Kadirvel, Ramanathan

OBJECTIVE Brain arteriovenous malformations (bAVMs) are rare but potentially devastating cerebrovascular lesions. Activating KRAS mutations are common in sporadic bAVMs, but their clinical implications remain unclear. The aim of this study was to investigate a novel therapeutic strategy for hemorrhagic bAVMs based on dual inhibition of the mitogen-activated protein kinase (MAPK) and vascular endothelial growth factor (VEGF) pathways using an engineered mouse model with a titratable KRAS G12V - GFP transgene. METHODS The AAV-BR1-CAG vector was used to deliver a KRAS G12V - GFP transgene specifically to cerebral endothelial cells. Mice received 5 × 10 7 to 5 × 10 10 genome copies of the vector, and bAVM formation, intracerebral hemorrhage (ICH), and overall survival were assessed. Mice with established hemorrhagic bAVMs were subsequently treated with trametinib (MEK inhibitor) or RMC-7977 (RAS inhibitor), with or without an anti–mouse VEGF antibody, starting 4 weeks after viral delivery. Overall survival was assessed. RESULTS Selective overexpression of KRAS G12V - GFP in cerebral endothelial cells led to the formation of bAVMs in a dose-dependent manner. Mice that received the highest transgene dose developed significantly more bAVMs, exhibited a higher ICH burden, and had worse overall survival compared with those that received lower transgene doses. In mice receiving the highest transgene dose, trametinib alone modestly improved the median overall survival (8.4 weeks vs 6.4 weeks, p = 0.049), while single-agent RMC-7977 showed no significant benefit. Anti-VEGF therapy alone reduced survival (6.9 weeks vs 9.6 weeks, p = 0.044). However, combination therapy with trametinib or RMC-7977 and anti-VEGF antibody significantly prolonged survival, with the most pronounced benefit seen in the RMC-7977 plus anti-VEGF group (13.1 weeks vs 6.7 weeks in controls, p = 0.024). CONCLUSIONS Our findings suggest that, in addition to promoting bAVM formation, KRAS mutations in cerebral endothelial cells might be causally implicated in bAVM rupture. Additionally, concomitant inhibition of the MAPK and VEGF pathways could be a promising novel therapeutic strategy for KRAS -mutated bAVMs.

Purpose Large aneurysms have a higher rupture risk, yet no available in vivo animal model consistently produces large aneurysms for testing endovascular therapies. Recent research suggests that adding calcium chloride (CaCl 2 ) to elastase yields larger aneurysms in a surgical rabbit model. We evaluated whether this effect translates to an endovascular approach by comparing aneurysm sizes created using elastase alone versus a CaCl 2 –elastase combination. Methods Aneurysms were created in the right common carotid artery of New Zealand rabbits. One group received 1 mL porcine elastase; the other received elastase plus 0.055 g CaCl 2 (0.5 M). After four weeks, patency was confirmed via digital subtraction angiography. Two blinded co-authors measured the neck, width, and height of the aneurysms. Aneurysm volumes were estimated using AngioCalc.com. Statistical analyses were performed using either the Mann–Whitney U -test or t -test based on data distribution. Results Twenty-nine (29) New Zealand rabbits were included in the study: six in the CaCl 2 and elastase groups, 23 in the elastase-alone group. All induced aneurysms remained patent at follow-up. Mean neck size was significantly larger in the CaCl 2 + elastase group than in the elastase-alone group (4.4 ± 1.1 mm vs 3.5 ± 0.95 mm; respectively, p = 0.02). Differences in width (4.1 ± 0.92 mm vs 3.4 ± 0.36 mm; p = 0.06), height (9.0 ± 1.1 mm vs 9.1 ± 2.1 mm; p = 0.46), and volume (83.5 ± 38.35 mm ³ vs 53.0 ± 16.94 mm³; p = 0.11) were not significant between CaCl 2 + elastase and elastase-alone, respectively. Conclusions CaCl 2 modestly increased neck size but did not significantly enlarge overall aneurysm dimensions. Further studies are needed to assess its utility in endovascular aneurysm models.

High-resolution imaging is critical for the diagnosis, treatment planning, and postoperative monitoring of cerebral aneurysms, which affect up to 5% of the population and pose a significant risk of rupture and subarachnoid hemorrhage. Surgical clipping remains a definitive treatment option, but metallic clips can introduce substantial imaging artifacts, complicating posttreatment assessment. This review synthesizes current knowledge on the impact of aneurysm clip materials and designs on artifact generation and explores strategies for artifact mitigation. Conventional materials like titanium are favored for their biocompatibility and reduced ferromagnetism but still cause beam hardening, streak artifacts, and signal loss in CT and MRI scans. Emerging alternatives, including ceramics, composites, polymers, and bioresorbable clips, show promise in reducing artifacts while maintaining mechanical reliability. Innovations in clip design, such as fenestrated or low-profile models, further aid in minimizing imaging distortion. Advanced imaging methods, including dual-energy CT, iterative reconstruction algorithms, and metal artifact reduction software, demonstrate significant improvements in image quality but may introduce limitations such as increased processing demands or subtle anatomical distortions. Future directions emphasize the development of next-generation clip materials, robotic-assisted surgical approaches, and artificial intelligence-driven reconstruction techniques to further optimize visualization and patient safety. Continued research and multidisciplinary collaboration will be essential to translate these innovations into routine neurosurgical practice.

Background/Objectives: Idiopathic intracranial hypertension (IIH) often features dural venous sinus stenosis; venous sinus stenting (VSS) improves venous outflow and intracranial pressure, but most stents are off-label, and few are engineered for intracranial venous anatomy. The aim was to synthesize animal models relevant to IIH/VSS, catalogue stents used clinically for VSS and summarize corresponding animal data, appraise current preclinical VSS research, and propose a pragmatic preclinical evaluation framework. Methods: We performed a targeted search (PubMed, Web of Science, Scopus; through to May 2025), dual-screened the records in Nested Knowledge, and extracted the model/device characteristics and outcomes as per the predefined criteria. Results: We identified 65 clinical VSS studies; most were retrospective and used off-label carotid/peripheral/biliary stents (Precise, Zilver, and Wallstent were the most frequent). Recent dedicated systems (River, BosStent) have limited animal evidence; VIVA has GLP porcine venous peripheral data demonstrating its patency, structural integrity, and benign healing outcomes. Rodent models reproduce obesity/androgen drivers with modest, sustained ICP elevation; large animal models show the technical feasibility of in sinus implantation, but no chronic focal venous stenosis model fully mirrors the IIH condition. Conclusions: Despite broad clinical uptake, the translational underpinnings of VSS in IIH remain incomplete: most devices lack intracranial venous-specific preclinical validation, and there is no existing animal model that recapitulates both IIH biology and focal sinus stenosis.

Background Guide catheter (GC) placement, whether distal or proximal, may influence the efficacy and safety of mechanical thrombectomy (MT) for acute ischemic stroke (AIS) due to large vessel occlusion (LVO). However, definitions of placement and procedural strategies vary across studies, limiting clarity. Methods We systematically searched PubMed, Embase, Scopus, and Web of Science from inception to September 1, 2024. Comparative studies of adult patients with anterior circulation AIS-LVO undergoing MT that reported GC placement were included. Both balloon GCs (BGCs) and non-BGCs were eligible. Data were pooled using random-effects models in R. Outcomes included functional independence (modified Rankin Scale 0–2 at 90 days), successful reperfusion (modified thrombolysis in cerebral infarction ≥2b or expanded thrombolysis in cerebral infarction ≥2c), first-pass recanalization (FPR), mortality, puncture-to-recanalization (PTR) time, and complications. Subgroup analyses were performed by thrombectomy technique and catheter type. Results Seven retrospective studies comprising 2148 patients (1042 proximal, 1106 distal) were analyzed. Distal placement was associated with higher rates of functional independence (risk ratio (RR): 1.25, 95% confidence interval (CI): 1.10–1.42), successful reperfusion (RR: 1.13, 95% CI: 1.04–1.22), and FPR (RR: 1.35, 95% CI: 1.15–1.58), as well as lower 90-day mortality (RR: 0.52, 95% CI: 0.28–0.82). PTR time was shorter with distal placement (mean difference: −7.7 min, 95% CI: −10.8 to −4.6). No significant differences were observed for symptomatic intracranial hemorrhage (RR: 0.96, 95% CI: 0.55–1.65) or emboli to new territory (RR: 0.84, 95% CI: 0.28–2.52). Benefits were consistent across both BGCs and non-BGCs. Heterogeneity existed in outcome definitions and techniques, and publication bias could not be excluded. Conclusions Distal GC placement is associated with improved reperfusion, efficiency, and functional outcomes in MT for anterior circulation AIS-LVO, without increased complications. Given the retrospective nature of included studies, anatomic confounding, and inconsistent outcome definitions, findings should be considered preliminary. Multicenter trials are needed to confirm whether catheter position independently predicts MT outcomes.