Moyamoya disease

Moyamoya disease (MMD) name derives from the Japanese word meaning “puff of smoke”[7]. Moyamoya is a progressive disorder affecting the cerebrovascular (blood vessels) in the brain [12]. The characteristics of Moyamoya is stenosis (narrowing) and/or occlusion (closing) of the terminal part and proximal branches of the internal carotid artery within the skull, a major artery that delivers blood to the brain [3,12].Gene changes specifically genetic variants associated with MMD include a variant in the Ring Finger 213 gene (RNF213) on chromosome 17 (17q25.3), this alters arginine at position 4810 (p.R4810K), this mutation is often seen within the Asian population [4].Moreover, the RNF213 p.R4810K mutation is found in heterozygous and homozygous MMD patients, and those with the homozygous mutations developed a more severe disease earlier in age and worse prognosis [11].Susceptibility in MMD has also been reported to reside on 3p (chromosome 3) and 8q23 (chromosome 8)[9].Two major gene mutations (variants) have also be reported this is R179 variants in the ACTA2 gene (location 10q23.31) seen in a very small cohort of patient distinct in a subtype of moyamoya disease/ moyamoya syndrome which is the cause of cardiac and aortic disorders [7,12].

MMD has been identified across all ethnicities, with research studies indicating a notable East-West gradient [1]. The age onset of MMD consist of major peaks in the first decade of life and a moderate peak from late 20s up to 50 years [12,14]. The variant RNF213 has been demonstrated to have a strong association in Japanese, Korean and Chinese patients but can be found in other Asian ethnicities and has a lower frequency in Europeans. Within Asian families the RNF213 P.R4810K has been predominately demonstrated as autosomal dominant inheritance with reduced penetrance [4]. Moyamoya disease can also be inherited as autosomal recessive. It is estimated to affect 1 per 100,000/ year in Japan and about ten times lower in western countries [3].

The disease has a high impact on children and adult leading to those affected to develop acute and chronic neurological deficits and progressive physical disabilities [3]. Cerebral hemodynamic impairment and repeat ischemic symptoms have been the main indications for treatment.

• Cerebral: Cerebral hemodynamic impairment and repeat ischemic symptoms such as transient ischemic attacks, ischemic stroke, haemorrhagic stroke [10].
• Neurological: encompass epilepsy, headache and cognitive dysfunction which vary depending on the age [14]
• Ocular: Vision loss, double vision as a result of an ischemic stroke

Diagnosis is made through a combination of clinical, pathological and radiographic findings.The diagnostic assessment for MMD include magnetic resonance angiography or digital subtraction angiography, magnetic resonance imagining and hemodynamic assessments using (semi) quantitative techniques such as SPECT or PET [2].The confirmation of cerebral arteriography will confirm the diagnosis as it establishes the exact degree of blood vessel (known as transdural collaterals and present in some cases) narrowing and reveals the existing blood flow patterns to various areas of the brain [12]. Radiological angiographic technique used to diagnose all disorders that present with morphological appearance on imagining this is described as moyamoya angiopathy (MMA). It is classified as MMD or primary MMD if the condition is isolated hence idiopathic.When the radiological appearance occurs in association with an acquired or hereditary disorders (such as Sickle Cell Anaemia, Costello syndrome, Down syndrome and many others) it is known as moyamoya syndrome (MMS) or secondary MMD [3,8].Further research has demonstrate that abnormal IgG deposition into elastic layers and infilitration by T cells, macrophages and S100A4- positive smooth muscle cells in the intimal layer, alongside immunological and inflammatory mediators, plays a role in the pathogenesis of MMD [5]. Patients with MMD have been found to have elevated plasma inflammatory factors including interleukin-1 beta, monocyte chemoattractant protein-1, and stromal cell-derived factor-1 alpha [5]. Histological findings in MMD include the thinning of the tunica media that tends to be more pronounced in adult patient than in children patients with MMD [13]. Revascularisation surgery is an effective treatment option for haemorrhagic MMD this include direct, indirect and combined procedures [6]. The aim of revascularisation are to restore the blood supply and thereby stabilising cerebrovascular hemodynamic (which refers to the brain blood flow regulation) [2]. This would lead to improvement of the cerebral hemodynamic resulting in prevention of secondary stroke and improved neurological/ neurocognitive outcome.

There is currently no standard drug to effectively control or reverse the pathogenesis of MMD. The drugs provided for MMD is only targeted at the clinical symptoms, including ischemia and haemorrhage [14]. Risk factors to control include hypertension, diabetes and dyslipidemia. Treatment include acetylsalicylic acid which aid to prevent recurrence of ischemic attacks and clopidogrel or another thienopyridine if acetylsalicylic acid is not tolerated or ineffective [5]. In addition, the use of calcium channel blockers to reduce the risk of severe headaches, strokes, and mini-strokes [10].

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