DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY

OPINION

Moyamoya: defining current knowledge gaps VIJEYA GANESAN1| EDWARD R SMITH2 1 Neurosciences Unit, UCL Institute of Child Health, London, UK. 2 Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA. doi: 10.1111/dmcn.12708

Moyamoya is a cerebrovascular arteriopathy, first described exclusively in Japan and East Asia but now increasingly recognized and diagnosed around the world.1 The condition was initially defined by radiographic criteria of ‘bilateral occlusive disease of the terminal internal carotid or proximal middle cerebral arteries and basal collaterals’.1,2 These findings often heralded a relentlessly progressive course, with recurrent multiple strokes leading to severe morbidity or death.3 To date, moyamoya remains the most malignant arteriographic signature in children with arterial ischaemic stroke (AIS).4,5 Surgical revascularization was developed as a treatment to mitigate the risk of AIS,6 but despite this, moyamoya remains poorly characterized, particularly in non-Asians. Here, we aim to highlight some critical knowledge gaps in the understanding of moyamoya in order to suggest areas of focus for future research. The first gap in knowledge is summarized by the question, ‘What is moyamoya?’ It is increasingly apparent that the term encompasses a broad spectrum of distinct diseases and underlying processes that share some common angiographic features. Application of the radiological criteria above to real-life cases is not straightforward and our clinical impression is that there is poor inter- and intraobserver reproducibility amongst radiologists in applying this diagnostic label. This is clinically important as it pushes patients down a specific management pathway but it can be very difficult (as in a child with sickle cell disease) to know exactly what differentiates moyamoya from more benign forms of sickle cell arteriopathy. This semantic heterogeneity highlights the fact that the key angiographic features defining clinically important subgroups have not yet been defined. As an illustration, the radiological features associated with R179 mutations in ACTA2 that differentiated between these and other cases of ‘moyamoya’ were only apparent with extremely detailed analysis of the angiography;7 this suggests that there may be other distinctive phenotypes buried within the catch-all term of ‘moyamoya’. Empirical observation that initially led to the crude distinction between moyamoya disease (idiopathic, bilateral) and moyamoya syndrome (unilateral or associated with specific systemic disorders) has been validated by recent genetic research.3 For example, mutations in RNF213 are strongly associated with the classic East Asian, bilateral, idiopathic familial disease presenting in adulthood.8 Other genetic syndromes, such as neurofibromatosis type I (NF1), trisomy 21, and sickle cell disease offer intriguing 786 DOI: 10.1111/dmcn.12708

evidence supporting the role of environmental influences on the development of arteriopathy in genetically susceptible individuals (the ‘two-hit’ hypothesis).9–12 Epigenetic factors may also be implicated in modulating the clinical phenotype in such individuals, and study of these mechanisms could identify important and novel interventional targets13,14 It is also becoming clear that different populations manifest varying rates of progression, with a particularly malignant course in the youngest patients, contrasted with a potentially more indolent rate of stroke in older adults.15 Our clinical experience in two large non-Asian centres is that ethnicity is likely to be an important determinant of prognosis, but there is heavy bias in the literature of data from East Asians and this remains to be proven. These factors support the need for stratifying risk through deep phenotyping of clinical (e.g. age, mode of presentation), radiographic (e.g. arteriographic patterns, vessel wall characteristics), and biomarker (e.g. circulating markers of inflammation or thrombosis) signatures to inform analysis of the biological drivers of disease through genomic and metabolomic analysis, and ultimately to develop mechanism-specific interventions. A second major deficiency in the understanding of moyamoya is the ability to accurately predict prognosis for an individual patient. Surgical therapies for moyamoya are effective in reducing the risk of AIS, but are associated with potentially significant complications.6 Current clinical practice relies on an imperfect combination of clinical history, angiographic staging, and a variety of radiographic studies which attempt to quantify cerebral blood flow and vasoreactivity (e.g. magnetic resonance imaging, diffusion/perfusion sequences, and radioisotope uptake coupled with physiological challenges like acetazolamide administration) to identify patients at risk of progression, and who could benefit from surgery.16,17 To date, the reported predictive prognostic value of these assessments varies greatly across institutions, with marked variability in application and interpretation and no controlled studies. There is a need to define specific radiological signatures and biomarker profiles that can improve risk stratification of patients with moyamoya so that accurate prognostic tools can be applied consistently. The third topic in need of study is the efficacy of surgical revascularization in patients with moyamoya, which remains a contentious subject for many in the field. While abundant data suggests that revascularization significantly reduces the tendency to recurrent ischemic events, operative treatment for moyamoya has never been subjected to the scrutiny of a clinical trial.6 Numerous international clinical guidelines cite case series as justification for surgery; patients, particularly children, now come with the expectation that they will be offered surgery at the point of diagnosis.17 However, recent data from syndromic cohorts suggests that disease course may vary greatly between populations, with some © 2015 Mac Keith Press

subpopulations manifesting lower rates of progression.18 Imaging of at-risk groups for other indications (e.g. patients with NF1 or sickle cell disease) has revealed increasing numbers of asymptomatic patients. Management of these asymptomatic patients is confounded by the observation that some rapidly progress while others remain stable for long periods. Most publications focus on outcomes of surgery, and there is a lack of observational data on natural history. Some patients with very early stages of arteriopathy (such as Suzuki stage I) may have very limited responses to surgery, in contrast to the robust collateralization seen after treatment of more advanced disease. Clinicians who routinely treat these populations need better data on the risks, benefits, and indications for surgery in order to more effectively counsel their patients. Prospective studies comparing treatment approaches in moyamoya would inform these critical decisions. At the very least, an agreed consensus on the management approach in specific scenarios would enable critical appraisal of experience across centres. Although we have discussed the prospect of mechanistic insights leading to novel treatment targets above, we recognize that it is likely to prove challenging to randomize patients with moyamoya in any interventional study to a ‘no surgery’ arm; thus it is likely that study of any future intervention will likely be as a potential adjunct to surgery, at least in the first instance. The diagnosis and study of moyamoya has rapidly increased, with the initial few cases now escalating to thousands – potentially millions – worldwide. In the first decade after its description in 1969, 122 papers were published; in the last decade (2004–2014) over ten times that amount

(1392) has been written. Despite this growth, this review underscores that much remains unknown about this disorder, particularly in non-Asian populations around the world. We propose that targeting three specific areas of research will help improve our understanding of this condition. 1 Critically clinically and radiologically phenotyping distinct populations of moyamoya to inform study of biological and genetic mechanisms. 2 Developing novel, standardized prognostic techniques to stratify disease risk and guide therapeutic decisionmaking. 3 Prospectively analyzing efficacy of surgical revascularization of moyamoya, in order to compare the risks of different treatment strategies, by applying standardized clinical, neurocognitive, and radiographic assessments to objectively evaluate the efficacy of differing treatment paradigms. There is opportunity to address these issues by standardization of clinical management and prospective, collaborative research. Multi-center, multi-professional, and international collaboration is needed to establish large clinical, imaging, and biorepository data sets required to close these critical knowledge gaps. These comprehensive joint efforts – particularly focused on the heterogeneous, complex, and rapidly evolving non-Asian moyamoya subgroups – provide the greatest opportunity to improve the outcomes of all adults and children with moyamoya. A CK N O W L E D G E M E N T The authors’ research is supported by the Chae Family Foundation.

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Moyamoya: defining current knowledge gaps.

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