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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 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.

Treatment for arteriovenous malformations of the brain (bAVMs) aims to achieve complete removal or occlusion of the lesion in order to eradicate the risk of rupture and subsequent morbidity associated with these lesions. Despite initially successful treatment, bAVMs may carry a risk of recurrence especially in younger patients. We studied the rate of recurrence of surgically treated bAVMs at Kuopio University Hospital (KUH) in 1981–2021. The study population was collected retrospectively from KUH databases and presented a cohort of 135 surgically treated bAVMs with complete occlusion of the lesion. We also performed a systematic literature review on this topic. In our series, 6 out of 135 (4.4%) patients with angiographically confirmed removal of the lesion later developed a recurrent bAVM with a median time to diagnosis of recurrence of 7.46 years. In pediatric patients, the rate was 5 out of 17 (29.4%). bAVM recurrence was associated with age (p = 0.001) and initial hemorrhagic presentation (p = 0.039). Median age of the study population was 37 years (min 0, max 70), and 51/135 (37.8%) of the patients were female. Seventeen (12.6%) of the 135 bAVM patients were considered pediatric (18 years old or younger) at the time of the operation. In the literature review, 79 of 1739 (4.5%) of surgically treated patients later developed a recurrence with a mean delay of 3.1 years until diagnosis of recurrence. Young surgically treated bAVM patients with a hemorrhagic presentation at initial diagnosis are at a relatively high risk of bAVM recurrence. Follow-up imaging should be arranged for these patients in order to prevent rupture from a recurrent bAVM and subsequent morbidity.

Hypertension is a risk factor for subarachnoid hemorrhage and is also considered a risk factor for saccular intracranial aneurysm (sIA) formation. However, there is little direct evidence that antihypertensive medication will reduce sIA formation.The impact of antihypertensive medication on de novo sIA formation was studied in an angiographically followed cohort of 1419 patients. Patients were identified from our population-based Kuopio Intracranial Aneurysm Database, and data on the purchases of antihypertensive medication were obtained from a national registry. Univariate and multivariate analyses were used to investigate the risk factors.Of the 966 sIA patients who were prescribed with antihypertensive medication, 841 patients used the medication regularly; 20 of them had de novo sIA. One hundred and twenty-five patients used the medication irregularly and 12 of them developed de novo sIAs. Four hundred and fifty-three patients did not use antihypertensive medication even though 27 of them had a diagnosis of hypertension, and 10 of them developed de novo sIAs. In the multivariate analysis antihypertensive medication did not significantly reduce de novo sIA formation (hazard ratio [HR] 1.60, 95% confidence interval [CI] 0.84-3.06). Age at primary diagnosis (HR: 0.95, 95%: CI 0.93-0.98) and smoking history (HR: 5.53, 95% CI: 2.77-11.05) were significant risk factors for de novo sIA formation. Also, irregular usage of antihypertensive medication was a significant risk factor (HR: 3.84, 95% CI: 1.59-9.29) for de novo sIA formation.Antihypertensive agents were not associated with a reduction of de novo sIA formation, but irregular use of antihypertensive agents was associated with an increased risk of de novo sIA formation.

BackgroundBleb presence in intracranial aneurysms (IAs) is a known indication of instability and vulnerability.ObjectiveTo develop and evaluate predictive models of bleb development in IAs based on hemodynamics, geometry, anatomical location, and patient population.MethodsCross-sectional data (one time point) of 2395 IAs were used for training bleb formation models using machine learning (random forest, support vector machine, logistic regression, k-nearest neighbor, and bagging). Aneurysm hemodynamics and geometry were characterized using image-based computational fluid dynamics. A separate dataset with 266 aneurysms was used for model evaluation. Model performance was quantified by the area under the receiving operating characteristic curve (AUC), true positive rate (TPR), false positive rate (FPR), precision, and balanced accuracy.ResultsThe final model retained 18 variables, including hemodynamic, geometrical, location, multiplicity, and morphology parameters, and patient population. Generally, strong and concentrated inflow jets, high speed, complex and unstable flow patterns, and concentrated, oscillatory, and heterogeneous wall shear stress patterns together with larger, more elongated, and more distorted shapes were associated with bleb formation. The best performance on the validation set was achieved by the random forest model (AUC=0.82, TPR=91%, FPR=36%, misclassification error=27%).ConclusionsBased on the premise that aneurysm characteristics prior to bleb formation resemble those derived from vascular reconstructions with their blebs virtually removed, machine learning models can identify aneurysms prone to bleb development with good accuracy. Pending further validation with longitudinal data, these models may prove valuable for assessing the propensity of IAs to progress to vulnerable states and potentially rupturing.

Background Brain arteriovenous malformations (bAVM) may rupture causing disability or death. BAVM vessels are characterized by abnormally high flow that in general triggers expansive vessel remodeling mediated by cyclo-oxygenase-2 (COX2), the target of non-steroidal anti-inflammatory drugs. We investigated whether COX2 is expressed in bAVMs and whether it associates with inflammation and haemorrhage in these lesions. Methods Tissue was obtained from surgery of 139 bAVMs and 21 normal Circle of Willis samples. The samples were studied with immunohistochemistry and real-time quantitative polymerase chain reaction (RT-PCR). Clinical data was collected from patient records. Results COX2 expression was found in 78% (109/139) of the bAVMs and localized to the vessels’ lumen or medial layer in 70% (95/135) of the bAVMs. Receptors for prostaglandin E2, a COX2-derived mediator of vascular remodeling, were found in the endothelial and smooth muscle cells and perivascular inflammatory cells of bAVMs. COX2 was expressed by infiltrating inflammatory cells and correlated with the extent of inflammation (r = .231, p = .007, Spearman rank correlation). COX2 expression did not associate with haemorrhage. Conclusion COX2 is induced in bAVMs, and possibly participates in the regulation of vessel wall remodelling and ongoing inflammation. Role of COX2 signalling in the pathobiology and clinical course of bAVMs merits further studies.

BackgroundBlebs are important secondary structures of intracranial aneurysms associated with increased rupture risk and can affect local wall stress and hemodynamics. Mechanisms of bleb development and evolution are not clearly understood. We investigate the relationship between blebs with different wall characteristics and local hemodynamics and rupture sites.MethodsBlebs with different wall appearances in intra-operative videos were analyzed with image-based computational fluid dynamics. Thin red blebs were compared against thick atherosclerotic/hyperplastic white/yellow blebs. Rupture points were identified in videos of ruptured aneurysms harboring blebs.ResultsThin blebs tended to be closer to the inflow than atherosclerotic blebs of the same aneurysm (P=0.0234). Blebs near the inflow had higher velocity (P=0.0213), vorticity (P=0.0057), shear strain rate (P=0.0084), wall shear stress (WSS) (P=0.0085), and WSS gradient (P=0.0151) than blebs far from the inflow. In a subset of 12 ruptured aneurysms harboring blebs, rupture points were associated with thin blebs in 42% of aneurysms, atherosclerotic blebs in 25%, and were away from blebs in the remaining 33%.ConclusionsNot all blebs are equal; some have thin translucent walls while others have thick atherosclerotic walls. Thin blebs tend to be located closer to the inflow than atherosclerotic blebs. Blebs near the inflow are exposed to stronger flows with higher and spatially variable WSS than blebs far from the inflow which tend to have uniformly lower WSS. Aneurysms can rupture at thin blebs, atherosclerotic blebs, and even away from blebs. Further study of wall failure in aneurysms with different bleb types is needed.

Background Hemorrhage 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 methods Tissue 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. Results Inflammation 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 Conclusions Since 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.

Animal models make an important contribution to our basic understanding of the pathobiology of human brain aneurysms, are indispensable in testing novel treatment approaches, and are essential for training interventional neuroradiologists and neurosurgeons. Researchers are confronted with a broad diversity of models and techniques in various species. This systematic review aims to summarize and categorize extracranial aneurysm models and their characteristics, discuss advantages and disadvantages, and suggest the best use of each model. We searched the electronical Medline/PubMed database between 1950 and 2020 to identify main models and their refinements and technical modifications for creation of extracranial aneurysms. Each study included was assessed for aneurysm-specific characteristics, technical details of aneurysm creation, and histological findings. Among more than 4000 titles and abstracts screened, 473 studies underwent full-text analysis. From those, 68 different techniques/models in five different species were identified, analyzed in detail, and then grouped into one of the five main groups of experimental models as sidewall, terminal, stump, bifurcation, or complex aneurysm models. This systematic review provides a compact guide for investigators in selecting the most appropriate model from a range of techniques to best suit their experimental goals, practical considerations, and laboratory environment.

Degeneration of intracranial aneurysm wall is under active research and recent studies indicate an increased risk of rupture of intracranial aneurysm among patients with periodontal diseases. In addition, oral bacterial DNA has been identified from wall samples of ruptured and unruptured aneurysms. These novel findings led us to evaluate if oral diseases could predispose to pathological changes seen on intracranial aneurysm walls eventually leading to subarachnoid hemorrhage. The aim of this review is to consider mechanisms on the relationship between periodontitis and aneurysm rupture, focusing on recent evidence.

Background and purpose: Pathophysiological studies of saccular intracranial aneurysm (sIA) disease have shown that inflammation plays a crucial role in sIA development. Pharmaceutical inhibition of COX-2–PGE2–NF-κB signaling (COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; NF-κB, nuclear factor κB) has been shown in animal models to inhibit sIA formation and progression suggesting that use of medication inhibiting COX-2 could reduce intracranial aneurysm formation also in patients. Methods: The impact of COX-2 inhibition on de novo sIA formation was studied in two cohorts: in a previously described angiographically followed cohort of 1419 sIA patients and in a cohort of 117 sIA patients treated with stenting or stent-assisted embolization. Patients were identified from our population-based Kuopio Intracranial Aneurysm Database. Data on the use of anti-inflammatory medications and hospital diagnoses were obtained from national registries. Risk factors were identified by univariate and multivariate analyses. Results: De novo sIA patients were younger and more often smokers. Use of COX-2 selective inhibitors or nonsteroidal anti-inflammatory drugs did not significantly reduce de novo sIA formation, but the percentage of patients with de novo sIA formation was smaller in patients with prescribed regular acetylsalicylic acid medication (1.1% vs. 3.6%). In the multivariate analysis, however, neither acetylsalicylic acid use nor other type of pharmaceutical inhibition of COX-2 reduced the formation of de novo sIAs. The risk was mostly affected by age, smoking history and irregular usage of antihypertensive medication regardless of used COX-2 inhibition level. Conclusions: For the prevention of de novo sIA formation, risk factor management with focus on cessation of smoking and treating hypertension adequately seems more important than pharmaceutical COX-2 inhibition.

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Background:Periodontal infections have been associated to the formation and rupture of intracranial aneurysms (IA). In this study we investigated whether also caries (tooth decay) associates to IA pathology.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 age, gender and geographically matched controls acquired from cross-sectional Health 2000 Survey. This study consisted three sequential steps. First step was a comparison of the caries prevalence and number of missing teeth in IA and aSAH patients with the control population, second step was a multivariate analysis with demographic factors and third step was a prospective 13-year follow-up of participants with any caries or missing teeth.Results:In logistic regression adjusted for known risk factors and demographic data, caries (OR: 0.412 95%Cl 0.2-0.9, p=0.028) was associated with lack of IAs, while age (OR:1.029 95%Cl 1.0-1.1 p=0.039), current smoking (OR:2.7 95%Cl 1.4-5.1, p=0.003) and severe periodontitis (OR:4.3 95%Cl 2.3-12.5, pConclusion:Unlike 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.

Objective: Although the clinical and biological importance of calcification is well recognized for the extracerebral vasculature, its role in cerebral vascular disease, particularly, intracranial aneurysms (IAs), remains poorly understood. Extracerebrally, 2 distinct mechanisms drive calcification, a nonatherosclerotic, rapid mineralization in the media and a slower, inflammation driven, atherosclerotic mechanism in the intima. This study aims to determine the prevalence, distribution, and type (atherosclerotic, nonatherosclerotic) of calcification in IAs and assess differences in occurrence between ruptured and unruptured IAs. Approach and Results: Sixty-five 65 IA specimens (48 unruptured, 17 ruptured) were resected perioperatively. Calcification and lipid pools were analyzed nondestructively in intact samples using high resolution (0.35 μm) microcomputed tomography. Calcification is highly prevalent (78%) appearing as micro (1 mm) calcifications. Calcification manifests in IAs as both nonatherosclerotic (calcification distinct from lipid pools) and atherosclerotic (calcification in the presence of lipid pools) with 3 wall types: Type I—only calcification, no lipid pools (20/51, 39%), Type II—calcification and lipid pools, not colocalized (19/51, 37%), Type III—calcification colocalized with lipid pools (12/51, 24%). Ruptured IAs either had no calcifications or had nonatherosclerotic micro- or meso-calcifications (Type I or II), without macro-calcifications. Conclusions: Calcification in IAs is substantially more prevalent than previously reported and presents as both nonatherosclerotic and atherosclerotic types. Notably, ruptured aneurysms had only nonatherosclerotic calcification, had significantly lower calcification fraction, and did not contain macrocalcifications. Improved understanding of the role of calcification in IA pathology should lead to new therapeutic targets.

Background Treatment of gunshot wounds of the brain (GSWB) remains controversial and there is high variation in reported survival rates (from 90%) depending on the etiology and country. We retrospectively analyzed the outcome of a series of consecutive GSWB patients admitted alive to a level 1 trauma center in a safe high-income welfare country with a low rate of homicidal gun violence. Methods Patients admitted due to a GSWB to the HUS Helsinki University Hospital during 2000–2012 were identified from hospital discharge registry and log books of the emergency room and ICU. CT scans and medical records of these patients were reviewed. Univariate analysis and backward logistic regression were performed, and their results compared with that of a systematic literature review of factors related to the outcome of GSWB patients. Results Sixty-four patients admitted alive after GSWB were identified. Eighty percent had self-inflicted GSWB, 81% were contact shots, and 70% were caused by handguns. In-hospital mortality was 72%. Factors associated with mortality in our series were low GCS (≤ 8) at admission, transventricular bullet trajectory, and associated damage to deep brain structures, as reported before in the literature. Of the 64 patients admitted alive, 42% (27/64) were admitted to ICU, 34% (22/64) underwent surgery, and in 25% (16/64), craniotomy and hematoma evacuation was performed. Mortality in the surgically treated group was 32% but near 100% without surgery and ICU treatment. Median GOS in the surgically treated patients was 3 (range 1–5). Conclusions GSWB caused by contact shot from handguns has a high mortality rate, but can be survived with reasonable outcome if limited to lobar injury without significant damage to deep brain structures or brain stem. In such GSWB patients, initial aggressive resuscitation, ICU admission, and surgery seem indicated. Electronic supplementary material The online version of this article (10.1007/s00701-019-03952-y) contains supplementary material, which is available to authorized users.

Oral bacteria DNA has been found in intracranial aneurysms (IA) and a high prevalence of periodontitis was reported in IA patients. We investigated whether periodontitis associates with IA formation and aneurysmal subarachnoid hemorrhage (aSAH). First, we compared in a case-control setting the prevalence of periodontal disease in IA patients (42 unruptured IA, 34 ruptured IA) and in age- and gender-matched controls (n = 70) from the same geographical area (Health 2000 Survey, BRIF8901). Next, we investigated whether periodontitis at baseline associated with aSAH in a 13-year follow-up study of 5170 Health 2000 Survey participants. Follow-up data was obtained from national hospital discharge and cause of death registries. Univariate analysis, logistic regression, and Cox-regression were used. Periodontitis (≥ 4mm gingival pocket) and severe periodontitis (≥ 6mm gingival pocket) were found in 92% and 49% of IA patients respectively and associated with IAs (OR 5.3, 95%CI 1.1–25.9, p

Background and purpose: Periodontal infections are associated with the formation and rupture of intracranial aneurysms (IAs). This study investigated the role of two key periodontal pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. Methods: Immunoglobulin A (IgA) and IgG antibodies against P. gingivalis and A. actinomycetemcomitans were measured with enzyme immune assay from the serum of 227 IA patients, of whom 64 also underwent clinical oral examination. As a control group, 1096 participants in a cross-sectional health survey, Health 2000, underwent serological studies and oral examination. Logistic regression was used for multivariate analysis. Immunohistochemistry was performed to demonstrate bacteria-derived epitopes in the IA wall. Results: Widespread gingivitis and severe periodontitis were more common in IA patients than in controls (2× and 1.5×, respectively). IgA antibodies against P. gingivalis and A. actinomycetemcomitans were 1.5× and 3–3.4× higher, respectively, in both unruptured and ruptured IA patients compared to controls (p ≤ 0.003). IgG antibodies against P. gingivalis were 1.8× lower in unruptured IA patients (p

BackgroundBlebs are rupture risk factors in intracranial aneurysms (IAs), but their prevalence, distribution, and associations with clinical factors as well as their causes and effects on aneurysm vulnerability remain unclear.MethodsA total of 122 blebs in 270 IAs selected for surgery were studied using patient-specific vascular reconstructions from 3D angiographic images. Bleb geometry, location on the aneurysm, and frequency of occurrence in aneurysms at different locations were analyzed. Associations between gender, age, smoking, hypertension, hormone therapy, dental infection, and presence of blebs were investigated.ResultsOf all aneurysms with blebs, 77% had a single bleb and 23% had multiple blebs. Only 6% of blebs were at the neck, while 46% were in the body and 48% in the dome. Aneurysms with blebs were larger (pConclusionsBlebs are common in IAs, and most aneurysms harboring blebs have a single bleb. Blebs in the aneurysm neck are rare, but they are equally common in the body and dome. The presence of blebs in IAs was associated with dental infection, and negatively associated with hormone replacement therapy.

Background Arteriovenous 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 methods We 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. Results Microhemorrhages 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 Conclusions Clinically 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.

Background and purposeDespite significant technical advances, recanalization rates after endovascular therapy of ruptured intracranial aneurysms (IAs) remain a clinical challenge. A histopathological hallmark of ruptured human IA walls is mural cell loss. Mural smooth muscle cells (SMCs) are known to promote intraluminal healing in thrombosed experimental aneurysms. In this rat model we assess the natural history and healing process after coil embolization in SMC-rich and decellularized aneurysms.MethodsSaccular aneurysms were created by end-to-side anastomosis of an arterial graft from the descending thoracic aorta of a syngeneic donor rat to the infrarenal abdominal aorta of recipient male Wistar rats. Untreated arterial grafts were immediately transplanted, whereas aneurysms with loss of mural cells were chemically decellularized before implantation. Aneurysms underwent coil implantation during aneurysm anastomosis. Animals were randomly assigned either to the non-decellularized or decellularized group and underwent macroscopic and histological analyses on days 3, 7, 21, or 90 post-coil implantation.ResultsA total of 55 rats underwent macroscopic and histologic analysis. After coil embolization, aneurysms with SMC-rich walls showed a linear course of thrombosis and neointima formation whereas decellularized aneurysms showed marked inflammatory wall degeneration with increased recanalization rates 21 days (p=0.002) and 90 days (p=0.037) later. The SMCs showed the ability to actively migrate into the intra-aneurysmal thrombus and participate in thrombus organization.ConclusionsCoil embolization of aneurysms with highly degenerated walls is prone to further wall degeneration, increased inflammation, and recanalization compared with aneurysms with vital SMC-rich walls.

Dural arteriovenous fistulas (DAVFs) are pathological, direct transcranial connections from extracranial arteries to intracranial venous sinuses or veins. DAVFs may lead to cortical venous reflux with supraphysiological flow and may subsequently rupture causing intracerebral, subarachnoidal, or subdural hemorrhages. Stereotactic radiosurgery (SRS) represents a valid option for selected DAVF cases. Overall, SRS leads to complete occlusion of the DAVF in approximately 60% of cases, (range 40–95%), at a follow-up ranging from 1 to 5 years.

Background Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. Methods We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations,...

Although endovascular therapy has been proven safe and has become in many centers the primary method of treatment for intracranial aneurysms, the long-term durability of endovascular embolization remains a concern; at least for some aneurysms despite initial good result. While healing after clipping relies on mechanical occlusion, restoration after endovascular occlusion mainly requires the induction of a biological response. Healing after embolization depends on the growth of new tissue over the thrombus formed by the embolization material, or alternatively, on the organization of thrombus into fibrous tissue. This review highlights the fundamental importance of aneurysm wall biology on the healing process and long-term occlusion after intracranial aneurysm (IA) treatment. It seems likely that the effect of luminal thrombus on the IA wall, as well as the IA wall condition at the time of thrombosis, determine if thrombus organizes into scar tissue (neointima formation by infiltration of cells originating from the IA wall) or if the wall undergoes continuous remodeling, which is primarily destructive (loss of mural cells). In the latter, intraluminal thrombus organization fails and the impaired healing increases the chance of recurrence. Mechanisms underlying IA reopening, the influence of intraluminal thrombosis on the IA wall, and clinical implications of the IA wall condition are discussed in detail, along with how knowledge of IA wall biology can offer new solutions for IA treatment and affect the patient selection for and follow-up after endovascular treatment.

OBJECTIVEIntracranial aneurysms (IAs) are more often diagnosed in women. Hormones and vessel geometry, which influences wall shear stress, may affect pathophysiological processes of the arterial wall. Here, the authors investigated sex-related differences in the remodeling of the aneurysm wall and in intraluminal thrombus resolution.METHODSA well-characterized surgical side-wall aneurysm model was used in female, male, and ovariectomized rats. Decellularized grafts were used to model highly degenerated and decellularized IA walls and native grafts to model healthy IA walls. Aneurysm growth and thrombus composition were analyzed at 1, 7, 14, and 28 days. Sex-related differences in vessel wall remodeling were compared with human IA dome samples of men and pre- and postmenopausal women.RESULTSAt 28 days, more aneurysm growth was observed in ovariectomized rats than in males or non-ovariectomized female rats. The parent artery size was larger in male rats than in female or ovariectomized rats, as expected. Wall inflammation increased over time in all groups and was most severe in the decellularized female and ovariectomized groups at 28 days compared with the male group. Likewise, in these groups the most elastin fragmentation was seen at 28 days. In female rats, on days 1, 7, and 14, the intraluminal thrombus was mainly composed of red blood cells and fibrin. On days 14 and 28, macrophage and smooth muscle cell invasion inside the thrombus was shown, leading to the removal of red blood cells and deposition of collagen and elastin. On days 14 and 28, similar profiles of thrombus reorganization were observed in male and ovariectomized female rats. However, collagen content in thrombi and vessel wall macrophage content were higher in aneurysms of male rats at 28 days than in those of female rats. On day 28, thrombus coverage by endothelial cells was lower in ovariectomized than in female or male rats. Finally, analysis of human IA domes showed that endothelial cell coverage was lower in men and postmenopausal women than in younger women.CONCLUSIONSAneurysm growth and intraluminal thrombus resolution show sex-dependent differences. While certain processes (endothelial cell coverage and collagen deposition) point to a strong hormonal dependence, others (wall inflammation and aneurysm growth) seem to be influenced by both hormones and parent artery size.

BACKGROUND AND PURPOSE: While previous studies have identified many risk factors for the progression and rupture of cerebral aneurysms, the changes in aneurysm flow characteristics during its evolution are not fully understood. This work analyzes the changes in the aneurysm hemodynamic environment from its initial development to later stages when the aneurysm has substantially enlarged. MATERIALS AND METHODS: A total of 88 aneurysms at four locations were studied with image based CFD. Two synthetic sequences representing the aneurysm geometry at three earlier stages were generated by shrinking the aneurysm sac while keeping the neck fixed or shrinking the neck simultaneously. The flow conditions were then quantitatively compared between these two modes of evolution. RESULTS: As aneurysms enlarged, the inflow rate increased in growing neck sequences, but decreased in fixed neck sequences. The inflow jet became more concentrated in both sequences. The mean aneurysm flow velocity and wall shear stress decreased in both sequences, but they decreased faster in enlarging aneurysms if the neck was fixed. Additionally, the intra-aneurysmal flows became more complex and more unstable, wall shear stress distribution became more oscillatory, and the area under low wall shear stress increased for both sequences. CONCLUSION: The evolution of flow characteristics of aneurysms with fixed and growing necks are different. The observed trends suggest that fixed neck aneurysms may evolve towards a flow environment characteristic of stable aneurysms faster than aneurysms with growing necks, which could also evolve towards a more disfavorable environment.

OBJECTIVEUnruptured intracranial aneurysms (UIAs) are relatively common lesions that may cause devastating intracranial hemorrhage, thus producing considerable suffering and anxiety in those affected by the disease or an increased likelihood of developing it. Advances in the knowledge of the pathobiology behind intracranial aneurysm (IA) formation, progression, and rupture have led to preclinical testing of drug therapies that would prevent IA formation or progression. In parallel, novel biologically based diagnostic tools to estimate rupture risk are approaching clinical use. Arterial wall remodeling, triggered by flow and intramural stresses and mediated by inflammation, is relevant to both.METHODSThis review discusses the basis of flow-driven vessel remodeling and translates that knowledge to the observations made on the mechanisms of IA initiation and progression on studies using animal models of induced IA formation, study of human IA tissue samples, and study of patient-derived computational fluid dynamics models.RESULTSBlood flow conditions leading to high wall shear stress (WSS) activate proinflammatory signaling in endothelial cells that recruits macrophages to the site exposed to high WSS, especially through macrophage chemoattractant protein 1 (MCP1). This macrophage infiltration leads to protease expression, which disrupts the internal elastic lamina and collagen matrix, leading to focal outward bulging of the wall and IA initiation. For the IA to grow, collagen remodeling and smooth muscle cell (SMC) proliferation are essential, because the fact that collagen does not distend much prevents the passive dilation of a focal weakness to a sizable IA. Chronic macrophage infiltration of the IA wall promotes this SMC-mediated growth and is a potential target for drug therapy. Once the IA wall grows, it is subjected to changes in wall tension and flow conditions as a result of the change in geometry and has to remodel accordingly to avoid rupture. Flow affects this remodeling process.CONCLUSIONSFlow triggers an inflammatory reaction that predisposes the arterial wall to IA initiation and growth and affects the associated remodeling of the UIA wall. This chronic inflammation is a putative target for drug therapy that would stabilize UIAs or prevent UIA formation. Moreover, once this coupling between IA wall remodeling and flow is understood, data from patient-specific flow models can be gathered as part of the diagnostic workup and utilized to improve risk assessment for UIA initiation, progression, and eventual rupture.

Mini-pterional approach or lateral supraorbital approach (LSO) is the consequent further development of the classic pterional approach to minimize size of the skull opening, operating time, and approach-related soft tissue trauma, while maintaining optimal view to the subfrontal space and a favorable trajectory for the dissection of the parasellar region, ACoA complex, and proximal Sylvian fissure.

OBJECTIVEIncidental aneurysms pose a challenge for physicians, who need to weigh the rupture risk against the risks associated with treatment and its complications. A statistical model could potentially support such treatment decisions. A recently developed aneurysm rupture probability model performed well in the US data used for model training and in data from two European cohorts for external validation. Because Japanese and Finnish patients are known to have a higher aneurysm rupture risk, the authors’ goals in the present study were to evaluate this model using data from Japanese and Finnish patients and to compare it with new models trained with Finnish and Japanese data.METHODSPatient and image data on 2129 aneurysms in 1472 patients were used. Of these aneurysm cases, 1631 had been collected mainly from US hospitals, 249 from European (other than Finnish) hospitals, 147 from Japanese hospitals, and 102 from Finnish hospitals. Computational fluid dynamics simulations and shape analyses were conducted to quantitatively characterize each aneurysm’s shape and hemodynamics. Next, the previously developed model’s discrimination was evaluated using the Finnish and Japanese data in terms of the area under the receiver operating characteristic curve (AUC). Models with and without interaction terms between patient population and aneurysm characteristics were trained and evaluated including data from all four cohorts obtained by repeatedly randomly splitting the data into training and test data.RESULTSThe US model’s AUC was reduced to 0.70 and 0.72, respectively, in the Finnish and Japanese data compared to 0.82 and 0.86 in the European and US data. When training the model with Japanese and Finnish data, the average AUC increased only slightly for the Finnish sample (to 0.76 ± 0.16) and Finnish and Japanese cases combined (from 0.74 to 0.75 ± 0.14) and decreased for the Japanese data (to 0.66 ± 0.33). In models including interaction terms, the AUC in the Finnish and Japanese data combined increased significantly to 0.83 ± 0.10.CONCLUSIONSDeveloping an aneurysm rupture prediction model that applies to Japanese and Finnish aneurysms requires including data from these two cohorts for model training, as well as interaction terms between patient population and the other variables in the model. When including this information, the performance of such a model with Japanese and Finnish data is close to its performance with US or European data. These results suggest that population-specific differences determine how hemodynamics and shape associate with rupture risk in intracranial aneurysms.

Background and Purpose— Shunt dependent hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH) is a common sequela that may lead to poor neurological outcome and predisposes to various interventions, admissions, and complications. We reviewed post-aSAH shunt dependency in a population-based sample and tested the feasibility of a clinical risk score to identify subgroups of aSAH patients with increasing risk of shunting for hydrocephalus. Methods— A total of 1533 aSAH patients from the population-based Eastern Finland Saccular Intracranial Aneurysm Database (Kuopio, Finland) were used in a recursive partitioning analysis to identify risk factors for shunting after aSAH. The risk model was built and internally validated in random split cohorts. External validation was conducted on 946 aSAH patients from the Southwestern Tertiary Aneurysm Registry (Dallas, TX) and tested using receiver-operating characteristic curves. Results— Of all patients alive ≥14 days, 17.7% required permanent cerebrospinal fluid diversion. The recursive partitioning analysis defined 6 groups with successively increased risk for shunting. These groups also successively risk stratified functional outcome at 12 months, shunt complications, and time-to-shunt rates. The area under the curve–receiver-operating characteristic curve for the exploratory sample and internal validation sample was 0.82 and 0.78, respectively, with an external validation of 0.68. Conclusions— Shunt dependency after aSAH is associated with higher morbidity and mortality, and prediction modeling of shunt dependency is feasible with clinically useful yields. It is important to identify and understand the factors that increase risk for shunting and to eliminate or mitigate the reversible factors. The aSAH-PARAS Consortium (Aneurysmal Subarachnoid Hemorrhage Patients’ Risk Assessment for Shunting) has been initiated to pool the collective insights and resources to address key questions in post-aSAH shunt dependency to inform future aSAH treatment guidelines.

BACKGROUND AND PURPOSE: Saccular intracranial aneurysm is a common disease that may cause devastating intracranial hemorrhage. Hemodynamics, wall remodeling, and wall inflammation have been associated with saccular intracranial aneurysm rupture. We investigated how saccular intracranial aneurysm hemodynamics is associated with wall remodeling and inflammation of the saccular intracranial aneurysm wall. MATERIALS AND METHODS: Tissue samples resected during a saccular intracranial aneurysm operation (11 unruptured, 9 ruptured) were studied with histology and immunohistochemistry. Patient-specific computational models of hemodynamics were created from preoperative CT angiographies. RESULTS: More stable and less complex flows were associated with thick, hyperplastic saccular intracranial aneurysm walls, while slower flows with more diffuse inflow were associated with degenerated and decellularized saccular intracranial aneurysm walls. Wall degeneration ( P = .041) and rupture were associated with increased inflammation (CD45+, P = .031). High wall shear stress ( P = .018), higher vorticity ( P = .046), higher viscous dissipation ( P = .046), and high shear rate ( P = .046) were associated with increased inflammation. Inflammation was also associated with lack of an intact endothelium ( P = .034) and the presence of organized luminal thrombosis ( P = .018), though overall organized thrombosis was associated with low minimum wall shear stress ( P = .034) and not with the flow conditions associated with inflammation. CONCLUSIONS: Flow conditions in the saccular intracranial aneurysm are associated with wall remodeling. Inflammation, which is associated with degenerative wall remodeling and rupture, is related to high flow activity, including elevated wall shear stress. Endothelial injury may be a mechanism by which flow induces inflammation in the saccular intracranial aneurysm wall. Hemodynamic simulations might prove useful in identifying saccular intracranial aneurysms at risk of developing inflammation, a potential biomarker for rupture.

Background and Purpose— To elucidate the predictors of antidepressant use after subarachnoid hemorrhage from saccular intracranial aneurysm (sIA-SAH) in a population-based cohort with matched controls. Methods— The Kuopio sIA database includes all unruptured and ruptured sIA cases admitted to the Kuopio University Hospital from its defined catchment population in Eastern Finland, with 3 matched controls for each patient. The use of all prescribed medicines has been fused from the Finnish national registry of prescribed medicines. In the present study, 2 or more purchases of antidepressant medication indicated antidepressant use. The risk factors of the antidepressant use were analyzed in 940 patients alive 12 months after sIA-SAH, and the classification tree analysis was used to create a predicting model for antidepressant use after sIA-SAH. Results— The 940 12-month survivors of sIA-SAH had significantly more antidepressant use (odds ratio, 2.6; 95% confidence interval, 2.2–3.1) than their 2676 matched controls (29% versus 14%). Classification tree analysis, based on independent risk factors, was used for the best prediction model of antidepressant use after sIA-SAH. Modified Rankin Scale until 12 months was the most potent predictor, followed by condition (Hunt and Hess Scale) and age on admission for sIA-SAH. Conclusions— The sIA-SAH survivors use significantly more often antidepressants, indicative of depression, than their matched population controls. Even with a seemingly good recovery (modified Rankin Scale score, 0) at 12 months after sIA-SAH, there is a significant risk of depression requiring antidepressant medication.

Background and Purpose— Formation of new (de novo) aneurysms in patients carrying saccular intracranial aneurysm (sIA) disease has been published, but data from population-based cohorts are scarce. Methods— Kuopio sIA database ( http://www.uef.fi/ns ) contains all unruptured and ruptured sIA patients admitted to Kuopio University Hospital from its Eastern Finnish catchment population. We studied the incidence and risk factors for de novo sIA formation in 1419 sIA patients with ≥5 years of angiographic follow-up, a total follow-up of 18 526 patient-years. Results— There were 42 patients with a total of 56 de novo sIAs, diagnosed in a median of 11.7 years after the first sIA diagnosis. The cumulative incidence of de novo sIAs was 0.23% per patient-year and that of subarachnoid hemorrhage from a ruptured de novo sIA 0.05% per patient-year. The risk of de novo sIA discovery per patient-year increased with younger age at the first sIA diagnosis: 2.2% in the patients aged Conclusions— Patients aged < 40 years at the first sIA diagnosis are in a significant risk of developing de novo sIAs, and they should be scheduled for long-term angiographic follow-up. Smoking increases the risk of de novo sIA formation, suggesting long-term follow-up for smokers. Antismoking efforts are highly recommended for sIA patients.

Background and Purpose— Size and shape of saccular intracranial aneurysms (sIA) reflect the condition of the sIA wall and were risk factors for rupture in previous follow-up studies. We investigated how well size or shape identify rupture-prone sIAs. Methods— In a population-based registry, we investigated the characteristics of ruptured sIAs treated in a single neurosurgical center (1980–2014). In addition to univariate analysis, logistic regression was used in multivariate analysis, and sensitivity and specificity of size or shape were calculated using receiver operating characteristic curves. Results— Ruptured sIAs were on average larger than unruptured sIAs (median, 7 versus 4 mm; P Conclusions— Irregular or multilobular shape is strongly associated with rupture in sIAs of all sizes and independent of location and patient background. Especially sIAs with irregular shape should be considered as high rupture risk lesions, even if small in diameter and in nonsmoking patients with low PHASES scores.

The human body abounds in micro-organisms that maintain the vital balance of the internal ecosystem. Though it is well known that several benefit the human body while others are linked to disease, how the microbiota affects the pathology of intra-cranial aneurysms is an interesting arena that still requires exploration. Studies have suggested possible association between the excess of bacteria, such as those causing gingivitis, as well the deficit of bacteria, such as loss of gut flora due to antibiotics, to intracranial aneurysms and their subsequent behavior. The authors review existing literature on the subject and outline the scope for further research on the subject.

Saccular intracranial aneurysm (sIA) rupture is often fatal. Rupture-prone sIA walls are infiltrated by macrophages expressing hemoglobin-receptor CD163, suggesting a role for erythrocyte lysis in the degenerative remodeling predisposing to rupture. We therefore studied erythrocyte remnants in 16 unruptured and 20 ruptured sIA walls using histology and immunohistochemistry. Glycophorin A (GPA), an erythrocyte membrane protein, was present in 34/36 (94%) sIA walls and correlated with loss of αSMA+ cells, reflecting loss of mural smooth muscle cells ([SMCs]; r = -0.592, p < 0.001), wall degeneration (p = 0.008), and rupture (p = 0.005). GPA correlated with high numbers of CD163+ and CD68+ phagocytes (r = 0.65 and r = 0.54, p ≤ 0.001 for both). CD163+ phagocytes were mostly HLA-DR-. Interestingly, single SMCs expressed HLA-DR and also CD163 was expressed in sporadic SMCs, which may reflect their response to hemoglobin accumulation. GPA associated with iron (p = 0.014) was detectable by MRI. An additional 11 sIAs were therefore imaged ex vivo with a 4.7 T MRI prior to histology. In the sIA walls, high GPA and iron accumulation associated with signal intensity in T1-weighted gradient echo MRI. We conclude that accumulation of lysed erythrocytes is a potential driver of inflammatory response in the sIA walls and is associated with the degenerative wall remodeling, thereby predisposing to rupture.

Background Saccular intracranial aneurysm (sIA) growth during follow-up is associated with high risk for subsequent rupture. Finnish patients have been suggested to have higher risk for subarachnoid hemorrhage, but follow-up studies of sIA growth in the Finnish population are scarce. Objective To identify the strongest risk factors for sIA growth in Eastern Finnish population by studying 205 patients with 350 unruptured sIAs with angiographic follow-up imaging. Methods In this population-based cohort study, we included unruptured sIA patients from the Kuopio University Hospital Intracranial Aneurysm Patient and Family database with at least 6 mo of angiographic follow-up after the diagnosis of sIAs. Angiograms were re-evaluated to detect aneurysms with growth of at least 1.0 mm. Cox regression analysis with patient- and aneurysm-related risk factors was used to calculate hazard ratios with 95% confidence intervals for growth. In addition, we tested the diagnostic value of previously introduced PHASES score for the prediction of sIA growth in Eastern Finnish population. Results Of the 350 unruptured aneurysms, 36 (10.3%) showed growth during median follow-up of 1.7 yr and total follow-up of 790 yr. In the multivariate Cox regression analysis, sIA size and location in the middle cerebral artery were significant risk factors for sIA growth. In receiver operator characteristic curves, both PHASES score and sIA size had relatively low areas under the curve. Conclusion Our study indicates that aneurysm size is the strongest risk factor for aneurysm growth in Eastern Finnish population. Further studies are required to identify new risk factors for aneurysm growth.

Background and Purpose— Aneurysm occlusion by intraluminal thrombus formation is the desired effect of all endovascular treatments. Intraluminal thrombus may, however, recanalize and be absorbed, unless it is infiltrated by cells that turn it into fibrous tissue (neointima). Because ruptured aneurysm walls are characterized by loss of smooth muscle cells, we assessed the impact of mural cell loss on wall remodeling of thrombosed aneurysms and investigated whether neointima formation could be enhanced by direct transplantation of cells into the thrombus. Methods— Sidewall aneurysms were microsurgically created in rats (n=81). Certain aneurysms were decellularized. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil–labeled smooth muscle cells were injected into 25 of 46 fibrin embolized aneurysms. Recanalization and aneurysm growth were monitored with magnetic resonance angiography. Endoscopy, optical projection tomography, histology, and immunohistochemistry were used to study the fate of transplanted cells, thrombus organization, and neointima formation. Results— Decellularized embolized aneurysms demonstrated higher angiographic recurrence compared with decellularized embolized aneurysms with transplanted cells ( P =0.037). Local cell replacement at the time of thrombosis resulted in better histological neointima formation than both nondecellularized embolized aneurysms ( P P =0.002). Aneurysm growth and rupture were observed exclusively in decellularized embolized aneurysms. Conclusions— Lack of smooth muscle cells in the aneurysm wall promotes wall degradation, aneurysm growth and rupture, even if the aneurysm is occluded by luminal thrombus. Transplantation of smooth muscle cells into the luminal thrombus can reduce this degenerative remodeling.

Chronic inflammation contributes to remodeling, degeneration, and rupture of saccular intracranial artery aneurysms. Mast cells are important proinflammatory and proangiogenic cells in chronic inflammatory vascular diseases. Here we studied mast cells and neovascularization in 36 intraoperatively resected aneurysms using histology and immunohistochemistry and analyzed the clinical characteristics of the aneurysms according to bleeding status (unruptured vs ruptured). Among the 36 aneurysms, 9 contained mast cells (tryptase-positive cells) and 15 contained neovessels (CD34- and CD31-positive capillarylike structures). The density of neovessels was significantly higher in aneurysm walls containing mast cells than in walls not containing them. In particular, wall areas with abundant mast cells and neovessels also contained iron deposits, indicating damage of newly formed endothelium with ensuing microhemorrhages. Walls with the highest neovessel density and the greatest iron deposition also showed evidence of degeneration. Finally, none of the mast cell-containing aneurysms showed an intact luminal endothelium. Thus, mast cells may adversely affect both neovascular and luminal endothelia. The novel association of mast cells with neovessels and injurious microhemorrhages, as well as with luminal endothelial erosion, suggests that mast cells contribute to remodeling and degeneration of saccular intracranial artery aneurysms.

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.

Background and Purpose— The biological mechanisms predisposing intracranial saccular aneurysms to growth and rupture are not yet fully understood. Mural cell loss is a histological hallmark of ruptured cerebral aneurysms. It remains unclear whether mural cell loss predisposes to aneurysm growth and eventual rupture. Methods— Sodium dodecyl sulfate decellularized and nondecellularized saccular aneurysm from syngeneic thoracic aortas were transplanted to the abdominal aorta of Wistar rats. Aneurysm patency and growth was followed up for 1 month with contrast-enhanced serial magnetic resonance angiographies. Endoscopy and histology of the aneurysms were used to assess the role of periadventitial environment, aneurysm wall, and thrombus remodeling. Results— Nondecellularized aneurysms (n=12) showed a linear course of thrombosis and remained stable. Decellularized aneurysms (n=12) exhibited a heterogeneous pattern of thrombosis, thrombus recanalization, and growth. Three of the growing aneurysms (n=5) ruptured during the observation period. Growing and ruptured aneurysms demonstrated marked adventitial fibrosis and inflammation, complete wall disruption, and increased neutrophil accumulation in unorganized intraluminal thrombus. Conclusions— In the presented experimental setting, complete loss of mural cells acts as a driving force for aneurysm growth and rupture. The findings suggest that aneurysms missing mural cells are incapable to organize a luminal thrombus, leading to recanalization, increased inflammatory reaction, severe wall degeneration, and eventual rupture.