Most Promising Approaches to Improve Brain AVM Management: ARISE I Consensus Recommendations.

Brain arteriovenous malformations (bAVMs) are complex, and rare arteriovenous shunts that present with a wide range of signs and symptoms, with intracerebral hemorrhage being the most severe. Despite prior societal position statements, there is no consensus on the management of these lesions. ARISE (Aneurysm/bAVM/cSDH Roundtable Discussion With Industry and Stroke Experts) was convened to discuss evidence-based approaches and enhance our understanding of these complex lesions. ARISE identified the need to develop scales to predict the risk of rupture of bAVMs, and the use of common data elements to perform prospective registries and clinical studies. Additionally, the group underscored the need for comprehensive patient management with specialized centers with expertise in cranial and spinal microsurgery, neurological endovascular surgery, and stereotactic radiosurgery. The collection of prospective multicenter data and gross specimens was deemed essential for improving bAVM characterization, genetic evaluation, and phenotyping. Finally, bAVMs should be managed within a multidisciplinary framework, with clinical studies and research conducted collaboratively across multiple centers, harnessing the collective expertise and centralization of resources.

Pretreatment with a dual antiplatelet and anticoagulant (APAC) reduces ischemia-reperfusion injury in a mouse model of temporary middle cerebral artery occlusion-implications for neurovascular procedures.

BACKGROUND: Several neurovascular procedures require temporary occlusion of cerebral arteries, leading to ischemia of unpredictable length, occasionally causing brain infarction. Experimental models of cerebral ischemia-reperfusion injury have established that platelet adhesion and coagulation play detrimental roles in reperfusion injury following transient cerebral ischemia. Therefore, in a model of cerebral ischemia-reperfusion injury (IRI), we investigated the therapeutic potential of a dual antiplatelet and anticoagulant (APAC) heparin proteoglycan mimetic which is able to bind to vascular injury sites. METHODS: Brain ischemia was induced in mice by transient occlusion of the right middle cerebral artery for 60 min. APAC, unfractionated heparin (UFH) (both at heparin equivalent doses of 0.5 mg/kg), or vehicle was intravenously administered 10 min before or 60 min after the start of ischemia. At 24 h later, mice were scored for their neurological and motor behavior, and brain damage was quantified. RESULTS: Both APAC and UFH administered before the onset of ischemia reduced brain injury. APAC and UFH pretreated mice had better neurological and motor functions (p < 0.05 and p < 0.01, respectively) and had significantly reduced cerebral infarct sizes (p < 0.01 and p < 0.001, respectively) at 24 h after transient occlusion compared with vehicle-treated mice. Importantly, no macroscopic bleeding complications were observed in either APAC- or UFH-treated animals. However, when APAC or UFH was administered 60 min after the start of ischemia, the therapeutic effect was lost, but without hemorrhaging either. CONCLUSIONS: Pretreatment with APAC or UFH was safe and effective in reducing brain injury in a model of cerebral ischemia induced by transient middle cerebral artery occlusion. Further studies on the use of APAC to limit ischemic injury during temporary occlusion in neurovascular procedures are indicated.

CNS-associated macrophages contribute to intracerebral aneurysm pathophysiology.

Intracerebral aneurysms (IAs) are pathological dilatations of cerebral arteries whose rupture leads to subarachnoid hemorrhage, a significant cause of disability and death. Inflammation is recognized as a critical contributor to the formation, growth, and rupture of IAs; however, its precise actors have not yet been fully elucidated. Here, we report CNS-associated macrophages (CAMs), also known as border-associated macrophages, as one of the key players in IA pathogenesis, acting as critical mediators of inflammatory processes related to IA ruptures. Using a new mouse model of middle cerebral artery (MCA) aneurysms we show that CAMs accumulate in the IA walls. This finding was confirmed in a human MCA aneurysm obtained after surgical clipping, together with other pathological characteristics found in the experimental model including morphological changes and inflammatory cell infiltration. In addition, in vivo longitudinal molecular MRI studies revealed vascular inflammation strongly associated with the aneurysm area, i.e., high expression of VCAM-1 and P-selectin adhesion molecules, which precedes and predicts the bleeding extent in the case of IA rupture. Specific CAM depletion by intracerebroventricular injection of clodronate liposomes prior to IA induction reduced IA formation and rupture rate. Moreover, the absence of CAMs ameliorated the outcome severity of IA ruptures resulting in smaller hemorrhages, accompanied by reduced neutrophil infiltration. Our data shed light on the unexplored role of CAMs as main actors orchestrating the progression of IAs towards a rupture-prone state.

Increased blood coagulation is associated with poor neurological outcome in aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Patients with aneurysmal subarachnoid hemorrhage (aSAH) have demonstrated increased blood coagulation which is thought to contribute to delayed cerebral ischemia (DCI) and to a worse outcome. Therefore, we sought to determine whether this increased blood coagulation, detectable with rotational thromboelastometry (ROTEM), was associated with DCI and neurological outcome. METHODS: We conducted a prospective observational study of 60 consecutive adult aSAH patients. ROTEM's EXTEM and FIBTEM assays and D-dimer were analyzed at admission and post-bleed days (PBDs) 2-3, 4-5, 7-8, and 11-12. ROTEM's clot formation time (CFT) represents the stabilization of the clot, and the maximum clot firmness (MCF) the maximum clot strength. Glasgow Outcome Scale extended (GOSe) at three months determined the neurological outcome. RESULTS: DCI incidence was 41.7%. EXTEM-CFT was significantly shorter in patients with unfavorable neurological outcome (GOSe 1-4) on PBDs 4-5 and 7-8, p < 0.05, respectively. FIBTEM-MCF was significantly higher in patients with unfavorable neurological outcomes on PBD 4-5 (p < 0.05), PBD 7-8 (p < 0.05), and PBD 11-12 (p < 0.05). EXTEM-CFT decreased, and FIBTEM-MCF rose during the study period in all patients. Patients with unfavorable neurological outcome had a higher D-dimer at all studied time points, p < 0.05. No difference was found in the ROTEM parameters or D-dimer when assessing patients with and without DCI. CONCLUSIONS: Patients were in a state of increased blood coagulation after aSAH, with those with unfavorable neurological outcome being more coagulable than those with favorable outcome. However, increased blood coagulation was not associated with DCI. CLINICALTRIALS: gov, NCT03985176.

Stability of infundibular dilatations: a single center follow-up study and systematic review of the literature.

PURPOSE: Although infundibular dilatations (IDs) have been thought to be benign anatomical variants, case reports suggest that they can grow and rupture. The aim of this study was to determine whether IDs have a tendency to grow or rupture. METHODS: The study population was collected from the Tampere University Hospital (TAUH) Aneurysm Database. The presence of IDs was screened from the medical records and imaging studies of 356 intracranial aneurysm patients left to follow-up from 2005 to 2020. The imaging studies were reviewed to confirm the IDs, and their clinical course. Finally, we performed a systematic review of published cases of ID leading to aneurysmatic rupture from PubMed. RESULTS: We found 97 typical IDs in 83 patients and 9 preaneurysmal lesions resembling ID in 9 patients. Out of the typical cone-shaped IDs, none grew or ruptured in a total follow-up of 409 patient-years. One preaneurysmal lesion ruptured during a follow-up: this lesion had components of both infundibular dilatation and aneurysm at the beginning of follow-up. In the systematic literature search, we found 20 cases of aneurysmatic SAHs originating from an ID. Of those, only 7 had imaging available prerupture. All 7 IDs were typically cone-shaped, but a branching vessel originating from the apex of ID was only seen in 4/7. CONCLUSION: Typical infundibular dilatations seem to be benign anatomical variants that are stable and, thus, do not need prophylactic treatment or imaging follow-up. Likely, the SAHs reported from IDs were actually caused by misdiagnosed preaneurysmal lesions.

The clinical course and outcomes of non-aneurysmal subarachnoid hemorrhages in a single-center retrospective study.

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.

Impact of Timing of Surgery and Adjuvant Treatment on Survival of Adult IDH-wild-type Glioblastoma: A Single-center Study of 392 Patients.

BACKGROUND: The purpose of our study was to analyze the impact of time interval from referral to surgery and from surgery to adjuvant treatment on survival of adult isocitrate dehydrogenase-wild-type (IDH-wt) glioblastomas. METHODS: Data on 392 IDH-wt glioblastomas diagnosed at the Tampere University Hospital in 2004-2016 were obtained from the electronic patient record system. Piecewise Cox regression was used to calculate hazard ratios for different time intervals between referral and surgery, as well as between surgery and adjuvant treatments. RESULTS: The median survival time from primary surgery was 9.5 months (interquartile range: 3.8-16.0). Survival among patients with an interval exceeding 4 weeks from referral to surgery was no worse compared to <2 weeks (hazard ratio: 0.78, 95% confidence interval: 0.54-1.14). We found indications of poorer outcome when the interval from surgery to radiotherapy exceeded 30 days (hazard ratio: 1.42, 95% confidence interval: 0.91-2.21 for 31-44 days; and 1.59, 0.94-2.67 for over 45 days). CONCLUSIONS: Interval from referral to surgery in the range of 4-10 weeks was not associated with decreased survivals in IDH-wt glioblastomas. In contrast, delay exceeding 30 days from surgery to adjuvant treatment may decrease long-term survival.

Effect of xenon on brain injury, neurological outcome, and survival in patients after aneurysmal subarachnoid hemorrhage-study protocol for a randomized clinical trial.

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.

Recurrence of arteriovenous malformations of the brain after complete surgical resection. Kuopio University Hospital experience and systematic review of the literature.

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.

Unlike severe periodontitis, caries does not associate with intracranial aneurysms or aneurysmal subarachnoid hemorrhage.

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.

Risk factor management matters more than pharmaceutical cyclooxygenase-2 inhibition in the prevention of de novo intracranial aneurysms.

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. CONCLUSION: 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.

Use of antihypertensive medication and formation of de novo intracranial aneurysms.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Prediction of bleb formation in intracranial aneurysms using machine learning models based on aneurysm hemodynamics, geometry, location, and patient population.

BACKGROUND: Bleb presence in intracranial aneurysms (IAs) is a known indication of instability and vulnerability. OBJECTIVE: To develop and evaluate predictive models of bleb development in IAs based on hemodynamics, geometry, anatomical location, and patient population. METHODS: Cross-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. RESULTS: The 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%). CONCLUSIONS: Based 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.

Systemic immune response against the oral pathogens Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans is associated with the formation and rupture of intracranial aneurysms.

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 < 0.001). In multivariate analysis, high IgA, but low IgG, antibody levels against P. gingivalis (odds ratio [OR] = 1.4, 95% confidence interval [Cl] = 1.1-1.8 and OR = 1.5, 95% Cl = 1.1-1.9; OR = 0.6, 95% Cl = 0.4-0.7 and OR = 0.5, 95% Cl = 0.4-0.7) and against A. actinomycetemcomitans (OR = 2.3, 95% Cl = 1.7-3.1 and OR = 2.1, 95% Cl = 1.5-2.9; OR = 0.6, 95% Cl = 0.4-0.8 and OR = 0.6, 95% Cl = 0.5-0.9) were associated with the risk of IA formation and rupture. Immunohistochemistry showed P. gingivalis epitopes in the IA wall. CONCLUSIONS: Exposure to the periodontal pathogens P. gingivalis and A. actinomycetemcomitans and dysfunctional acquired immune response against them may increase the risk of IA formation and IA rupture.

Cyclo-oxygenase 2, a putative mediator of vessel remodeling, is expressed in the brain AVM vessels and associates with inflammation.

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.