Molecular and Pathophysiological Mechanisms Underlying Chronic Subdural Hematoma Recurrence: A Comprehensive Review

Chronic subdural hematoma (cSDH) is now better understood as a biologically active inflammatory disorder rather than purely a consequence of trauma. With recurrence occurring in up to 30% of cases after treatment, this pathology remains a major source of morbidity and cause for concern. A growing body of literature suggests that there is a complex interplay between inflammation, angiogenesis, fibrinolytic dysregulation, and structural membrane remodeling in driving cSDH persistence and recurrence. We performed a comprehensive narrative review to identify molecular, histopathological, biochemical, and radiographic correlates of cSDH activity and recurrence. Emphasis was placed on inflammatory mediators, immune cell dynamics, angiogenic signaling pathways, fibrinolytic imbalance, systemic modifiers, and their interaction with contemporary management techniques. Recurrent cSDH is characterized by a persistent pro-inflammatory and pro-angiogenic microenvironment within the neomembrane. Factors include elevated interleukins (particularly IL-6 and IL-8), macrophage polarization imbalance (M1/M2 ratio), VEGF/HIF-1α-driven immature angiogenesis, and excessive fibrinolytic activity mediated by tPA, uPA, and reduced endogenous inhibitors. Structural membrane phenotypes, metabolic and systemic inflammatory states, imaging biomarkers, and cerebrospinal fluid dynamics further affect and characterize recurrence risk. Emerging therapies, including middle meningeal artery embolization, statins, tranexamic acid, and targeted anti-angiogenic agents appear to act by interrupting key elements of this pathological loop. cSDH recurrence reflects failure of inflammatory resolution and vascular maturation rather than incomplete evacuation alone. Integrating molecular biomarkers, imaging surrogates of membrane biology, and patient-specific systemic modifiers may enable biologically informed risk stratification and guide personalized therapeutic strategies aimed at preventing recurrence.