Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain
They are arbitrarily defined as those hematomas presenting 21 days or more after injury. These numbers are not absolute, and a more accurate classification of a subdural hematoma usually is based on imaging characteristics.
Later, in 1914, Trotter launched the theory of traumatic brain injury and the consecutive lesion of the “bridging veins”, as being the cause of what he called “hemorrhagic subdural cyst”.
Usually, this collection has a traumatic etiology.
Recognized risk factors for development of CSDH are head injury, old age and using anticoagulant, but its underlying pathophysiological processes are still unclear. It is assumed that a complex local process of interrelated mechanisms including inflammation, neomembrane formation, angiogenesis and fibrinolysis could be related to its development and propagation.
Chronic subdural hematomas mainly occur amongst elderly people and usually develop after minor head injuries.
In younger patients, subdural collections may be related to hypertension, coagulopathies, vascular abnormalities, and substance abuse.
A retrospective review of 239 patients undergoing surgery for CSDH over a period of six years (2006-2011). The majority of patients (63%) in the non-trauma group were receiving anticoagulants and/or antiplatelet agent therapy prior to CSDH presentation, compared to 42% in the trauma group. 2).
Unilateral chronic subdural hematoma.
Chronic subdural hematoma (CSDH) is considered to be an angiogenic disease.
In the acute stage, hemostasis is achieved through activation of coagulation cascades and 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 3).
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 4) 5). 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) 6).
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 7).
Chronic subdural hematoma (CSDH) is characterized by an “old” encapsulated collection of blood and blood breakdown products between the brain and its outermost covering (the dura).
It is delimited by an outer and inner membrane. In between are blood, plasma, cerebrospinal fluid, membranes, and a mixture of inflammatory angiogenic fibrinolytic and coagulation factors. These factors maintain a self-perpetuating cycle of bleeding, lysis, and growing of neo-membranes and neo-capillaries 8).
Its clinical symptomatology often debuting with memory and attention disorders, so that the patient is usually referred to psychiatrists or neurologists, only a paraclinical investigation (CT scan or MRI) being able to establish the diagnosis. Even the appearance of the lateral signs is subjected to many diagnosis confusions because patients deny the existence of a trauma in over 50% of the cases 9).
The association between the biomarkers of inflammation and angiogenesis, and the clinical and radiological characteristics of CSDH patients, need further investigation. The high number of biomarkers compared to the number of observations, the correlation between biomarkers, missing data and skewed distributions may limit the usefulness of classical statistical methods.
Pripp et al. explored lasso regression to assess the association between 30 biomarkers of inflammation and angiogenesis at the site of lesions, and selected clinical and radiological characteristics in a cohort of 93 patients. Lasso regression performs both variable selection and regularization to improve the predictive accuracy and interpretability of the statistical model. The results from the lasso regression showed analysis exhibited lack of robust statistical association between the biomarkers in hematoma fluid with age, gender, brain infarct, neurological deficiencies and volume of hematoma. However, there were associations between several of the biomarkers with postoperative recurrence requiring reoperation. The statistical analysis with lasso regression supported previous findings that the immunological characteristics of CSDH are local. The relationship between biomarkers, the radiological appearance of lesions and recurrence requiring reoperation have been inclusive using classical statistical methods on these data, but lasso regression revealed an association with inflammatory and angiogenic biomarkers in hematoma fluid. They suggest that lasso regression should be a recommended statistical method in research on biological processes in CSDH patients 10).
Subdural effusion in the setting of dural metastasis is very rare and may be difficult to be distinguished from chronic subdural hematoma. Such lesions could be missed and could be the cause of recurrence in CSDH. A contrast-enhanced brain CT scan is recommended to diagnose dural metastases.
Rosai–Dorfman disease may be mistaken for a CSDH on imaging. This disease is an uncommon, benign systemic histioproliferative disease characterized by massive lymphadenopathy, particularly in the head and neck region, and is often associated with extranodal involvement. CSDH can also develop in multifocal fibrosclerosis (MFS) which is a rare disorder of unknown etiology, characterized by chronic inflammation with dense fibrosis and lymphoplasmacytic infiltration into the connective tissue of various organs. The mechanism of the formation of CSDH is presumed to involve reactive granular membrane together with subdural collection. On the other hand, the extramedullary erythropoiesis within CSDH can be confused with metastatic malignant tumors, such as lymphoma, carcinoma, and malignant melanoma 11).
A 44-year old woman with gastric adenocarcinoma was presented with headache and a hypodense subdural collection in right fronto-parietal in brain CT. Burr-hole irrigation was performed with the impression of chronic subdural hematoma, but nonhemorrhagic xantochromic fluid was evacuated without malignant cell. Brain CT on the 11th day depicted fluid re-accumulation and noticeable midline shift, necessitating craniotomy and removing the affected dura.
Because the affected dura can be supposed as the main source of subdural effusion, resection of the involved dura is obligatory for the appropriate palliative management of such patients 12).
Routine post-operative CT brain for burr hole drainage of CSDH may be unnecessary in view of the good predictive value of pre-operative volume, and also because it is not predictive of the clinical outcome 13).
Scheduled postoperative cranial imaging with indwelling drains was not shown to be beneficial and misses information of intracranial damage inflicted by removal of drains. Brokinkel et al recommend CT-scanning after drainage removal 14).
A study aimed to quantify the heterogeneity of data elements in the pre-operative, operative, and post-operative phases of care, and build the basis for the development of a set of common data elements (CDEs) for CSDH. This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was registered with the PROSPERO register of systematic reviews (CRD42014007266). All full-text English studies with more than 10 patients (prospective) or more than 100 patients (retrospective) published after 1990 examining clinical outcomes in CSDH were eligible for inclusion. One hundred two eligible studies were found. Only 40 studies (39.2%) reported the main presenting symptom/feature and 24 (23.5%) reported additional symptoms/features. Admitting neurological/functional status was classified by the Glasgow Coma Scale (25 studies; 24.5%), the Markwalder Score (26 studies; 25.5%) and the modified Rankin Scale (three studies; 2.9%). Fifty-four studies (52.9%) made some mention of patient comorbidities and 58 studies (56.9%) reported the proportion or excluded patients on anticoagulant medication. Eighteen studies (17.6%) reported baseline coagulation status. Sixty-four studies (62.7%) stratified or assessed severity based on radiological findings, although the methods used varied widely. There was variable reporting of surgical technique and post-operative care; 32 studies (31.4%) made no mention of whether the operations were performed under general or local anesthetic. This study, a part of the Core Outcomes and Common Data Elements in CSDH (CODE-CSDH) project, confirms and quantifies the heterogeneity of data elements collected and reported in CSDH studies to date. It establishes the basis for the consensus-based development of a set of common data elements, facilitating robust cross-study comparisons and resulting improvements in patient outcomes 15).
Attempts to create CSDH have been made in mice, rats, cats, dogs and monkeys. Methods include injection or surgical implantation of clotted blood or various other blood products and mixtures into the potential subdural space or the subcutaneous space. No intracranial model produced a progressively expanding CSDH. Transient hematoma expansion with liquification could be produced by subcutaneous injections in some models. Spontaneous subdural blood collections were found after creation of hydrocephalus in mice by systemic injection of the neurotoxin, 6-aminonicotinamide. The histology of the hematoma membranes in several models resembles the appearance in humans. None of the models has been replicated since its first description.
D'Abbondanza et al. did not find a report of a reproducible, well-described animal model of human CSDH 16).