Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy

Chronic subdural haematoma (CSDH) is an encapsulated collection of fluid, blood and blood degradation products layered between the arachnoid and dura mater coverings on the brain’s surface (Fig. 1). An early theory about the formation of CSDH was of a traumatic injury causing tearing of the bridging veins traversing from the brain to the draining dural-venous sinuses [1, 2]. This in turn would result in the accumulation of venous blood within the subdural space over time, but this theory has long been disputed and for good reason. Firstly, it is well recognised that it takes a mean of 4 to 7 weeks following trauma for a CSDH to become symptomatic [3, 4]. A slow venous haemorrhage from the outset would accumulate sufficiently quickly to cause a symptomatic collection within days. Modern-day easy-access imaging also allows the majority of patients to be scanned at the time of acute trauma. These scans can be entirely normal, with no sign of haemorrhage, but the patient can still go on to develop a CSDH weeks to months later. The pattern of blood seen in CSDH, spanning the cerebral convexities, is also inconsistent with a source of bleeding from a bridging vein, which neighbours the medial venous sinuses [5]. Finally, although CSDH can contain areas of acute haemorrhage, many are almost entirely “old” haematoma, seen as homogenous hypodensity on CT (Fig. 1). Despite this, the collections continue to enlarge over time, suggesting that acute haemorrhage is not the only source of growth.

It has been hypothesised that inflammation is a key factor in the development of a CSDH. This is not a new concept and indeed one of the earliest reports by Virchow in 1857, referred to the condition as “pachymeningitis haemorrhagica interna” [6]. This was based on the assumption that bacterial infection (meningitis) was driving a chronic inflammatory response in the dura, resulting in fibrin exudation and growth of new capillaries. However, it has long become accepted that inflammation can occur in response to any injury, including trauma or cellular injury, and not just infection. The primary purpose of inflammation is for the body’s immune system to activate repair, but despite this intention to heal, persistent or chronic activation of inflammation can occur and lead to pathology. This is exemplified by conditions such as rheumatoid arthritis and asthma, where inflammatory cells contribute to joint destruction or airway oedema and remodelling, respectively [7, 8].

The large number of reports linking CSDH to trauma clouded this early insight regarding inflammation and led to the popular view that CSDH was an entirely traumatic condition [9]. However, some authors did recognise that inflammation and trauma may be co-existing factors in CSDH development and that the trauma need only be very trivial [10].

In 1946, Inglis published an important summary of the key features required for CSDH formation [11]. Following histological analysis of several cases, he identified that the dura is lined with a layer of specialised, modified connective tissue cells. These cells have two essential roles: they can phagocytose, and they can develop into fibro-cellular connective tissue, allowing formation of new membranes as seen in CSDH. These cells have latterly been named “dural border cells” and are considered the location in which a CSDH initially develops [12]. Inglis reported that haemorrhage in the subdural space was sufficient to initiate the proliferation of these dural border cells [9]. Many animal studies have shown that the presence of blood alone, in the subdural space, is not sufficient to initiate progression to a CSDH, although these models are limited by the nature that animals do not have other contributing factors found in human patients, such as cerebral atrophy [5, 13, 14]. However, we do know this to be true in humans as well, as shown by a study on 38 acute subdural haematoma patients where only eight (21%) progressed to form CSDHs [15]. Therefore, it is clear there is more to this condition than trauma causing bleeding into the subdural space.

Whilst inflammation can aid tissue repair, it is the sustained inflammatory response in CSDH which results in new membrane growth and fluid accumulation over time. Damage to the dural border cells, rather than acute haemorrhage itself, may be what initiates this inflammatory response and may not occur in all patients. Inflammatory cells recruited to the subdural space will attempt to repair the border cell damage, but instead proliferate and result in the new membrane formation. Many of the inflammatory cells have pro-angiogenic roles which support the development of new blood vessels in this subdural region. These vessels are “leaky”, allowing micro-haemorrhages and fluid exudation into the new membrane-bound subdural space. This process is summarised in Fig. 2, the so-called CSDH cycle.

Following the pathological delamination of the dural border cells, two membranes are formed, enclosing the new subdural cavity which fills with the fluid and blood. High concentrations of type 1 (PICP) and type 3 (PIIINP) procollagen are present in this fluid and suggest a fibro-proliferative process is occurring, similar to that seen in wound healing [16, 17]. This process is likely to be initiated when the dural border cells are separated, and is an attempt at a reparative process. However, the collagen synthesis outweighs its breakdown, leading to the continuous formation of a collagen matrix and hence formation of the new membranes [17]. The SMAD signalling pathway is an important mediator of the persistent fibrosis which contributes to membrane development, and is activated by transforming growth factor (TGF-β1), expressed by eosinophils [18]. The internal and external membranes are subsequently formed, which relate to the layers contiguous with the arachnoid and dura mater, respectively.

The internal membranes are generally reported as containing collagen and fibroblasts only and therefore relatively non-functional with respect to driving CSDH growth [19]. One histological study using a scanning electron microscope (SEM) did identify occasional blood vessels in the internal membrane, but even these seem to disappear with maturation of the CSDH [20]. The external membrane, however, is considered more crucial in driving CSDH growth. It contains layers of fibroblasts and collagen fibres with the addition of inflammatory cells such as neutrophils, lymphocytes, macrophages and eosinophils [20‐25].

Importantly, CSDH membranes also contain numerous highly permeable capillaries with thin walls containing thin or absent basement membrane and lacking smooth muscle cells and pericytes [20, 26]. Gap junctions are also numerous, allowing continued migration of erythrocytes, leucocytes and plasma from these vessels into the subdural haematoma cavity [19, 26]. The external membrane also shows evolutionary changes over time with progressive inflammation followed by scarring, and persistence of areas capable of recurrent bleeding [20]. Importantly, the outer membranes are a well-recognised source of mediators that drive inflammation and angiogenesis such as tissue plasminogen activator (tPA), thrombomodulin, angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) [23, 27‐30].

The inflammatory process involved in CSDH membrane and fluid formation is localised to the subdural space, exemplified by the fact that the mediators (in Table 1 and Fig. 3) are consistently significantly higher in and around the CSDH compared with peripheral blood. Each of these mediators may have a unique and important role in CSDH formation and propagation. The following review will discuss recent findings in the literature relating to the cells and markers of inflammation, angiogenesis (formation of new blood vessels) and fibrinolysis (clot breakdown) and how understanding of these processes can help us develop pharmacological therapies for the future. There are several other markers and cell types not directly related to inflammation and angiogenesis and not discussed at length in the present review, but which may still have potentially important roles. These include aquaporin-1, a water channel, heavily expressed in the outer membranes which may contribute to fluid accumulation in CSDH growth [31]; high levels of linoleic acid residue, which have been found in association with recurrent CSDH [32] and a wide range of proteins, similar to those found in serum, suggesting exudation from the outer membrane vessels [33, 34]. CSF is also highlighted as a potential driver of CSDH formation, accumulating due to arachnoid tearing at the time of trauma and potentially continuing to leak into the subdural space. Ninety-three per cent of CSDH collections were reported as positive for CSF, as measured by βTP (beta trace protein), with highest levels seen in patients with recurrent CSDH [35].

It is evident that bleeding is an essential part of CSDH formation and this involves two key biomolecular processes: coagulation and fibrinolysis. Activation of the coagulation cascade involves converting prothrombin to thrombin, the latter of which can then cleave fibrinogen into fibrin, allowing clot formation [37]. Fibrinolysis is the converse process, whereby fibrin is broken down into fibrin/fibrinogen degradation products (FDPs) and clot breakdown-facilitated. Plasmin is the primary mechanism by which fibrinolysis occurs, and it is formed from plasminogen by tissue plasminogen activator (tPA) [37].

The high levels of FDPs which have been found in CSDH fluid are thought to represent excessive fibrinolysis (clot breakdown) and hence continued haemorrhage [33, 38, 39]. One study clearly identified fresh red cells within CSDH fluid, suggesting new haemorrhage occurs [38]. Patients were transfused with labelled red blood cells 24 h before surgical drainage of the CSDH, which estimated daily haemorrhage rates to be 10% on average. The highest levels of new haemorrhage were seen in those patients who showed recent clinical deterioration, suggesting this new bleeding is likely to contribute to CSDH expansion. Very high levels of FDPs were also identified and correlated with the amount of recent haemorrhage; this may suggest fibrinolysis encourages rebleeding. The levels of fibrin and FDPs are also higher in certain CSDH subtypes: mixed density and layered [39]. This may signify different bleeding frequency in CSDH over time, causing haematoma growth to vary and different patterns to form.

Higher levels of plasminogen at initial operation have been identified in patients subsequently experiencing CSDH recurrence [40]. This suggests that markers of hyperfibrinolysis may be able to predict those at highest risk of recurrence and therefore help guide treatment/follow-up. Similar findings have been seen, with high levels of tPA at initial surgery indicating a high risk of recurrence [41]. The tPA has been shown to be produced by blood vessel walls in the CSDH external membrane, and soluble tPA can diffuse from here into the CSDH cavity [27]. Thrombomodulin is another substance which can enhance fibrinolysis, and has been found in high levels in CSDH fluid [28]. Vessel endothelium in the CSDH external membrane was positive for the thrombomodulin antigen in 93% of patients, again suggesting this as the source. It was also suggested that thrombomodulin is continuously secreted in CSDH formation due to repeated vessel injury, possibly even from the brain pulsations through the CSDH collection.

Paradoxically, this hyperfibrinolytic mechanism can also be exploited during surgical evacuation of CSDH with tPA used as an adjuvant therapy [42]. The theory is that the tPA liquefies haematoma further, aiding washout of clots, reflected by substantially increased post-operative drainage volumes and significantly lower recurrence rates. However, this study only reviewed 15 patients treated with tPA, and therefore, this treatment is not well validated.

Many of the mediators related to CSDH formation have a primary role in helping the formation of new vessels (angiogenesis) and therefore provide a bleeding source from the CSDH membranes.

As previously discussed, inflammation in CSDH appears to be mediated by a range of inflammatory cells including neutrophils, lymphocytes, macrophages and eosinophils [20‐25]. These inflammatory cells both produce and are activated by cytokines: small, inducible proteins. Different families of cytokines are described, based on their structure and receptor type, and chemokines are a subfamily specifically involved in leucocyte recruitment. It is difficult to know the relevance of each individual cytokine as it is well recognised that they work in cascades, influence one another, can compete for receptors and act antagonistically or synergistically. A gross analysis of pro- and anti-inflammatory cytokines in CSDH shows they are both raised in CSDH fluid compared with serum, but that the balance is significantly more pro- than anti-inflammatory [61, 62]. It is important to consider the balance of both the pro- and anti-inflammatory molecules and how this changes over time. Inflammatory markers are not always detrimental, and certain markers which are perceived to be harmful may be required in reparative processes at later time points.

For patients who become symptomatic from CSDH, which can range from headaches to neurological deficits and finally coma, surgery is often considered the mainstay of treatment. In cases where patients are critically unwell, they require emergency evacuation of the haematoma to resolve the acute decompensation due to raised intracranial pressure. However, there is a large cohort of patients who are clinically stable with appearances of CSDH found on imaging who would be appropriate for a more conservative treatment pathway, such as a drug therapy to help resolve the haematoma. Further to this, in those patients who are treated surgically, approximately 11% will have a recurrence of the collection necessitating further surgery [84]. Therefore, there is a call for a drug therapy which could help prevent this from happening, thus avoiding multiple surgeries for CSDH. Scientists have sought to discover drugs which influence the pathophysiological factors already discussed, in the hope they can provide a conservative and potentially preventative treatment option for CSDH. These therapies will be further discussed here.

Overall, it is clear that there are multiple drivers promoting expansion of a CSDH. Following trauma, which is often minor and not always evident, there appears to be a complex process of interrelated mechanisms including inflammation, membrane formation, angiogenesis and fibrinolysis that propagate an increase in CSDH volume. Many different molecular cascades occur throughout CSDH progression, and it is unlikely that there is a single prime pathway. However, certain molecules such as IL-6 and -8 do appear to be valuable in helping predict recurrence. The highly vascular and highly permeable outer membrane is evidently a source of inflammatory mediators as well as regular bleeding. The subsequent array of molecules found within the CSDH fluid provide evidence for a role of localised hyperfibrinolysis and continuous inflammation contributing to the haematoma expansion. This understanding has helped to guide the development of therapies that have the potential to modulate CSDH growth, such as anti-inflammatory drugs (dexamethasone) and anti-fibrinolytic drugs (tranexamic acid). Further to this, if we can understand the molecular patterns in the CSDH haematoma, then we may be able to tailor certain treatments to specific high-risk patients in the future. For example, those with very high levels of IL-6 and -8 may be more responsive to certain anti-inflammatory treatments and/or need a longer course of treatment than those with lower levels. The wide range of markers and their apparent difference between patients mean that there is unlikely to be a one-size-fits-all treatment for CSDH. The ultimate aim should be that through good understanding of the underlying molecular biology, focused and specific treatment algorithms for CSDH can be developed.