Background: Moyamoya disease (MMD), a chronic cerebral vascular disorder that could lead to both ischemic and haemorrhagic strokes, has a largely unknown aetiology and natural course. Leptospiral cerebral vasculitis, caused by Leptospira infection, showed similar moyamoya-like angiography features. While the relationship between Leptospira infection and MMD is unclear. Methods: We first performed a cross-sectional study on the spatiotemporal characteristics of MMD in Hubei, China. Between October 2016 and July 2020, we identified patients with MMD from the inpatient database statistical bureau of the Hubei Health Committee, China. The age-adjusted incidence rate (AAIR), demographics (age and sex), clinical (symptom type and comorbidities) were described in this study. The geographic clusters of the high and low incidence (hot and cold spots) were identified based on AAIR at the county level using global Moran's I index and Getis-Ord Gi* statistical methods. To preliminarily evaluate Leptospira infection's role in MMD, we then compared the patient baseline features and the county level variables (environmental, socioeconomic, sanitary, and et al.) between the hot and cold spots using the χ2 test and the Wilcoxon rank-sum test, respectively. Finally, to confirm whether Leptospira infection is the aetiology of MMD, we carried out a hypothesis deductive (HD) method. We hypothesised that specific birth cohorts have a higher risk of MMD, and the risk factor is that they suffered from Leptospira infection in their early-life. To prove our hypothesis, we performed a retrospective birth cohort study. We constructed the birth cohort’s distribution of MMD (1931‒2019) and the birth cohorts who were at high risk of Leptospira infection by the leptospirosis surveillance data (1960‒2019) in Hubei province. Our major objective is to evaluate whether these two diseases had a similar risk of birth cohorts by a Gaussian mixture (GM) model. Meanwhile, we investigated the relationship of the spatiotemporal distribution characteristics between leptospirosis and MMD. Findings: Overall, 6427 patients with MMD were identified between October 2016 and July 2020. The AAIR at the province level was 2·11 to 3·38 per 100 000 person-years from 2017 to 2019. The onset age distribution exhibited two major specific peaks, and the median age at diagnosis was 52 years (IQR 46–60), showing an increasing trend with time (50 [IQR 42‒57] in 2016, 51 [IQR 44‒59] in 2017, 52 [IQR 46‒61] in 2018, 53 [IQR 46‒61] in 2019, and 54 [IQR 47‒62] in 2020). No noticeable sex differences were observed. Hot spots were identified mainly in Wuhan, Xiangyang, Huanggang, and Xiaogan City in the eastern part, while cold spots were located in Yichang and Jingzhou City in south-central Hubei province. There existed an obvious age structure difference between hot and cold spots. Cold spots had a higher proportion of young-aged (7·9% vs 5·0%, p=0·042) and old-aged (34·4% vs 23·8%, p<0·0001), while hot spots had higher proportion of the middle-aged. Compared to cold spots, the hot spots had a higher cattle density, more generous paddy fields, and rice acreage, indicating that the Leptospira infection might be the aetiology of MMD. The GM model demonstrated that the massive bias of birth cohorts was probably due to the leptospirosis epidemics in 1963, 1973, 1982‒83, 1986, 1996, and 2008 (R2=0·986). Moreover, the spatiotemporal distribution bias of leptospirosis could explain the epidemiological differences between the spots. Interpretation: We proved Leptospira infection at early-life is the aetiology of MMD. Based on this, we further clarified a complete natural history of MMD, which would be of great importance for understanding the disease. Funding Information: None. Declaration of Interests: Dr. Ma and Dr. Chen report non-financial support from Health Committee, Hubei, China, non-financial support from Centre for Disease Control and Prevention, Hubei, China, during the conduct of the study; personal fees for consulting, non-financial support from writing assistance, outside the submitted work. Dr. Chen reports personal fees for consulting, outside the submitted work. All other authors declare no competing interests. Ethics Approval Statement: All methods were carried out by following relevant guidelines, and the ethics committee approved this study at Zhongnan Hospital of Wuhan University. Informed consent from all participants was waived due to the study's retrospective nature by the ethics committee. All individual identifying information (including name, exact address, and telephone) was anonymised and de-identified to protect patient privacy.
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