Headache, Seizures, Weakness, Numbness or paralysis in your face, arm or leg, typically on one side of your body, visual disturbances, Difficulties with speaking or understanding others (aphasia), Cognitive or developmental delays, involuntary movements.[1]
Moyamoya disease is a disease in which certain arteries in the brain are constricted. Blood flow is blocked by constriction and blood clots (thrombosis).[2] 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 conventional angiography, these collateral vessels have the appearance of a "puff of smoke" (described as "もやもや (moyamoya)" in Japanese).[2]
When moyamoya is diagnosed by itself, 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 unilateral arterial constriction, or occurs when one of the several specified conditions is also present.[3] 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.
Presentation
Patients usually present with TIA, ischemic/hemorrhagic stroke, or seizure.[4] The age distribution is bimodal being either young adolescence or mid-forties.[5]
Cause
About 10% of cases of moyamoya disease are familial, and some cases result from specific genetic mutations. Susceptibility to moyamoya disease-2 (MYMY2; 607151) is caused by variation in the RNF213 gene (613768) on the long arm of chromosome 17 (17q25). 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.[6]
In the United States moyamoya has an incidence rate of 0.086 per 100,000.[7] In Japan the overall incidence is higher (0.35 per 100,000).[8] In North America, women in the third or fourth decade of life are most often affected, but the condition may also occur during infancy or childhood. These women frequently experience transient ischaemic attacks (TIA), cerebral hemorrhage, or may not experience any symptoms at all. They have a higher risk of recurrent stroke and may be experiencing a distinct underlying pathophysiology compared to patients from Japan.[9]
The disease moyamoya, which is 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 to the brain and subsequent headaches. Over the last six decades since the disease was first described, pathogenesis of moyamoya disease remained elusive, although the gene ring finger protein 213 (RNF213) has been implicated.[12] 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 provide a tangible explanation of the occurrence of moyamoya phenomenon in the idiopathic and syndromic variants of the disease.[13] In short, the authors report that moyamoya disease likely occurs due to a number of 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.[13]
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.[14]
The disease causes constrictions primarily in the internal carotid artery, and often extends to the middle and anterior cerebral arteries, branches of the internal carotid artery inside the skull.[2] 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.[2]
The arterial constrictions in moyamoya disease are unlike 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.[2]
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.[citation needed]
Diagnosis
Left: MIP reconstructed MR angiography of a 11-year-old girl with moyamoya disease. Right: healthy patient, for comparison.
Cerebral angiography is the gold standard of diagnosing moyamoya disease and its progression. According to Suzuki's system, it can be classified into six stages:[15]
Stage 1 Narrowing of carotid fork
Stage 2 Initiation of the moyamoya and dilatation of 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 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.[15]
Proliferation of smooth muscle cells in the walls of the moyamoya-affected arteries has been found to be representative of the disease. A study of six autopsies of six patients who died from moyamoya disease lead 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.[16]
Often nuclear medicine studies such as SPECT (single photon emission computerized tomography) are used to demonstrate the decreased blood and oxygen supply to areas of the brain involved with moyamoya disease. Conventional angiography provides the conclusive diagnosis of moyamoya disease in most cases and should be performed before any surgical considerations.[citation needed]
Darren B. Orbach explains how the disease progresses as well as the role angiography plays in detecting the progression of moyamoya in a short video.[17] 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."[18] 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.[19]
Associated biomarkers
Smith (2015) conducted a study that looked into specific biological markers that correlate to 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.[20]
Similar to moyamoya disease, there are conditions that are closely associated with moyamoya disease. 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 identifies hyperthyroidism and congenital dwarfing syndromes as two of the more loosely associated syndromes that correlate with the possibility of being diagnosed with moyamoya disease later in life.[20]
There is also research that has shown that certain radiographic biomarkers that lead to the diagnosis of moyamoya disease have been identified. The specific radiographic markers are now considered an acceptable key component to 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" [20] 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 vessels of the brain (ICA, ACA, MCA, specifically). It is important to also note that the radiographic biomarkers, in order 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.[20] 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."[21]
There are also several protein biomarkers that have been linked to the moyamoya disease diagnosis. Although the sample size of the studies performed are small due to the rarity of the disease, the findings are indicative of a correlation between the disease and several specific protein biomarkers.[20] Other studies have confirmed the correlation of moyamoya and adhesion molecule 1 (ICAM-1) being increased as compared to normal vascular function counterparts.[22][23] Furthermore, it has been concluded that the localization of inflammatory cells suggests that the inflammation stimulus itself may be responsible for the proliferation and occlusion in the ICA, ACA, and MCA found in those with moyamoya disease.[3]
Treatment
Antiplatelet drugs (including aspirin) are usually given to prevent clots, but surgery is usually recommended. Because moyamoya tends to affect only the internal carotid artery and nearby sections of the adjacent anterior and middle cerebral arteries, surgeons can direct other arteries, such as the external carotid artery or the superficial temporal artery to replace its circulation. The arteries are either sewn directly into the brain circulation, or placed on the surface of the brain to reestablish new circulation after a few weeks.[2]
There are many operations that have been developed for the condition, but currently the most favored are the in-direct procedures EDAS, EMS, and multiple burr holes and the direct procedure STA-MCA. Combined revascularisation procedure, which includes both the direct superficial temporal artery (STA) to middle cerebral artery (MCA) bypass (also known as ECIC bypass) performed with a combination of in-direct procedures is considered the treatment of choice. Although its efficacy, particularly for hemorrhagic disease, remains uncertain, the procedure is thought to reduce the hemodynamic burden on the engorged collateral blood vessels. Multiple burr holes have been used in frontal and parietal lobes with good neovascularisation achieved.[citation needed]
The EDAS (encephaloduroarteriosynangiosis) procedure is a synangiosis procedure that requires dissection of a scalp artery over a course of several centimeters and then making a small temporary opening in the skull directly beneath the artery. The artery is then sutured to a branch of the middle cerebral artery on the surface of the brain and the bone is replaced.[citation needed]
In the EMS (encephalomyosynangiosis) procedure, the temporalis muscle, which is in the temple region of the forehead, is dissected and through an opening in the skull placed onto the surface of the brain.[citation needed]
In the multiple burr holes procedure, multiple small holes (burr holes) are placed in the skull to allow for growth of new vessels into the brain from the scalp.[citation needed]
In the STA-MCA procedure, the scalp artery (superficial temporal artery or STA) is directly sutured to an artery on the surface of the brain (middle cerebral artery or MCA). This procedure is also commonly referred to as an EC-IC (External Carotid-Internal Carotid) bypass.[citation needed]
All of these operations have in common the concept of a blood and oxygen "starved" brain reaching out to grasp and develop new and more efficient means of bringing blood to the brain and bypassing the areas of blockage. The modified direct anastomosis and encephalo-myo-arterio-synangiosis play a role in this improvement by increasing cerebral blood flow (CBF) after the operation. A significant correlation is found between the postoperative effect and the stages of preoperative angiograms. It is crucial for surgery that the anesthesiologist have experience in managing children being treated for moyamoya, as the type of anesthesia they require is very different from the standard anesthetic children get for almost any other type of neurosurgical procedure.[citation needed]
Prognosis
The natural history of this disorder is not well known. The long term outlook for patients with treated moyamoya seems to be good when direct bypass is used.[24] Although symptoms may seem to improve almost immediately after the in-direct EDAS, EMS, and multiple burr holes surgeries, it will take probably 6 to 12 months before new vessels can develop to give a sufficient blood supply.[citation needed] With the direct STA-MCA surgery, increased blood supply is immediate.[citation needed]
Once a major stroke or bleeding takes place, even with treatment, the patient may be left with permanent loss of function so it is very important to treat this condition promptly.[citation needed]
Research
Recent[when?] investigations have established that both moyamoya disease and arteriovenous fistulas (AVFs) of the lining of the brain, the dura, are associated with dural angiogenesis. These factors may represent a mechanism for ischemia contributing to the formation of dural AVFs. At least one case of simultaneous unilateral moyamoya syndrome and ipsilateral dural arteriovenous fistula has been reported at the Barrow Neurological Institute. In this case a 44-year-old man presented with headache, tinnitus, and an intraventricular hemorrhage, as seen on computed tomographic scans. Cerebral angiography showed a right moyamoya pattern and an ipsilateral dural AVF fed by branches of the external carotid artery and draining into the transverse sinus. This extremely rare coincidental presentation may have deeper pathogenic implications.[25]
The research into the pathogenesis of moyamoya disease has found a breakthrough with the proposal of a "Mechano-biological theory" of pathogenesis of this disease. A research group in southern India have proposed this unifying theory based on computational fluid dynamics studies and longitudinal data. This proposal unifies the pathogenesis of moyamoya disease and moyamoya syndromes described in literature under a single mechanism.[13]
Related Research Articles
The circle of Willis is a circulatory anastomosis that supplies blood to the brain and surrounding structures in reptiles, birds and mammals, including humans. It is named after Thomas Willis (1621–1675), an English physician.
Cerebral angiography is a form of angiography which provides images of blood vessels in and around the brain, thereby allowing detection of abnormalities such as arteriovenous malformations and aneurysms. It was pioneered in 1927 by the Portuguese neurologist Egas Moniz at the University of Lisbon, who also helped develop thorotrast for use in the procedure.
The middle cerebral artery (MCA) is one of the three major paired cerebral arteries that supply blood to the cerebrum. The MCA arises from the internal carotid artery and continues into the lateral sulcus where it then branches and projects to many parts of the lateral cerebral cortex. It also supplies blood to the anterior temporal lobes and the insular cortices.
Carotid endarterectomy is a surgical procedure used to reduce the risk of stroke from carotid artery stenosis. In endarterectomy, the surgeon opens the artery and removes the plaque. The plaque forms and thickens the inner layer of the artery, or intima, hence the name of the procedure which simply means removal of part of the internal layers of the artery.
Cerebral infarction is the pathologic process that results in an area of necrotic tissue in the brain. It is caused by disrupted blood supply (ischemia) and restricted oxygen supply (hypoxia), most commonly due to thromboembolism, and manifests clinically as ischemic stroke. In response to ischemia, the brain degenerates by the process of liquefactive necrosis.
Transcranial Doppler (TCD) and transcranial color Doppler (TCCD) are types of Doppler ultrasonography that measure the velocity of blood flow through the brain's blood vessels by measuring the echoes of ultrasound waves moving transcranially. These modes of medical imaging conduct a spectral analysis of the acoustic signals they receive and can therefore be classified as methods of active acoustocerebrography. They are used as tests to help diagnose emboli, stenosis, vasospasm from a subarachnoid hemorrhage, and other problems. These relatively quick and inexpensive tests are growing in popularity. The tests are effective for detecting sickle cell disease, ischemic cerebrovascular disease, subarachnoid hemorrhage, arteriovenous malformations, and cerebral circulatory arrest. The tests are possibly useful for perioperative monitoring and meningeal infection. The equipment used for these tests is becoming increasingly portable, making it possible for a clinician to travel to a hospital, to a doctor's office, or to a nursing home for both inpatient and outpatient studies. The tests are often used in conjunction with other tests such as MRI, MRA, carotid duplex ultrasound and CT scans. The tests are also used for research in cognitive neuroscience.
Vertebrobasilar insufficiency (VBI) describes a temporary set of symptoms due to decreased blood flow (ischemia) in the posterior circulation of the brain. The posterior circulation supplies the medulla, pons, midbrain, cerebellum and supplies the posterior cerebellar artery to the thalamus and occipital cortex. As a result, symptoms vary widely depending which brain region is predominantly affected.
A carotid-cavernous fistula results from an abnormal communication between the arterial and venous systems within the cavernous sinus in the skull. It is a type of arteriovenous fistula. As arterial blood under high pressure enters the cavernous sinus, the normal venous return to the cavernous sinus is impeded and this causes engorgement of the draining veins, manifesting most dramatically as a sudden engorgement and redness of the eye of the same side.
A watershed stroke is defined as a brain ischemia that is localized to the vulnerable border zones between the tissues supplied by the anterior, posterior and middle cerebral arteries. The actual blood stream blockage/restriction site can be located far away from the infarcts. Watershed locations are those border-zone regions in the brain supplied by the major cerebral arteries where blood supply is decreased. Watershed strokes are a concern because they comprise approximately 10% of all ischemic stroke cases. The watershed zones themselves are particularly susceptible to infarction from global ischemia as the distal nature of the vasculature predisposes these areas to be most sensitive to profound hypoperfusion.
Brain ischemia is a condition in which there is insufficient bloodflow to the brain to meet metabolic demand. This leads to poor oxygen supply or cerebral hypoxia and thus leads to the death of brain tissue or cerebral infarction/ischemic stroke. It is a sub-type of stroke along with subarachnoid hemorrhage and intracerebral hemorrhage.
Animal models of ischemic stroke are procedures inducing cerebral ischemia. The aim is the study of basic processes or potential therapeutic interventions in this disease, and the extension of the pathophysiological knowledge on and/or the improvement of medical treatment of human ischemic stroke. Ischemic stroke has a complex pathophysiology involving the interplay of many different cells and tissues such as neurons, glia, endothelium, and the immune system. These events cannot be mimicked satisfactorily in vitro yet. Thus a large portion of stroke research is conducted on animals.
Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory disease of the blood vessels that causes abnormal growth within the wall of an artery. FMD has been found in nearly every arterial bed in the body, although the most commonly affected are the renal and carotid arteries.
Subclavian steal syndrome (SSS), also called subclavian steal steno-occlusive disease, is a constellation of signs and symptoms that arise from retrograde (reversed) blood flow in the vertebral artery or the internal thoracic artery, due to a proximal stenosis (narrowing) and/or occlusion of the subclavian artery. This flow reversal is called the subclavian steal or subclavian steal phenomenon, regardless of signs/symptoms being present. The arm may be supplied by blood flowing in a retrograde direction down the vertebral artery at the expense of the vertebrobasilar circulation. It is more severe than typical vertebrobasilar insufficiency.
Carotid artery dissection is a separation of the layers of the artery wall in the carotid arteries supplying oxygen-bearing blood to the head. It is the most common cause of stroke in younger adults. The term 'cervical artery dissection' should also be considered in the context of this article.
Vertebral artery dissection (VAD) is a flap-like tear of the inner lining of the vertebral artery, which is located in the neck and supplies blood to the brain. After the tear, blood enters the arterial wall and forms a blood clot, thickening the artery wall and often impeding blood flow. The symptoms of vertebral artery dissection include head and neck pain and intermittent or permanent stroke symptoms such as difficulty speaking, impaired coordination, and visual loss. It is usually diagnosed with a contrast-enhanced CT or MRI scan.
Anterior cerebral artery syndrome is a condition whereby the blood supply from the anterior cerebral artery (ACA) is restricted, leading to a reduction of the function of the portions of the brain supplied by that vessel: the medial aspects of the frontal and parietal lobes, basal ganglia, anterior fornix and anterior corpus callosum.
Cervical artery dissection is dissection of one of the layers that compose the carotid and vertebral artery in the neck (cervix). They include:
The leptomeningeal collateral circulation is a network of small blood vessels in the brain that connects branches of the middle, anterior and posterior cerebral arteries, with variation in its precise anatomy between individuals. During a stroke, leptomeningeal collateral vessels allow limited blood flow when other, larger blood vessels provide inadequate blood supply to a part of the brain.
Reversible cerebral vasoconstriction syndrome is a disease characterized by a weeks-long course of thunderclap headaches, sometimes focal neurologic signs, and occasionally seizures. Symptoms are thought to arise from transient abnormalities in the blood vessels of the brain. In some cases, it may be associated with childbirth, vasoactive or illicit drug use, or complications of pregnancy. If it occurs after delivery it may be referred to as postpartum cerebral angiopathy.
Arterial occlusion is a condition involving partial or complete blockage of blood flow through an artery. Arteries are blood vessels that carry oxygenated blood to body tissues. An occlusion of arteries disrupts oxygen and blood supply to tissues, leading to ischemia. Depending on the extent of ischemia, symptoms of arterial occlusion range from simple soreness and pain that can be relieved with rest, to a lack of sensation or paralysis that could require amputation.
↑ Janda, Paul; Bellew, Jonathan; Veerappan, Venkatachalam (2009). "Moyamoya disease: case report and literature review". The Journal of the American Osteopathic Association. 109 (10): 547–553. PMID19861596.
↑ Sun, Hai; Wilson, Christopher; Ozpinar, Alp; Safavi-Abbasi, Sam; Zhao, Yan; Nakaji, Peter; Wanebo, John E.; Spetzler, Robert F. (August 2016). "Perioperative complications and long-term outcomes after bypasses in adults with moyamoya disease: a systematic review and meta-analysis". World Neurosurgery. 92: 179–188. doi:10.1016/j.wneu.2016.04.083. ISSN1878-8769. PMID27150649.
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