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In A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), randomisation was halted at a mean follow-up of 33·3 months after a prespecified interim analysis showed that medical management alone was superior to the combination of medical management and interventional therapy in preventing symptomatic stroke or death. We aimed to study whether these differences persisted through 5-years' follow-up. ARUBA was a non-blinded, randomised trial done at 39 clinical centres in nine countries. Adults (age ≥18 years) diagnosed with an unruptured brain arteriovenous malformation, who had never undergone interventional therapy, and were considered by participating clinical centres to be suitable for intervention to eradicate the lesion, were eligible for inclusion. Patients were randomly assigned (1:1) by a web-based data collection system, stratified by clinical centre in a random permuted block design with block sizes of two, four, and six, to medical management alone or with interventional therapy (neurosurgery, embolisation, or stereotactic radiotherapy, alone or in any combination, sequence, or number). Although patients and investigators at a given centre were not masked to treatment assignment, investigators at other centres and those in the clinical coordinating centre were not informed of assignment or outcomes at any of the centres. The primary outcome was time to death or symptomatic stroke confirmed by imaging, assessed by a neurologist at each centre not involved in the management of participants' care, and monitored by an independent committee using an adaptive approach with interim analyses. Enrolment began on April 4, 2007, and was halted on April 15, 2013, after which follow-up continued until July 15, 2015. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00389181. Of 1740 patients screened, 226 were randomly assigned to medical management alone (n=110) or medical management plus interventional therapy (n=116). During a mean follow-up of 50·4 months (SD 22·9), the incidence of death or symptomatic stroke was lower with medical management alone (15 of 110, 3·39 per 100 patient-years) than with medical management with interventional therapy (41 of 116, 12·32 per 100 patient-years; hazard ratio 0·31, 95% CI 0·17 to 0·56). Two patients in the medical management group and four in the interventional therapy group (two attributed to intervention) died during follow-up. Adverse events were observed less often in patients allocated to medical management compared with interventional therapy (283 vs 369; 58·97 vs 78·73 per 100 patient-years; risk difference −19·76, 95% CI −30·33 to −9·19). After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured brain arteriovenous malformation. The data concerning the disparity in outcomes should affect standard specialist practice and the information presented to patients. The even longer-term risks and differences between the two therapeutic approaches remains uncertain. National Institute of Neurological Disorders and Stroke for the randomisation phase and Vital Projects Fund for the follow-up phase.

The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy. Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181. Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months [SD 19·7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14–0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management. The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up. National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterised by vascular malformations in multiple organ systems, resulting in mucocutaneous telangiectases and arteriovenous malformations predominantly in the lungs (pulmonary arteriovenous malformation; PAVM), brain (cerebral arteriovenous malformation; CAVM), and liver (hepatic arteriovenous malformation; HAVM). Mutations in the ENG and ALK-1 genes lead to HHT1 and HHT2 respectively. In this study, a genotype-phenotype analysis was performed. A uniform and well classified large group of HHT patients and their family members were screened for HHT manifestations. Groups of patients with a clinically confirmed diagnosis and/or genetically established diagnosis (HHT1 or HHT2) were compared. The frequency of PAVM, CAVM, HAVM, and gastrointestinal telangiectases were determined to establish the genotype-phenotype relationship. The analysis revealed differences between HHT1 and HHT2 and within HHT1 and HHT2 between men and women. PAVMs and CAVMs occur more often in HHT1, whereas HAVMs are more frequent in HHT2. Furthermore, there is a higher prevalence of PAVM in women compared with men in HHT1. In HHT1 and HHT2, there is a higher frequency of HAVM in women. HHT1 has a distinct, more severe phenotype than HHT2. There is a difference in the presence of symptoms between men and women. With these data, genetic counselling can be given more accurately when the family mutation is known.

Abstract BACKGROUND No guidelines have been published regarding stereotactic radiosurgery (SRS) in the management of Spetzler-Martin grade I and II arteriovenous malformations (AVMs). OBJECTIVE To establish SRS practice guidelines for grade I-II AVMs on the basis of a systematic literature review. METHODS Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant search of Medline, Embase, and Scopus, 1986-2018, for publications reporting post-SRS outcomes in ≥10 grade I-II AVMs with a follow-up of ≥24 mo. Primary endpoints were obliteration and hemorrhage; secondary outcomes included Spetzler-Martin parameters, dosimetric variables, and “excellent” outcomes (defined as total obliteration without new post-SRS deficit). RESULTS Of 447 abstracts screened, 8 were included (n = 1, level 2 evidence; n = 7, level 4 evidence), representing 1102 AVMs, of which 836 (76%) were grade II. Obliteration was achieved in 884 (80%) at a median of 37 mo; 66 hemorrhages (6%) occurred during a median follow-up of 68 mo. Total obliteration without hemorrhage was achieved in 78%. Of 836 grade II AVMs, Spetzler-Martin parameters were reported in 680: 377 were eloquent brain and 178 had deep venous drainage, totaling 555/680 (82%) high-risk SRS-treated grade II AVMs. CONCLUSION The literature regarding SRS for grade I-II AVM is low quality, limiting interpretation. Cautiously, we observed that SRS appears to be a safe, effective treatment for grade I-II AVM and may be considered a front-line treatment, particularly for lesions in deep or eloquent locations. Preceding publications may be influenced by selection bias, with favorable AVMs undergoing resection, whereas those at increased risk of complications and nonobliteration are disproportionately referred for SRS.

Arteriovenous malformations (AVMs) are congenital vascular anomalies with a poor prognosis. AVMs are considered intractable diseases, as there is no established approach for early diagnosis and treatment. Therefore, this study aimed to provide new evidence by analyzing microRNAs (miRNAs) associated with AVM. We present fundamental evidence for the early diagnosis and treatment of AVM by analyzing miRNAs in the endothelial cells of AVMs. This study performed sequencing and validation of miRNAs in endothelial cells from normal and AVM tissues. Five upregulated and two downregulated miRNAs were subsequently analyzed under hypoxia and vascular endothelial growth factor (VEGF) treatment by one-way analysis of variance (ANOVA). Under hypoxic conditions, miR-135b-5p was significantly upregulated in the AVM compared to that under normal conditions, corresponding to increased endothelial activity (p-value = 0.0238). VEGF treatment showed no significant increase in miR-135b-5p under normal conditions, however, a surge in AVM was observed. Under both hypoxia and VEGF treatment, comparison indicated a downregulation of miR-135b-5p in AVM. Therefore, miR-135b-5p was assumed to affect the pathophysiological process of AVM and might play a vital role as a potential biomarker of AVMs for application related to diagnosis and treatment.

Arteriovenous malformations (AVMs) are fast-flow vascular malformations formed by direct artery-to-vein shunts without an intervening capillary bed, which increases the risk of hemorrhage and organ-specific damage. A synthesis of recent advances shows that AVMs arise from interplay between germline susceptibility (ENG, ACVRL1, SMAD4, RASA1, EPHB4), somatic mosaicism (KRAS, MAP2K1, PIK3CA), perturbed signaling (TGF-β/BMP, Notch, VEGF, PI3K/AKT, RAS/MAPK), hemodynamic stress, and inflammation. Multimodal imaging—digital subtraction angiography (DSA), MRI/MRA with perfusion and susceptibility sequences, CTA, Doppler ultrasound, and 3D rotational angiography—underpins diagnosis and risk stratification, while arterial spin labeling and 4D flow techniques refine hemodynamic assessment. Management is individualized and multidisciplinary, combining endovascular embolization, microsurgical resection, and stereotactic radiosurgery (SRS); a non-surgical approach and monitoring remain reasonable for some asymptomatic AVMs. Device and technique innovations (detachable-tip microcatheters, pressure-cooker approaches, and newer liquid embolics such as PHIL and Squid) have broadened candidacy, and precision-medicine strategies, including pathway-targeted pharmacotherapy, are emerging for syndromic and somatic-mutation–driven AVMs. Animal models and computational/radiomics tools increasingly guide hypothesis generation and treatment selection. We outline practical updates and future priorities: integrated genomic-imaging risk scores, genotype-informed medical therapy, rational hybrid sequencing, and long-term outcome standards focused on hemorrhage prevention and quality of life.

BackgroundThe cure of an eloquent brain arteriovenous malformation (BAVM) and multiple intracranial aneurysms with preservation of neurological function and the minimal procedures is challenging.MethodA 53-year-old male was admitted to treat a left frontal language-area BAVM and concomitant five bilateral intracranial aneurysms. After repairing the ruptured right middle cerebral artery (MCA) bifurcation aneurysms and the other two unruptured ones, at the second-stage multimodality-guided awake hybrid operation, we successfully obliterated the left frontal BAVM and two other left MCA aneurysms.ConclusionThe multimodality-guided awake hybrid operation may be a promising technique to treat complicated cerebrovascular disease.

Abstract BACKGROUND The optimal management of unruptured brain arteriovenous malformations (AVMs) is controversial after the ARUBA trial. OBJECTIVE To confirm or repudiate the ARUBA conclusion that “medical management only is superior to medical management with interventional therapy for unruptured brain arteriovenous malformations.” METHODS Data were collected from 1351 patients treated with Gamma Knife Surgery (GKS; Elekta AB, Stockholm, Sweden) for unruptured and untreated AVMs The follow-up was 8817 yr (median 5.0 and mean 6.5). The results of the analyses were compared to that found in patients randomized to medical management only in the ARUBA trial and extrapolated to a 10-yr time period. Our data were also compared to the natural course in a virtual AVM population for a 25-yr time period. RESULTS The incidence of stroke was similar among ARUBA and our patients for the first 5 yr. Thereafter, the longer the follow-up, the relatively better outcome following treatment. Both the mortality rate and the incidence of permanent deficits in patients with small AVMs were the same as in untreated patients for the first 2 to 3 yr after GKS, after which GKS patients did better. Patients with large AVMs had a higher incidence of neurological deficits in the first 3 yr following GKS. The difference decreased thereafter, but the time until break even depended on the analysis method used and the assumed risk for hemorrhage in patent AVMs. CONCLUSION The ARUBA trial conclusion that medical management is superior to medical management with interventional therapy for all unruptured AVMs could be repudiated.

Purpose While Ruptured Arteriovenous Malformation Grading Scale (RAGS) has recently been validated in children, the literature lacks validation on adults exclusively. Therefore, we aimed to determine the validity of RAGS on the external multicenter adult cohort and compare its accuracy with other scales. Methods A retrospective analysis was performed in five neurosurgical departments to extract patients who presented with the first episode of acute brain arteriovenous malformation (bAVM) rupture between 2012 and 2019. Standard logistic regression and area under the receiver operating curve (AUROC) calculations were performed to determine the value of the following scales: intracerebral hemorrhage (ICH), AVM-associated ICH (AVICH), Spetzler-Martin (SM), Supplemented SM (Supp-SM), Hunt and Hess (HH), Glasgow Coma Scale (GCS), World Federation of Neurological Surgeons (WFNS), and RAGS to predict change in categorical and dichotomized modified Rankin Scale (mRS) across three follow-up periods: within the 6 months, 6 months to 1 year, and above 1 year. Results Sixty-one individuals with a mean age of 43.6 years were included. The RAGS outperformed other grading scales during all follow-up time frames. It showed AUROC of 0.78, 0.74, and 0.71 at the first 6 months, between 6 and 12 months, and after 12 months of follow-up, respectively, when categorized mRS was applied, while corresponding values were 0.79, 0.76, and 0.73 for dichotomized mRS, respectively. Conclusion The RAGS constitutes a reliable scale predicting clinical outcomes following bAVM rupture among adults. Furthermore, the RAGS proved its generalizability across medical centers with varying treatment preferences.

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.