Early-Life Exposure to Leptospirosis is an Essential Cause for Moyamoya Disease

Background: Moyamoya disease (MMD) is a cerebral vascular disorder that could lead to both ischemic and haemorrhagic strokes, which has a largely unknown aetiology and natural history. Leptospiral cerebral vasculitis (LCV), a delayed complication of leptospirosis, showed typical moyamoya-like angiographic features. However, the association between leptospirosis and MMD has not been clarified. Methods: Inspired from the epidemiological characteristics of Chinese MMD and leptospirosis, we proposed a hypothesis that the patients with MMD might suffer from leptospirosis at their early-life in the 20 th century. To prove our hypothesis, we deduced two inferences based on the hypothetic-deductive method. The first inference (I 1 ) is that the age onset of MMD presented an increasing trend since 2000. To prove I 1 , we collected and analysed the age onset changing trend of MMD between 2001 and 2020. The second inference (I 2 ) is that every time when leptospirosis outbreaks (LOs) occurred, it would trigger a cluster of birth cohort of MMD (BCM) in the future. To prove I 2 , we constructed the BCM in the observation time from 2016 to 2020 and performed a cluster analysis for it by the Gaussian Mixture Model (GMM). Subsequently, taking LOs timelines into consideration, we evaluated whether each cluster of the BCM was triggered by the corresponding LO. Findings: Between 2001 and 2020, the median age onset of MMD showed an increasing trend by time (35 [IQR, 31‒41] years old in 2001 to 2005; 41 [IQR, 35‒48] years old in 2006 to 2010; 46 [IQR, 40‒53] years old in 2011 to 2015; 51 [IQR, 43‒57] years old in 2016 to 2020). Using the GMM, we identified four clusters (cluster 1 to 4) in the BCM. Over 95% cases in cluster 1, 2, 3, and 4 were born before 1973, 1982‒1983, 1986, and 1996 LO, respectively. During the corresponding LO, the mean (95% CI) exposure age of cluster 1, 2, 3, and 4 was at 20 (12, 28), 18 (10, 26), 13 (5, 21), and 12 (4, 20) years old, respectively, which were the susceptible population of leptospirosis. Thus, the cluster 1, 2, 3, and 4 were supposed to be triggered by 1973, 1982‒1983, 1986, and 1996 LO, respectively. More importantly, the more recent LO occurred to our observation time (2016 to 2020), the younger mean exposure age of the corresponding cluster was, which indicated that the younger whose exposure age during LO was, the shorter latent period who developed with MMD would be. Interpretation: We identified that there existed birth cohort clusters for MMD which were probably triggered by intermittent LO in the 1970-90s. The majority of MMD since 2000 are actually caused by leptospirosis epidemics in the 20 th century. MMD is a delayed complication of leptospirosis that the younger exposure age leads to a shorter latent period. Funding: This study was supported by grants from Major Program for Technological Innovation of Hubei Province (Grant No. 2018ACA139). Declaration of Interest: None to declare. Ethical Approval: 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.