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Background Children with moyamoya arteriopathy have reduced subsequent ischemic risk after revascularization surgery and it is also suggested that hemorrhagic risk may also be reduced by minimizing hemodynamic stress on collateral vasculature recruited within the brain parenchyma, but this has been studied only in intermediate follow‐up or follow‐up for more than a decade in East Asian populations. We aimed to evaluate the incidence of hemorrhagic stroke in long‐term follow‐up and identify at‐risk subpopulations. Methods A single surgeon's personal case series with decades of follow‐up was reviewed for children (18 years or younger) treated with revascularization surgery. This included medical records and the surgeon's personal correspondence. Results Hemorrhagic stroke occurred in 2.6% of 302 children followed for a median of 21 years after surgery. Occurring at a median of 19 years (interquartile range 14–22.75) after surgery, these hemorrhages would not be recognized in series that discontinue follow‐up at transition from pediatric to adult neurosurgical care. There was a higher proportion (5.5‐fold hazard, 95% CI, 1.1–27.6) of patients who had prior radiation therapy in the group with hemorrhagic stroke compared with the overall group. Close retrospective evaluation of vascular imaging suggests aneurysms of the collateral periventricular vessels as a common culprit. Conclusion Children who have moyamoya treated with revascularization surgery remain at long‐term risk of hemorrhagic stroke during adulthood, even though their ischemic stroke risk is significantly mitigated. These patients would benefit from continued clinical and radiological follow‐up, potentially with advanced imaging modalities.

Abstract To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10−7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10−5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a “second-hit” allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.