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Subarachnoid hemorrhage or intracerebral hemorrhage caused by rupture of a saccular intracranial aneurysm (sIA) is often fatal and causes significant loss of productive live years in addition to significant mortality. Around 3.5 % of the middle aged otherwise healthy population carries unruptured sIAs. Many sIAs never rupture, and since their prophylactic treatment is associated with risks of morbidity and even mortality, it is paramount to elucidate the biology that leads to sIA rupture in order be able to identify rupture-prone sIAs and to improve current therapies. Smooth muscle cells (SMCs) play a critical role both in the formation of sIAs, as well as in the repair and adaptation of the sIA wall to hemodynamic and proteolytic stress to which it is subjected. Loss of mural SMCs is characteristic to ruptured sIA walls, and experiments in animal models suggest that this loss of mural SMCs is causative to sIA growth and eventual rupture. Genetic factors that impair the function or survival of SMCs may predispose to sIA formation. Local or systemic therapy that increases the number of functioning SMCs in the sIA wall may have a potential to reduce the risk of sIA rupture. This review discusses the mechanisms and cellular interactions that SMCs have in the pathobiology of the sIA wall.

Saccular intracranial aneurysms (sIA) are pouch-like pathological dilatations of intracranial arteries that develop when the cerebral artery wall becomes too weak to resist hemodynamic pressure and distends. Some sIAs remain stable over time, but in others mural cells die, the matrix degenerates, and eventually the wall ruptures, causing life-threatening hemorrhage. The wall of unruptured sIAs is characterized by myointimal hyperplasia and organizing thrombus, whereas that of ruptured sIAs is characterized by a decellularized, degenerated matrix and a poorly organized luminal thrombus. Cell-mediated and humoral inflammatory reaction is seen in both, but inflammation is clearly associated with degenerated and ruptured walls. Inflammation, however, seems to be a reaction to the ongoing degenerative processes, rather than the cause. Current data suggest that the loss of mural cells and wall degeneration are related to impaired endothelial function and high oxidative stress, caused in part by luminal thrombosis. The aberrant flow conditions caused by sIA geometry are the likely cause of the endothelial dysfunction, which results in accumulation of cytotoxic and pro-inflammatory substances into the sIA wall, as well as thrombus formation. This may start the processes that eventually can lead to the decellularized and degenerated sIA wall that is prone to rupture.

Rupture of a saccular intracranial artery aneurysm (IA) causes subarachnoid hemorrhage, a significant cause of stroke and death. The current treatment options, endovascular coiling and clipping, are invasive and somewhat risky. Since only some IAs rupture, those IAs at risk for rupture should be identified. However, to improve the imaging of rupture-prone IAs and improve IA treatment, IA wall pathobiology requires more thorough knowledge. Chronic inflammation has become understood as an important phenomenon in IA wall pathobiology, featuring inflammatory cell infiltration as well as proliferative and fibrotic remodulatory responses. We review the literature on what is known about inflammation in the IA wall and also review the probable mechanisms of how inflammation would result in the degenerative changes that ultimately lead to IA wall rupture. We also discuss current options in imaging inflammation and how knowledge of inflammation in IA walls may improve IA treatment.

Background Aneurysmal subarachnoid hemorrhage (aSAH) is a neurological emergency, affecting a younger population than individuals experiencing an ischemic stroke; aSAH is associated with a high risk of mortality and permanent disability. The noble gas xenon has been shown to possess neuroprotective properties as demonstrated in numerous preclinical animal studies. In addition, a recent study demonstrated that xenon could attenuate a white matter injury after out-of-hospital cardiac arrest. Methods The study is a prospective, multicenter phase II clinical drug trial. The study design is a single-blind, prospective superiority randomized two-armed parallel follow-up study. The primary objective of the study is to explore the potential neuroprotective effects of inhaled xenon, when administered within 6 h after the onset of symptoms of aSAH. The primary endpoint is the extent of the global white matter injury assessed with magnetic resonance diffusion tensor imaging of the brain. Discussion Despite improvements in medical technology and advancements in medical science, aSAH mortality and disability rates have remained nearly unchanged for the past 10 years. Therefore, new neuroprotective strategies to attenuate the early and delayed brain injuries after aSAH are needed to reduce morbidity and mortality. Trial registration ClinicalTrials.gov NCT04696523. Registered on 6 January 2021. EudraCT, EudraCT Number: 2019-001542-17. Registered on 8 July 2020.

Background Non-aneurysmal subarachnoid hemorrhages (SAHs) are thought to have a benign clinical course compared to aneurysmal SAHs. The aim of this study is to report the clinical course and outcomes of non-aneurysmal SAHs in a large single-center study. Methods The patients with non-aneurysmal SAHs were screened from Tampere University Hospital from 2005 to 2020. The clinical data were collected from the patient’s medical records and from the imaging studies. The primary interest was the neurological outcome assessed by dichotomized GOS at 2 months. Multivariable logistic regression was used to study the factors associated with unfavorable outcome. Results We found 216 non-aneurysmal SAHs in 214 patients (2 patients with > 1 bleed). Ninety-seven percent of patients with a typical perimesencephalic bleeding pattern SAH (PSAH) (75/77) had a favorable outcome, while 86% of patients with non-perimesencephalic SAH (NPSAH) had a favorable outcome (84/98). In a multivariable logistic regression analysis, loss of consciousness (LOC) (aOR 214.67, 95% CI 17.62–2615.89) and Fisher grade 4 bleeding pattern (aOR 23.32, 95% CI 1.40–387.98) were associated with increased risk for unfavorable outcome (GOS 1–3). Vasospasm was seen in 20% of non-aneurysmal SAH patients, hydrocephalus in 17%, and 13% needed ventriculostomy. Conclusions Non-aneurysmal SAH seems to have a good prognosis for majority of patients, especially for patients with a PSAH. Non-aneurysmal SAH patients are however affected by vasospasm and hydrocephalus and have similar risk factors for poor outcome as patients with aneurysmal SAH. This suggests that it is the severity of the bleed rather than the etiology that associates with poor outcome.

BackgroundHemorrhage from an arteriovenous malformation of the brain (bAVM) has been associated with focal inflammation of the bAVM. Intrigued by the possibility of anti-inflammatory drug therapy to stabilize bAVMs and prevent hemorrhage, we investigated the association of bAVM inflammation with other histological features and clinical presentation.Materials and methodsTissue samples from 85 surgically treated bAVMs were studied with histology and CD45 immunostainings. The histological data was compared with the clinical history of the patient. Univariate analysis and logistic regression were performed.ResultsInflammation was found in all studied bAVMs and did not associate with rupture (p = 0.442). While multiple types of inflammatory cells were present, macrophages were clearly the dominant inflammatory cell type, especially in samples with strong inflammation (87% of the samples). Of those bAVMs that had strong inflammation, only 56% had presented with clinically evident rupture. However, hemosiderin which is a sign of prior hemorrhage was detected in 78.4% (58/74) of samples with strong inflammation and was associated with it (p = 0.003). Inflammation in the nidus and parenchyma was associated with perivascular inflammation (p < 0.001). Multivariate analysis did not reveal any independent histological or clinical risk factor for inflammation.ConclusionsSince strong inflammation is present in both unruptured and ruptured bAVMs, it is not just a reaction to rupture. Our observations suggest that inflammation of the bAVM may indeed predispose to fragility and hemorrhage of the nidal vessels. Further studies in the role of inflammation in the untreated clinical course of bAVMs are indicated.

Purpose Periodontal diseases and caries are common oral diseases that predispose to tooth loss if untreated. In this study, we investigated whether loss of teeth or caries associate with intracranial aneurysm (IA) pathology similar to periodontal diseases. Methods A total of 166 patients with either IA or aneurysmal subarachnoid hemorrhage (aSAH) underwent oral examination in Kuopio University Hospital and Tampere University Hospital. Findings were compared to geographically matched controls acquired from cross-sectional Health2000 survey. This study consisted of three sequential steps. First, we compared the number of missing teeth and prevalence of caries in IA and aSAH patients and geographically matched control population, second step was a multivariate analysis including other risk factors, and third step was a 13-year follow-up of the Health2000 survey participants with missing teeth or caries at baseline. Results Loss of teeth did not significantly differ between IA patients and controls. In logistic regression model adjusted for known risk factors and demographic data, 1–4 caries lesions (OR: 0.40 95%Cl 0.2–0.9, p  = 0.031) was associated with lack of IAs, while age (OR: 1.03 95%Cl 1.01.1 p  = 0.024), current smoking (OR: 2.7 95%Cl 1.4–5.1, p  = 0.003), and severe periodontitis (OR: 5.99 95%Cl 2.6–13.8, p  < 0.001) associated to IA formation. In the cox-regression, severe periodontitis at baseline increased the risk of aSAH (HR: 14.3, 95%Cl 1.5–135.9, p  = 0.020) during a 13-year follow-up, while caries or missing teeth did not. Conclusion Unlike severe periodontitis, caries does not increase the risk of IAs and aSAHs. However, cariogenic bacteria may participate to IA pathology by disseminating to circulation via inflamed gingival tissue.

BackgroundArteriovenous malformations of the brain (bAVM) may rupture from aneurysms or ectasias of the feeding, draining, or nidal vessels. Moreover, they may rupture from the immature, fragile nidal vessels that are characteristic to bAVMs. How the histopathological changes of the nidal vessels associate with clinical presentation and hemorrhage of the lesion is not well known.Materials and methodsWe investigated tissue samples from surgically treated bAVMs (n = 85) using standard histological and immunohistochemical stainings. Histological features were compared with the clinical presentation of the patient.ResultsMicrohemorrhages from nidal vessels were found both in bAVMs with a history of clinically evident rupture and in bAVMs considered unruptured. These microhemorrhages were associated with presence of immature, pathological nidal vessels (p = 0.010) and perivascular inflammation of these vessels (p = 0.001), especially with adhesion of neutrophils (p < 0.001). In multivariate analysis, perivascular inflammation (OR = 19, 95% CI 1.6 to 230), neutrophil infiltration of the vessel wall (OR = 13, 95% CI 1.9 to 94), and rupture status (OR = 0.13, 95% CI 0.017 to 0.92) were significantly associated with microhemorrhages.ConclusionsClinically silent microhemorrhages from nidal vessels seem to be very common in bAVMs, and associate with perivascular inflammation and neutrophil infiltration. Further studies on the role of perivascular inflammation in the clinical course of bAVMs are indicated.

Abstract Rupture of a saccular intracranial aneurysm (sIA) is often fatal. Thus, early detection of rupture-prone sIAs is vital. Myeloperoxidase (MPO), derived mainly from neutrophils, associates with sIA rupture, and therefore its role in sIA pathogenesis warrants further studies. We analyzed MPO and its association with other histological markers in 36 (16 unruptured and 20 ruptured) sIA samples by immunohistochemistry. MPO was present in all studied sIAs, and its expression associated with wall inflammatory cell infiltrations (r = 0.50, 0.63, and 0.75, all p ≤ 0.002), degenerative remodeling (p = 0.002) and rupture (p = 0.003). MPO associated strongly with the presence of organized luminal thrombi (p < 0.001), which also stained positive for MPO. Polymorphonuclear MPO+ cells were detected in the sIA walls, indicating neutrophils as MPO-source. MPO correlated strongly with accumulation of oxidized lipids (r = 0.67, p < 0.001) and loss of smooth muscle cells (r = −0.68, p < 0.001), suggesting that MPO is a relevant source of oxidative stress leading to cell death in the sIA wall. Furthermore, MPO associated with erythrocyte fragmentation (r = 0.74, p < 0.001) and iron deposition (p = 0.041), 2 outcomes known to amplify MPO-dependent oxidative stress. Taken together, these results suggest that MPO associates with degenerative remodeling predisposing to sIA wall rupture and may serve as a biomarker of a rupture-prone sIA wall.