Hypoxia Paradox in Middle Meningeal Artery Embolization for Chronic Subdural Hematoma: A Mechanistic Framework for Treatment Resistance

BACKGROUND AND OBJECTIVES: The clinical efficacy of middle meningeal artery embolization (MMAE) in chronic subdural hematoma (CSDH) is increasingly established; yet, recent landmark randomized controlled trials consistently report only a 30% to 50% reduction in recurrence, implying that middle meningeal artery occlusion alone does not fully resolve the pathological microenvironment of the outer hematoma membrane. The mechanistic basis of this incomplete treatment response remains undefined. METHODS: To develop a mechanistic framework for this clinical paradox, we performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review. Of 876 records identified across PubMed, Embase, and ClinicalTrials.gov, 47 underwent full-text review and 18 studies (16 clinical studies and 2 registry records) published through October 2025 were included, integrating clinical outcomes with pathological and molecular insights. A secondary analysis of a publicly available single-cell RNA sequencing data set of normal human dural tissue was performed to map the cellular infrastructure underlying key molecular drivers. RESULTS: CSDH progression is driven by an interconnected triad of inflammatory infiltration, pathological angiogenesis, and vascular hyperpermeability within the outer hematoma membrane. While MMAE suppresses these pathogenic programs by reducing middle meningeal artery-derived arterial supply, we propose that occlusion-induced ischemic stress may paradoxically stabilize hypoxia-inducible factor 1α, triggering compensatory angiogenesis in cases of incomplete devascularization, a mechanism we formally term the "hypoxia paradox". Secondary single-cell RNA sequencing analysis identified fibroblast-like and endothelial dural populations as the primary cellular platforms for this response, providing a translational cellular basis for the proposed framework. CONCLUSION: The hypoxia paradox represents a testable mechanistic hypothesis, offering a coherent explanation for heterogeneous MMAE outcomes and generates specific, testable predictions regarding post-MMAE molecular signatures in the outer hematoma membrane. Prospective paired tissue sampling integrated with multimodal molecular analyses is essential to validate this model and advance CSDH management toward individualized, mechanism-guided therapy.