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

IntroductionThe pathophysiology of chronic subdural hematoma (CSDH) remains to be fully understood. Basic knowledge of the composition and features of cells in the CSDH fluid may contribute to the understanding of the seemingly complex processes involved in CSDH formation and recurrence.This study is the first to examine the composition of cells and of cellular features in both systemic blood and subdural fluid from CSDH patients. We hypothesized that the cellular composition and features in the hematoma fluid may be; 1) different from that in the systemic blood; 2) different between patients with and without recurrence; 3) and different between the first and second operation in patients with recurrent CSDH.MethodsSystemic blood and subdural hematoma fluid were collected from CSDH patients with and without recurrent CSDH at the time of primary and secondary surgery. Analyses of cells and cellular features included total number of white blood cells, erythroblasts, reticulocytes, platelets, neutrophilocytes, lymphocytes, monocytes, eosinophils, basophils, reticulocytes, immature granulocytes, mean corpuscular cell volume (MCV), mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hemoglobin and hematocrit.ResultsOf the 85 included patients, 20 patients were operated for a recurrent CSDH within 90 days follow-up. All cells found in the systemic blood were present in the CSDH fluid, but the composition was different (p < 0.0001). MCV was higher in the hematoma fluid from the primary operation of patients later developing a recurrent CSDH compared to patients not developing recurrence (p = 0.009). Also, the percentage distribution of inflammatory cells in hematoma fluid from patients with recurrent CSDH was different between the first and second operation (p = 0.0017).ConclusionThis study is the first to investigate the cellular composition of CSDH fluid. Compared to systemic blood and to a reference distribution, an increased number of immune cells were present in the hematoma fluid, supporting an inflammatory component of the CSDH pathophysiology. MCV was higher in the subdural fluid at time of the first operation of CSDH patients later developing recurrence.Clinical trial registrationThe study was approved by the Scientific Ethical Committee of the Capital Region of Denmark (Journal no. H-20051073.

We appreciate the interest in our article detailing the diagnosis of external hydrocephalus (Gomes et al. 2019). Dr. Hasegawa raises an important point: that definitive differentiation between subdural haemorrhage and external hydrocephalus currently requires histopathological confirmation. Veterinary nomenclature is currently ill-defined, since external hydrocephalus and subdural haemorrhage are both rare in dogs (De Lahunta et al. 2015). The subdural space is a “potential” space which does not occur in the normal living animal, only developing between the dura mater and the arachnoid under certain circumstances (Haines et al. 1993, De Lahunta et al. 2015). Dr Hasegawa quotes three publications describing subdural fluid accumulation, two case reports and a small case series. In the first case, (Kitagawa et al. 2008) MRI of the brain revealed a compressive mass and marked enlargement of the ventricles. The mass had heterogeneous signal, T1W hypointense and T2W hyperintense centre and a T1W isointense and T2W hypointense periphery, with partial contrast enhancement. This mass was interpreted to be a chronic subdural haematoma with suspected re-haemorrhage, confirmed during craniotomy. These imaging characteristics are clearly distinct from those in our case, describing a clear-fluid filled cavity and no imaging characteristics of haemorrhage. The second case (Asakawa et al. 2010) described a brain MRI with ventricular asymmetry, a large bilateral subdural accumulation of fluid, slightly T1W hyperintense compared with ventricular cerebrospinal fluid (CSF), not supressing on fluid attenuated inversion recovery (FLAIR). A gravity-dependent fluid line was present as well as a T2*W susceptibility artefact. Post-mortem histopathology confirmed the presence of serosanguinous fluid containing clotted blood in the subdural space, with investigations confirming a neuronal ceroid lipofuscinosis. In our case, there was a more extensive generalised dilation of the subarachnoid space, with the ventricular system size being largely preserved. The fluid signal characteristics in our case indicated a slightly more proteinaceous fluid than CSF, clearly supressed on FLAIR, with no susceptibility artefact on T2*W sequences. Considering the fluid characteristics on MRI, we feel confident that no haemorrhage was evident, although we agree that fluid analysis would have been necessary to definitively confirm this. The case series (Lehner et al. 2020) described dogs that underwent ventriculo- and cystoperitoneal shunting, alongside follow-up MRI. Relevant cases for comparison were: case 2 where follow-up MRI revealed the presence of “subdural fluid” compressing the cerebral parenchyma and case 6 where follow-up MRI revealed a unilateral lesion and bilateral extra-axial fluid accumulation interpreted to be a subdural haematoma and bilateral hygroma (causing brain compression), despite being later described as being a massive subarachnoid fluid accumulation. These cases underwent invasive procedures that could indeed have created a subdural space precluding comparison with our case. MRI signal characteristics of the fluid were not described in detail. Published images in these cases reveal a severe degree of brain compression, resembling reports previously described and published under the term external hydrocephalus (Dewey 2002, Dewey et al. 2003). External hydrocephalus had been described previously in veterinary medicine in two dogs, two cats and a foal (Dewey 2002, Dewey et al. 2003, Oey et al. 2011). Based on the questions raised by Dr. Hasegawa, the diagnosis of an external hydrocephalus would also be debatable in those cases where a post-mortem analysis was not performed. In the absence of histopathological confirmation, this becomes a terminology/nomenclature discussion. We are reminded of a similar exchange between researchers describing the controversy around subdural myelography years ago (Lamb 1997, Scrivani et al. 1997). On imaging findings alone, it is currently challenging to differentiate between extra-axial fluid in a subdural or subarachnoid location. We consider that a subdural space fluid accumulation would most likely be secondary to a pathological process (inflammation, neoplasia, trauma) particularly in the presence of haemorrhage or haematoma, or following surgical intervention. In the absence of predisposing factors leading to the formation of a subdural space, as in our case, we believe it is more reasonable to interpret a bilateral extra-axial generalised fluid accumulation as an external hydrocephalus. Appendix S1. Supporting information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

AT THE PRESENT time two radioactive compounds are in widespread use for the detection of intracranial lesions by brain scanning: radioiodinated serum albumin (RISA) and chlormerodrin Hg203 or Hg197. Three groups of workers, commenting on the concentration of RISA in chronic subdural fluid hematoma, are in agreement that it is highest in the membrane and is considerably less in the contents of the subdural fluid than in peripheral venous blood (2-4). Recently we have had occasion to measure the radioactivity of subdural fluid in a patient shortly after a chlormerodrin HgIUi scan. In contrast with the experience of other workers with RISA, the concentration of radioactivity in the subdural fluid was markedly higher than in the peripheral venous fluid. The purpose of this paper is to document this observation, which to our knowledge has not been reported previously. Case Report Because of increasing lethargy and occipital frontal headaches of two months duration, E. R. S., a 47-year-old white male, was first seen by a physician sometime in March 1!)(j4. No historv of head trauma could be elicited. A neurological examination resulted in normal findings except for a slightly more active ankle jerk on the left. Attempted lumbar puncture and pneumoencephalography were unsuccessful. The patient showed improvement in the hospital and was discharged with instructions to return in one week for a repeat lumbar puncture and pneumoencephalography. but failed to do so. Nine weeks later he returned because of increased severity of headaches, growing somnolence and anorexia, and frequent vomiting. He was then referred to the University of Florida Teaching Hospital. Physical examination at this time revealed questionable papilledema, motor weakness in both arms and legs, particularly the left, and instability of gait. A blocking dose of 1 cc of Mercuhydrin was given intramuscularly on the evening of May 24, 1964, and the next morning 700 microcuries of Hg197-labcled Neohydrin (Squibb) was injected intravenously. Right retrograde hrachial and left vertebral arteriography were then performed but were not diagnostic because of the poor filling of the anterior circulation. A brain scan about six hours after the injection showed an area of increased uptake peripherally on the left, suggesting subdural hematoma (Fig. 1). Left carotid arteriography on the morning of May 26 disclosed typical changes of a subdural hematoma (Fig. 2) with displacement of vessels from the calvaria corresponding to the area of increased uptake seen on the scan. At craniotomy several hours later, 75 cc of the fluid from the subdural hematoma was saved (by now about thirty hours from the time of the original isotope injection). Some smail clots were in the specimen. Samples of the peripheral blood were also obtained at this time. The clots were separated from the liquid blood in the specimen and homogenized.

Objective: For traumatic brain injury (TBI), therapeutic hypothermia (TH) has not shown efficacy in multicenter randomized controlled trials (RCTs). From the latest RCT (NABISH II and BHYPO), we hypothesized that preoperatively early-induced TH may be beneficial specifically in acute subdural hematoma (ASDH) patients who need evacuation. The aim of this project was thus 1) to test the efficacy of TH in an experimental rat model and 2) to translate these results to a multicenter RCT. Methods and Results-Experimental Study: Under anesthesia ASDH was induced, and the rats were placed into: 1) normothermia (37C) and 2) early-induced TH (33C, 30 minutes prior to decompressive craniotomy and ASDH removal). Results: The number of degenerating cells, extracellular biomarkers (UCH-L1 and GFAP), and injury volume were significantly smaller in the early hypothermia group than for normothermia. Conclusion and Future Implication for Multicenter RCT: Our experimental results suggested that preoperatively early-induced TH could mediate the reduction of neural damage in ASDH. Therefore, we are initiating a multicenter RCT both in JAPAN and US. This trial will employ several novel features as below: 1) The trial will enroll only ASDH patients who need emergency surgery 2) The trial will determine whether preoperatively induced hypothermia alters biomarkers and improves outcome, using a new intravascular cooling device, Quattro , for extra-rapid cooling. The study is conducted with the generous support of the Vivian L. Smith Foundation for Neurologic Research and in kind support from ZOLL Circulation.

Anti-inflammatory treatment reduces the risk of recurrent chronic subdural hematoma (CSDH), but clinical implementation is improper due to side effects. Exact knowledge of subdural molecules involved in recurrent CSDH may lead to targeted medical treatment and possibly improve the prospect of a personalized approach by eliminating the broad use of anti-inflammatory drugs on the entire CSDH population.With this study, we aim to (1) describe the associations between cytokine levels at the primary surgery and the risk of subsequent recurrence and (2) describe the association between cytokines in patients with recurrent CSDH between the first and second operations.Systemic and subdural levels of pro- and anti-inflammatory cytokines were measured and compared between patients with the first-time CSDH and recurrent CSDH. Cytokine levels were analyzed using a multiplex antibody bead kit. In case of recurrent CSDH within 90days of follow-up, the samples were re-collected and analyzed.We included 101 adult CSDH patients of which 20 had a recurrence. The levels of cytokines in the CSDH fluid from patients who were operated on for the first-time CSDH were not associated with the risk of later developing a recurrence. We found interleukin-1 receptor antagonist (IL-1ra) to be elevated in subdural fluid in patients with recurrent CSDH at the time of their second operation (p = 0.0005).This study provides knowledge on cytokine composition in the subdural fluid in patients with CSDH with and without recurrence. IL-1ra is elevated in subdural fluid in patients with recurrent CSDH at the time of the second operation, identifying a possible medical target.

The involvement of coagulation and fibrinolysis in the development of chronic subdural haematoma (CSH) from subdural effusion was investigated. Subdural fluid and venous blood samples were obtained from 34 patients with CSH and 9 patients with subdural effusion, and analyzed using enzyme-linked immunosorbent assays for thrombin-antithrombin III complex (TAT), prothrombin fragment F1 + 2 (F1 + 2), tissue factor, tissue factor pathway inhibitor (TFPI) and D-dimer. CSH was classified into the layering type, believed to be active, and other types according to x-ray computed tomography. All markers in the blood of both patient groups were similar to the values of normal subjects. Levels of TAT and F1 + 2 were much higher in the subdural fluid than in the blood of patients with CSH (P < 0.001, P < 0.001) and with subdural effusion (P < 0.05, P < 0.05). The level of D-dimer in the subdural fluid was significantly higher than in the blood (P < 0.001) in patients with CSH, but not in patients with subdural effusion. All markers in the subdural fluid of layering type CSH, except TFPI, were significantly higher than in the other types (P < 0.05). Local hypercoagulative activity in the subdural space is present in subdural effusion and precedes hyperfibrinolytic activity in CSH. Thrombin generation as indicated by TAT and F1 + 2 might be involved in the development of CSH. Propagation of CSH may be modulated by the coagulation system including the extrinsic pathway and fibrinolysis.

A 9-month-old baby with subdural hematomas, retinal hemorrhages, and developmental delay.

CT scans of 26 cases of subdural hematomas were carefully reviewed with particular emphasis on their densities. All the five cases of verified infantile chronic subdural hematoma, and four out of 15 cases of adult chronic subdural hematomas showed accumulations of CSF-dense fluid over the hemispheres, as well as in the cerebral sulci and cisterns, which were clearly demarcated from the overlying, rather highdense, subdural hematomas. The accumulation over the hemisphere was thicker where the underlying brain was severely atrophied. One of these had been erroneously diagnosed as ‘brain atrophy’. This and one adult case later progressed to a lentiform chronic subdural hematoma without CSF accumulation. Among six acute infantile subdural hematoma cases, three clinically mild cases showed accumulation of fluid in the sulci, fissures, and over the hemispheres, which gave the appearance of ‘brain atrophy’. Among three cases of severe form acute subdural hematomas, one showed a localized accumulation of CSF-dense fluid underneath the clot and over the hemisphere with sulcal patterns. In two cases of adult subdural effusions, metrizamide CT cisternography was performed. In both cases the dye not only filled the widely open cisterns and sulci, but also showed the existence of the subarachnoid space over the hemispheres and even beneath the subdural fluid space. From these observations it seemed logical that the subdural effusion (hematoma) was usually accompanied by enlargement of the subarachnoid spaces. In the acute phase, either primary subarachnoid hemorrhage or secondary bleeding from permeation of the subdural blood would cause blockage of the arachnoid villi, and the subsequent evolution of communicating hydrocephalus. In the chronic phase, however, hydrocephalus ex vacuo should play an important role, since the CSF accumulation appeared to have increased under decreased intracranial pressure with brain atrophy and/or enlargement of the calvarium, i.e., craniocerebral disproportion. Previous reports such as benign subdural collection of fluid, should be interpreted as the combination of subdural fluid with enlargement of the subarachnoid spaces. Similarly, in case termed benign enlargement of the subarachnoid spaces, benign communicating hydrocephalus, etc., the coexistence of subdural fluid must be considered and sought.

S-100β in chronic subdural haematoma: Prospective cohort study

The involvement of inflammation in the development and propagation of chronic subdural haematoma (CSH) was investigated by measuring the levels of inflammatory cytokines (tumour necrosis factor [TNF] alpha, interleukin [IL]-1 beta, IL-6, and IL-8). Peripheral venous blood and subdural fluid were obtained at the time of burr hole surgery from 34 patients with CSH and from 9 with subdural effusion. The levels of the inflammatory cytokines were analysed by enzyme-linked immunosorbent assay. The blood levels of TNF alpha, IL-1 beta, IL-6, and IL-8 in both CSH and subdural effusion groups were almost within the range of normal subjects, and no differences were observed between the two groups. IL-6 and IL-8 in the subdural fluid were much higher than in the blood of both groups, and the levels in CSH patients were significantly higher (10 times) than in subdural effusion patients. Local elevation of inflammatory cytokines in the subdural space of both CSH and subdural effusion without systemic change suggests the presence of local inflammation in the two diseases. The same behavioural patterns of cytokines for these and higher levels of cytokines in the CSH also suggest that inflammatory cytokines may be involved in the continuous development from subdural effusion to CSH and propagation of CSH.

To the Editor: Chronic subdural hematomas (CSDHs) are encapsulated collections of blood breakdown products and fluid between the dura mater and the arachnoid.1 Their global incidence is estimated to be about 5/100 000/yr in patients younger than 65 yr,2 increasing to 58/100 000/yr in patients over 65 yr.1 Surgery usually allows a good outcome even in elderly. The clinical outcome of CSDH is conditioned by comorbidities including pulmonary diseases. Nowadays, we are facing a new possible condition related to coronavirus disease 2019 (COVID-19) that could affect the outcome. The spread of this infection started in 2019, December 31st when China alerted WHO about cases of unusual amount of interstitial pneumonia (IP) in Wuhan. After 7 d, on January 7th, scientists announced they had identified a new virus named COVID-19 similar to SARS-CoV. Italy is dealing with pandemic spread of COVID-19. As a matter of fact, on 19th March, it became the country with the highest number of confirmed deaths in the world. On March 23rd 2020 Italy was the world's centre of the epidemic with 69.176 confirmed cases, 6.820 deaths, and 21.137 recoveries.3 Clinically COVID-19 could lead to a severe IP and acute respiratory distress syndrome (ARDS), especially in older patients with multiple comorbidities.4 No studies about surgery in COVID-19 patients have been reported so far. We aim to describe our surgical experience with CSDH in a COVID-19 neurosurgical center. We admitted 5 patients with CSDH to the Neurosurgical Department of Brescia University Hospital between February 21, 2020 (first COVID-19 case reported in Italy) and March 23, 2020. The patients were positive for COVID-19 real-time polymerase chain reaction obtained by nasopharyngeal swab.5,6 We gathered the following data for each patient: age and sex, Cumulative Illness Rating Scale,7 antithrombotic therapy and perioperative mortality (within 30 d). All the patients had signed a consent form approved by the Local Ethic Committee regarding the use of their clinical data. We compared the mortality rate of this new cohort with the data extracted from our pre-COVID-19 CSDH case series. All the patients underwent pre-operative chest X-Ray (CXR) or computed tomography (CT) and routine blood test. An anesthesiological evaluation was performed for each patient. We cohortized our neurosurgical ward to separate COVID-19 positive from negative cases. COVID-19 positive patients started anti-retroviral therapy with lopinavir/ritonavir and hydroxychloroquine. Daily arterial blood gas analysis and CXR were performed. Surgery or endovascular treatment were indicated when the CSDH was symptomatic (presence of focal neurological deficits or mental status changes) and the maximum thickness was greater than 1 cm (Figures 1-4). One case did not present severe neurological impairment and was treated conservatively (Figure 5). No preoperative respiratory impairment was observed.FIGURE 1.: A and B, Head CT scan, axial view: pre- and postoperative CDSH. C, CXR showing bilateral and diffuse IP.FIGURE 2.: A, Head CT scan, axial view: bilateral CSDH. B, CXR showing bilateral and diffuse IP. C and D, MMA embolization procedure.FIGURE 3.: A, Head CT scan, axial view: preoperative CSDH. B, Head CT scan, axial view: postoperative CSDH with signs of recent rebleeding. C, CXR showing bilateral and IP. D, Chest CT scan, axial view, showing ground glass opacity.FIGURE 4.: A, Head CT scan, axial view: preoperative left CSDH. B, Head CT scan, axial view: postoperative CSDH with signs of recent rebleeding. C, CXR showing bilateral IP.FIGURE 5.: A, Head CT scan, axial view: left CSDH. B, normal CXR.We treated all the CSDH patients under general anesthesia. Three patients were operated (2 through craniotomy and 1 with a burr hole). Endovascular occlusion of the middle meningeal artery (MMA) was performed in 1 case (Figure 2). In the surgical cases we placed a subdural drainage for 48 h. After its removal patients underwent a CT head scan (Figures 1, 3, and 4). Afterwards the patients started low-molecular-weight heparin at prophylactic dose before mobilization. The cases are reported in the supplementary material section (Supplemental Digital Content). CSDHs mostly occur in elderly, with an average age of 63.1 Head trauma is the major risk factor, identified in less than 50% (often minor head trauma).8 Other risk factors are described like alcohol abuse, seizures, CSF shunts and coagulopathies, including therapeutic anticoagulation. CSDHs are bilateral in 20% to 25% of cases.9 At present there is no scientific experience regarding surgical outcome of COVID-19 patients. We compared the recent cohort of COVID-19 CSDH patients with our historical series. Between May 2018 and September 2019, we operated 142 patients for CSDH and we observe 5 death at our Institution. Our mortality rate was 3.7% according to the literature.10 In our recent experience, we observed 4 death in 5 COVID-19 patients suffering from CSDH. Therefore, we observed a mortality rate of 80% about 21,6 times greater than our control data. HEMATOLOGICAL DISORDERS We observed 2 cases of mild thrombocytopenia (Table). In these cases, we observed a re-bleeding (Figures 3 and 4) that led from a rapid neurological worsening to death within 5 d. This condition could be related to COVID-19 infection, as reported in literature.11 Independently from the hemorrhagic risk, Lippi et al12 showed that low platelet count is associated with increased risk of severe disease and mortality in patients with COVID-19, and this should serve as clinical indicator of worsening illness during hospitalization.12 In our series, we suppose that thrombocytopenia led to re-bleeding and was associated with poor outcome. TABLE. - Clinical Features of our Cohort Sex Age CIRS AT Side COVID-19 IP TP* Surgery Time to death(d) M 82 13 Yes Left + + No Burr-hole 14 M 86 18 No Bilateral + + No MMA embolization 10 M 77 20 No Right + + Yes Craniotomy 5 M 85 22 Yes Left + + Yes Burr-hole 5 M 78 19 Yes Left + – No NO Alive *TP (Thrombocytopenia): 100.000<PLTs<150.000All patients developed IP after surgery. Thrombocytopenia was observed in 2 cases (40%). The patients suffered rebleeding and showed a shorter time to death. CIRS (Cumulative Illness Rating Scale), AT (antithrombotic drugs), IP (Interstitial Pneumonia), COVID-19 (Coronavirus Disease 2019). INTERSTITIAL PNEUMONIA Dyspnoea and fatigue occurred in all our patients within 48 hours from surgery. CXR revealed severe IP (Figures 1-4). Ground glass opacity and bilateral patchy shadowing were observed on the chest CT (Figure 3).5,13 All our patients had COVID-19 infection without pre-operative respiratory symptoms. Immune system could be impaired following surgical procedures and this may have unmasked a subclinical infection.14,15 On the other hand no respiratory failure was observed in the conservative-treated case (Figure 5). In our experience IP occurred in all cases after treatment and worsened the outcome. This evenience represents a possible complication, often fatal, of COVID-19 infection.5 HEALTH EMERGENCY Nowadays, Italian health care system is the most afflicted in the pandemic scenario.16 The overload of the intensive care units in Lombardy, despite the efforts made, has necessarily influenced the resuscitation possibilities of elderly patients.17 Therefore, we cannot exclude that our results could be affected by the health emergency status. Seung et al. reported good bleeding control from CSDH membrane with MMA embolization, prevention of further growth of hematoma and even spontaneous resolution without surgery.18 Anyway our endovascular treated patient showed the same poor outcome of the surgical cases. Although statistical analysis of these preliminary data is not possible, COVID-19 patients appear to suffer from a negative surgical outcome. It is our belief that conservative treatment should be preferred whenever surgery could be postponed. Disclosures The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

C-reactive protein (CRP) level in blood is a standard marker for systemic inflammation. Inflammation is central in chronic subdural hematoma (CSDH) pathophysiology, and inflammatory biomarkers may hold clinical potential in assessing the level of inflammation induced by a CSDH. This study explores the role of CRP in patients with CSDH by (1) measuring systemic and subdural CRP levels, (2) investigating CRP as a potential predictor for recurrent CSDH and (3) comparing CRP levels between the first and second operations in patients with CSDH recurrence. CRP levels were measured both in systemic blood and subdural fluid from adult CSDH patients. Recurrence rate and mortality within 90 days were recorded. In total, 111 patients were included, of whom 25 were operated on for CSDH recurrence. Systemic CRP levels (2.54 mg/L (1.40-9.75)) were higher than subdural levels (2.09 mg/L [0.99-5.22]) (p < 0.0001) but within the clinically defined normal CRP range of < 3 mg/L. Neither systemic nor subdural CRP levels could predict recurrence. Both systemic and subdural CRP levels in recurrent CSDH patients were higher at the time of the second surgery compared to the first surgery (p systemic = 0.004 and p subdural <0.0001). This is the first study to establish a correlation between systemic and subdural CRP levels in CSDH patients. The increased levels of CRP at the time of the second surgery may demonstrate a constantly evolving inflammatory process toward the development of a recurrence.

Chronic subdural hematoma (CSDH) development involves inflammatory, angiogenetic, and fibrinolytic mechanisms, several components of which are now unraveled through intensive research. The urokinase plasminogen activator receptor (uPAR) is part of the plasminogen activator system and possesses inflammatory, angiogenetic, and fibrinolytic capabilities. As a first, this study aims to identify uPAR in the hematoma fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH and, if present, to investigate if the uPAR level at the time of surgery may be a predictor for later developing recurrent CSDH. uPAR expression in the hematoma membrane and dura mater was analyzed using immunohistochemistry and presented as the H-score of the positive immunostaining. The uPAR levels in the hematoma fluid and systemic blood were determined using a multiplex antibody bead kit (Luminex). Samples were collected at the time of the first CSDH surgery, and in the case of recurrent CSDH within 90 days, the samples were again collected at reoperation. A comparison of uPAR expression between the hematoma membrane and dura mater, as well as uPAR levels in systemic blood and hematoma fluid, was performed using the Wilcoxon rank sum test. We included 112 patients, 26 of whom had recurrent CSDH. The median hematoma uPAR level was 22,125 (14,845–33,237) and significantly higher than the median systemic blood level of 789 pg/L (465–2,088) (p < 0.001). Similarly, the uPAR level of the hematoma membrane was 14.3 (7.54–44.8) and significantly higher than the dural uPAR level of 0.81 (0.3–1.98) (p < 0.001). For the first time, we identified uPAR in the subdural fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH. The high expression of uPAR in the subdural fluid and hematoma membrane indicates that the mechanisms of CSDH are predominantly in the subdural fluid collection and surrounding hematoma membrane.

AbstarctBackground: Post-operative volume of subdural fluid is considered to correlate with recurrence in chronic subdural haematoma (CSDH). Information on the applications of computer-assisted volumetric analysis in patients with CSDHs is lacking.Objective: To investigate the relationship between haematoma recurrence and longitudinal changes in subdural fluid volume using CT volumetric analysis.Methods: Fifty-four patients harbouring 64 CSDHs were studied prospectively. The association between recurrence rate and CT findings were investigated.Results: Eleven patients (20.4%) experienced post-operative recurrence. Higher pre-operative (over 120 ml) and/or pre-discharge subdural fluid volumes (over 22 ml) were significantly associated with recurrence; the probability of non-recurrence for values below these thresholds were 92.7% and 95.2%, respectively. CSDHs with larger pre-operative (over 15.1 mm) and/or residual (over 11.7 mm) widths also had significantly increased recurrence rates. Bilateral CSDHs were not found to be more likely to recur in this series. On receiver-operating characteristic curve, the areas under curve for the magnitude of changes in subdural fluid volume were greater than a single time-point measure of either width or volume of the subdural fluid cavity.Conclusions: Close imaging follow-up is important for CSDH patients for recurrence prediction. Using quantitative CT volumetric analysis, strong evidence was provided that changes in the residual fluid volume during the ‘self-resolution’ period can be used as significantly radiological predictors of recurrence.

BackgroundEmerging data suggest a complex pathophysiology of chronic subdural hematoma (CSDH) to which an inflammatory response might contribute. The complement system is activated in acute traumatic setting, although its role in CSDH is unknown. To investigate the complement system in CSDH pathophysiology, we analyzed blood and hematoma fluid biomarkers, as well as immunohistochemistry of the CSDH membrane and dura.Materials and MethodsWe simultaneously collected CSDH fluid and peripheral blood from 20 CSDH patients at the time of surgery. Biopsies of the dura mater and the CSDH capsule were obtained and analyzed by immunohistochemistry for C5b-C9 or C5a deposition. Biomarkers of inflammation and complement activation were analyzed by a 21-multiplex assay, including Adiponectin, Clusterin, Complement factor C9 and CRP. Complement factor C5a was analyzed separately by a commercial R-plex electrochemiluminescence assay.ResultsTen biomarkers differed significantly between peripheral blood and paired CSDH of which two were significantly increased in CSDH fluid (Clusterin and Cystatin C). Eight of the significantly altered biomarkers were significantly decreased in CSDH fluid, including C5a, Complement 9 and Adiponectin. There was no immunoreactivity for C5a or the C5b-C9 membrane attack complex in the dura or CSDH membrane.ConclusionsIn CSDH levels of the complement inhibitor Clusterin were increased, whereas levels of C5a and C9 were decreased. Membrane attack complex C5b-C9 was not detected in the membrane or dura surrounding the CSDH. Inhibition of complement could lead to reduced clearance of debris in the CSDH as well as secondary inflammatory reactions.