The role of inflammation and neo-angiogenesis in the pathophysiology of chronic subdural hematomas

Introduction

Chronic subdural hematoma (cSDH) is a condition that develops when blood and fluid accumulate between the brain’s arachnoid and dura mater layers. While trauma is considered the leading cause, there are many other risk factors for the development of cSDH which include anticoagulation/antiplatelet use, alcohol consumption, arterial hypertension, cerebrovascular atherosclerosis, diabetes, and brain atrophy, making cSDH an increasing global health concern, particularly in ageing populations (1-4). Although many acute and subacute SDH resolve spontaneously, a significant proportion transition into cSDH, forming a persistent collection of blood products and inflammatory fluids, with septations and neo-membranes (5). The incidence of cSDH ranges from 1.7 to 20.6 per 100,000 people annually, with rates escalating dramatically in older populations, particularly men over 80 years of age, who experience a sixfold higher risk (6,7). By 2030, cSDH is projected to become the most common neurosurgical condition worldwide, reflecting a growing burden on healthcare systems (8,9). While risk factors such as age, brain atrophy, and anticoagulant therapy explain the progression from acute to chronic SDH in some patients (10,11), not all acute SDH patients in whom these risk factors are present go on to develop a chronic SDH. This suggests that these factors, alone, do not explain the progression from acute to chronic SDH. Heterogeneity in vascular susceptibility and inter-individual variability in thrombogenic, inflammatory and angiogenic response likely play a role. As an example, ischemic heart disease, which is often paired with systemic arterial disease, and thrombocytopenia, a sign of dysregulated thrombogenic response, were associated with chronificiation of acute SDH in some studies (11,12). Overall, cSDH formation appears to be multifactorial, and more studies are needed to identify mechanisms and patient susceptibility.

Traditionally, cSDH was believed to result from the rupture of bridging veins, with subsequent blood accumulation in the subdural space. However, emerging evidence suggests that inflammation and neo-angiogenesis are central to the pathogenesis and persistence of cSDH (13). This article explores the role of these processes in the development and progression of cSDH and highlights potential treatment targets.

Anatomy

The dura mater, the outermost meningeal layer is comprised of multiple layers itself, which all play unique roles in cerebrovascular anatomy and injury (Figure 1). The outer periosteal layer tightly adheres to the inner surface of the skull, while the inner meningeal layer is adjacent to the arachnoid membrane. Between these layers lies the dural border cell layer, which plays a critical role in the pathogenesis of cSDH (13,14). These cells are particularly vulnerable to injury, and—when injured—can trigger a fibroproliferative and inflammatory cascade that leads to hematoma formation and maintenance (15). The middle meningeal artery (MMA) is the primary blood supply of the dura, with other branches (e.g., anterior and posterior meningeal arteries, superficial and deep recurrent meningeal arteries) providing additional, minor supply. The dominant role of the MMA with regard to dural blood supply provides a critical target for therapeutic interventions, such as embolization, to disrupt the cycle of inflammation and angiogenesis.

Figure 1 Anatomy of the meninges. (A) Image showing the meningeal layers and spaces within meninges. (B) Magnified view of duramater, subdural space and arachnoid mater. Dural border cells are composed of flattened fibroblasts. There are no tight junctions, no intercellular collagen and no basement membrane. Arachnoid border cells are supported by basement membrane and are bound together by tight junctions (yellow circles). The normal subdural space is a very thin space between dura mater and arachnoid mater. (C) Image showing formation of outer and inner membrane after damage to dural border cells due to the initiation of an inflammatory response. This results in accumulation of fluid and blood in the new membrane bound subdural space.

Pathophysiology

Challenges to the conventional theory of cSDH development

Historically, the first description of cSDH was by Johannes Jacob Wepfer in 1658, followed by Morgagni in 1761 (16). Virchow first proposed an inflammatory etiology for cSDH in 1857, with “pachymeningitis hemorrhagica interna” (17). Gardner in 1932, proposed that trauma-associated rupture of bridging veins starts a chronic process (18). More than a century since Virchow’s 1857 pachymeningitis hemorrhagica interna description, the first detailed article describing cSDH capsular morphology at various stages of clinical presentation was published in 1975 by Sato and Suzuki (19). Despite Virchow’s early theory of an inflammatory cSDH etiology, until recently, classical medical teaching was that cSDH arises solely from traumatic rupture of bridging veins (i.e., the veins that drain blood from the cortical surface into the dural sinuses, particularly the superior sagittal sinus) (20). Tears in these veins, according to the traditional “medical textbook thinking”, would then result in blood accumulation in the subdural space. Particularly with reduced total brain volume in the elderly, bridging veins have to traverse a longer distance from brain surface to the dura mater which ultimately results in tightly strained veins that are prone to tearing at the most rigid fixation point: the dura mater, which was thought to explain the higher prevalence of cSDH in the elderly. Blood was assumed to slowly drip from the site of the venous tear into the subdural space, explaining the frequently delayed symptom onset. However, this theory has been challenged for several reasons. First, the segment of bridging veins that traverse the dura is very short (~10–600 µm) (21), making their rupture within the dura statistically less likely compared to a rupture in its course in the subarachnoid space.

Second, many cSDH patients show no signs of bleeding on initial computed tomography (CT) imaging after trauma, and subdural hematomas only appear weeks or months later. Third, the distribution of hemorrhages, overlying the entire hemispheric convexity in most cases, is inconsistent with the anatomical location of bridging veins, which are mostly located near the superior sagittal sinus. Finally, published autopsy reports only rarely found evidence of torn bridging veins (13,14). Instead, recent research highlights a complex interplay of inflammation, angiogenesis, and fibroproliferation in cSDH formation. Hemorrhage damages the dural border cells in the inner dura layer, triggering a cascade of fibroproliferative processes similar to wound healing. This leads to the formation of fibrous membranes that encase the hematoma. These membranes, in turn, release pro-inflammatory cytokines and pro-angiogenic factors like vascular endothelial growth factor (VEGF), resulting in the development of fragile, leaky capillaries prone to repeated micro-hemorrhages. This creates a vicious cycle of inflammation, angiogenesis, and hematoma expansion (13,14,22).

The vicious cycle: inflammation, angiogenesis, and hemorrhage

The first documented report of a dural hematoma was in 1857 by Virchow (17). However, it has only recently been recognized in the broader neurosurgical and neurointerventional community that inflammation, triggered by an acute traumatic event, even a trivial one such as a minor fall, is a critical mechanism in the development of cSDH. The process begins with damage to the dural border cells which initiates a cascade of pathological processes. Formation of cSDH shear-induced damage likely begins with shear stress-induced injury to the dural border cell layer, with or without overt hemorrhage. Although this can result in hemorrhage into the innermost layer of the dura, overt hemorrhage may not be a necessary pre-requisite for cSDH formation, and indeed, not all patients present with radiologically visible bleeding on initial CT imaging. Shear stress at the dural border cell layer then leads to inflammation, neomembrane formation, and neoangiogenesis eventually resulting in a chronic subdural collection, most likely irrespective of whether hemorrhage was present at the time of initial injury or not (13). This initial insult triggers the activation of pro-inflammatory pathways, leading to the release of cytokines and chemokines. These molecules attract immune cells to the site of hemorrhage, amplifying the inflammatory response and creating a microenvironment conductive to further tissue damage and repair (13). Adding to this vicious cycle is angiogenesis, driven by the release of VEGF (23).

VEGF plays a central role in endothelial cell proliferation and the development of fragile new capillaries. The pathological interplay between inflammation, angiogenesis, and fibroproliferation allows for the persistence of cSDH and often leads to an increase in hematoma size. The central role of inflammation and angiogenesis in cSDH formation and evolution makes these mechanisms crucial therapeutic targets (Table 1, Figure 2).

Figure 2 Diagrammatic representation of various angiogenic factors, inflammatory mediators involved in angiogenesis, proliferation of leaky vessels and membrane formation. In cSDH, Ang-2 is overexpressed. Ang-1 and Ang-2 (acting through receptors Tie-1 and Tie-2) have opposing effects on angiogenesis. Ang-1 stimulates migration, adhesion, and survival of endothelial cells. Ang-2 is primarily an antagonist and prevents Ang-1 from binding which results in immature and abnormally dilated vessel formation. VEGF activates the PI3K-Akt pathway in endothelial cells, required for nitric oxide production, as well as for regulating cell proliferation, permeability, and repair. VEGF also activates the MAPK cascade and causes disruption in endothelial lining. Excess VEGF therefore can activate both angiogenesis and increased vascular permeability, which can lead to recurrent bleeding that sustains cSDH growth. MMPs cause breakdown of extracellular matrix and hence increase haemorrhage in cSDH cavity. PDGF signaling activates pericytes, which play a role in promoting angiogenesis, modulating microvascular stability, and increasing vascular permeability. This pericyte activation may contribute to the growth, fluid leakage, and membrane formation associated with cSDH. IL-6 activates the JAK-STAT signaling pathway, which promotes cellular proliferation within the hematoma membranes, hence causing hematoma expansion. Osteopontin acts through Integrin α9 and β1 receptors. It Increases angiogenesis, inflammation and promote hematoma growth. Ang-1/2, angiopoietin-1/2; cSDH, chronic subdural hematoma; IL-6, interleukin-6; JAK-STAT, Janus kinase signal transducer and activator of transcription; MAPK, mitogen activated protein kinase; MMPs, matrix metalloproteinases; PDGF, platelet-derived growth factor; PI3K-Akt, phosphatidylinositol 3-kinase-Akt; Tie-1/2, tyrosine kinase receptor 1/2; VEGF, vascular endothelial growth factor; VEGF-R, vascular endothelial growth factor receptor.

Important cytokines and chemokines for cSDH development

VEGF

VEGF describes a sub-family of growth factors that stimulate the formation of new blood vessels. VEGF-A is the most important of the VEGF subtypes and acts through two similar tyrosine kinase receptors [vascular endothelial growth factor receptor (VEGF-R)]. A number of studies have demonstrated that VEGF and its receptors are found in much higher concentrations in cSDH fluid than in peripheral blood or CSF fluid (24). VEGF-A activates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in endothelial cells, required for nitric oxide production, as well as for regulating cell proliferation, permeability, and repair (25). Excess VEGF-A therefore can activate both angiogenesis and increased vascular permeability, which can lead to recurrent bleeding that sustains cSDH growth (24). Studies have shown high correlation between the concentration of VEGF and the exudation rate, which indicates that higher concentrations of VEGF are associated with higher exudation of plasma into the hematoma. Additionally, patients treated with angiotensin converting enzyme (ACE) inhibitors had lower concentrations of VEGF. These results are in accordance with the hypothesis that VEGF-mediated angiogenesis, resulting in fragile, leaky vessels, is the cause of recurrent bleeding and chronic exudation, driving hematoma expansion (23).

Angiopoietin

Angiopoietins are another family of vascular growth factors that play an important role both in embryonic and post-natal angiogenesis. Angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2) bind on the same tyrosine kinase receptor 2 (Tie-2) which is expressed principally on vascular endothelium. Of note, Ang-1 and Ang-2 have opposing effects on angiogenesis.

Ang-1 stimulates migration, adhesion, and survival of endothelial cells. Ang-2 is primarily an antagonist and prevents Ang1 from binding. Tie-2, the target receptor of Ang-1 and Ang-2, has been detected in the outer membrane of cSDH. In mature vessels, proper vascular wall formation, mediated by Ang-1, occurs when Ang-2 is downregulated. However, in cSDH, Ang-2 overexpressed. This Ang-1/Ang-2 imbalance the interaction between endothelial and perivascular cells, which results in immature and abnormally dilated vessel formation with increased bleeding tendencies (26).

Matrix metalloproteinases (MMPs)

MMPs are a group of proteolytic enzymes that break down the extracellular matrix. They are secreted by endothelial cells during the initial phases of new vessel formation to facilitate “sprouting” of new vessels and play a crucial role in angiogenesis. The inhibition of their function inhibits the angiogenic response, with a reduced number of newly formed vessels that are shorter in length (27). Enhancing MMP function on the other hand, leads to a more intense angiogenic response. Thus, it is not surprising that elevated MMP levels are a hallmark feature of nearly all inflammatory diseases. VEGF, MMP-2, and MMP-9 levels are found to be significantly higher in the hematoma fluid of cSDH compared to serum levels. From the mechanisms described above, it becomes clear that the concerted action of MMP,VEGF and angiopoetin is probably a major contributor to the occurrence of cSDH, and the gradual expansion that is seen in many patients (28). Immunhistochemistry and in situ zymography studies have shown that the outer membranes of subdural hematoma specimens were positive for MMP-1, MMP-2, MMP-9, and their inhibitors known as tissue inhibitors of metalloproteinases 1 and 2 and (TIMP-1 and TIMP-2). These findings suggest that MMPs are the key enzymes involved in extracellular matrix degradation in the outer membrane, which may impair capillary integrity and lead to hemorrhage and fluid exudation into the hematoma cavity. It has been hypothesized that irrigation and drainage are effective treatments for cSDH because they reduce the concentration of MMP levels in the hematoma fluid. It has been further suggested that there might be therapeutic benefit in using MMP inhibitors or TIMP supplementation in patients with recurrent cSDH (29).

Platelet-derived growth factor (PDGF)

During angiogenesis, when the newly formed blood vessels mature, cells that make up the vessel wall are recruited, including pericytes and smooth muscle cells (23). Although many factors are associated with pericyte recruitment, PDGF is perhaps the most important one. PDGF signalling induces the activation of pericytes, which can support angiogenesis, alter microvascular stability, and increase vessel permeability. The activation of pericytes is potentially implicated in growth, leakage and membrane formation of cSDH. PDGF is a potent mitogen for mesenchymal cells including fibroblasts, smooth muscle cells, and pericytes and may thus contribute to membrane formation in cSDH. Thus, disruption of PDGF-induced pericyte activation has been suggested as a potential novel treatment strategy for the treatment of cSDH (30).

Interleukins

Interleukins are cytokines that modulate the inflammatory response by regulating cell growth, differentiation and motility. Interleukin-1α (IL-1α) and interleukin-1β (IL-1β) cause inflammatory signalling through interaction with a common receptor, interleukin-1 receptor (IL-1R1). While IL-1α is mostly released in the central nervous system (CNS) in astrocytes during cell death, IL-1β is released by immune cells like monocytes, macrophages, dendritic cells, and microglia. Both these interleukins augment the activity of certain types of B- and T-cells and activate neutrophils, monocytes, and macrophages (31). The antagonist of the IL-1R1, IL-1 receptor antagonist (IL-1ra), binds to IL-1R1 and thereby indirectly inhibits both IL-1α and IL-1β, leading to reduced inflammation. Elevated levels of IL-1ra have been shown to correlate with improved neurological outcome in human traumatic brain injury (32). In the setting of cSDH, increased IL-1ra could be an attempt of the body to “heal itself” by inhibiting the IL-1. Indeed, it has been hypothesized that IL-1-blocking agents may be potentially effective for the prophylaxis of cSDH recurrence as an adjunct therapy (33). Interleukin-6 (IL-6) and interleukin-8 (IL-8) are additional interleukins that participate in inflammation. IL-6 is released by various cells, including fibroblasts, monocytes, and endothelial cells when tissues are injured or bleeding occurs. It plays an important role in the human body’s response to injury by helping immune cells develop, producing platelets, and attracting white blood cells to the site of inflammation, exerts protective effects on the brain in traumatic brain injury but, in certain circumstances, it can also contribute to autoimmune diseases and cancer (34). In the setting of cSDH, IL-6 has been shown to activate a specific signalling pathway [Janus kinase signal transducer and activator of transcription (JAK-STAT)], which promotes cell growth in cSDH membranes, suggesting that it may contribute to hematoma expansion (35). IL-8 is another member of the interleukin family that helps attract immune cells (especially neutrophils) to sites of injury, and promotes neo-angiogenesis by stimulating growth of endothelial cells and fibroblasts (36). Both IL-6 and IL-8 are found in high amounts in cSDH fluid, and their levels are linked to a higher risk of cSDH recurrence (37).

Implications for treatment

The management of cSDH has evolved over time. While in the past, treatments were mostly “mechanical”, aimed at reducing mass effect and evacuating the hematoma cavity, recently, treatment strategies targeting inflammation, neo-angiogenesis and molecular pathways have increasingly gained interest and attention (Table 1). Common surgical methods are as follows:

• Twist drill craniotomy: a small hole (<5 mm) is drilled in the skull and drain is placed for hematoma evacuation. This procedure relieves the mass effect and intracranial pressure but does not effectively the process of neo angiogenesis; hence, there is high risk of recurrence. This procedure can be done in high surgical risk patients and in patients with homogeneous, hypodense hematomas without significant septations (38).
• Burr hole drainage: a single or double burr holes are drilled, followed by irrigation and subdural drain insertion. This allows partial evacuation of hematoma and irrigation of inflammatory fluid, but neomembranes cannot be effectively resected.
• Subdural drains: these are helpful in preventing re-accumulation and ensuring constant removal of inflammatory mediators. This is the most commonly used method with moderate-to-large hematomas and mixed density collections and is widely accepted as first-line treatment for uncomplicated cSDH (39).
• Endoscopic evacuation: the hematoma is directly visualised using an endoscope via burr hole or mini-craniotomy. The hematoma contents and septations are evacuated and in some cases, neomembranes are resected or coagulated. This approach provides for specific removal or disruption of the inflammatory membranes and is most likely to decrease recurrence by addressing cause of micro-bleeding and inflammation. This may be particularly useful in septated or recurrent cSDHs and cSDHs which are refractory to conventional drainage (40).

Statins have been explored as anti-inflammatory agents, and in some regions, including China (41), have become standard of care for the treatment of cSDH. However, their efficacy is still debated, and several of the landmark studies reporting benefit of statins in cSDH treatment were later retracted (13,42). Statins suppress inflammation and stabilize angiogenesis by reducing pro-inflammatory cytokines [IL-6, tumor necrosis factor alpha (TNF-α)] and suppressing VEGF, and they inhibit formation of weak neovessels. Qiu et al. [2017] demonstrated atorvastatin (20 mg/day) reduced hematoma size and need for surgery in cSDH patients (42). A 2024 meta-analysis of 7 trials (n=1,192) also confirmed that atorvastatin significantly reduces recurrence [risk ratio (RR) =0.46; P=0.009] (43). A retrospective cohort study showed 75% cSDH resolution with atorvastatin versus 42% in controls, through anti-inflammatory and vascular stabilizing effects (44).

Steroids have shown some effectiveness in reducing cSDH recurrence rates, but without benefits in mortality and treatment success, and in fact an increased rates of adverse events (45). Steroids decrease inflammatory mediators and vascular permeability by causing Inhibition of cytokines such as IL-1β, IL-6, TNF-α. Steroids also cause reduction of VEGF expression and hence, lower the neoangiogenic capillary leak. A multicenter randomized controlled trial (Dex-CSDH) showed dexamethasone significantly lowered recurrence (1.7% vs. 7.1%) but increased side effects and slightly worse functional outcomes (46). A systematic review and meta-analysis found steroids reduced recurrence by 61% versus control, but at the cost of increased adverse events (45).

Perhaps the most promising novel treatment is MMA embolization (MMAE). MMAE is a minimally invasive endovascular technique to permanently occlude the MMA, thereby largely “devascularizing” the dura, disrupting the pathological angiogenesis-inflammation cycle. This—so the theory—allows for hematoma resolution and reduces the risk of recurrence (47,48). However, MMAE also carries risks such as non-target embolization of branches supplying the structures of the eye with the potential for vision loss, cranial nerves, and anesthesia-related complications (7). Currently, it is also unknown whether there are long-term consequences of devascularizing the dura, and what those consequences are. Nevertheless, MMAE has been proven as an effective and safe treatment to reduce cSDH recurrence and progression (47-49), and is gaining traction as a first-line treatment for recurrent or refractory cases. Another promising strategy is the direct intra-arterial injection of anti-angiogenic agents like bevacizumab, which inhibits VEGF-mediated angiogenesis, which does not carry the risk of non-target embolization and preserves vessel patency for future treatments (50).

Conclusions

cSDH is no longer viewed as a simple consequence of venous rupture but rather as a dynamic process driven by inflammation, angiogenesis, and fibroproliferation. Advances in our understanding of these mechanisms have opened the door to innovative treatments that target the root causes of the condition. While MMA embolization will likely transform the future cSDH management, novel therapies, including anti-VEGF agents and possibly inflammation-modulating strategies, also hold promise for further improving outcomes.

Continued research to develop such new, targeted treatment strategies is needed, as cSDH is becoming increasingly prevalent in ageing populations.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jni.amegroups.com/article/view/10.21037/jni-25-23/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jni.amegroups.com/article/view/10.21037/jni-25-23/coif). J.O. serves as an unpaid editorial board member of Journal of Neurointervention from November 2024 to December 2026 and is a consultant for Penumbra. M.G. serves as an unpaid editorial board member of Journal of Neurointervention from November 2024 to December 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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