C5a-C5AR1 axis as a potential trigger of the rupture of intracranial aneurysms.

Recent studies have indicated the involvement of neutrophil-mediated inflammatory responses in the process leading to intracranial aneurysm (IA) rupture. Receptors mediating neutrophil recruitment could thus be therapeutic targets of unruptured IAs. In this study, complement C5a receptor 1 (C5AR1) was picked up as a candidate that may cause neutrophil-dependent inflammation in IA lesions from comprehensive gene expression profile data acquired from rat and human samples. The induction of C5AR1 in IA lesions was confirmed by immunohistochemistry; the up-regulations of C5AR1/C5ar1 stemmed from infiltrated neutrophils, which physiologically express C5AR1/C5ar1, and adventitial fibroblasts that induce C5AR1/C5ar1 in human/rat IA lesions. In in vitro experiments using NIH/3T3, a mouse fibroblast-like cell line, induction of C5ar1 was demonstrated by starvation or pharmacological inhibition of mTOR signaling by Torin1. Immunohistochemistry and an experiment in a cell-free system using recombinant C5 protein and recombinant Plasmin indicated that the ligand of C5AR1, C5a, could be produced through the enzymatic digestion by Plasmin in IA lesions. In conclusion, we have identified a potential contribution of the C5a-C5AR1 axis to neutrophil infiltration as well as inflammatory responses in inflammatory cells and fibroblasts of IA lesions. This cascade may become a therapeutic target to prevent the rupture of IAs.

[Inflammatory Responses in Hemorrhagic Stroke].

Inflammation is triggered by various intrinsic and extrinsic stimuli as a protective machinery to maintain homeostasis in the human body. Usually, it is magnified in intensity initially and regresses rapidly afterwards; this phenomenon is called acute inflammation. However, it occasionally lasts a long time; this phenomenon is called chronic inflammation. Induction of some specific machineries, i.e., formation of a positive feedback loop, inflammatory cell infiltration, and changes in tissue architecture, is required for the transition to chronic inflammation; this differentiates chronic and acute inflammation in nature. Chronic inflammation is a common pathogenesis of various diseases, including cancer, vascular disease, and stroke. Recent experimental studies have clarified the crucial role of inflammatory responses in the development and progression of hemorrhagic stroke mediated by tissue destruction or some other aspects of diseases. In this review, we summarize the research findings of the role of inflammation in hemorrhagic stroke.

Hypoxic microenvironment as a crucial factor triggering events leading to rupture of intracranial aneurysm.

Subarachnoid hemorrhage being the rupture of intracranial aneurysm (IA) as a major cause has quite poor prognosis, despite the modern technical advances. Thereby, the mechanisms underlying the rupture of lesions should be clarified. Recently, we and others have clarified the formation of vasa vasorum in IA lesions presumably for inflammatory cells to infiltrate in lesions as the potential histopathological alternation leading to rupture. In the present study, we clarified the origin of vasa vasorum as arteries located at the brain surface using 3D-immunohistochemistry with tissue transparency. Using Hypoxyprobe, we then found the presence of hypoxic microenvironment mainly at the adventitia of intracranial arteries where IA is formed. In addition, the production of vascular endothelial growth factor (VEGF) from cultured macrophages in such a hypoxic condition was identified. Furthermore, we found the accumulation of VEGF both in rupture-prone IA lesions induced in a rat model and human unruptured IA lesions. Finally, the VEGF-dependent induction of neovessels from arteries on brain surface was confirmed. The findings from the present study have revealed the potential role of hypoxic microenvironment and hypoxia-induced VEGF production as a machinery triggering rupture of IAs via providing root for inflammatory cells in lesions to exacerbate inflammation.

Identification of The Unique Subtype of Macrophages in Aneurysm Lesions at the Growth Phase.

OBJECTIVES: Recent experimental studies have defined intracranial aneurysms as a macrophage-mediated chronic inflammatory disease affecting intracranial arteries. Although there are various subtypes in macrophages, what type of macrophages is present in lesions during the disease development remains to be elucidated. METHODS: The previously-established aneurysm model of rats was used. Macrophages were labeled with the fluorescent protein and isolated by a laser-microdissection method. The comprehensive gene expression profile analyses and gene ontology analyses was then done to identify a macrophage subtype present in lesions at the growth phase. RESULTS: The gene expression profile data of total 52 macrophages infiltrating into the lesions was acquired. The principal component analysis revealed the monotonous macrophage subtype. By comparing the profile identified with one from in vitro-differentiated M0 or M1 macrophages, the macrophages in the lesions were belonged to the simple and unique subtype. Because the perception of signaling from nervous system was highlighted as up-represented terms through gene ontology analyses, the macrophage subtype in lesions at the growth phase might be differentiated under the influence of nervous system in the microenvironment. The histopathological examinations supported the above notion by confirming the presence of nerves in the adventitia. CONCLUSIONS: The findings from the present study have provided the useful insights about the macrophage subtype in aneurysm lesions at the growth phase and also proposed its ability as a therapeutic target.

[Current Knowledge on the Genetic Analysis and Development of Medical Therapy for Intracranial Aneurysms].

Genetic studies on intracranial aneurysms(IAs), like genome-wide association studies, or studies analyzing familial intracranial aneurysms, have successfully revealed the potential contribution of a set of genes to the pathology of IAs. Some of the genes may promote the formation of IAs or the process leading to rupture of the lesions through exacerbating inflammatory responses or facilitating the degenerative changes of arterial walls. Many genes or single-nucleotide polymorphisms have been identified through extensive analyses, but they can only explain one-fifth of the IA pathology; therefore, the pathogenesis of IAs is influenced by many factors, including environmental factors, and not only genetic ones. Intriguingly, a somatic mutation in the PDGFRB gene has recently been identified in more than half of the cases with fusiform aneurysms, making the development of medical therapy targeting PDGFRß signaling realistic. Nowadays, following a series of recent experimental studies, IA is considered a chronic inflammatory disease affecting intracranial arteries, indicating the potential of anti-inflammatory drugs as therapeutic drugs for the treatment of IAs. No wonder, recently published observational studies have revealed the preventive effect of statins and aspirin, with potent anti-inflammatory effects on the rupture of IAs.

Intracranial chondrosarcoma located in the region of the posterior clinoid process: a case report.

Intracranial chondrosarcomas located in the region of the posterior clinoid process have not been focused on. Here, we report the case of a 29-year-old woman with a skull base tumor in that region. Seven years after the diagnosis, the tumor had grown and showed calcification and tumor stain; chondrosarcoma, posterior clinoid meningioma, and chordoma were suspected. The patient underwent subtotal tumor resection, and the histopathological study revealed that the tumor was a low-grade chondrosarcoma. Chondrosarcomas can be located in the region of the posterior clinoid process, and not only chordomas but also posterior clinoid meningiomas should be considered as a differential diagnosis of tumors located in that region, especially when the tumor has calcification or receives a vascular supply.

Pineal region pilocytic astrocytoma showing uncommon growth: a case report.

Pineal region pilocytic astrocytomas are extremely rare, and there is limited information about their radiological features. We report the case of a 22-year-old woman with a cystic lesion in the pineal region. In the 2 years after diagnosis, the lesion irregularly extended along the bilateral internal cerebral veins and the inferolateral surface of the corpus callosum. Gross total resection was achieved, and the histopathological study revealed that the lesion was a pilocytic astrocytoma. The lesion exhibited uncommon growth, leading to difficulty in establishing an accurate preoperative diagnosis. It should be noted that pineal region pilocytic astrocytomas can demonstrate atypical appearances.

Predictors of subacute hematoma expansion requiring surgical evacuation after initial conservative treatment in patients with acute subdural hematoma.

BACKGROUND: The aim of this study was to clarify the factors associated with requiring subacute surgery in patients with acute subdural hematoma (ASDH) treated conservatively at admission. METHODS: Among the patients with ASDH admitted to our hospital from 2007 to 2018, we retrospectively reviewed data for 200 patients initially treated conservatively. We compared patients' characteristics, medical history, radiological findings, and clinical outcomes and differences between patients undergoing subacute surgery or no surgery. RESULTS: Of the 200 patients treated conservatively, 17 (8.5%) patients underwent subacute surgery due to deterioration of their clinical and/or computed tomography (CT) findings, while 183 (91.5%) patients did not undergo subacute surgery. There were significant differences in the presence of focal neurological deficits, modified Rankin Scale scores, degree of midline shift, hematoma thickness, hematoma volume, cella media index, Sylvian fissure ratio, and hematoma density between the two groups. CONCLUSIONS: Large hematoma, brain atrophy, and hematoma density may be useful predictors for the need for subacute surgery in patients with ASDH treated conservatively at admission. Intensive investigation of clinical findings or CT images is warranted in patients with adverse prognostic factors, even if their initial symptoms are mild.

Predictors of the Resolution of Cavernous Sinus Syndrome Caused by Large/Giant Cavernous Carotid Aneurysms After Parent Artery Occlusion with High-Flow Bypass.

OBJECTIVE: To evaluate the clinical results and factors related to the resolution of preoperative cranial neuropathy after internal carotid artery ligation with high-flow bypass in patients with symptomatic large or giant cavernous carotid aneurysms. METHODS: This study included 18 consecutive patients (15 women) with cranial neuropathy. All patients underwent therapeutic internal carotid artery ligation with high-flow bypass using a radial artery graft. Patient demographics, duration of symptoms, clinical outcomes, complications, and radiographic findings were retrospectively analyzed. The mean follow-up period was 31.0 months (range: 3-74 months). RESULTS: Patients' mean age was 66.6 years, and the mean aneurysm size was 23.7 mm. Six patients (33%) had partially thrombosed aneurysms. Preoperatively, 16 (89%) and 8 (44%) patients presented with ophthalmoplegia and facial pain, respectively. Bypass patency was confirmed in 15 patients (83%), and obliteration of the aneurysm was confirmed in all patients at the final follow-up. Preoperative ophthalmoplegia resolved in 10 patients (63%), and trigeminal pain resolved in all patients. Postoperative resolution of patients' ophthalmoplegia was significantly associated with age (P = 0.044), symptom duration before treatment (P = 0.042), and the degree of ophthalmoplegia (P = 0.046). The degree of postoperative residual ophthalmoplegia was positively correlated with the duration of ophthalmoplegia from onset to surgery (r = 0.619; P = 0.011). Preoperative trigeminal pain resolved regardless of the preoperative duration of this symptom in all patients. CONCLUSIONS: Early treatment is recommended when treating large or giant cavernous carotid aneurysms with cranial neuropathy. Complete resolution is possible in younger patients with partial neuropathy.

[Surgical Management of a Thromobotic Extracranial Carotid Artery Aneurysm:A Case Report].

Extracranial carotid artery aneurysms are relatively rare. We present a case involving a giant aneurysm arising from the extracranial carotid artery. The patient was a 79-year-old woman. She had a pulsating mass in the right side of her neck. However, she was neurologically intact. Contrast-enhanced CT scans of the neck showed an enhanced mass lesion with a thrombus in the right side of her neck. Angiography revealed a saccular aneurysm 3.4 cm in size near the bifurcation site of the right common carotid artery into the external carotid artery. She underwent an urgent resection of the aneurysm and a carotid artery reconstruction. Postoperatively, she recovered well and the total resection of the lesion was angiographically confirmed. Histopathological examination revealed that the wall of the aneurysm had undergone fibrosis and contained a few elastic fibers and microhemorrhages. The wall of the aneurysm was also infiltrated by inflammatory cells. The surgical strategy for and appropriate preoperative evaluation of this rare disease was discussed.

Disturbed Consciousness and Coma: Diagnosis and Management of Intracranial Hypotension Caused by a Spinal Cerebrospinal Fluid Leak.

OBJECTIVE: The diagnosis and treatment of intracranial hypotension associated with a spinal cerebrospinal fluid (CSF) leak, especially in comatose patients, have yet to be established. METHODS: Clinical manifestations, neuroimaging findings, and treatment outcomes in 11 patients (Glasgow Coma Scale score 10 ± 4) were described and compared with 36 patients with normal consciousness. RESULTS: Patients with disturbed consciousness were diagnosed at a significantly older age (55 ± 11 years; P < 0.001) than those without (42 ± 8.8 years). Neuroimaging findings in patients with disturbed consciousness were characterized by a smaller midbrain-pons angle (7.8 ± 10°; P < 0.001), brainstem swelling (122%; P = 0.002), and thicker subdural hematomas (16 ± 7.0 mm°; P < 0.001). Epidural blood patch (EBP) alone did not achieve sustained improvements in patients with disturbed consciousness but did in most patients without (94%; P = 0.001). Over the treatment course, 5 patients progressed to coma, which correlated with a high signal intensity on T2-weighted magnetic resonance imaging in the brainstem. Hematoma drainage before EBP caused neurologic deterioration in 2 patients. Simultaneous EBP after hematoma drainage achieved sustained improvements in 5 of 6 patients. Simultaneous microsurgical dural repair after hematoma drainage achieved more rapid improvements in 3 of 3 patients. CONCLUSIONS: Among patients with intracranial hypotension caused by a spinal CSF leak, disturbed consciousness may occur in elderly patients because of severe diencephalic-mesencephalic deformities. Simultaneous EBP after safe hematoma drainage is indicated for these patients. Alternatively, dural repair is indicated for patients for whom the spinal level of dural disease has been identified. Hematoma drainage before EBP is not recommended because it caused deterioration.

Hyperperfusion syndrome after aneurysm surgery: a case report.

A 74-year-old woman exhibited sensory aphasia with abrupt blood pressure elevation 3 h after clipping of an unruptured large left middle cerebral artery aneurysm. Perfusion computed tomography and single-photon emission computed tomography demonstrated hyperperfusion in one of the distal parent artery areas. She gradually improved and was discharged without neurological deficits. Increased distal blood flow after occlusion of the large cerebral aneurysm and postischemic reperfusion after temporary occlusion of the parent artery during surgery presumably played an important role in the occurrence of this fairly rare condition associated with aneurysm surgery.