Membrane Of Chronic Subdural Hematoma Research Articles

A unique case of Sylvian arachnoid cyst complicated by chronic subdural hematoma

Background: Arachnoid cysts (ACs) complicated by chronic subdural hematoma (CSDH) are a rare but distinct entity. Case Description: A 27-year-old man previously diagnosed with Sylvian AC presented to the hospital with a persistent headache. He was not aware of any preceding head trauma. However, he frequently performed bench presses at the gymnasium, especially 4 weeks prior. The patient did not exhibit any neurological deficits at presentation. Computed tomography revealed slightly low-density areas in the right cerebral convexity. Magnetic resonance imaging revealed compressive masses in the right middle fossa and cerebral convexity. The patient underwent a craniotomy. Reflection of the dura mater exposed thickened arachnoid membrane. Making an incision resulted in the egress of fluid hematoma. The membrane separating the subdural hematoma and inner AC possessed fine vasculature and adjacent holes. Furthermore, there were fragile clots adhered to the inner wall of the cyst. Microscopic findings of the separating membrane were consistent with inflammatory granulation tissue, similar to those of the outer membrane of CSDH. Conclusion: Exertional hypertension associated with the bench press may result in the rupture of fine arteries distributed over the AC wall. Under certain circumstances, the AC wall may transform into the outer membrane of CSDH.

Neovascularization in Outer Membrane of Chronic Subdural Hematoma : A Rationale for Middle Meningeal Artery Embolization.

Neovascularization in Outer Membrane of Chronic Subdural Hematoma : A Rationale for Middle Meningeal Artery Embolization.

Neovascularization in Outer Membrane of Chronic Subdural Hematoma : A Rationale for Middle Meningeal Artery Embolization.

Neovascularization in Outer Membrane of Chronic Subdural Hematoma : A Rationale for Middle Meningeal Artery Embolization.

Neovascularization in Outer Membrane of Chronic Subdural Hematoma : A Rationale for Middle Meningeal Artery Embolization.

Chronic subdural hematomas (cSDHs) are generally known to result from traumatic tears of bridging veins. However, the causes of repeat spontaneous cSDHs are still unclear. We investigated the changes in vasculature in the human dura mater and outer membrane (OM) of cSDHs to elucidate the cause of their spontaneous repetition. The dura mater was obtained from a normal control participant and a patient with repeat spontaneous cSDHs. The pathological samples from the patient included the dura mater and OM tightly adhered to the inner dura. The samples were analyzed with a particular focus on blood and lymphatic vessels by immunohistochemistry, 3-dimensional imaging using a transparent tissue clearing technique, and electron microscopy. The dural border cell (DBC) layer of the dura mater and OM were histologically indistinguishable. There were 5.9 times more blood vessels per unit volume of tissue in the DBC layer and OM in the patient than in the normal control. The DBC layer and OM contained pathological sinusoidal capillaries not observed in the normal tissue; these capillaries were connected to the middle meningeal arteries via penetrating arteries. In addition, marked lymphangiogenesis in the periosteal and meningeal layers was observed in the patient with cSDHs. Neovascularization in the OM seemed to originate from the DBC layer; this is a potential cause of repeat spontaneous cSDHs. Embolization of the meningeal arteries to interrupt the blood supply to pathological capillaries via penetrating arteries may be an effective treatment option.

Angiogenesis in the Outer Membrane of Chronic Subdural Hematomas through Thrombin-Cleaved Osteopontin and the Integrin α9 and Integrin β1 Signaling Pathways.

A chronic subdural hematoma (CSDH) is considered to be an inflammatory and angiogenic disease. The CSDH outer membrane, which contains inflammatory cells, plays an important role in CSDH development. Osteopontin (OPN) is an extracellular matrix protein that is cleaved by thrombin, generating the N-terminal half of OPN, which is prominently involved in integrin signal transduction. We explored the expression of the N-terminal half of OPN in CSDH fluid and the expression of integrins α9 and β1 and the downstream components of the angiogenic signaling pathways in the outer membrane of CSDHs. Twenty samples of CSDH fluid and eight samples of CSDH outer membrane were collected from patients suffering from CSDHs. The concentrations of the N-terminal half of OPN in CSDH fluid samples were measured using ELISA kits. The expression levels of integrins α9 and β1, vinculin, talin-1, focal adhesion kinase (FAK), paxillin, α-actin, Src and β-actin were examined by Western blot analysis. The expression levels of integrins α9 and β1, FAK and paxillin were also examined by immunohistochemistry. We investigated whether CSDH fluid could activate FAK in cultured endothelial cells in vitro. The concentration of the N-terminal half of OPN in CSDH fluid was significantly higher than that in the serum. Western blot analysis confirmed the presence of these molecules. In addition, integrins α9 and β1, FAK and paxillin were localized in the endothelial cells of vessels within the CSDH outer membrane. FAK was significantly phosphorylated immediately after treatment with CSDH fluid. Our data suggest that the N-terminal half of OPN in CSDH fluid promotes neovascularization in endothelial cells through integrins α9 and β1. The N-terminal half of OPN, which is part of the extracellular matrix, plays a critical role in the promotion of CSDHs.

Endoscopically observed outer membrane of chronic subdural hematoma after endovascular embolization of middle meningeal artery.

Embolization of the middle meningeal artery (MMA) has been established for chronic subdural hematoma (CSDH). Neuroendoscopic observation of the outer membrane of the hematoma was carried out after embolization. The treatment mechanism of embolization is discussed, focusing on the vasculature and inflammation of the membrane. Four patients with recurrent CSDH were included in this study. The MMA was embolized using Embosphere® particles in three patients. The outer membrane was observed with normal and narrow band images (NBIs). The net-like vessels were not obstructed in the whole area of the outer membrane, but in a patchy fashion of embolized areas surrounded by nonembolized areas. In two patients, the nonembolized areas showed a hemorrhagic inflammatory red color. Histopathological examination confirmed hypertrophic dura with leukocyte infiltration. Dilated dural arteries and proliferated sinusoid arteries were located in the deep and superficial border cell layers. These arteries were visualized as green and brown on NBI, respectively. In the embolized area, the red membrane turned pink, indicating ischemia and subsiding inflammatory hyperemia. In the third patient, the outer membrane was white in both the nonembolized and embolized areas in endoscopic view, and the net-like vessels were sparse in both endoscopy and histology, indicating a scar inflammatory phase. The membrane transition was not observed in the patient that did not undergo embolization. Endoscopic observation revealed that embolization of the MMA blocked both the dural and sinusoidal arteries. Ischemic transformation causing the suppression of inflammation of the outer membrane is a suggested mechanism of MMA embolization.

Expression of integrin α9β1 signaling pathway in the outer membrane of chronic subdural hematoma

Expression of integrin α9β1 signaling pathway in the outer membrane of chronic subdural hematoma

Expression of Angiopoietins and Angiogenic Signaling Pathway Molecules in Chronic Subdural Hematomas.

Chronic subdural hematoma (CSDH) is an angiogenic disease that is involved with many inflammatory mediators. Tie2 is predominantly expressed in the embryonic endothelium and plays an important role in the maturation and stabilization of the vasculature. Angiopoietin (Ang)1 and Ang2 are well-known ligands of the Tie2 receptor. We examined the expression of Ang1 and Ang2 in CSDH fluid and the expression of Tie-2 receptor and components of the angiogenic signaling pathways in the outer membrane of CSDH. Twenty-five samples of CSDH fluid and eight samples of outer membrane of CSDH were included. The concentrations of Ang1 and Ang2 in the CSDH fluid were measured using enzyme-linked immunosorbent assay (ELISA) kits. The expression of Tie2, phosphoinositide 3-kinase (PI3K), protein kinase B (Akt) mechanistic target of rapamycin (mTOR), GβL, 70 kDa ribosomal protein S6 kinase (p70S6K), eukaryotic initiation factor 4E (eIF-4E), and β-actin was examined by a Western blot analysis. The expression of Tie2, Akt, and mTOR was also examined by immunohistochemistry. The concentration of Ang2 in CSDH fluid was significantly higher than that in the serum or cerebrospinal fluid (CSF), and also higher than that of Ang1 in CSDH fluid. Tie2, PI3K, Akt, mTOR, GβL, p70S6K, and eIF-4E were detected in all cases. In addition, Tie2, Akt, and mTOR were localized in the endothelial cells of vessels in the CSDH outer membrane. Our data suggest that Ang2, although not Ang1, in CSDH fluid promotes angiogenesis in endothelial cells through the Tie2 receptor. The Ang2/Tie2 signaling pathway might therefore be a useful therapeutic target for treating the growth of intractable CSDH.

Expression of high mobility group B1 and toll-like receptor-nuclear factor κB signaling pathway in chronic subdural hematomas.

Chronic subdural hematoma (CSDH) is an angiogenic and inflammatory disease. Toll-like receptors (TLRs) transduce intracellular signals, resulting in the activation of nuclear factor κB (NF-κB), which leads to the production of inflammatory cytokines. High-mobility group box 1 (HMGB1) functions as a mediator of inflammatory responses through TLRs. In this study, we examined the expression of HMGB1 and components of the Toll-like receptor and NF-κB signaling pathways in the outer membrane of CSDH. Eight patients whose outer membrane was successfully obtained during trepanation surgery were included in this study. The expression of TLR4, myeloid differentiation factor 88 (MyD88), interleukin-1 receptor-associated kinase 4 (IRAK4), TNF receptor-associated factor 6 (TRAF6), TGFβ-activated kinase 1 (Tak1), interferon regulatory factors 3 (IRF3), IκB kinase β (IKKβ), IKKγ, IκBε, IκBα, NF-κB/p65 and β-actin was examined by Western blot analysis. The expression of TLR4, NF-κB/p65 and interleukin-6 (IL-6) was also examined by immunohistochemistry. The concentrations of HMGB1 and IL-6 in CSDH fluids were measured using ELISA kits. Above-mentioned molecules were detected in all cases. In addition, TLR4, NF-κB/p65 and IL-6 were localized in the endothelial cells of vessels within CSDH outer membranes. The concentrations of HMGB1 and IL-6 in CSDH fluids were significantly higher than that in the CSF and serum. There existed a correlation between the concentrations of HMGB1 and IL-6 in CSDH fluids. Our data suggest that HMGB1 in CSDH fluids produces the inflammatory cytokine IL-6 in endothelial cells through the Toll-like receptor and NF-κB signaling pathways. Anti-HMGB1 therapy might be a useful method to treat the growth of CSDH.

慢性硬膜下血腫被膜におけるToll–like receptorシグナル伝達系の発現について

慢性硬膜下血腫被膜におけるToll–like receptorシグナル伝達系の発現について

The Protective Role of Heme Oxygenase-1 (HO-1) in Chronic Subdural Hematoma

Abstract INTRODUCTION Many studies have revealed that angiogenesis and inflammation are closely linked to the pathophysiology of chronic subdural hematoma (CSDH). The development of CSDH is an inflammatory process that begins as a local inflammatory reaction of the dura meter to injury or external stimuli such as blood or CSF. This process causes neovascularization of the outer membrane of CSDH and vascular hyperpermeability. Heme oxygenase-1 (HO-1) is a key enzyme that catalyzes the degradation of heme and produces biliverdin, ferrous iron, and carbon monoxide. HO-1 expression is induced by oxidative stress, and the increasing expression seems to be protective in animal studies. We hypothesized that HO-1 has a protective impact on the severity of CSDH. METHODS This study is designed to correlate the histopathology of the outer membrane of CSDH and HO-1 level in the CSDH hematoma as an indicator of inflammatory status with the clinical presentation of patient and computed tomography (CT) radiological findings of a consecutive series of patients suffered from CSDH. This is a single-center, perspective cohort study. From 2014 to 2017, we enrolled 97 patients with CSDH, who has undergone surgical intervention (burr-hole drainage or craniotomy evacuation). We collect the clinical data, radiological information, and outer membrane and supernatant of the CSDH. We use enzyme-linked immunosorbent assay (ELISA) to measure the concentration of HO-1 in the supernatant of CSDH. RESULTS A significant negative correlation between the HO-1 and the thickness of CSDH is noted (P = .001). On increasing HO-1 by 1 ng/L, the CSDH thickness decreases by 81 mm (P < .005). CONCLUSION Our study demonstrates that HO-1, an important enzyme in angiogenesis and in the inflammation pathway, has a key impact on CSDH severity. A significant negative correlation between the HO-1 and thickness of CSDH has been proved.

Armored brain associated with secondary craniostenosis development at 7-year following ventriculoperitoneal shunt surgery during infancy: Extremely unusual association and review

Calcification is uncommon in chronic subdural hematoma and popularly known as calcified chronic subdural hematoma (CSSDH), and about hundred cases are reported in the form of isolated cases report. The calcified inner membrane of chronic subdural hematoma gets adherent to underlying cerebral cortex preventing re-expansion of the brain and producing mass effect. Calcification can develop in chronic subdural hematoma of traumatic origin or postmeningitic effusion or extremely rarely after shunt surgery. CCSDH is also known as armored brain or Matrioska head and those related to cerebrospinal fluid diversion ventriculoperitoneal (VP) shunt surgery, constitute one of the rare complications of shunt, and development is attributed to overdrainage of shunt. Authors report a unique case with bilateral calcified chronic subdural hematoma in an 8-year-old boy, who had VP shunt surgery for obstructive hydrocephalus at the age of 1 year of life, presented with feature of nonlocalized raised intracranial pressure; a diagnosis of suspected VP shunt malfunction was also considered; however, cranial computed tomography scan on current admission revealed the presence of bilateral calcified chronic subdural hematoma with secondary craniostenosis and managed successfully with burr-hole craniostomy and drainage of CCSDH. In a detailed PubMed and Medline search, authors could not get any publication regarding CSSDH associated with secondary craniostenosis developing following VP shunt surgery in infancy. The current case represents the first case in the Western literature developing secondary craniostenosis-associated CCSDH following shunt surgery in infancy, requiring surgical management. The clinical features, neuroimaging, and management of such rare case along with pertinent literature are reviewed briefly.

Expression of Autophagy Signaling Molecules in the Outer Membranes of Chronic Subdural Hematomas

Chronic subdural hematoma (CSDH) is fundamentally treatable, although it sometimes recurs. We observed, however, several cases of spontaneous resolution of CSDH outer membranes, even in a trabecular type of CSDH, after a trepanation surgical procedure. In this study, we examined the expression of molecules of the autophagy signaling pathway in CSDH outer membranes. Eight patients whose outer membranes were obtained successfully during trepanation were included in this study. By Western blot analysis, we examined the expression of mammalian target of rapamycin (mTOR); GβL; UNC-51-like kinase-1 (ULK1); Beclin-1; autophagy-related genes (Atg) 3, 5, 7, 12, 13, and 16L1β,α; the autophagy marker Light Chain3A/B (LC3A/B); and β-actin, which constitute the autophagy signaling pathway. The expression levels of Beclin-1, Atg12, and LC3A/B were also examined by immunohistochemistry. Almost all of these molecules could be detected in all samples. Beclin-1, Atg12, and LC3A/B were found to be localized in the endothelial cells of vessels and fibroblasts in CSDH. We detected molecules of the autophagy signaling pathway in CSDH outer membranes. Autophagy contributes to the tissue homeostatic process, maintaining cellular integrity by clearing debris. Our data suggest that autophagy might play an important role in the spontaneous resolution of CSDH. Therefore, these molecules may be novel therapeutic targets for the treatment of those with CSDH.

Expressions of Eotaxin-3, Interleukin-5, and Eosinophil-Derived Neurotoxin in Chronic Subdural Hematoma Fluids.

Eosinophils induce inflammation by releasing cytokines and cytotoxic granule proteins. Infiltration of eosinophilic granulocytes occurs in the outer membrane of chronic subdural hematomas (CSDHs). Eosinophils play an important role in the growth of CSDHs. However, the manner in which eosinophils accumulate within CSDH fluid remains undetermined. In the current study, we assessed the expression of eosinophil chemoattractants in CSDH fluids according to growth stage of CSDHs and examined the correlation between the two. CSDH fluids were obtained from 38 patients during trepanation surgery. Ecalectin, eotaxin-3, interleukin-5 (IL-5), and eosinophil-derived neurotoxin (EDN) concentrations were measured using enzyme-linked immunosorbent assay kits. For use as controls, serum samples were collected from 5 healthy adults, and cerebrospinal fluid (CSF) samples were collected from 5 adults with unruptured aneurysms. The percentage of eosinophils (%eosinophil) in CSDH fluids was calculated using Giemsa staining. Concentrations of ecalectin, eotaxin-3, IL-5, and EDN were nearly equivalent in serum and CSF samples; however, their concentrations were high in CSDH fluids. In particular, ecalectin and EDN levels in CSDH fluids were significantly higher than those in serum and CSF. Levels of eotaxin-3, IL-5, EDN, and %eosinophil were significantly higher in laminar type of CSDH, whereas that of ecalectin was not. The correlations between eotaxin-3 and IL-5, IL-5 and EDN, and EDN and %eosinophil were statistically significant (p < 0.01). Our data suggest that eotaxin-3 is a chemoattractant of eosinophils. IL-5 induces the activation of eosinophils subsequent to degranulation of EDN into CSDH fluids. These factors may serve as novel therapeutic targets for managing CSDH.

Comment on "Evaluation of Recurrence Factors and Gorei-san Administration for Chronic Subdural Hematoma after Percutaneous Subdural Tapping"

We previously reported the recurrence factors and the effect of Gorei-san on chronic subdural hematoma (CSDH) using percutaneous subdural tapping. Herein, we comment on less invasive surgical option and postsurgical administration for CSDH. Many factors for CSDH recurrence have been identified and categorized into four groups, namely: patient background, hematoma character, postsurgical administration, and surgical option. Patient background and hematoma character cannot be intervened for patients’ specific problem. Gorei-san has been reported to prevent CSDH recurrence without adverse events even if administered for elder patients. Gorei-san inhibits aquaporin-4, which is expressed on the outer membrane of chronic subdural hematoma. We have good impression of prevention effect of CSDH recurrence especially for those who started Gorei-san before surgery. Several surgical options for CSDH are reported as follows: burr hole surgery, percutaneous subdural tapping, endovascular embolization of middle meningeal artery, and craniotomy. Although burr hole surgery has been performed worldwide as a standard procedure for CSDH, percutaneous subdural tapping has been developed to realize less invasive surgical option, which allows noninvasive measurement of initial hematoma pressure and eases the perioperative management due to rapid discharge.

Expression of Caspase Signaling Components in the Outer Membranes of Chronic Subdural Hematomas

Chronic subdural hematoma (CSDH) is fundamentally treatable through surgery, although CSDH recurs in some cases. We have observed several cases of spontaneous resolution of CSDH outer membranes, including in trabecular CSDH, after trepanation surgery. In this study, we examined the expression of molecules involved in caspase signaling in CSDH outer membranes. Eight patients whose outer membranes were obtained successfully during trepanation surgery were included in this study. The expression of Fas; Fas-associated death domain (FADD); tumor necrosis factor receptor type 1-associated death domain (TRADD); receptor-interacting protein (RIP); caspases 3, 7, 8, and 9; poly-(ADP-ribose) polymerase (PARP); DNA fragmentation factor 45 (DFF45) and β-actin was examined by Western blot analysis. The expression levels of PARP, caspase-3, and cleaved caspase-3 were also examined by immunohistochemistry. Fas; FADD; TRADD; RIP; caspases 3, 7, 8, and 9; PARP, and DFF45 were detected in nearly all samples. Caspase-3 and PARP were localized in the endothelial cells of vessels and in fibroblasts in CSDH outer membranes. In addition, cleaved caspase-3 was detected in fibroblasts. We detected molecules of the caspase signaling pathway in CSDH outer membranes. In particular, cleaved caspase-3 was detected, which suggests that apoptosis may occur within these membranes. Thus, during the growth of CSDH outer membranes, the caspase signaling pathway may be restrained. Once the pathway is activated, gradual resolution of CSDH outer membranes may occur. Therefore, these molecules may be novel therapeutic targets for intractable CSDH.

Inhibitory Mechanism of the Outer Membrane Growth of Chronic Subdural Hematomas.

We previously demonstrated that the inflammatory cytokine interleukin-6 (IL-6) activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway in fibroblasts within the outer membranes of chronic subdural hematomas (CSDHs), and the activation of this pathway may induce CSDH outer membrane growth. The inhibitory system for this signal transduction pathway is unknown. CSDH fluids were obtained from 10 patients during trepanation surgery as the case group, and cerebrospinal fluid (CSF) samples were obtained from seven patients suffering from subarachnoid hemorrhage (SAH) on Day 1 as the control group. The concentrations of IL-6, soluble IL-6 receptor (sIL-6R), and soluble gp130 (sgp130) in CSDH fluid and CSF were measured using enzyme immunoassay kits. The co-localization of IL-6 and sgp130 in CSDH fluid was examined by immunoprecipitation. The expression levels of STAT3, JAK2, suppressor of cytokine signaling 3 (SOCS3), and protein inhibitor of activated Stat3 (PIAS3) in the outer membranes of CSDHs were examined by immunostaining. Soluble IL-6R and sgp130 concentrations in CSDH fluid were significantly higher than those in CSF after SAH. Sgp130 and IL-6 were co-immunoprecipitated from CSDH fluid. Immunostaining revealed STAT3, JAK2, SOCS3, and PIAS3 expression in fibroblasts located in the outer membranes of CSDHs. Soluble gp130 binds to IL-6/sIL-6R and acts as an antagonist of the JAK/STAT signaling pathway. SOCS3 also binds to JAK and inhibits its signaling pathway. In addition, PIAS3 regulates STAT3 activation. These factors might down-regulate the IL-6/JAK/STAT signaling pathway in fibroblasts within CSDH outer membranes. Therefore, these molecules may be novel therapeutic targets for the inhibition of CSDH growth.

Embolization Therapy for Refractory Hemorrhage in Patients with Chronic Subdural Hematomas

There is no definite operative procedure for patients with intractable chronic subdural hematoma (CSDH). We describe the safety and efficacy of embolization treatment of the middle meningeal artery (MMA) for such cases. Patients were divided into an embolization group (n= 20) and a conventional group (n= 23) based on the therapeutic approach to their CSDHs. The targets of the endovascular treatment were 26 recollected hematomas with increased risk of recurrence. To eliminate the arterial supply of the external membrane of CSDHs, 2 branches of the MMA were selected and occluded by injection of polyvinyl alcohol particles. Older age and antiplatelet drug use were comparatively related to the embolization group (P<0.05). Among imaging study variables, severe brain atrophy and hematoma bilaterality were the risk factors for necessity of MMA embolization (P < 0.05). The complication rate and functional outcome were not significantly different between the 2 groups (P > 0.05). After multivariate analysis, early brain re-expansion (P= 0.003) and lesser hematoma recurrence (P= 0.024) remained independently associated with patients who underwent embolization therapy. This pilot study indicated that perioperative MMA embolization could be offered as the least invasive and most effectual means of treatment for resistant patients of CSDHs with 1 or more recurrences.

Activation of Signal Transducer and Activator of Transcription 3 in Endothelial Cells of Chronic Subdural Hematoma Outer Membranes

Chronic subdural hematoma (CSDH) is considered an angiogenic and inflammatory disease. Interleukin-6, a well-known inflammatory cytokine, activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. We previously reported that the JAK/STAT pathway is activated in fibroblasts in the outer membrane of CSDH. More recently, signal transducer and activator of transcription 3 (STAT3) has been shown to have a role in angiogenesis. We examined the expression of STAT3 in endothelial cells in the outer membrane of CSDH. This study included 7 patients whose outer membranes were successfully obtained during trephination surgery. The expression of STAT3 and phosphorylated STAT3 was examined by Western blot analysis and immunohistochemistry. We also examined whether CSDH fluid could activate STAT3 in cultured endothelial cells invitro. STAT3 and phosphorylated STAT3 were detected in all cases. Immunostaining showed that STAT3 and phosphorylated STAT3 were expressed not only in fibroblasts but also in vascular endothelium. Expression of phosphorylated STAT3 in endothelial cells was significantly induced immediately after treatment of CSDH fluid invitro. The activation of STAT3 was significantly inhibited by treatment with antibodies that were directed against interleukin-6; however, this was suppressed by antibodies that were directed against vascular endothelial growth factor, but not significantly. Interleukin-6 might dominantly activate STAT3 in endothelial cells, which might have a central role in endothelial cell proliferation and angiogenesis of CSDH outer membranes.

Expression of Mitogen-Activated Protein Kinases in Chronic Subdural Hematoma Outer Membranes.

Growth factors and inflammatory cytokines activate the mitogen-activated protein kinase (MAPK) cascade. Previous studies have shown that chronic subdural hematoma (CSDH) fluid contains these factors and cytokines. In this study, expression of three major 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 this 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 blot and immunostaining. We examined whether CSDH fluid could activate MAPKs in cultured endothelial cells (ECs) or fibroblasts in vitro. Western blot analysis showed that p-ERK was present in all samples, whereas 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 ECs and fibroblasts was significantly induced immediately after treatment with CSDH fluid, whereas p-p38 and p-JNK expression was significantly induced in ECs 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 ECs, but not in fibroblasts. Inflammatory cytokines and growth factors in CSDH fluids might activate major MAPKs in ECs, which might be associated with neovascularization in the outer membrane of CSDH. These MAPK pathways could become novel targets for treatment of CSDHs.