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Research on moyamoya disease has progressed remarkably in the past several decades. Indeed, many new facts concerning the epidemiology of the disease have been revealed and surgical treatments have been drastically improved. However, despite extensive research, the mechanism of moyamoya disease is still unknown. Consequently, the cardinal treatment of this disease has not yet been developed. For further clarification of its etiology, innovative studies are therefore indispensable. The aim of this paper is to review research on the pathogenesis of moyamoya disease to identify milestones in the direction of its true solution. Many hypotheses of the pathogenesis of moyamoya disease have been proposed in the past half century, including infection (viral and bacterial), autoimmune disorders, proteins abnormality, and gene abnormality. Some of these are now considered to be historical achievements. Others, however, can be still subjected to contemporary research. Currently, several genetic abnormalities are considered to offer the most probable hypothesis. In addition, interesting papers have been presented on the role of the endothelial progenitor cell on the pathogenesis of moyamoya disease. Intuitively, however, it appears that a single theory cannot always explain the pathogenesis of this disease adequately. In other words, the complex mechanism of several factors may comprehensively explain the formation of moyamoya disease. The "double hit hypothesis" is probably the best explanation for the complicated pathology and epidemiology of this disease.

Review of Past Research and Current Concepts on the Etiology of Moyamoya Disease