Inflammatory human leucocyte antigen genotypes are not a risk factor in chronic subdural hematoma development.

BACKGROUND: Chronic subdural hematoma (CSDH) pathophysiology has undergone a paradigm shift from being regarded as solely traumatic to be driven mainly by inflammation. Human leucocyte antigen (HLA) is a gene complex involved in antigen processing and presentation to T lymphocytes, thereby mediating the adaptive immune responses. As specific HLA profiles are associated with inflammatory diseases, patients with a specific HLA profile may have a lower threshold for subdural inflammation, and therefore are predisposed for CSDH development. We hypothesized that (1) CSDH patients have a specific HLA profile compared to a Danish background population, and (2) patients with recurrent CSDH have a specific HLA profile compared to CSDH patients without recurrent CSDH. METHODS: Three specific HLA class II haplotypes known to drive inflammatory-mediated diseases were determined in 68 patients with CSDH. The distribution of these three haplotypes in our CSDH population was compared to a Danish population of blood donors using Monte Carlo Pearson's chi-square test. Furthermore, the distribution of the haplotypes was compared between CSDH patients with and without recurrent CSDH. RESULTS: We found no significant association between either of the haplotypes and the risk of CSDH, and neither of the haplotypes were associated with increased risk of CSDH recurrence. CONCLUSION: This study did not show an association between selected HLA class II haplotypes and the risk of CSDH or recurrence of CSDH compared with a healthy background population.

Expression of the TGF-ß-ALK-1 pathway in dura and the outer membrane of chronic subdural hematomas.

Neovascularization of the outer membrane plays a critical role in the development and enlargement of chronic subdural hematomas (CSHs) and vascular endothelial growth factor (VEGF) may promote their progression. However, the precise mechanisms remain to be determined. We focused on the signaling pathway upstream of VEGF, transforming growth factor ß (TGF-ß), and activin receptor-like kinase 1 (ALK-1) to identify the mechanisms underlying the neovascularization of the outer membrane of CSH. Retrospective comparative study was conducted on 15 consecutive patients diagnosed as CSH with burr-hole drainage. Dura and the outer membrane were collected. We immunohistochemically examined the expression of VEGF, integrin-α, TGF-ß, and ALK-1 on the outer membrane and dura of CSH and compared our findings with control samples and the signal intensity of hematomas on computed tomography (CT) scans. VEGF and integrin-α expression was markedly up-regulated in both the dura and outer membrane of CSH, the expression of TGF-ß and ALK-1 in the dura was slightly increased in the dura and markedly up-regulated in the outer membrane. There was no significant correlation between their expression and CT density. Here we first report the expression of TGF-ß and ALK-1 in the outer membrane and dura mater of CSH. We suggest that the TGF-ß-ALK-1 pathway and VEGF affect neovascularization and the progression of CSH.

Dexamethasone treatment in chronic subdural haematoma / Tratamiento con dexametasona del hematoma subdural crónico

Introduction: Neurosurgeons are familiar with chronic subdural haematoma (CSH), a well-known clinical entity, which is usually treated by some modality of trepanation. Despite the excellent outcomes obtained by surgery, complications may occur, some of which may be potentially severe or fatal. Furthermore, up to 25% recurrence rate is reported. The authors present a novel approach to the management of CSH based on the use of dexamethasone as the treatment of choice in the majority of cases. Patients and methods: Medical records of 122 CSH patients were retrospectively reviewed. At admission, symptomatic patients were classified according to the Markwalder Grading Score (MGS). Those scoring MGS 1-2 were assigned to the Dexamethasone protocol (4mg every 8h, re-evaluation after 48–72h, slow tapering), and those scoring MGS 3–4 were, in general, assigned to the Surgical protocol (single frontal twistdrill drainage to a closed system, without irrigation). Patients were followed in the Outpatient Office with neurological assessment and serial CT scans. Results: Between March 2001 and May 2006, 122 consecutive CSH patients (69% male, median aged of 78, range 25–97) were treated. Seventy-three percent of the patients exhibited some kind of neurological defect (MGS 2-3-4). Asymptomatic patients (MGS 0) were left untreated. Initial treatment assignment was: 101 dexamethasone, 15 subdural drain, 4 craneotomy and 2 untreated. Twenty-two patients on dexamethasone ultimately required surgical drain (21.8%). Favourable outcome (MGS 0-1-2) was obtained in 96% and 93.9% of those treated with dexamethasone and surgical drain, respectively. Median hospital stay was 6 days (range 1–41) for the dexamethasone group and the whole series, and 8 days (range 5–48) for the surgical group. Overall mortality rate was 0.8% and re-admissions related to the haematoma reached 14.7% (all maintained or improved their MGS). Medical complications occurred in 34 patients (27.8%), mainly mild hyperglycemic impairments. Median outpatient follow up was 25 weeks (range 8–90), and two patients were lost. Discussion: The rationale for the use of dexamethasone in CSH lies in its anti-angiogenic properties over the subdural clot membrane, as it is derived from experimental studies and the very few clinical observations published. Surgical evacuation of CSH is known to achieve excellent results but no well-designed trials compare medical versus surgical therapies. The experience obtained from this series lets us formulate some clinical considerations: dexamethasone is a feasible treatment that positively compares to surgical drain (and avoided two thirds of operations); the natural history of CSH allows a 48–72h dexamethasone trial without putting the patient at risk of irreversible deterioration; eliminates all morbidity related to surgery and recurrences; does not provoke significant morbidity itself; reduces hospital stay; does not preclude ulterior surgical procedures; it is well tolerated and understood by the patient and relatives and it probably reduces costs. The authors propose a protocol that does not intend to substitute surgery but to offer a safe and effective alternative. Conclusion: Data obtained from this large retrospective series suggests that dexamethasone is a feasible and safe option in the management of CSH. In the author's experience dexamethasone was able to cure or improve two thirds of the patients. This fact should be confirmed by others in the future. The true effectiveness of the therapy as compared to surgical treatment could be ideally tested in a prospective randomized trial (AU)

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Increased mRNA expression of VEGF within the hematoma and imbalance of angiopoietin-1 and -2 mRNA within the neomembranes of chronic subdural hematoma.

The aim of the study was to determine the source of vascular endothelial growth factor (VEGF) in hematoma fluid of patients suffering from chronic subdural hematoma (CSH) and to identify the level of gene expression of the pro-angiogenic factors angiopoietin 1 (ANG-1) and ANG-2 in hematoma membranes. Samples of venous blood, hematoma fluid, and outer membrane were obtained during surgery for CSH. The numbers of mononuclear cells were determined in hematoma fluid and in venous blood samples taken from 11 patients. The concentration of VEGF was measured by ELISA technique in hematoma fluid and in plasma. RT-PCR methodology was used to study the expression of different mRNA species in 11 patients. The mRNA species analyzed include VEGF and its receptors, VEGFR-1 and VEGFR-2, and ANG-1, ANG-2 and their receptor, Tie-2. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) served as housekeeping gene and was used for semiquantitative analysis. The VEGF concentration was several hundred fold higher in the hematoma fluid than in corresponding plasma samples. A significant correlation was found between the number of neutrophils and the VEGF content in the hematoma fluid. The expression levels of VEGF, mainly VEGF165 and VEGF121 mRNA were highest in cells obtained from the hematoma fluid. In membrane samples, mRNA encoding for VEGF and its receptors was only inconsistently detected while the mRNA species encoding for ANG-1, ANG-2, and Tie-2 were found throughout all samples. The mean ratio of ANG-1/ANG-2 mRNA expression was 0.48 as opposed to 1.9 in a normal human brain tissue sample. The results suggest that the hematoma cells are the primary source of VEGF. A marked increase in the expression of ANG-2 mRNA over ANG-1 mRNA demonstrates a pro-angiogenic pattern in the hematoma membranes. Persistent activation of the ANG/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. Thus, the present study provides new evidence in favor of pro-angiogenic mechanisms playing an important role in the pathophysiology of CSH.

Chronic subdural hematoma in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) has been associated with an increased incidence of aneurysmal subarachnoid hemorrhage and intracerebral hematomas. We describe five patients with chronic subdural hematomas, a previously unrecognized complication of ADPKD. In four of the five cases, no trigger was apparent. Clinical presentation was subtle, with mild hemiparesis, headache, or both in four patients and transient neurological deficits mimicking transient ischemic attacks in one patient. In three of the five patients, a retrocerebellar arachnoid cyst was found, suggesting a plausible causal relation between the intracranial arachnoid cysts and the subdural hematomas. In one patient, subdural hematoma was in close proximity to the frontally located arachnoid cyst.