply then leads to reduced oxygen delivery to the brain, and it is this oxygen deprivation that causes the signs of moyamoya. One of the symptoms is typically stroke, which results in paralysis of the face, arms or legs, loss of speech, etc., or temporary loss of neurologic function of body parts or speech (transient ischemic attacks, or “TIA”). Other symptoms that may result include headaches, visual disturbances, developmental delay, and seizures. Approximately 10-30% of cases of moyamoya in Asian countries have a genetic cause. Patients with this arteriopathy that occurs either on a familial or idiopathic basis are said to have moyamoya disease. Patients in whom the artery changes occur in association with another process such as sickle cell disease or Down syndrome are said to have moyamoya disease. In this report, we use the term “moyamoya disease” as shorthand for both forms.
Although moyamoya disease may occur at any age, there are two peak incidence periods –between the ages of five and ten years in children, and between 30 to 50 years in adults. Children with moyamoya disease may present with a variety of symptoms, but most present with those related to reduced brain blood supply, including stroke, TIAs, headaches, seizures, involuntary movements or occasionally progressive developmental delay.
Although adults with moyamoya also present with signs and symptoms of brain ischemia, they also have a greater tendency to suffer intracranial hemorrhage than children, presumably due to rupture of the tiny moyamoya blood vessels possibly in the setting of higher blood pressures seen in adulthood.
The causes of moyamoya disease are unknown in many cases. However, it is increasingly recognized that gene changes (mutations or variants) particularly variants that may impair the ability of smooth muscle cells in the walls of affected arteries, to contract normally, are present in many patients. It is also important to note that moymoya is found in association with a number of different underlying disorders, as noted above.
Primary moyamoya disease may be genetically transmitted as an autosomal recessive trait, and accounts for approximately 10% of all cases in Japan. Recently, two major gene mutations (variants) have been reported to be associated with specific subpopulations of moyamoya patients. The first, R179 variants in the ACTA2 gene, correlate with a radiographically distinct subtype of moyamoya disease, identified in a very small cohort of patients related to a larger group of ACTA2 variants that cause cardiac and aortic disorders. (Munot, 2012) More significantly, variants in the RNF213 gene are strongly associated with the classic East Asian, bilateral, idiopathic familial disease presenting in adulthood and may be present in up to 70% of all East Asian familial cases of moyamoya. (Kamada, 2011)
Secondary moyamoya disease occurs in association with a number of different underlying disorders or conditions, including certain infections involving the central nervous system, neurofibromatosis type I, sickle cell disease and Down syndrome, although there is a long list of conditions now published in the medical literature with which moyamoya disease is associated. In susceptible patients, the disease may occur following radiation therapy to the brain to treat certain brain tumors such as optic glioma or craniopharyngioma. Unlike primary moyamoya disease, the disease can occasionally present with angiographic changes involving only on one side. This process can remain unilateral, or – in about 30% of patients – progress to involve the other side. (For more information on these disorders, use “neurofibromatosis type I,” “sickle cell,”, etc., as your search terms in the Rare Disease Database.)
In Japan, moyamoya disease typically occurs in females under the age of 20. In Japan, the disease is estimated to occur in 1 per 300,000 people. Although moyamoya was originally reported in individuals of Japanese ancestry, cases have been reported from elsewhere in Asia as well as from Europe, North and South America and most series reported in the western hemisphere have a minority of patients of Asian descent. Of note, most patients in North America are isolated cases, with recent literature suggesting that less than 4% of cases in this population are familial. (Gaillard 2017)
In most patients, the diagnosis of moyamoya can be made from a careful assessment of an MRI and MRA. Cerebral arteriography will confirm the diagnosis, establish the exact degree of blood vessel narrowing, demonstrate the existing blood flow patterns to various areas of the brain, and allow treatment decisions to be made; for these reasons, it is the standard diagnostic tool for this condition. In particular, catheter angiography can help with the identification of important blood vessels called “transdural collaterals,” which are present in some cases and can markedly influence surgical planning and prognosis. (Storey 2017)
Treatment
Medical treatment of moyamoya disease has been utilized to treat many of the symptoms of moyamoya and is often an important part of the patient’s management. Treatment measures include aspirin (to prevent or reduce the development of small blood clots developing within the narrowed vessels) and anti-seizure medications (when indicated because of a patient’s seizure disorder). In rare instances, anticoagulants such as lovenox or coumadin are administered in very unstable patients having frequent symptoms, but because of the obvious risk of cerebral bleeding in this condition, they are rarely indicated as long-term measures. Calcium channel blockers are sometimes used to help reduce headache and, in some patients, reduce symptoms related to transient ischemic attacks, However, calcium channel blockers need to be used carefully, as they can also lower blood pressure, which may increase stroke risk. There is no medication available which will stop the progression of the cerebral artery narrowing and the disease will continue to progress in the vast majority of patients regardless of treatment.
Surgical procedures are designed to reestablish blood supply to the brain by diverting scalp blood supply to the brain surface and thereby circumventing the progressive loss of brain hemisphere blood flow. There are many surgical procedures proposed to treat moyamoya, and they have been divided into so-called “indirect” and “direct” operations. Indirect procedures, usually carried out in children and younger patients, include pial synangiosis, encephalomyosynangiosis (EMS), encephaloduroarteriosynangiosis (EDAS), dural inversion, and other similar variants. These operations involve the placement of vascularized structures from the scalp and/or the membranes that surround the brain onto the brain surface, which in most moyamoya patients will induce the growth of new blood vessels into the brain. The most common direct procedure involves the direct suturing of a scalp blood vessel, the superficial temporal artery, to a middle cerebral artery branch on the brain surface. Long-term results following surgery of either type have been quite good, with long-term prevention of strokes seen in published series of both pediatric and adult patients. The current American Stroke Association Guidelines for pediatric stroke supports the use of surgical revascularization in affected children.
Importantly, recent data demonstrates that the most important factor predicting a successful surgical outcome is to receive treatment at a center that cares for a high volume of moyamoya patients every year. (Titsworth 2016) Long-term results following surgery of either type have been quite good, with long-term prevention of strokes seen in published series of both pediatric and adult patients, including decades of follow-up with patients successfully giving birth and engaging in all manner of sports and employment.
Genetic counseling is recommended for patients and their families if they have a hereditary form of moyamoya disease.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
TEXTBOOKS
Scott RM. Moyamoya Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:559.
Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2342.
Bennett JC, Plum F. Eds. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., Philadelphia, PA; 1996:888.
Behrman RE, Kliegman RM, Arvin AM. Eds. Nelson Textbook of Pediatrics. 15th ed. W.B. Saunders Company. Philadelphia, PA; 1996:1729.
REVIEW ARTICLES
Ferriero DM, Fullerton HJ, Bernard TJ, et al. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association. Stroke. 2019;50(3):e51-e96. doi:10.1161/STR.0000000000000183
Riordan CP, Storey A, Cote DJ, Smith ER, Scott RM. Results of more than 20 years of follow-up in pediatric patients with moyamoya disease undergoing pial synangiosis [published online ahead of print, 2019 Mar 1]. J Neurosurg Pediatr. 2019;1-7. doi:10.3171/2019.1.PEDS18457
See P, Ropper AE, Underberg DL, Robertson RL, Scott RM, Smith ER, Down syndrome and moyamoya: clinical presentation and surgical management. J Neurosurg Pediatr. 2015;Jul;16(1):58-63.
Scott RM, Smith ER. Medical progress: moyamoya disease and moyamoya syndrome. NEJM. 2009; Mar;360 (12):1126-37
Smith ER, Scott RM, Progression of disease in unilateral moyamoya syndrome. Neurosurg Focus 2008;24(2):E17.
JOURNAL ARTICLES
Gaillard J et al. Incidence, clinical features, and treatment of familial moyamoya in pediatric patients: a single-institution series. J Neurosurg Pediatr. 2017;19(5):553-559.
Storey A, et al. Preoperative transdural collateral vessels in moyamoya as radiographic biomarkers of disease. J Neurosurg Pediatr. 2017;19(3):289-295.
Titsworth WL., Scott RM, and Smith ER. National analysis of 2454 pediatric moyamoya admissions and the effect of hospital volume on outcomes. Stroke 2016;47(5):1303-11.
Munot P, Saunders DE, Milewicz DM, et al. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations. Brain 2012 135(Pt 8):2506–14.
Kamada F, Aoki Y, Narisawa A, et al. A genome-wide association study identifies RNF213 as the first Moya-moya disease gene. J Hum Genet. 2011;56: 34–40.
Morioka M, Hamada J, Todaka T, et al. High-risk age for rebleeding in patients with hemorrhagic Moyamoya disease: long-term follow-up study. Neurosurgery 2003;52:1049-55.
Oya S, Tsutsumi K, Ueki K. Adult-onset moyamoya disease with repetitive ischemic attacks successfully treated by superficial temporal-middle cerebral artery by-pass: case report. Neurol Med Chir (Tokyo). 2003;43:138-41.
Marioka M, Hamada J, KawanoT, et al. Angiographic dilatation and branch extension of the anterior choroidal and posterior communicating arteries are predictive of hemorrhage in adult moyamoya patients. Stroke 2003;34:90-95.
Zafeiriou DI, et al. Familial moyamoya disease in a Greek family. Brain Dev. 2003;25:288-90.
Asumal KB, et al. Moyamoya disease: an elusive diagnosis. J Pak Med Assoc. 2003;53:160-2.
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: Pediatrics 2004; 100: 142-149.
Dobson SR, Holden KR, Nietert PJ, et al. Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events. Blood 2002;99:3144-50.
Soriano SG, Cowan DB, Proctor MR, et al. Levels of soluble adhesion molecules are elevated in the cerebrospinal fluid of children with moyamoya syndrome. Neurosurgery 2002;50:54-49.
Isono M, Ishii K, Kamida T, et al. Long-term outcomes of pediatric moyamoya disease treated by encephalo-duro-arterio-synangiosis. Pediatr Neurosurg. 2002;36:14-21.
INTERNET
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Moyamoya Disease. Entry Number; 252350: Last Edit Date 09/08/21.Available at: https://omim.org/entry/252350 Accessed Dec 7, 2022.
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Moyamoya Disease 2. Entry Number; 607151: Last Edit Date09/29/21. Available at: https://omim.org/entry/607151 Accessed Dec 7, 2022.
NINDS Moyamoya Disease Information Page. Date last modified:Jul 25, 2022. https://www.ninds.nih.gov/Disorders/All-Disorders/Moyamoya-Disease-Information-Page Accessed Dec 7, 2022.
Sucholeiki R, Chawla J. Moyamoya Disease.Medscape.Updated: Nov 9, 2018. www.emedicine.com/neuro/topic616.htm Accessed Dec 7, 2022.
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