Aquaporin 2 in Cerebral Edema: Potential Prognostic Marker in Craniocerebral Injuries.

Despite continuous medical advancements, traumatic brain injury (TBI) remains a leading cause of death and disability worldwide. Consequently, there is a pursuit for biomarkers that allow non-invasive monitoring of patients after cranial trauma, potentially improving clinical management and reducing complications and mortality. Aquaporins (AQPs), which are crucial for transmembrane water transport, may be significant in this context. This study included 48 patients, with 27 having acute (aSDH) and 21 having chronic subdural hematoma (cSDH). Blood plasma samples were collected from the participants at three intervals: the first sample before surgery, the second at 15 h, and the third at 30 h post-surgery. Plasma concentrations of AQP1, AQP2, AQP4, and AQP9 were determined using the sandwich ELISA technique. CT scans were performed on all patients pre- and post-surgery. Correlations between variables were examined using Spearman's nonparametric rank correlation coefficient. A strong correlation was found between aquaporin 2 levels and the volume of chronic subdural hematoma and midline shift. However, no significant link was found between aquaporin levels (AQP1, AQP2, AQP4, and AQP9) before and after surgery for acute subdural hematoma, nor for AQP1, AQP4, and AQP9 after surgery for chronic subdural hematoma. In the chronic SDH group, AQP2 plasma concentration negatively correlated with the midline shift measured before surgery (Spearman's ρ -0.54; p = 0.017) and positively with hematoma volume change between baseline and 30 h post-surgery (Spearman's ρ 0.627; p = 0.007). No statistically significant correlation was found between aquaporin plasma levels and hematoma volume for AQP1, AQP2, AQP4, and AQP9 in patients with acute SDH. There is a correlation between chronic subdural hematoma volume, measured radiologically, and serum AQP2 concentration, highlighting aquaporins' potential as clinical biomarkers.

An association of low high-density lipoprotein levels with recurrence of chronic subdural hematoma.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common illness in neurosurgical practice with a substantial recurrence rate. Previous studies found that serum lipids were associated with the risk of stroke and subarachnoid hemorrhage. In the current study, we aimed to identify the relationship between serum lipids and CSDH recurrence. METHODS: The medical records of 274 consecutive surgical patients with CSDH in our department were reviewed and analyzed. Patients were separated into recurrence and non-recurrence groups. Univariable and multivariable Cox proportional hazards regression analyses were performed to identify serum lipids (triglycerides, total cholesterol, LDL, HDL) and other potential predictors associated with CSDH recurrence, and the performance of predictors was assessed with receiver operating characteristic (ROC) curve. RESULTS: Of the 274 patients included in the study, 42 (15.3%) experienced at least 1 recurrence of CSDH. Univariate analysis showed that age, hypertension, diabetes mellitus, anticoagulant use, triglycerides, HDL, and midline shift were all significantly associated with CSDH recurrence. Multivariable Cox regression analysis found that only age, diabetes mellitus, midline shift, and HDL level were independent risk factors for CSDH recurrence. A higher HDL level (HR = 0.929, 95% CI 0.905-0.953) was significantly associated with a lower risk of recurrence, and ROC curve analysis revealed that the optimal HDL cut-off value as a predictor was 37.45 mg/dl. CONCLUSIONS: Low level of high-density lipoprotein is significantly associated with recurrence of chronic subdural hematoma.

Evaluation of Peripheral Blood Inflammatory Markers in Patients with Chronic Subdural Hematoma.

BACKGROUND AND AIM: Chronic subdural hematoma (CSH) refers to intracranial hemorrhages frequently caused by minor head trauma and is mostly seen in middle and advanced age. One of the hypotheses regarding the development of CSH is that the inflammatory cascade plays a pivotal role in this process. MATERIALS AND METHODS: The inclusion criteria covered patients in all ages who were diagnosed as CSH by computed tomography and/or magnetic resonance imaging and treated by surgical intervention in our clinic between 2018 and 2020. Patient files were reviewed retrospectively, and medical records of age, gender, trauma history, unilateral or bilateral lesion, and leukocyte, neutrophil, lymphocyte, monocytes, and platelet counts were obtained. Receiver operating characteristic (ROC) analysis was used for the most appropriate neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and age discrimination in the presence of CSH, and multiple logistic regression analyses were used to determine the effect of independent factors on dependent variables. RESULTS: A total of 68 cases, 57 (83.8%) male and 11 (16.2%) female, aged between 13 and 93, were included in the study. The mean age of the patients included in the study was 72.59 ± 13.13 years. NLR of the cases ranged from 1.37 to 34.18, with a mean of 6.53 ± 6.74 and a median of 3.57. NLR and PLR were found to be statistically significantly higher in CSH patients compared to the healthy control group, and the cut-off values for NLR, PLR, and age were 2.8, 132, and 55, respectively. Age and NLR were found to be independent factors associated with CSH (P < 0.05). CONCLUSION: As seen from the results of this study, peripheral blood values in CSH patients may be significantly higher than in the healthy control group, while they are below the normal laboratory cut-off values.

Local and systemic pro-inflammatory and anti-inflammatory cytokine patterns in patients with chronic subdural hematoma: a prospective study.

OBJECTIVE AND DESIGN: Innate immune pro- and anti-inflammatory responses in patients with chronic subdural hematoma (CSDH) were investigated by measuring and comparing the systemic and subdural fluid levels of cytokines. MATERIALS AND METHOD: Cytokine values were analyzed in samples obtained during surgery of 56 adult patients who were operated on for unilateral CSDHs using a Multiplex antibody bead kit. RESULTS: There were significantly higher levels of the pro-inflammatory IL-2R (p = 0.004), IL-5 (p < 0.001), IL-6 (p < 0.001), and IL-7 (p < 0.001), and anti-inflammatory mediators IL-10 (p < 0.001) and IL-13 (p = 0.002) in CSDH fluid compared with systemic levels. The pro-inflammatory TNF-alpha (p < 0.001), IL-1beta (p < 0.001), IL-2 (p = 0.007) and IL-4 (p < 0.001) were significantly lower in hematoma fluid compared with systemic levels. The ratios between pro- versus anti-inflammatory cytokines were statistically significant higher in CSDH (7.8) compared with systemic levels (1.3). CONCLUSIONS: The innate immune responses occur both locally at the site of CSDH, as well as systematically in patients with CSDH. The local hyper-inflammatory and low anti-inflammatory responses exist simultaneously. The findings suggest poorly coordinated innate immune responses at the site of CSDH that may lead to propagating of local inflammatory process and basically contribute to formation and progression of CSDH.

Analysis of Brain Natriuretic Peptide Serum Levels in Patients with Symptomatic Chronic Subdural Hematoma: A Potential Reliable Biomarker.

The purpose of this study was to analyze brain natriuretic peptide (BNP) serum levels of patients with chronic subdural hematoma (cSDH) and their clinical implication. Patients with cSDH who underwent surgery in our department between November 2016 and October 2019 were eligible for enrollment in the study. Patients with recurrent bleedings, traumatic brain injury, cSDH associated with other intracranial pathologies, and those with a history of congestive heart failure, renal or endocrine disease were excluded. We measured BNP serum levels pre- and post-operatively and at discharge. The BNP values were analyzed with respect to patient medical history and neurological condition. The Glasgow Coma Scale score and the modified Rankin Scale score classified the clinical and neurological condition at the time of admission and discharge, respectively. The data of 100 surgically treated patients with cSDH (mean age 73.2, range 42 - 94 years, male/female 3.5:1) were analyzed. Pre-operative BNP serum levels (BNP-1) were elevated in 67% of the patients (n = 67; median = 101.6 pg/mL; p < 0.001). These serum levels increased after surgery (p < 0.001) and decreased thereafter (p < 0.001), reaching a level at discharge (day 7) that was not statistically different from BNP-1 (p > 0.05). In addition, elevated BNP-1 showed a significant statistical association with the presence of atrial fibrillation (p < 0.01) and antiplatelet and/or anticoagulant therapy (p < 0.01). This study provides new evidence regarding BNP serum levels and their secretion pattern in patients with cSDH. Whether BNP-1 can predict the long-term functional outcome of patients with cSDH is being investigated in this ongoing prospective study.

Assessment of peripheral blood cell inflammatory markers in patients with chronic subdural hematoma.

OBJECTIVES: We aimed to study the role of peripheral blood cell inflammatory markers in patients with chronic subdural hematoma (CSDH). PATIENTS AND METHODS: We enrolled 466 patients with CSDH and 150 healthy controls and retrospectively analyzed peripheral blood cell inflammatory markers, including neutrophils, platelets, lymphocytes, neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR). Subsequently, we performed a subgroup analysis of the patients with CSDH based on gender, age, trauma history, and unilateral or bilateral hematoma. RESULTS: The CSDH group had higher numbers of neutrophils and platelets, as well as a higher NLR and PLR, than those in the healthy control group. Further, compared with the healthy control group, the CSDH group had lower lymphocyte counts. Subgroup analysis indicated trauma history as the only significant factor. CONCLUSION: Peripheral blood cell inflammatory markers could serve as indexes for evaluating the inflammatory state in patients with CSDH. There is a need for further studies on the prognostic role of this index in patients with CSDH.

Possible role of cyclooxygenase-2 in developing chronic subdural hematoma.

Inflammatory cytokines are reportedly involved in the pathogenesis of chronic subdural hematomas (CSH), and the angiogenesis of hematomas has particularly been in focus. Cyclooxygenase-2 (COX-2) is an essential enzyme for the synthesis of prostaglandin E2 (PGE2). The COX-2-PGE2 pathway has been shown to influence angiogenic factors such as vascular endothelial growth factor (VEGF). We investigated the association of COX-2 expression in the dura mater and outer membrane with the pathogenesis of CSH, and suggested a treatment strategy on the basis of this association. Hematoma fluid and serum samples obtained from 37 patients, and samples of the dura mater and outer CSH membrane obtained from 13 patients during the operation were examined in this study. The concentrations of PGE2 in relation to COX-2 in the hematoma fluid were significantly higher than those in the serum. Immunohistochemical analyses revealed COX-2-positive cells in the outer membrane of CSHs. There was a linear and significant relationship between PGE2 concentration in hematoma fluid and the interval from trauma to initial surgery. COX-2 may play a crucial role during the development of CSHs. Our study might lead to the development of anti-COX-2 treatment options that aim to minimize repeat surgery and choose medical therapy by reducing CSH morbidity and recurrence rate in patients with CSH.

Hematoma-derived exosomes of chronic subdural hematoma promote abnormal angiogenesis and inhibit hematoma absorption through miR-144-5p.

Exosomes are small (30-150 nm diameter) lipid bilayer-enclosed vesicles found in all bodily fluids. We investigated whether exosomes play a role in chronic subdural hematoma (CSDH). Exosomes were identified and characterized using transmission electron microscopy and NanoSight particle tracking. The functions of hematoma-derived exosomes were evaluated in a rat model of acute subdural hematoma (SDH). The hematoma-derived exosomes inhibited hematoma absorption and exacerbated neurological deficits in SDH rats. We examined the effects of the exosomes on angiogenesis and cell permeability in human umbilical vein endothelial cells (HUVECs). Co-culture of exosomes with HUVECs revealed that the hematoma-derived exosomes were taken-in by the HUVECs, resulting in enhanced tube formation and vascular permeability. Additionally, there was a concomitant increase in ANG-2 expression and decrease in ANG-1 expression. Exosomes were enriched with microRNAs including miR-144-5p, which they could deliver to HUVECs to promote angiogenesis and increase membrane permeability. Overexpression of miR-144-5p in HUVECs and in SDH rats promoted abnormal angiogenesis and reduced hematoma absorption, which mimicked the effects of the hematoma-derived exosomes both in vitro and in vivo. Thus, hematoma-derived exosomes promote abnormal angiogenesis with high permeability and inhibit hematoma absorption through miR-144-5p in CSDH.

The Pathogenesis of Chronic Subdural Hematomas: A Study on the Formation of Chronic Subdural Hematomas and Analysis of Computed Tomography Findings.

BACKGROUND: The origin of chronic subdural hematomas (CSDH) and the pathophysiology of its enlargement remain unknown. The chemical fluid composition of CSDH, the contribution of cerebrospinal fluid (CSF) to its enlargement, and the relationship to its appearance on computed tomography (CT) also are not entirely clear. METHODS: In this prospective study, 58 samples in 41 patients treated surgically for CSDH were analyzed. CSDHs were evaluated for the presence of CSF via ß-2 transferrin and substances related to cell breakdown and hemolysis. These were compared with normal value of those substances in the serum and the CT appearances of the CSDH. RESULTS: In this study, 24% of the samples contained ß-2 transferrin, which was statistically significant. Total protein, lactate dehydrogenase, total bilirubin, and red blood cells also were statistically different when compared with their normal serum concentration, indicating an active process of rebleeding and hemolysis rather than plasma ultrafiltration; however, their concentrations did not correlate with specific CT scan appearance. The absence of CSF in CSDH in 76% of cases did not support the theory that most CSDHs originate from subdural hygromas. The presence of hemolysis and cell breakdown, byproducts supports the hypothesis that the primary enlargement of CSDH develops through neomembrane and neovascular formation, rebleeding, and inhibition of the blood coagulation process. Our study did not test for serum transudation as a component of the enlargement of CSDH. CONCLUSIONS: Our study confirms that the origin and enlargement of CSDH is multifactorial, but the contribution of individual factors and condition under which it occurs still remains unclear. CT scan findings do not correlate with the chemical composition or the presence of CSF in the CSDH.

Role of cathepsin K in the development of chronic subdural hematoma.

Despite extensive investigations, the process of development of chronic subdural hematoma (CSDH) is not known. The present study aims to investigate CSDH by measuring biomarkers in it, gas analysis, and immunohistochemical examination. A total of 42 patients with symptomatic CSDH who underwent burr-hole drainage were enrolled. Intraoperatively, hematoma fluid and peripheral venous blood (PVCSDH) were simultaneously collected. As controls, peripheral venous blood (PVControl) and intracranial cerebrospinal fluid (CSF) were collected from other subjects during other surgeries. CatK, lipocalin-type prostaglandin D synthase (PGDS), and cystatin C (CysC) present in these specimens were measured using enzyme-linked immunosorbent assay. Data obtained were statistically analyzed after age correction. In 15 patients, gas analysis was performed for CSDH and PVCSDH. Furthermore, immunohistochemical examination for the outer membrane was performed for four patients. CatK, PGDS, and CysC levels were markedly elevated in the CSF and CSDH. CatK levels in PVCSDH were significantly higher than in PVControl (P<0.0001). In contrast, CysC levels in PVCSDH were significantly lower than in PVControl (P=0.004). The gas analysis revealed that the internal environment of CSDH is characterized by marked hypoxia, hypoglycemia, and lactic acidosis. Furthermore, the outer membrane consistently showed a diffuse staining for CatK. Based on these, CatK was thought to play a role in the development of CSDH, with the levels in peripheral venous blood elevated in patients with CSDH.