Venous tortuosity as a novel biomarker of rupture risk in arteriovenous malformations: ARI score

BackgroundRisk of rupture in arteriovenous malformations (AVMs) varies considerably among series. Hemodynamic factors, especially within the venous side of the circuit, seem to be responsible but are not yet well defined. We analyzed tortuosity in the draining vein as a potential new marker of rupture in AVMs, and propose a simple index to predict AVM bleeding.MethodsA retrospective analysis of the venous angioarchitecture of brain AVMs was carried out at our center from 2013 to 2021, with special attention to venous tortuosity. After univariate analysis, the features of interest were combined to construct several predictive models using multivariate logistic regression. The best model proposed was the new AVM rupture index (ARI), which was then validated in an independent cohort.Results68 AVMs were included in the first step and 32 in the validation cohort. Venous tortuosity, expressed as at least one curve >180°, was a significant predictor of rupture (p=0.023). The proposed bleeding index consisted of: venous tortuosity (any curve of >180°), single draining vein, and paraventricular/infratentorial location. It seems to be a robust evaluation tool, with an area under the receiver operating characteristic (AUROC) curve of 0.806 (95% CI 0.714 to 0.899), consistently replicated in the independent sample (AUROC 0.759 (95% CI 0.607 to 0.911)), and with an inter-rater kappa coefficient of 0.81 .ConclusionsVenous tortuosity may serve as a predictor of bleeding in AVMs that warrants further investigation. This likely new marker was one of the three elements of the proposed ARI. ARI outperformed the predictive accuracy of previous scores, and remained consistent in an independent cohort.

Novel experimental model of brain arteriovenous malformations using conditional Alk1 gene deletion in transgenic mice

OBJECTIVE Hereditary hemorrhagic telangiectasia is the only condition associated with multiple inherited brain arteriovenous malformations (AVMs). Therefore, a mouse model was developed with a genetics-based approach that conditionally deleted the causative activin receptor-like kinase 1 (Acvrl1 or Alk1) gene. Radiographic and histopathological findings were correlated, and AVM stability and hemorrhagic behavior over time were examined. METHODS Alk1-floxed mice were crossed with deleter mice to generate offspring in which both copies of the Alk1 gene were deleted by Tagln-Cre to form brain AVMs in the mice. AVMs were characterized using MRI, MRA, and DSA. Brain AVMs were characterized histopathologically with latex dye perfusion, immunofluorescence, and Prussian blue staining. RESULTS Brains of 55 Tagln-Cre+;Alk12f/2f mutant mice were categorized into three groups: no detectable vascular lesions (group 1; 23 of 55, 42%), arteriovenous fistulas (AVFs) with no nidus (group 2; 10 of 55, 18%), and nidal AVMs (group 3; 22 of 55, 40%). Microhemorrhage was observed on MRI or MRA in 11 AVMs (50%). AVMs had the angiographic hallmarks of early nidus opacification, a tangle of arteries and dilated draining veins, and rapid shunting of blood flow. Latex dye perfusion confirmed arteriovenous shunting in all AVMs and AVFs. Microhemorrhages were detected adjacent to AVFs and AVMs, visualized by iron deposition, Prussian blue staining, and macrophage infiltration using CD68 immunostaining. Brain AVMs were stable on serial MRI and MRA in group 3 mice (mean age at initial imaging 2.9 months; mean age at last imaging 9.5 months). CONCLUSIONS Approximately 40% of transgenic mice satisfied the requirements of a stable experimental AVM model by replicating nidal anatomy, arteriovenous hemodynamics, and microhemorrhagic behavior. Transgenic mice with AVFs had a recognizable phenotype of hereditary hemorrhagic telangiectasia but were less suitable for experimental modeling. AVM pathogenesis can be understood as the combination of conditional Alk1 gene deletion during embryogenesis and angiogenesis that is hyperactive in developing and newborn mice, which translates to a congenital origin in most patients but an acquired condition in patients with a confluence of genetic and angiogenic events later in life. This study offers a novel experimental brain AVM model for future studies of AVM pathophysiology, growth, rupture, and therapeutic regression.

Angioarchitectural features amongst patients with unruptured brain arteriovenous malformations presenting with headache: findings from a single center retrospective review of 76 patients

Background Brain arteriovenous malformations (AVMs) consist of abnormal connections between arteries and veins via an interposing nidus. While hemorrhage is the most common presentation, unruptured AVMs can present with headaches, seizures, neurological deficits, or be found incidentally. It remains unclear as to what AVM characteristics contribute to pain generation amongst unruptured AVM patients with headaches. Methods To assess this relationship, the current study evaluates angiographic and clinical features amongst patients with unruptured brain AVMs presenting with headache. Loyola University Medical Center medical records were queried for diagnostic codes corresponding to AVMs. In patients with unruptured AVMs, we analyzed the correlation between the presenting symptom of headache and various demographic and angiographic features. Results Of the 144 AVMs treated at our institution between 1980 and 2017, 76 were unruptured and had sufficient clinical data available. Twenty-three presented with headaches, while 53 patients had other presenting symptoms. Patients presenting with headache were less likely to have venous stenosis compared to those with a non-headache presentation (13 % vs. 36 %, p = 0.044). Conclusions Our study suggests that the absence of venous stenosis may contribute to headache symptomatology. This serves as a basis for further study of correlations between AVM angioarchitecture and symptomatology to direct headache management in AVM patients.

Return of the lesion: a meta-analysis of 1134 angiographically cured pediatric arteriovenous malformations

OBJECTIVE Brain arteriovenous malformations (AVMs) carry a risk of rupture and subsequent morbidity or mortality unless fully treated. AVMs in pediatric patients are known to occasionally recur after obliteration. The objective of this study was to characterize the risk of AVM recurrence following angiographically confirmed obliteration in children. METHODS Consecutive pediatric AVMs treated at a single center were identified from a prospective database. Patients with angiographically confirmed AVM obliteration following treatment were included in this study. Associations between AVM recurrence and patient or procedural factors were characterized using the two-tailed Fisher exact test or Mann-Whitney U-test. A literature search was conducted using PubMed, Scopus, Embase, and the Clarivate Web of Science with defined search criteria, and eligible studies were included alongside this study cohort in a meta-analysis. Rates of AVM recurrence following obliteration were pooled across studies with a random-effects model and reported with 95% confidence intervals (CIs). RESULTS Recurrence after angiographic confirmation of AVM obliteration was observed in 10.4% (7/67) of pediatric AVMs treated at the authors’ center. Patients with recurrent AVMs were significantly younger than those without recurrence (p = 0.002). In the meta-analysis, which included 1134 patients across 24 studies, the rate of recurrence was 4.8% (95% CI 3.0%–6.7%). The rate of AVM recurrence following radiosurgery was 0.7% (95% CI 0%–1.6%), which was significantly lower than the 8.5% rate (95% CI 5.0%–12.0%) following microsurgery. CONCLUSIONS Recurrence of obliterated brain AVMs is common in children. Recurrence is more common in young children and following microsurgery.

Multidisciplinary Approach to Suspected Sudden Death Caused by Arteriovenous Malformation Rupture: A Case Report

Arteriovenous malformations (AVMs) are rare congenital conditions with a prevalence of less than 1% and are mostly asymptomatic. However, these malformations can suddenly cause intense pain or bleeding, leading to life-threatening medical problems. This report presents a case of an unexpected death in a 37-year-old previously healthy woman due to an intra-cerebellum arteriovenous malformation rupture identified during autopsy. While infective processes where preliminarily excluded, a Post Mortem Computed Tomography (PMCT) identified a tetra ventricular hemorrhage and intra-cerebellum hemorrhage. Toxicological examination was negative for most substances of abuse. During autopsy an intense hemorrhagic infiltrate in the subarachnoid space was observed. After formalin fixation of the brain the cerebellum showed hemorrhagic infarction on fourth ventricle sides, as well as several small reddish infarctions across the entire cerebellum parenchyma. Histological examination of the brain and cerebellum showed a suffusion of erythrocytes in the sub-arachnoid region. Evidence of an arterio-venous malformation, with several intertwine vessels of variable diameter, surrounded by hemorrhagic evidence. The autopsy played a crucial role in identifying the location and the possibly affected vessel, as well as defining the cause of death. It is necessary to have a greater number of autopsies to make an epidemiological contribution. Furthermore, it is crucial to create a multicenter data network with other authors from other departments to improve information about epidemiological, clinical, diagnostic and therapeutic data. Most brain AVMs as cause of death are often undiscovered.

Adenosine-induced Asystole during AVM Embolization

Background Adenosine induced cardiac standstill has been used intraoperatively for both aneurysm and arteriovenous malformation (AVM) surgery and embolization. We sought to report the results of adenosine induced cardiac standstill as an adjunct to endovascular embolization of brain AVMs. Material and Methods We retrospectively identified patients in our prospectively maintained database to identify all patients since January 2007 in whom adenosine was used to induce cardiac standstill during the embolization of a brain AVM. We recorded demographic data, clinical presentation, Spetzler Martin grade, rupture status, therapeutic intervention and number of embolization sessions, angiographic and clinical results, clinical and radiological outcomes and follow-up information. Results We identified 47 patients (22 female, 47%) with average age 42 ± 17 years (range 6–77 years) who had undergone AVM embolization procedures using adjunctive circulatory standstill with adenosine. In total there were 4 Spetzler Martin grade 1 (9%), 9 grade 2 (18%), 15 grade 3 (32%), 8 grade 4 (18%), and 11 grade 5 (23%) lesions. Of the AVMs six were ruptured or had previously ruptured. The average number of embolization procedures per patient was 5.7 ± 7.6 (range 1–37) with an average of 2.6 ± 2.2 (range 1–14) embolization procedures using adenosine. Overall morbidity was 17% (n = 8/47) and mortality 2.1% (n = 1/47), with permanent morbidity seen in 10.6% (n = 5/47) postembolization. Angiographic follow-up was available for 32 patients with no residual shunt seen in 26 (81%) and residual shunts seen in 6 patients (19%). The angiographic follow-up is still pending in 14 patients. At last follow-up 93.5% of patients were mRS ≤2 (n = 43/46). Conclusion Adenosine induced cardiac standstill represents a viable treatment strategy in high flow AVMs or AV shunts that carries a low risk of mortality and permanent neurological deficits.

Focused Ultrasound Ablation of an Arteriovenous Malformation Model

Brain AVMs are rare but serious vascular lesions that often pose a management dilemma between the risk of various treatment modalities and uncertain natural history during observation. We describe preliminary data on the use of focused ultrasound as a novel therapeutic strategy. In an AVM model, one session of ultrasound gradually reduced flow through the lesion without inducing rupture. Due to its non-invasive yet immediate ablative effects, focused ultrasound may allow safer treatment of AVMs. However, further studies are needed to clarify its efficacy and side effect profile.

‘De Novo’ Brain AVMs—Hypotheses for Development and a Systematic Review of Reported Cases

Background and Objectives: Brain arteriovenous malformations AVMs have been consistently regarded as congenital malformations of the cerebral vasculature. However, recent case reports describing “de novo AVMs” have sparked a growing debate on the nature of these lesions. Materials and Methods: We have performed a systematic review of the literature concerning de novo AVMs utilizing the PubMed and Google Academic databases. Termes used in the search were “AVM,” “arteriovenous,” “de novo,” and “acquired,” in all possible combinations. Results: 53 articles including a total of 58 patients harboring allegedly acquired AVMs were identified by researching the literature. Of these, 32 were male (55.17%), and 25 were female (43.10%). Mean age at de novo AVM diagnosis was 27.833 years (standard deviation (SD) of 21.215 years and a 95% confidence interval (CI) of 22.3 to 33.3). Most de novo AVMs were managed via microsurgical resection (20 out of 58, 34.48%), followed by radiosurgery and conservative treatment for 11 patients (18.97%) each, endovascular embolization combined with resection for five patients (8.62%), and embolization alone for three (5.17%), the remaining eight cases (13.79%) having an unspecified therapy. Conclusions: Increasing evidence suggests that some of the AVMs discovered develop some time after birth. We are still a long way from finally elucidating their true nature, though there is reason to believe that they can also appear after birth. Thus, we reason that the de novo AVMs are the result of a ‘second hit’ of a variable type, such as a previous intracranial hemorrhage or vascular pathology. The congenital or acquired characteristic of AVMs may have a tremendous impact on prognosis, risk of hemorrhage, and short and long-term management.