Moyamoya disease is a disease in which certain arteries in the brain are constricted. Blood flow is blocked by constriction and blood clots (thrombosis). A collateral circulation develops around the blocked vessels to compensate for the blockage, but the collateral vessels are small, weak, and prone to bleeding, aneurysm, and thrombosis. On a conventional angiography, these collateral vessels have the appearance of a "puff of smoke", described as in Japanese.
When moyamoya is diagnosed, with no underlying correlational conditions, it is diagnosed as moyamoya disease. This is also the case when the arterial constriction and collateral circulation are bilateral. Moyamoya syndrome is a unilateral arterial constriction, or it occurs when one of the several specified conditions is also present. This may also be considered as moyamoya being secondary to the primary condition. Mainly, occlusion of the distal internal carotid artery occurs. On angiography, a "puff of smoke" appearance is seen, and the treatment of choice is surgical bypass.
Signs and symptoms Patients usually present with TIA, ischemic/hemorrhagic stroke, seizure, or idiopathic and isolated stroke-like symptoms.(2023). Stroke and cerebrovascular diseases. Ropper A.H., & Samuels M.A., & Klein J.P., & Prasad S(Eds.), Adams and Victor's Principles of Neurology, 12e. McGraw-Hill Education. The age distribution is bimodal, being more common in either young adolescence or mid-forties.
There are no reliable methods to distinguish moyamoya disease from other intracranial vascular diseases. Diagnosis relies on radiologic imaging.
Cause About 10–15% of cases of moyamoya disease are familial, and some cases result from specific genetic mutations.
Known genetic causes Susceptibility to moyamoya disease-2 (MYMY2; 607151) is caused by variation in the RNF213 gene (613768) on the long arm of chromosome 17 (17q25), although evidence suggests that RNF213 mutation alone is not enough to cause disease. Moyamoya disease-5 (MYMY5; 614042) is caused by mutation in the ACTA2 gene (102620) on the long arm of chromosome 10 (10q23.3); and moyamoya disease-6 with achalasia (MYMY6; 615750) is caused by mutation in the GUCY1A3 gene (139396) on the long arm of chromosome 4 (4q32). Loci for the disorder have been mapped to the short arm of chromosome 3 (MYMY1) and the long arm of chromosome 8 (8q23) (MYMY3; 608796). See also MYMY4 (300845), an X-linked recessive syndromic disorder characterized by moyamoya disease, short stature, hypergonadotropic hypogonadism, and facial dysmorphism, and linked to q25.3, on chromosome 17.Online Mendelian Inheritance in Man, https://omim.org/entry/252350
Molecular mechanisms Both familial and sporadic moyamoya diseases have unclear molecular causes. Inflammatory cytokines and matrix metalloproteinases have been proposed as contributory factors, though the mechanism and significance of observed associations with these molecules are unknown. Researchers also frequently target known contributors to fibrotic and angiogenic changes, such as FGF and TGF-beta, but no conclusive causes have been found.
Clinically similar conditions Some hemoglobinopathies, such as sickle cell disease, are known to cause a syndrome which is clinically similar to moyamoya disease, but which is due to occlusion of cerebral arteries, rather than constriction of them. Rarely, atherosclerotic changes in distal intracranial carotid arteries may also cause a vasooclusive form of moyamoya.
Pathophysiology
The disease moyamoya, a Japanese mimetic word, gets its characteristic name due to the appearance of smoke on relevant angiographs resultant from the tangle of tiny vessels in response to stenosis. This makes the blood leak out of the arteries, causing pressure on the brain and subsequent headaches. Over the last six decades, since the disease was first described, the pathogenesis of moyamoya disease has remained elusive, although the gene ring finger protein 213 (RNF213) has been implicated. In September 2021, a south Indian researcher has proposed a pathbreaking theory on moyamoya pathogenesis. Coined the "Mechano-biological theory", the disease has a multifactorial pathogenesis. The authors explain the occurrence of the moyamoya phenomenon in the idiopathic and syndromic variants. In short, the authors report that moyamoya disease likely occurs due to several factors (e.g., differences in vascular anatomy) that ultimately contribute to broad cerebral blood vessel occlusion and consequent shifts in vessel connections to try to provide blood for the compromised brain.
Once it begins, the vascular occlusion tends to continue despite any known medical management. In some people, this leads to transient ischemic attacks or repeated strokes with severe functional impairment or even death. In others, the blockage may not cause any symptoms.
The disease primarily constricts the internal carotid artery, and often extends to the middle and anterior cerebral arteries, branches of the internal carotid artery within the skull. When the internal carotid artery becomes completely blocked, the fine collateral circulation that it supplies is obliterated. Patients often survive on the collateral circulation from the back (posterior) of the circle of Willis, arising from the basilar artery.
The arterial constrictions in moyamoya disease differ from the constrictions in atherosclerosis. In atherosclerosis, the walls of arteries are damaged, leading to the deposition of fat and immune cells, and ultimately the accumulation of immune cells laden with fat. In moyamoya, the inner layer of the carotid artery proliferates within the arterial lumen. The artery also fills with blood clots, which may cause strokes.
Moyamoya disease tends to affect adults in the third to fourth decade of life. In children, it tends to cause strokes or seizures. In adults, it tends to cause strokes or bleeding. The clinical features are strokes, recurrent transient ischemic attacks (TIAs), sensorimotor paralysis (numbness and paralysis of the extremities), convulsions, and/or migraine-like headaches. Moreover, following a stroke, secondary bleeding may occur. Such bleeding, called hemorrhagic strokes, may also stem from rupture of the weak neovascular vessel walls.
Diagnosis
Cerebral angiography is the gold standard for diagnosing moyamoya disease and its progression. According to Suzuki's system, it can be classified into six stages: Stage 1 Narrowing of the carotid fork Stage 2: Initiation of the moyamoya and dilatation of the intracranial main arteries Stage 3 Intensification of the moyamoya and defects of the anterior cerebral artery and middle cerebral artery Stage 4 Minimization of the moyamoya and defects of the posterior cerebral artery Stage 5 Reduction of the moyamoya and development of external carotid artery collaterals Stage 6: Disappearance of the moyamoya and circulation only via the external carotid artery and vertebral artery
Magnetic resonance angiography (MRA) is also useful in diagnosing the disease with good correlation with Suzuki's grading system.
Proliferation of smooth muscle cells in the walls of the moyamoya-affected arteries is representative of the disease. A study of six autopsies of six patients who died from moyamoya disease led to the finding that there is evidence that supports the theory that there is a thickening, or proliferation, of the innermost layer of the vessels affected by moyamoya. These vessels are the ACA (anterior cerebral artery), MCA (middle cerebral artery), and ICA (internal carotid artery). The occlusion of the ICA results in concomitant diminution of the "puff-of-smoke" collaterals, as they are supplied by the ICA.
Often, nuclear medicine studies such as SPECT (single-photon emission computed tomography) are used to demonstrate the decreased blood and oxygen supply to areas of the brain involved with moyamoya disease. Conventional cerebral angiography provides the conclusive diagnosis of moyamoya disease in most cases and should be performed before any surgical considerations.
Darren B. Orbach explains how moyamoya disease progresses and the role angiography plays in detecting its progression in a short video.Moyamoya disease program: Moyamoya treatment videos | Boston Children's Hospital [Video file]. (n.d.). Retrieved from http://www.childrenshospital.org/centers-and-services/programs/f-_-n/moyamoya-disease-program/patient-resources/videos-about-moyamoya/moyamoya-treatment-videos In 2019, author and artist Sarah Lippett published a graphic novel about her decade-long struggle to get a diagnosis and treatment for moyamoya disease, called A Puff of Smoke (published with Jonathan Cape). The book was praised in the newspaper The Guardian as a "wonderfully drawn memoir of a serious childhood illness." It was one of the paper's "graphic novels of the year" in 2019 and The Observer newspaper's graphic novel of the month in November 2019.
Associated biomarkers Smith (2015) conducted a study of specific biological markers that correlate with moyamoya disease. Some of the categories of these biomarkers include phenotypes – conditions commonly related to moyamoya, radiographical markers for the diagnosis of moyamoya, and proteins, as well as cellular changes that occur in cases of moyamoya.
Similar to moyamoya disease, certain conditions are closely associated with it. Some of the more common medical conditions that are closely associated with moyamoya disease include trisomy 21 (Down syndrome), sickle cell disease, and neurofibromatosis type 1. There is also evidence that suggests hyperthyroidism and congenital dwarfing syndromes are two more loosely associated syndromes that correlate with moyamoya disease later in life.
Research has shown that certain radiographic biomarkers help diagnose moyamoya disease. The specific radiographic markers are now considered an acceptable key component of moyamoya disease and have been added to the International Classification of Diseases (ICD). These biomarkers of moyamoya are "stenosis of the distal ICA's up to and including the bifurcation, along with segments of the proximal ACA and MCA...dilated basal collateral vessels must be present" Some other common findings that have not been added to the classification index of those with moyamoya disease which are found using radiography involve very distinct changes in the vessels of the brain. These changes include newly formed vessels made to compensate for another change noted, ischemia and cerebrovascular reserve, both found on MRI. Functional changes include evidence of ischemia in the brain blood vessels (ICA, ACA, and MCA, specifically). It is also important to note that for radiographic biomarkers to be classified as moyamoya disease, all findings must be bilateral. If this is not the case and the findings are unilateral, it is diagnosed as moyamoya syndrome. This recently changed in 2021, as the Research Committee of Moyamoya Disease (RCMD) has "removed limitations of the previous definition that required bilateral involvement of the intracranial carotid artery. Now, proximal middle cerebral artery or anterior cerebral artery involvement suffices, and unilateral disease is acceptable to make the diagnosis, given the increasing evidence of progression to bilateral involvement in unilateral MMD."