rasa1-related arteriovenous malformation is driven by aberrant venous signalling.

Arteriovenous malformations (AVMs) develop where abnormal endothelial signalling allows direct connections between arteries and veins. Mutations in RASA1, a Ras GTPase activating protein, lead to AVMs in humans and, as we show, in zebrafish rasa1 mutants. rasa1 mutants develop cavernous AVMs that subsume part of the dorsal aorta and multiple veins in the caudal venous plexus (CVP) - a venous vascular bed. The AVMs progressively enlarge and fill with slow-flowing blood. We show that the AVM results in both higher minimum and maximum flow velocities, resulting in increased pulsatility in the aorta and decreased pulsatility in the vein. These hemodynamic changes correlate with reduced expression of the flow-responsive transcription factor klf2a. Remodelling of the CVP is impaired with an excess of intraluminal pillars, which is a sign of incomplete intussusceptive angiogenesis. Mechanistically, we show that the AVM arises from ectopic activation of MEK/ERK in the vein of rasa1 mutants, and that cell size is also increased in the vein. Blocking MEK/ERK signalling prevents AVM initiation in mutants. Alterations in venous MEK/ERK therefore drive the initiation of rasa1 AVMs.

GPRASP1 loss-of-function links to arteriovenous malformations by endothelial activating GPR4 signals.

Arteriovenous malformations (AVMs) are fast-flow vascular malformations and refer to important causes of intracerebral haemorrhage in young adults. Getting deep insight into the genetic pathogenesis of AVMs is necessary. Herein, we identified two vital missense variants of G protein-coupled receptor (GPCR) associated sorting protein 1 (GPRASP1) in AVM patients for the first time and congruously determined to be loss-of-function variants in endothelial cells. GPRASP1 loss-of-function caused endothelial dysfunction in vitro and in vivo. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral haemorrhage, AVMs and exhibited vascular anomalies in multiple organs. GPR4 was identified to be an effective GPCR binding with GPRASP1 to develop endothelial disorders. GPRASP1 deletion activated GPR4/cAMP/MAPK signalling to disturb endothelial functions, thus contributing to vascular anomalies. Mechanistically, GPRASP1 promoted GPR4 degradation. GPRASP1 enabled GPR4 K63-linked ubiquitination, enhancing the binding of GPR4 and RABGEF1 to activate RAB5 for conversions from endocytic vesicles to endosomes, and subsequently increasing the interactions of GPR4 and ESCRT members to package GPR4 into multivesicular bodies or late endosomes for lysosome degradation. Notably, the GPR4 antagonist NE 52-QQ57 and JNK inhibitor SP600125 effectively rescued the vascular phenotype caused by endothelial Gprasp1 deletion. Our findings provided novel insights into the roles of GPRASP1 in AVMs and hinted at new therapeutic strategies.

A temporally-restricted pattern of endothelial cell collagen 4 alpha 1 expression during embryonic development determined with a novel knockin Col4a1-P2A-eGFP mouse line.

Classical collagen type IV comprising of a heterotrimer of two collagen IV alpha 1 chains and one collagen IV alpha 2 chain is the principal type of collagen synthesized by endothelial cells (EC) and is a major constituent of vascular basement membranes. In mouse and man, mutations in genes that encode collagen IV alpha 1 and alpha 2 result in vascular dysfunction. In addition, mutations in genes that encode the Ephrin receptor B4 (EPHB4) and the p120 Ras GTPase-activating protein (RASA1) that cause increased activation of the Ras mitogen-activated protein kinase (MAPK) signaling pathway in EC result in vascular dysfunction as a consequence of impaired export of collagen IV. To understand the pathogenesis of collagen IV-related vascular diseases and phenotypes it is necessary to identify at which times collagen IV is actively synthesized by EC. For this purpose, we used CRISPR/Cas9 targeting in mice to include immediately after the terminal Col4a1 codon a sequence that specifies a P2A peptide followed by enhanced green fluorescent protein (eGFP). Analysis of eGFP expression in Col4a1-P2A-eGFP mice revealed active embryonic EC synthesis of collagen IV alpha 1 through mid to late gestation followed by a sharp decline before birth. These results provide a contextual framework for understanding the basis for the varied vascular abnormalities resulting from perturbation of EC expression and export of functional collagen IV.

Rupture-Related Features of Cerebral Arteriovenous Malformations and Their Utility in Predicting Hemorrhage.

BACKGROUND: Evaluating rupture risk in cerebral arteriovenous malformations currently lacks quantitative hemodynamic and angioarchitectural features necessary for predicting subsequent hemorrhage. We aimed to derive rupture-related hemodynamic and angioarchitectural features of arteriovenous malformations and construct an ensemble model for predicting subsequent hemorrhage. METHODS: This retrospective study included 3 data sets, as follows: training and test data sets comprising consecutive patients with untreated cerebral arteriovenous malformations who were admitted from January 2015 to June 2022 and a validation data set comprising patients with unruptured arteriovenous malformations who received conservative treatment between January 2009 and December 2014. We extracted rupture-related features and developed logistic regression (clinical features), decision tree (hemodynamic features), and support vector machine (angioarchitectural features) models. These 3 models were combined into an ensemble model using a weighted soft-voting strategy. The performance of the models in discriminating ruptured arteriovenous malformations and predicting subsequent hemorrhage was evaluated with confusion matrix-related metrics in the test and validation data sets. RESULTS: A total of 896 patients (mean±SD age, 28±14 years; 404 women) were evaluated, with 632, 158, and 106 patients in the training, test, and validation data sets, respectively. From the training set, 9 clinical, 10 hemodynamic, and 2912 pixel-based angioarchitectural features were extracted. A logistic regression model was built using 4 selected clinical features (age, nidus size, location, and venous aneurysm), whereas a decision-tree model was constructed from 4 hemodynamic features (outflow time, stasis index, cerebral blood flow, and outflow volume ratio). A support vector machine model was designed using 5 pixel-based angioarchitectural features. In the validation data set, the accuracy, sensitivity, specificity, and area under the curve of the ensemble model for predicting subsequent hemorrhages were 0.840, 0.889, 0.823, and 0.911, respectively. CONCLUSIONS: The ensemble model incorporating clinical, hemodynamic, and angioarchitectural features showed favorable performance in predicting subsequent hemorrhage of cerebral arteriovenous malformations.

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.

Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition.

Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments.

Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations.

Current treatments of brain arteriovenous malformation (BAVM) are associated with considerable risks and at times incomplete efficacy. Therefore, a clinically consistent animal model of BAVM is urgently needed to investigate its underlying biological mechanisms and develop innovative treatment strategies. Notably, existing mouse models have limited utility due to heterogenous and untypical phenotypes of AVM lesions. Here we developed a novel mouse model of sporadic BAVM that is consistent with clinical manifestations in humans. Mice with BrafV600E mutations in brain ECs developed BAVM closely resembled that of human lesions. This strategy successfully induced BAVMs in mice across different age groups and within various brain regions. Pathological features of BAVM were primarily dilated blood vessels with reduced vascular wall stability, accompanied by spontaneous hemorrhage and neuroinflammation. Single-cell sequencing revealed differentially expressed genes that were related to the cytoskeleton, cell motility, and intercellular junctions. Early administration of Dabrafenib was found to be effective in slowing the progression of BAVMs; however, its efficacy in treating established BAVM lesions remained uncertain. Taken together, our proposed approach successfully induced BAVM that closely resembled human BAVM lesions in mice, rendering the model suitable for investigating the pathogenesis of BAVM and assessing potential therapeutic strategies.

Another face of RASA1: Report of familial germline variant in RASA1 with dysmorphic features.

RASopathies encompass a diverse set of disorders affecting genes that encode proteins within the RAS-MAPK pathway. RASA1 mutations are the cause of an autosomal dominant disorder called capillary malformation-arteriovenous malformation type 1 (CM-AVM1). Unlike other RASopathies, facial dysmorphism has not been described in these patients. We phenotypically delineated a large family of individuals with multifocal fast-flow capillary malformations, severe lymphatic anomalies of perinatal onset, and dysmorphic features not previously described. Sequencing studies were performed on probands and related family members, confirming the segregation of dysmorphic features in affected members of a novel heterozygous variant in RASA1 (NM_002890.3:c.2366G>A, p.(Arg789Gln)). In this work, we broaden the phenotypic spectrum of CM-AVM type 1 and propose a new RASA1 variant as likely pathogenic.

Retrospective chart review of GI bleeding in people with von Willebrand disease.

INTRODUCTION: Gastrointestinal (GI) bleeding events (BEs) in von Willebrand disease (VWD) are difficult to diagnose and often recurrent. Limited data from clinical trials has led to lack of consensus on treatment options. AIM: Describe current treatments and outcomes for GI BEs in people with VWD. METHODS: This retrospective, observational, multicentre chart review study was conducted from January 2018 through December 2019 and included patients with inherited VWD with ≥1 GI BE in the preceding 5 years. Baseline characteristics, number and aetiology of BEs, associated GI-specific morbidities/lesions, treatment and outcomes were analysed descriptively. RESULTS: Sixty bleeds were reported in 20 patients with type 1 (20%), type 2 (50%) and type 3 (30%) VWD. During the 5-year study period, 31 (52%) BEs had one identified or suspected cause; multiple causes were reported in 11 (18%). Most GI BEs (72%) were treated with a combination of von Willebrand factor (VWF), antifibrinolytics and/or other haemostatic or non-haemostatic treatments. Time to resolution did not differ by VWF treatment use; however, BEs treated with non-VWF treatments tended to resolve later. In patients with GI-specific morbidities/lesions, 84% resolved with first-line treatment; time to resolution tended to be longer than in patients without such morbidities/lesions. Thirteen BEs occurred in patients receiving prophylaxis and 47 in patients receiving on-demand treatment; 18 BEs resulted in a switch to prophylaxis after bleed resolution. CONCLUSIONS: This study confirms the unmet need for the management of recurrent GI BEs in people with VWD and the need for prospective data, especially on prophylaxis.

Pulmonary arteriovenous malformations in patients with previous brain abscess: a cross-sectional population-based study.

BACKGROUND AND PURPOSE: Pulmonary arteriovenous malformations (PAVMs) may cause recurrent brain abscess. The primary aim was to determine the prevalence of PAVM amongst survivors of brain abscess. The proportion with cardiac right-to-left shunts was also assessed post hoc. METHODS: This was a cross-sectional population-based study of adult (≥18 years) survivors of cryptogenic bacterial brain abscess in Denmark from 2007 through 2016. Patients were invited for bubble-echocardiography to detect vascular right-to-left shunting and, if abnormal, subsequent computed tomography thorax for diagnosis of PAVM. Data are presented as n/N (%) or median with interquartile range (IQR). RESULTS: Study participation was accepted by 47/157 (30%) eligible patients amongst whom two did not appear for scheduled bubble-echocardiography. The median age of participants was 54 years (IQR 45-62) and 19/57 (33%) were females compared with 59 years (IQR 48-68, p = 0.05) and 41/85 females (48%, p = 0.22) in non-participants. Bubble-echocardiography was suggestive of shunt in 10/45 (22%) participants and PAVM was subsequently confirmed by computed tomography in one patient with grade 1 shunting. The corresponding prevalence of PAVM was 2% (95% confidence interval 0.06-11.8) amongst all examined participants. Another 9/45 (20%) were diagnosed with patent in persistent foramen ovale (n = 8) or atrial septum defect (n = 1), which is comparable with the overall prevalence of 25% amongst adults in the Danish background population. CONCLUSIONS: Undiagnosed PAVM amongst adult survivors of cryptogenic bacterial brain abscess is rare but may be considered in select patients. The prevalence of cardiac right-to-left shunts amongst brain abscess patients corresponds to the prevalence in the general population.

Vascular Plugs Improve Pulmonary Arteriovenous Malformation Occlusion over Coil Embolization Alone: A Proof-of-Concept Study using Dual Energy Computed Tomography.

PURPOSE: To evaluate efficacy of pulmonary arteriovenous malformation (PAVM) embolization using dual-energy computed tomography (DECT) and spectral curve analysis by characterizing contrast enhancement and vascular perfusion as a surrogate of the degree of vascular occlusion after embolotherapy. METHODS: Nine consecutive adult patients underwent embolization for 21 PAVMs (size range 0.4-2.0cm; 15/21 simple angioarchitecture) and subsequent post-embolization chest DECT angiography. Twelve PAVMS were treated with vascular plugs ± coils, whereas nine PAVMs were treated with coils-only. Virtual spectral curves (VSC) were generated using dual-energy image post-processing in order to measure embolization effectiveness. RESULTS: Complete occlusion of target PAVM was achieved in all cases on digital subtraction angiography at the end of the embolization procedure. With a median follow-up of 12.7 months, the vascular plug group demonstrated significantly less vascular opacification compared to the coils-only group, as measured by opacification between upstream feeding artery and and different downstream vasculature locations (Δslope1: median 79.1 versus 28.6, p=0.0030; Δslope2: 76.4 versus 28.6, p=0.0197; Δslope3: 78.9 versus 28.6, p=0.0041). Persistence occurred in three PAVMs based on size criteria, which demonstrated higher vascular vascular opacification by DECT (Δslope1: 72 versus 28.6, p=0.253; Δslope2: 65.1 versus 32.7, p=0.326; Δslope3: 72.9 versus 53.5, p=0.733), although statistical significance was not reached. CONCLUSION: Similar to emerging literature, DECT showed improved occlusion in PAVMs treated with vascular plugs compared to coils alone.

Pulsatile Tinnitus: Differential Diagnosis and Approach to Management.

PURPOSE OF REVIEW: The purpose of this review is to provide an updated approach to the evaluation and management of pulsatile tinnitus (PT), an uncommon but often treatable subtype of tinnitus. RECENT FINDINGS: Secondary PT can be due to either vascular or non-vascular etiologies, including, but not limited to: neoplasm, arteriovenous malformation or fistula, idiopathic intracranial hypertension, dural venous sinus stenosis, otoacoustic etiologies (e.g., otosclerosis, patulous eustachian tube) and bony defects (e.g., superior semicircular canal dehiscence). Computed tomography (CT) and magnetic resonance imaging (MRI) imaging have comparable diagnostic yield, though each may be more sensitive to specific etiologies. If initial vascular imaging is negative and a vascular etiology is strongly suspected, digital subtraction angiography (DSA) may further aid in the diagnosis. Many vascular etiologies of PT can be managed endovascularly, often leading to PT improvement or resolution. Notably, venous sinus stenting is an emerging therapy for PT secondary to idiopathic intracranial hypertension with venous sinus stenosis. Careful history and physical exam can help establish the differential diagnosis for PT and guide subsequent evaluation and management. Additional studies on the efficacy and long-term outcome of venous sinus stenting for venous stenosis are warranted.

Treatment of Brain Arteriovenous Malformations.

Brain arteriovenous malformations (AVMs) are a rare entity of vascular anomalies, characteristic of anatomical shunting where arterial blood directly flows into the venous circulation. The main aim of the active treatment policy of brain AVMs is the prevention of haemorrhage. There are well-established treatment strategies that continually improve in their safety and efficacy, primarily due to the advances in imaging modalities, targeted and novel techniques, the development of alternative treatment approaches, and even better experience with the disease itself. There are interesting imaging novelties that may be prospectively applicable in the decision-making and planning of the most effective treatment approach for individual patients with intracranial AVM. Surgery is often considered the first-line treatment; however, each patient should be evaluated individually, and the risks of the active treatment policy should not overcome the benefits of the spontaneous natural history of the disease. All treatment modalities, i.e., surgery, radiosurgery, endovascular embolization, and observation, are justified but need to be meticulously selected for each individual patient in order to deliver the best treatment outcome. This chapter deals with historical and currently applied dogmas, followed by introductions of advances in each available treatment modality of AVM management.

Implementation of 3D modelling to improve understanding and conceptualisation of arteriovenous malformation (AVM) morphology for the execution of safe microsurgical excision of complex paediatric AVMs.

INTRODUCTION: Brain arteriovenous malformations (bAVMs) present complex challenges in neurosurgery, requiring precise pre-surgical planning. In this context, 3D printing technology has emerged as a promising tool to aid in understanding bAVM morphology and enhance surgical outcomes, particularly in pediatric patients. This study aims to assess the feasibility and effectiveness of using 3D AVM models in pediatric bAVM surgery. METHODOLOGY: The study was conducted at Great Ormond Street Hospital, and cases were selected sequentially between October 2021 and February 2023. Eight pediatric bAVM cases with 3D models were compared to eight cases treated before the introduction of 3D printing models. The 3D modelling fidelity and clinical outcomes were assessed and compared between the two cohorts. RESULTS: The study demonstrated excellent fidelity between 3D models and actual operative anatomy, with a median difference of only 0.31 mm. There was no statistically significant difference in angiographic cure rates or complications between the 3D model group and the non-3D model group. Surgical time showed a non-significant increase in cases involving 3D models. Furthermore, the 3D model cohort included higher-grade bAVMs, indicating increased surgical confidence. CONCLUSION: This study demonstrates the feasibility and efficacy of utilizing 3D AVM models in pediatric bAVM surgery. The high fidelity between the models and actual operative anatomy suggests that 3D modelling can enhance pre-surgical planning and intraoperative guidance without significantly increasing surgical times or complications. Further research with larger cohorts is warranted to confirm and refine the application of 3D modelling in clinical practice.

Brain AVM compactness score in children with hereditary hemorrhagic telangiectasia.

OBJECTIVE: The brain arteriovenous malformation (BAVM) nidus compactness score (CS), determined on angiography, predicts BAVM recurrence after surgical resection among children with sporadic BAVMs. We measured the angiographic CS for BAVMs among children with hereditary hemorrhagic telangiectasia (HHT) to determine CS characteristics in this population. METHODS: A pediatric interventional neuroradiologist reviewed angiograms to determine the CS of BAVMs in children with HHT recruited to the BVMC. CS is based on overall nidus and perinidal anomalous vessel compactness. CS categories included 1 = diffuse nidus, 2 = intermediate nidus, and 3 = compact nidus. RESULTS: Forty-eight of 78 children (61.5%) with HHT and brain vascular malformations had a conventional angiogram; 47 (97.9%) angiograms were available. Fifty-four BAVMs were identified in 40 of these 47 children (85.1%). Of 54 BAVMs in children with HHT, CS was 1 in 7 (13%), 2 in 29 (53.7%), and 3 in 18 BAVMs (33.3%) compared with CS of 1 in six (26.1%), 2 in 15 (65.2%), and 3 in 2 BAVMs (8.7%) among 23 previously reported children with sporadic BAVMs, p = 0.045 (Fisher's exact). Seven children with HHT had intracranial hemorrhage: 4 had CS = 3, 1 had CS = 2, and 2 had CS = 1. CONCLUSIONS: A range of CSs exists across HHT BAVMs, suggesting it may be an angiographic measure of interest for future studies of BAVM recurrence and hemorrhage risk. Children with HHT may have more compact niduses compared to children with sporadic BAVMs. Additional research should determine whether CS affects hemorrhage risk or post-surgical recurrence risk in HHT-associated BAVMs, which could be used to direct BAVM treatment.

Clinical analysis of surgical outcome of 89 patients having large cerebral arteriovenous malformations.

OBJECTIVE: The article analyzes the clinical features, morphological characteristics, surgical subtleties and long-term outcome of surgery in 89 cases of 'large' sized AVMs. MATERIALS AND METHODS: During the period 2004 to 2022, 89 cases of 'large' arteriovenous malformations were operated in the neurosurgery departments of the authors. Large AVMs were defined as those that were more than 4 cm on either lateral or antero-posterior view of digital subtraction angiogram. The factors that determined the extent of surgical difficulties included site and eloquence of the area, number of feeding vascular territories and draining veins, degree and rate of flow, presence of flow-related aneurysms, and the physical nature of the arteriovenous malformation. RESULTS: There were 59 males and 30 females and the average age was 32 years. Headache, giddiness and convulsions were the common presenting complaints. Six patients were unconscious after surgery. Of these, five patients died in the immediate post-operative period and one patient gradually recovered. Additionally, seven patients developed unilateral limb weakness that included hemiplegia (4 patients) and hemiparesis (3 patients) following surgery. Clinical follow-up ranged from 6 months to 18 years (average 43 months). All surviving patients are leading normal and essentially symptom free life and have recovered from their symptoms of headache, convulsions and giddiness. CONCLUSIONS: Large AVMs are amenable to 'curative' surgery with 'acceptable' results. The surgery can be challenging and appropriate case selection that is based on the surgeons experience is vital and decisive.

The role of surgical disconnection for posterior fossa pial arteriovenous fistulas and dural fistulas with pial supply: an illustrative case series.

BACKGROUND: Pial arteriovenous fistulas (pAVFs) are rare vascular malformations characterized by high-flow arteriovenous shunting involving a cortical arterial supply directly connecting to venous drainage without an intermediate nidus. Dural arteriovenous fistulas (dAVFs) can infrequently involve additional pial feeders which can introduce higher flow shunting and increase the associated treatment risk. In the posterior fossa, arteriovenous fistula (AVF) angioarchitecture tends to be particularly complex, involving either multiple arterial feeders-sometimes from both dural and pial origins-or small caliber vessels that are difficult to catheterize and tend to be intimately involved with functionally critical brainstem or upper cervical cord structures. Given their rarity, published experience on microsurgical or endovascular treatment strategies for posterior fossa pAVFs and dAVFs with pial supply remains limited. METHODS: Retrospective chart review from 2019-2023 at a high-volume center identified six adult patients with posterior fossa pAVFs that were unable to be fully treated endovascularly and required microsurgical disconnection. These cases are individually presented with a technical emphasis and supported by comprehensive angiographic and intraoperative images. RESULTS: One vermian (Case 1), three cerebellopontine angle (Cases 2-4) and two craniovertebral junction (Cases 5-6) posterior fossa pAVFs or dAVFs with pial supply are presented. Three cases involved mixed dural and pial arterial supply (Cases 1, 4, and 6), and one case involved a concomitant microAVM (Case 2). Endovascular embolization was attempted in four cases (Cases 1-4): The small caliber and tortuosity of the main arterial feeder prevented catheterization in two cases (Cases 1 and 3). Partial embolization was achieved in Cases 2 and 4. In Cases 5 and 6, involvement of the lateral spinal artery or anterior spinal artery created a prohibitive risk for endovascular embolization, and surgical clip ligation was pursued as primary management. In all cases, microsurgical disconnection resulted in complete fistula obliteration without evidence of recurrence on follow-up imaging (mean follow-up 27.1 months). Two patients experienced persistent post-treatment sensory deficits without significant functional limitation. CONCLUSIONS: This illustrative case series highlights the technical difficulties and anatomical limitations of endovascular management for posterior fossa pAVFs and dAVFs with pial supply and emphasizes the relative safety and utility of microsurgical disconnection in this context. A combined approach involving partial preoperative embolization-when the angioarchitecture is permissive-can potentially decrease surgical morbidity. Larger studies are warranted to better define the role for multimodal intervention and to assess associated long-term AVF obliteration rates in the setting of pial arterial involvement.

Enhancing the quality of evidence, comparability, and reproducibility in brain arteriovenous malformations treated with open surgery research: a systematic review and proposal of a reporting guideline for surgical and clinical outcomes.

Brain Arteriovenous Malformations (bAVMs) are rare but high-risk developmental anomalies of the vascular system. Microsurgery through craniotomy is believed to be the mainstay standard treatment for many grades of bAVMs. However, a significant challenge emerges in the existing body of clinical studies on open surgery for bAVMs: the lack of reproducibility and comparability. This study aims to assess the quality of studies reporting clinical and surgical outcomes for bAVMs treated by open surgery and develop a reporting guideline checklist focusing on essential elements to ensure comparability and reproducibility. This is a systematic literature review that followed the PRISMA guidelines with the search in Medline, Embase, and Web of Science databases, for studies published between January 1, 2018, and December 1, 2023. Included studies were scrutinized focusing on seven domains: (1) Assessment of How Studies Reported on the Baseline Characteristics of the Patient Sample; (2) Assessment and reporting on bAVMs grading, anatomical characteristics, and radiological aspects; (3) Angioarchitecture Assessment and Reporting; (4) Reporting on Pivotal Concepts Definitions; (5) Reporting on Neurosurgeon(s) and Staff Characteristics; (6) Reporting on Surgical Details; (7) Assessing and Reporting Clinical and Surgical Outcomes and AEs. A total of 47 studies comprising 5,884 patients were included. The scrutiny of the studies identified that the current literature in bAVM open surgery is deficient in many aspects, ranging from fundamental pieces of information of methodology to baseline characteristics of included patients and data reporting. Included studies demonstrated a lack of reproducibility that hinders building cumulative evidence. A bAVM Open Surgery Reporting Guideline with 65 items distributed across eight domains was developed and is proposed in this study aiming to address these shortcomings. This systematic review identified that the available literature regarding microsurgery for bAVM treatment, particularly in studies reporting clinical and surgical outcomes, lacks rigorous scientific methodology and quality in reporting. The proposed bAVM Open Surgery Reporting Guideline covers all essential aspects and is a potential solution to address these shortcomings and increase transparency, comparability, and reproducibility in this scenario. This proposal aims to advance the level of evidence and enhance knowledge regarding the Open Surgery treatment for bAVMs.

Unilateral segmental presentation and a novel EPHB4 gene variant in capillary malformation-arteriovenous malformation type 2.

Capillary malformation-arteriovenous malformation is a rare autosomal dominant disorder associated with EPHB4 loss-of-function mutations. We report the unique presentation of a 6-year-old girl with multiple capillary malformations in a unilateral segmental distribution affecting the right hemiface, right upper chest, and right arm associated with overgrowth. Targeted next-generation sequencing on a tissue sample revealed a novel heterozygotic variant in the EPHB4 gene (NM_004444.5 (EPHB4): c.715T>A, p.[Cys239Ser]). This case highlights a distinct presentation of CM-AVM type 2 and showcases a new variant in EPHB4 not previously reported in the literature.

Arteriovenous malformations as a presenting sign of PTEN hamartoma tumor syndrome: A case series.

High-flow vascular malformations have been associated with multiple syndromes including capillary malformation-arteriovenous malformation (CM-AVM) syndrome, hereditary hemorrhagic telangiectasia syndrome, and less commonly, phosphatase and tensin homolog hamartoma tumor syndrome (PHTS). We present a series of three patients with clinically challenging complex AVMs who were found to have underlying PHTS. In all patients, diagnosis was delayed, and the presence of the AVM prompted sampling and genetic testing for PHTS in the absence of other clinical features of the condition. This series highlights the importance of screening for PHTS in the setting of high-flow vascular malformations.