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Abstract BACKGROUND The safety and efficacy of flow diversion (FD) in the treatment of cerebral aneurysms have been reported by many studies. FD has enabled the treatment of complex aneurysms and aneurysms that were previously untreatable by conventional means. It has achieved high rates of obliteration with essentially no recanalization, and its indications have continued to expand, now including ruptured aneurysms, blister aneurysms, and dissecting aneurysms. OBJECTIVE To provide a review on the outcomes of studies covering the use of FD in the settings of ruptured, blister, and dissecting aneurysms. In addition, to discuss dual antiplatelet therapy (DAPT) used in preparation for FD deployment in these scenarios, including associated complications with DAPT use in the acute rupture setting. METHODS References for this topical review were identified by PubMed searches between January 2000 and January 2019. The search terms “aneurysm”, “flow diverter”, “stent”, “pipeline”, “ruptured”, “blister”, and “dissecting aneurysms” were used. RESULTS FD carries a higher complication rate in the acute rupture setting than for unruptured aneurysms. Patient selection is of paramount importance for achieving good functional and angiographic outcomes. DAPT still remains challenging, especially in ruptured aneurysms. Advancements in surface modification of flow diverters can reduce the risk of thromboembolism and perhaps lead to a safer antiplatelet regimen. CONCLUSION In summary, FD shows promise to be an effective treatment for ruptured, blister, and dissecting aneurysms.

Intracranial aneurysms (IAs) linger as a potentially devastating clinical problem. Despite intense investigation, our understanding of the mechanisms leading to aneurysm development, progression and rupture remain incompletely defined. An accumulating body of evidence implicates inflammation as a critical contributor to aneurysm pathogenesis. Intracranial aneurysm formation and progression appear to result from endothelial dysfunction, a mounting inflammatory response, and vascular smooth muscle cell phenotypic modulation producing a pro-inflammatory phenotype. A later final common pathway appears to involve apoptosis of cellular constituents of the vessel wall. These changes result in degradation of the integrity of the vascular wall leading to aneurysmal dilation, progression and eventual rupture in certain aneurysms. Various aspects of the inflammatory response have been investigated as contributors to IA pathogenesis including leukocytes, complement, immunoglobulins, cytokines, and other humoral mediators. Furthermore, gene expression profiling of IA compared with control arteries has prominently featured differential expression of genes involved with immune response/inflammation. Preliminary data suggest that therapies targeting the inflammatory response may have efficacy in the future treatment of IA. Further investigation, however, is necessary to elucidate the precise role of inflammation in IA pathogenesis, which can be exploited to improve the prognosis of patients harboring IA.

Background M1 and M2 cells are two major subsets of human macrophages that exert opposite effects on the inflammatory response. This study aims to investigate the role of macrophage M1/M2 imbalance and mast cells in the progression of human cerebral aneurysms to rupture. Methods Ten patients with cerebral aneurysms (five ruptured and five unruptured) underwent microsurgical clipping. During the procedure, a segment of the aneurysm dome was resected and immunostained with monoclonal antibodies for M1 cells (anti-HLA DR), M2 cells (anti-CD 163), and mast cells (anti-tryptase clone AA). A segment of the superficial temporal artery (STA) was also removed and immunostained with monoclonal antibodies for M1, M2, and mast cells. Results All ten aneurysm tissues stained positive for M1, M2, and mast cells. M1 and M2 cells were present in equal proportions in unruptured aneurysms. This contrasted with a marked predominance of M1 over M2 cells in ruptured aneurysms ( p  = 0.045). Mast cells were also prominently upregulated in ruptured aneurysms ( p  = 0.001). Few M1 and M2 cells were present in STA samples. Conclusions M1/M2 macrophages and mast cells are found in human cerebral aneurysms; however, M1 and mast cell expression seems to markedly increase in ruptured aneurysms. These findings suggest that macrophage M1/M2 imbalance and upregulation of mast cells may have a role in the progression of cerebral aneurysms to rupture.

Reperfusion therapies, such as intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT), are crucial for improving outcomes in patients with acute ischemic stroke (AIS). However, access to these treatments can vary significantly due to ethnicity, socioeconomic status (SES), and geographical location, impacting patient outcomes. The Disparities in Access to Reperfusion Therapy for Acute Ischemic Stroke (DARTS) study aims to systematically assess disparities in access to IVT and EVT on the basis of ethnicity, SES, and geographical location. A comprehensive meta-analysis was conducted, incorporating data from 38 studies involving 5,256,531 patients with AIS. The analysis evaluated IVT and EVT utilization rates across ethnic groups, SES levels, and geographical locations. The findings reveal substantial disparities in access to reperfusion therapies. IVT and EVT utilization rates varied significantly by ethnicity (9% ethnic, 11% non-ethnic for IVT; 7% ethnic, 6% non-ethnic for EVT), SES (13% low SES, 16% high SES for IVT; 7% low SES, 10% high SES for EVT), and geography (9% rural, 12% urban for IVT; 1% rural, 4% urban for EVT). Black patients had significantly lower odds of receiving IVT (OR 0.69, p = 0.001) and EVT (OR 0.87, p = 0.005) compared with white patients. Similarly, patients with low SES and those from rural areas faced reduced odds of receiving IVT (OR 0.74, p < 0.001; OR 0.72, p = 0.002) and EVT (OR 0.74, p < 0.001; OR 0.39, p < 0.001). Rural patients also had significantly lower odds of timely hospital arrival (p < 0.001), posing a barrier to accessing reperfusion therapies. The DARTS study (and this meta-analysis) reveals significant access disparities in AIS treatment related to ethnicity, geography, and SES, particularly affecting Black communities, low SES individuals, and rural populations. Despite advances in reperfusion therapies, suboptimal implementation rates persist. To address these issues, we recommend the EQUITY framework: Educate, Ensure Quality, provide Universal Access, Implement Inclusive Policy Reforms, Enhance Timely Data Collection, and Yield Culturally Sensitive Care Practices. Adopting these recommendations will improve access, reduce disparities, and enhance stroke management and outcomes globally. Equitable access is essential for all eligible patients to fully benefit from reperfusion treatments.

Cerebral cavernous malformations are the most common vascular malformations and can be found in many locations in the brain. If left untreated, cavernomas may lead to intracerebral hemorrhage, seizures, focal neurological deficits, or headaches. As they are angiographically occult, their diagnosis relies on various MR imaging techniques, which detect different characteristics of the lesions as well as aiding in planning the surgical treatment. The clinical presentation and the location of the lesion are the most important factors involved in determining the optimal course of treatment of cavernomas. We concisely review the literature and discuss the advantages and limitations of each of the three available methods of treatment—microsurgical resection, stereotactic radiosurgery, and conservative management—depending on the lesion characteristics.

Cerebral arteriovenous malformations (AVMs) entail a significant risk of intracerebral hemorrhage owing to the direct shunting of arterial blood into the venous vasculature without the dissipation of the arterial blood pressure. The mechanisms involved in the growth, progression and rupture of AVMs are not clearly understood, but a number of studies point to inflammation as a major contributor to their pathogenesis. The upregulation of proinflammatory cytokines induces the overexpression of cell adhesion molecules in AVM endothelial cells, resulting in enhanced recruitment of leukocytes. The increased leukocyte-derived release of metalloproteinase-9 is known to damage AVM walls and lead to rupture. Inflammation is also involved in altering the AVM angioarchitecture via the upregulation of angiogenic factors that affect endothelial cell proliferation, migration and apoptosis. The effects of inflammation on AVM pathogenesis are potentiated by certain single-nucleotide polymorphisms in the genes of proinflammatory cytokines, increasing their protein levels in the AVM tissue. Furthermore, studies on metalloproteinase-9 inhibitors and on the involvement of Notch signaling in AVMs provide promising data for a potential basis for pharmacological treatment of AVMs. Potential therapeutic targets and areas requiring further investigation are highlighted.

The role of smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation and pathogenesis of stroke has not been determined. Cigarette smoke is a major risk factor for atherosclerosis, but potential mechanisms are unclear, and its role in SMC phenotypic modulation has not been established. In cultured cerebral vascular SMCs, exposure to cigarette smoke extract (CSE) resulted in decreased promoter activity and mRNA expression of key SMC contractile genes (SM-α-actin, SM-22α, SM-MHC) and the transcription factor myocardin in a dose-dependent manner. CSE also induced pro-inflammatory/matrix remodeling genes (MCP-1, MMPs, TNF-α, IL-1β, NF-κB). CSE increased expression of KLF4, a known regulator of SMC differentiation, and siKLF4 inhibited CSE induced suppression of SMC contractile genes and myocardin and activation of inflammatory genes. These mechanisms were confirmed in vivo following exposure of rat carotid arteries to CSE. Chromatin immune-precipitation assays in vivo and in vitro demonstrated that CSE promotes epigenetic changes with binding of KLF4 to the promoter regions of myocardin and SMC marker genes and alterations in promoter acetylation and methylation. CSE exposure results in phenotypic modulation of cerebral SMC through myocardin and KLF4 dependent mechanisms. These results provides a mechanism by which cigarette smoke induces a pro-inflammatory/matrix remodeling phenotype in SMC and an important pathway for cigarette smoke to contribute to atherosclerosis and stroke.

Little is known about vascular smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation or pathogenesis of intracranial aneurysms. Tumor necrosis factor-alpha (TNF-α) has been associated with aneurysms, but potential mechanisms are unclear. Cultured rat cerebral SMCs overexpressing myocardin induced expression of key SMC contractile genes (SM-α-actin, SM-22α, smooth muscle myosin heavy chain), while dominant-negative cells suppressed expression. Tumor necrosis factor-alpha treatment inhibited this contractile phenotype and induced pro-inflammatory/matrix-remodeling genes (monocyte chemoattractant protein-1, matrix metalloproteinase-3, matrix metalloproteinase-9, vascular cell adhesion molecule-1, interleukin-1 beta). Tumor necrosis factor-alpha increased expression of KLF4, a known regulator of SMC differentiation. Kruppel-like transcription factor 4 (KLF4) small interfering RNA abrogated TNF-α activation of inflammatory genes and suppression of contractile genes. These mechanisms were confirmed in vivo after exposure of rat carotid arteries to TNF-α and early on in a model of cerebral aneurysm formation. Treatment with the synthesized TNF-α inhibitor 3,6-dithiothalidomide reversed pathologic vessel wall alterations after induced hypertension and hemodynamic stress. Chromatin immunoprecipitation assays in vivo and in vitro demonstrated that TNF-α promotes epigenetic changes through KLF4-dependent alterations in promoter regions of myocardin, SMCs, and inflammatory genes. In conclusion, TNF-α induces phenotypic modulation of cerebral SMCs through myocardin and KLF4-regulated pathways. These results demonstrate a novel role for TNF-α in promoting a pro-inflammatory/matrix-remodeling phenotype, which has important implications for the mechanisms behind intracranial aneurysm formation.

Little is known about vascular smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation or pathogenesis of intracranial aneurysms. Tumor necrosis factor-alpha (TNF-α) has been associated with aneurysms, but potential mechanisms are unclear. Cultured rat cerebral SMCs overexpressing myocardin induced expression of key SMC contractile genes (SM-α-actin, SM-22α, smooth muscle myosin heavy chain), while dominant-negative cells suppressed expression. Tumor necrosis factor-alpha treatment inhibited this contractile phenotype and induced pro-inflammatory/matrix-remodeling genes (monocyte chemoattractant protein-1, matrix metalloproteinase-3, matrix metalloproteinase-9, vascular cell adhesion molecule-1, interleukin-1 beta). Tumor necrosis factor-alpha increased expression of KLF4, a known regulator of SMC differentiation. Kruppel-like transcription factor 4 (KLF4) small interfering RNA abrogated TNF-α activation of inflammatory genes and suppression of contractile genes. These mechanisms were confirmed in vivo after exposure of rat carotid arteries to TNF-α and early on in a model of cerebral aneurysm formation. Treatment with the synthesized TNF-α inhibitor 3,6-dithiothalidomide reversed pathologic vessel wall alterations after induced hypertension and hemodynamic stress. Chromatin immunoprecipitation assays in vivo and in vitro demonstrated that TNF-α promotes epigenetic changes through KLF4-dependent alterations in promoter regions of myocardin, SMCs, and inflammatory genes. In conclusion, TNF-α induces phenotypic modulation of cerebral SMCs through myocardin and KLF4-regulated pathways. These results demonstrate a novel role for TNF-α in promoting a pro-inflammatory/matrix-remodeling phenotype, which has important implications for the mechanisms behind intracranial aneurysm formation.

Introduction. Idiopathic intracranial hypertension (IIH) may result in a chronic debilitating disease. Dural venous sinus stenosis with a physiologic venous pressure gradient has been identified as a potential etiology in a number of IIH patients. Intracranial venous stenting has emerged as a potential treatment alternative. Methods. A systematic review was carried out to identify studies employing venous stenting for IIH. Results. From 2002 to 2014, 17 studies comprising 185 patients who underwent 221 stenting procedures were reported. Mean prestent pressure gradient was 20.1 mmHg (95% CI 19.4–20.7 mmHg) with a mean poststent gradient of 4.4 mmHg (95% CI 3.5–5.2 mmHg). Complications occurred in 10 patients (5.4%; 95% CI 4.7–5.4%) but were major in only 3 (1.6%). At a mean clinical follow-up of 22 months, clinical improvement was noted in 130 of 166 patients with headaches (78.3%; 95% CI 75.8–80.8%), 84 of 89 patients with papilledema (94.4%; 95% CI 92.1–96.6%), and 64 of 74 patients with visual symptoms (86.5%; 95% CI 83.0–89.9%). In-stent stenosis was noted in six patients (3.4%; 95% CI 2.5–4.3%) and stent-adjacent stenosis occurred in 19 patients (11.4%; 95% CI 10.4–12.4), resulting in restenting in 10 patients. Conclusion. In IIH patients with venous sinus stenosis and a physiologic pressure gradient, venous stenting appears to be a safe and effective therapeutic option. Further studies are necessary to determine the long-term outcomes and the optimal management of medically refractory IIH.