Chronic subdural hematoma pathophysiology
- Initial venous bleeding → subdural collection
- Formation of outer and inner neomembranes
- Neoangiogenesis and fragile capillaries → recurrent microbleeds
- Progressive expansion due to osmotic factors and inflammation
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Chronic subdural hematoma (CSDH) is considered to be an angiogenic disease.
HO-1 is an independent risk factor in CSDH hematomas and is negatively correlated with CSDH thickness. HO-1 may play a role in the chronic subdural hematoma pathophysiology and development of CSDH, possibly by preventing neovascularization and reducing capillary fragility and hyperpermeability 1)
The development of subdural hematomas most likely occurs following minimal trauma in those patients with predisposing factors. Experimental data substantiates the fact that an accumulation of clotted blood in the subdural or subcutaneous space induced the formation of the fibroplastic neomembrane. The hypothesis that blood must come in contact with cerebrospinal fluid in order for the growth to occur, is still controversial. It has been virtually disproven that osmosis, referring to the electrolyte gradient as measured by freezing point depression, has any significance as a growth inducing factor. The protein oncotic gradient theory, having been the most widely accepted explanation as to the progressive enlargement of the subdural hematoma sac, has little experimental data supporting it. A larger body of clinical evidence exists supporting the concept that plasma and/or erythrocytes continuously penetrate into the subdural cavity, where enhanced fibrinolytic activity is present. However, this chronic rebleeding cannot fully explain the observed growth, because the composition of the hematoma fluid is smoewhat different from serum or plasma, and the protein content is also progressively diluted by fluid arising from an unknown source. There is some clinical and experimental evidence to suggest that a production-reabsorption balance may be a significant growth variable. No work has been done to define the role, if any, of local inflammatory mechanisms in the chronic subdural hematoma. Sound clinical evidence has shown that after the initial formation of the subdural clot, growth follows, than a slow, complete reabsorption usually occurs. Aside from the plausible production-reabsorption balance concept, it is not known why the evolution proceeds in this manner 2).
The cSDH tends to gradually increase in volume. Several hypotheses about the mechanism of the increase in the hematoma volume have been proposed for a long time. One hypothesis is the osmotic pressure theory after the formation of internal and external capsules. As the hematoma volume increases, the tension in the hematoma capsule is increased followed by micro-tear of its capillary vessels. Then hemorrhage occurs and it becomes a factor involved in increasing the osmotic pressure in the hematoma 3).
This osmotic theory recently been doubted due to the following factors : 1) there was no significant increase in the volume in this theory when hematoma membranes were used; 2) fresh erythrocytes were always introduced in the hematoma fluid on repeated tapping; 3) it was not possible to prove that the arachnoid acts as a membrane permeable to cerebrospinal fluid; and 4) it has been shown that albumin, the most osmotically active protein, cannot be found in destroyed red blood cells but is derived from the plasma 4).
To explain why some chronic subdural haematomas (CSDH) grow/resorb, a physically decreasing outer-membrane (OM) surface-area:CSDH.volume (SA:V) has been re-explored, and a 'critical' CSDH size inferred (OM.SA≈V). Gardner showed that, since CSDH-protein exceeded CSF-protein, CSF→CSDH osmosis occurred across a semi-permeable inner-membrane (n=1). By contrast, Zollinger & Gross demonstrated that serum→CSDH osmosis could also occur across the OM (n=1). Notably, Weir refuted Zollinger & Gross by finding equal CSDH and serum total-protein (n=20): however, Weir did not refute Gardner. Whilst all extant mechanisms, especially re-haemorrhages, explain CSDH growth, only OM.SA≥V simultaneously permits resorption. We aimed to re-evaluate the 'osmotic' hypothesis.
METHODS: Paired serum and CSDH samples were measured in a prospective cohort.
RESULTS: Results were consecutively obtained in n=116/116 (M:87, age:73±13yrs). Serum-osmolality and CSDH-osmolality were similar (285.70±7.99mmol/kg v 283.85±7.52mmol/kg, P=0.11) and significantly correlated (r=0.75, P<0.0001). Serum-total-protein significantly exceeded CSDH-total-protein (66.6±6.8g/L v 43.68±20.24g/L, P<0.0001) as did serum-albumin (35.62±4.46g/L v 30.85±8.5g/L, P<0.0001) and serum total-globulins (31.5±6g/L v 18.6±11.4g/L, P<0.0001). Serum and CSDH proteins were not correlated (total-protein: r=0.003; albumin: r=0.08; globulins: r=0.21).
CONCLUSIONS: Only crystalloids equilibrated. CSDH-colloids were significantly decreased. CSDH-dilution or colloidal-flocculation are implied. CSDH-dilution (by CSF→CSDH IM-osmosis or OM-transudation/exudation) could favour CSDH growth; as would repeated OM-haemorrhages. Contrariwise, isolated colloidal-flocculation could favour CSDH shrinkage by OM CSDH→serum osmosis. The latter may result in OM.SA≥V favorable for ultimate resolution. Our results refute Weir, Zollinger and Gross: but not Gardner. Osmotic gradients simultaneously exist for both CSDH growth and resorption. Each equilibrium could depend upon each gradient relative to each IM/OM semi-permeability 5).
In the acute stage, hemostasis is achieved through the activation of coagulation cascades and the formation of a blood clot. It is subsequently reorganized and reabsorbed following activation of the fibrinolytic cascade. For unknown reasons, however, this process often fails in the elderly, where an inflammatory reaction triggers the formation of a neovascularized membrane surrounding the clot 6).
It is postulated that activation of fibrinolysis within the hematoma might sustain a local coagulopathy which would promote low-volume bleeding from the outer membrane of the clot 7) 8). This prevents resolution of the subdural collection, which then becomes “chronic”.
Persistent activation of the angiopoietin and their receptor Tie 2 system in addition to high levels of VEGF may keep the vasculature in a destabilized condition and may account for the continuous formation of new and immature blood vessels resulting in massive plasma extravasation and repeated bleeding episodes. This provide new evidence in favor of pro-angiogenic mechanisms playing an important role in the pathophysiology of chronic subdural hematoma (CSH) 9).
see Vascular Endothelial Growth Factor in chronic subdural hematoma.
Studies have suggested that local anticoagulation and inflammatory changes may be important in its pathogenesis. Most studies have used a basic bivariate statistical analysis to assess complex immunological responses in patients with this disorder, hence a more sophisticated multivariate statistical approach might be warranted.
Thirteen assigned pro-inflammatory (TNF-α, IL-1β, IL-2, IL-2R, IL-6, IL-7, IL-12, IL-15, IL-17, CCL2, CXCL8, CXCL9 and CXCL10) and five assigned anti-inflammatory (IL-1RA, IL-4, IL-5, IL-10 and IL-13) cytokines from blood and hematoma fluid samples were examined. Exploratory factor analysis indicated two major underlying immunological processes expressed by the cytokines in both blood and hematoma fluid, but with a different pattern and particularly regarding the cytokines IL-13, IL-6, IL-4 and TNF-α. Scores from confirmatory factor analysis models exhibited a higher correlation between pro- and anti-inflammatory activities in blood (r = 0.98) than in hematoma fluid samples (r = 0.92). However, correlations of inflammatory processes between blood and hematoma fluid samples were lower and non-significant.
Three major mitogen activated protein kinase (MAPK) cascade transmitters in the outer membrane of CSDH was assessed. Eleven patients whose outer membrane and CSDH fluid were successfully obtained during trepanation surgery were included in a study. Expression of extracellular signal regulated kinase (ERK), phosphorylated (p)-ERK, p38, p-p38, c-Jun N-terminal kinase (JNK), p-JNK, and actin was examined by western blotting and immunostaining. Aoyama et al. examined whether CSDH fluid could activate MAPKs in cultured endothelial cells or fibroblasts in vitro. Western blot analysis showed that p-ERK was present in all samples, while p-p38 and p-JNK were detected, but not in all cases. Immunostaining showed that all three p-MAPKs were expressed in vascular endothelium. However, only p-ERK was expressed in fibroblasts. Expression of p-extracellular signal-regulated kinase kinase (MEK) and p-ERK in endothelial cells and fibroblasts was significantly induced immediately after treatment with CSDH fluid, while p-p38 and p-JNK expression was significantly induced in endothelial cells 60 min after treatment, but not in fibroblasts. Activation of MEK was significantly inhibited by treatment with antibodies directed against interleukin-6 and vascular endothelial growth factor in endothelial cells, but not in fibroblasts. Inflammatory cytokines and growth factors in CSDH fluids might activate major MAPKs in endothelial cells, which might be associated with neovascularization in the outer membrane of CSDH. These MAPK pathways could become novel targets for treatment of CSDHs 10).