Pathophysiology of Chronic Subdural Hematoma – New Insights

Misa Trieu¹Ajith Thomas^1,2*

• ¹Cooper Medical School of Rowan University, Camden, United States
• ²Cooper University Health Care, Camden, United States

Chronic subdural hematoma (CSDH) is a progressive condition characterized by persistent accumulation of blood products and inflammatory exudate within the dural border cell (DBC) layer. CSDH pathogenesis is a self-sustaining cycle of inflammation, angiogenesis, and impaired resolution. Minor head trauma initiates cleavage of the DBC layer, triggering fibroproliferative membrane formation mediated by collagen synthesis and TGF-β1/SMAD signaling. The outer membrane's fragile neovasculature, driven by VEGF primarily, PDGF-BB, and inflammatory mediators, facilitates recurrent microhemorrhage and fibrinolysis, perpetuating hematoma expansion. Persistent inflammation is maintained by M2 macrophages, dendritic cells, osteopontin, and neutrophil extracellular traps, with cytokines such as IL-1β and IL-6 enhancing vascular permeability. Age-related immune dysregulation, including prolonged interferon signaling, contributes to chronicity. Hypoxia further stimulates angiogenesis via HIF-1α and VEGF, while metabolic deficits in fatty acid oxidation impair tissue repair. Lymphatic dysfunction, including meningeal lymphatic vessel damage and fibrotic arachnoid granulations, compromises clearance of blood breakdown products and inflammatory mediators, particularly in elderly patients. Additional contributors include cerebrospinal fluid ingress, creating osmotic gradients that exacerbate hematoma volume, and matrix remodeling mediated by MMP-2 and MMP-9, which balances repair and pathological persistence. Targeted interventions aimed at disrupting inflammatory and angiogenic cascades, modulating fibrinolysis, enhancing lymphatic drainage, and correcting metabolic insufficiency hold promise in reducing recurrence. Potential pharmacological approaches include anti-VEGF agents, PDGFR inhibitors, IL-6 blockade, antifibrinolytics, and MMP inhibitors, alongside minimally invasive procedures such as middle meningeal artery embolization. A comprehensive mechanistic understanding of CSDH underscores the need for multimodal treatment strategies integrating surgery with targeted adjuvant therapies. As its burden on healthcare systems rises, translational research and controlled clinical trials will be critical to developing evidence-based, mechanism-driven management paradigms.