Focal cortical dysplasia type II (FCDII) is a major cause of drug-resistant epilepsy, but genetic factors explain only some cases, suggesting other mechanisms. In this study, we conduct a molecular analysis of brain lesions and adjacent areas in FCDIIb patients. By analyzing over 217,506 single-nucleus transcriptional profiles from 15 individuals, we find significant changes in smooth muscle cells (SMCs) and astrocytes. We identify abnormal vascular malformations and a unique type of SMC that we call "Firework cells", which migrate from blood vessels into the brain parenchyma and associate with VIM+ cells. These abnormalities create localized ischemic-hypoxic (I/H) microenvironments, as confirmed by clinical data, further impairing astrocyte function, activating the HIF-1α/mTOR/S6 pathway, and causing neuronal loss. Using zebrafish models, we demonstrate that vascular abnormalities resulting in I/H environments promote seizures. Our results highlight vascular malformations as a factor in FCDIIb pathogenesis, suggesting potential therapeutic avenues.
© 2025. The Author(s).