Morgan, Michael K.

OBJECTIVE Objective values on procedural risk are essential to facilitate informed consent and optimize clinical decision-making in patients with unruptured intracranial aneurysms (UIAs). While robust heuristics, such as the PHASES (population, hypertension, age, size of aneurysm, earlier subarachnoid hemorrhage, and site of aneurysm) score, are established for predicting rupture risk, contemporary and granular benchmarks for procedural safety remain scarce. The multinational Prediction of Adverse Events After Microsurgery for Intracranial Unruptured Aneurysms (PRAEMIUM) study aims to comprehensively characterize contemporary adverse event rates following microsurgical treatment at high-volume expert centers, stratified by aneurysm location, morphology, and complexity factors to better inform individual risk/benefit analyses. METHODS A cohort study among 20 participating expert centers from 9 countries was established. Patients treated microsurgically for UIAs were included. The authors describe the epidemiology of treated patients and UIAs and a comprehensive adverse event profile using 3 outcomes measured at hospital discharge: 1) poor neurological outcome (modified Rankin Scale score ≥ 3), 2) new sensorimotor neurological deficits, and 3) all-cause adverse events (Clavien-Dindo grade ≥ 1). Subgroup reports were given for aneurysm location, morphology, and complexity factors (prior aneurysm treatment, calcifications, complex angioanatomy involving critical branch vessels or perforators, and thrombosis). The authors purposely chose discharge as the time point to capture early postoperative risks and complications in patients with asymptomatic UIAs, for whom preserving neurological function is paramount. RESULTS The cohort included 3705 patients (mean age 56 [SD 12] years, 28% male). Overall, at discharge 13.9% of patients (95% CI 12.8%–15.0%) had poor neurological functional outcomes, 14.4% (95% CI 13.3%–15.5%) had new sensorimotor deficits, and 24.1% (95% CI 22.8%–25.5%) experienced all-cause adverse events. Poor neurological outcomes ranged from 8.5% (M1 aneurysms) to 37.4% (posterior circulation aneurysms), neurological deficits from 9.3% (distal anterior cerebral artery [ACA] aneurysms) to 34.2% (posterior circulation aneurysms), and all-cause adverse events from 21.2% (distal ACA aneurysms) to 31.3% (posterior circulation aneurysms). Dissecting and fusiform aneurysms showed notably high rates of poor neurological outcomes (22.0%–33.3%), new deficits (25.4%–26.7%), and adverse events (26.7%–37.0%). Complexity factors significantly influenced outcomes, with prior treatment (22.9%, 19.7%, and 30.1%), calcification (16.3%, 18.1%, and 30.5%), complex angioanatomy (13.1%, 15.9%, and 26.9%), and thrombosis (19.6%, 23.9%, and 39.6%) notably increasing the risks for poor neurological outcomes, deficits, and adverse events, respectively. CONCLUSIONS This large international cohort provides contemporary benchmarks for microsurgical treatment of UIAs, emphasizing variability in outcomes based on aneurysm location, morphology, and complexity. The presented granular and quotable adverse event rates support informed patient counseling and individualized risk/benefit assessments in comparable high-volume centers.

Importance Annual rates of first intracranial hemorrhage (ICH) from unruptured brain arteriovenous malformations (AVMs) are often quoted as 2% to 4% in clinical practice. Precise estimates and risk factors are unavailable to inform treatment decisions. Objective To provide estimates of rates and risk factors for first ICH in a large cohort study of unruptured brain AVMs. Design, Setting, and Participants The Multicenter Arteriovenous Malformation Research Study (MARS) included data from 9 cohorts, each contributing 100 or more unruptured brain AVMs. The study was conducted from 2017 to 2023 with retrospective and prospective data collection for existing cohorts and/or new recruitment. This was an international study (2 population-based and 7 referral-based cohorts) that included participants diagnosed with an unruptured brain AVM. Exposures Demographic, clinical, and angiographic characteristics. Main Outcome and Measure The primary outcome was time to first ICH after diagnosis of unruptured brain AVM. Data were collected using standardized definitions; missing data were imputed. Cox regression analysis was performed, censoring at first brain AVM treatment, death, or last visit, and allowing baseline hazards to vary by cohort. Results A total of 3225 individuals were eligible for participation in this study. After 195 exclusions, 3030 participants (median [IQR] age, 38 [25-50] years; 1524 female [50.3%]) were included. Among 2989 participants with unruptured brain AVMs, 1333 (45%) presented with seizure. The median (IQR) maximal brain AVM diameter was 3.1 (2.2-4.4) cm, 248 of 2466 AVMs (10%) had exclusively deep venous drainage, 297 of 2690 (11%) were in supratentorial deep or cerebellar locations, and 457 of 2440 (19%) had associated arterial aneurysms. First ICH occurred in 159 participants over 11 339 person-years of follow-up for an ICH rate of 1.40 (95% CI, 1.20-1.64) per 100 person-years. Significant independent risk factors included (1) increasing age category at diagnosis (hazard ratio [HR], 0.87; 95% CI, 0.53-1.41 for those aged 20 to 39 years; HR, 1.23; 95% CI, 0.74-2.04 for those aged 40 to 59 years; and HR, 2.01; 95% CI, 1.14-3.57 for those aged 60 years vs younger than 20 years; P = .008), (2) presence of associated aneurysms (HR, 1.66; 95% CI, 1.06-2.59; P = .03), and (3) cerebellar or supratentorial deep location (HR, 1.87; 95% CI, 1.16-3.00; P = .01). Conclusions and Relevance The annual ICH rate from unruptured brain AVM was lower than that commonly cited in clinical practice. Increasing age, associated arterial aneurysms, and cerebellar or supratentorial deep brain AVM location were associated with risk of first ICH. These results may be used to counsel patients about the natural history of unruptured brain AVMs.

Introduction: The long-term effects of interventional treatment (with surgery, stereotactic radiosurgery, or endovascular embolization) for unruptured brain arteriovenous malformations (uBAVM) are uncertain. We address this in a large multi-center international cohort study comparing risk of intracranial hemorrhage (ICH) in the treated and untreated course of uBAVM patients. Methods: We pooled individual patient data (n=3,291) from 10 cohorts and imputed missing data. Survival analysis was performed from time of uBAVM diagnosis to intracranial hemorrhage (ICH) using Cox models, stratified by cohort, censoring at death or last follow-up, and including BAVM interventional treatment as a time-varying covariate. We tested for an interaction of treatment with follow-up time, then estimated the association of interventional treatment with ICH, adjusting for propensity quintile. Individual treatment propensity scores were calculated using logistic regression with Spetzler-Martin grade, sex, diagnosis age and year, cohort, and presence of presenting symptoms (seizures, headaches, and/or deficits). Results: Median cohort age was 36 years, 48% were female, and 77% received ≥1 treatment modality for uBAVM during follow-up. 373 ICH occurred during 32,054 person-years of follow-up (median=6.6y), for an ICH rate of 1.16 per 100 P-Y. Overall, treatment was not associated with risk of ICH (HR=1.12, 95% CI=0.89-1.51, p=0.33). However, we observed a strong interaction between treatment and follow-up time (p<0.001): between 0-1 year, treatment was associated with higher risk of ICH (HR=3.48, 95% CI: 2.26-5.37, p<0.001); between 1-10 years, we found no association between treatment and risk of ICH (HR=1.02, 95% CI: 0.73-1.45, p=0.87); after 10 years, treatment was associated with a lower risk of ICH (HR=0.46, 95% CI: 0.30-0.70, p<0.001). Survival curves for untreated and treated courses crossed around 17 years. Conclusion: After accounting for treatment propensity for uBAVM, we found an initial increased risk of ICH in the treated relative to untreated course, which continually declined over time with survival curves crossing around 17 years. These results require confirmation in a randomized controlled trial of uBAVM with long-term follow-up.

Background: Accurate and reliable models of intracranial hemorrhage (ICH) risk in the untreated course of brain arteriovenous malformation (BAVM) patients are needed to help weigh the risk-benefit of treatment. We present preliminary estimates of rates and risk factors for ICH or death in the Multicenter AVM Research Study (MARS), which is the largest individual patient data meta-analysis (IPDMA) of cohort studies of unruptured BAVM. Methods: Longitudinal data from 9 cohorts comprising 2,839 unruptured BAVM at time of diagnosis were included: UCSF (n=557), Macquarie (n=462), Kaiser Permanente Northern California (n=354), Columbia (n=335), Barrow Neurological Institute (n=324), Tiantan Hospital (n=303), Mayo Clinic-Rochester (n=244), Scottish Intracranial Vascular Malformation Study (n=194), and Toronto Western Hospital (n=66). Clinical and angiographic data were collected using standardized definitions across cohorts. Cox proportional hazards analysis of time-to-event (ICH or death) in the untreated course after diagnosis was performed, censoring at first treatment or last visit. Baseline hazard rates were stratified by cohort to account for different rates and follow-up times. Results: The combined cohort was 49% female, 72% white race, and 17% Hispanic ethnicity; mean age at diagnosis was 37±17 years and mean follow-up was 3.4±7.0 years. The most common presenting symptom was seizures (43%). Mean AVM size was 3.5±1.9 cm and 46% were Spetzler-Martin grade I-II. Overall, 123 ICH and 131 deaths occurred over 9,608 person-years (PY) for an event rate of 2.64 per 100 PY [95% CI: 2.34-2.99]. Cox regression analyses adjusting for age at diagnosis (HR=1.67 [1.54, 1.82], P<0.001) identified cerebellar location (HR=1.73 [1.03-2.93], P=0.040) and exclusively deep venous drainage (HR=1.83 [1.09-3.09], P=0.022) as predictors. Conclusion: Our current model identified increasing age, exclusively deep venous drainage, and cerebellar location as risk factors for ICH or death in the untreated course of unruptured bAVM patients. Review of imaging data, multiple imputation of missing angioarchitectural data, and additional data from pending cohorts will provide greater power to search for additional risk factors in this ongoing IPDMA.

Introduction: Accurately balancing risks of interventional treatment and intracranial hemorrhage (ICH) in the untreated course of unruptured brain arteriovenous malformation (uBAVM) patients is critical for optimal management. Observational studies of uBAVM afford an opportunity to address important gaps and previous criticisms of randomized data to help guide treatment decisions and assess long-term risk/benefit ratio. We previously published an individual patient data meta-analysis (IPDMA) in 4 MARS cohorts and identified ICH presentation and increasing age as significant predictors of ICH during follow-up, but was not powered to detect predictors in those with uBAVM. Thus, the goals of this project are to identify risk factors for ICH in uBAVMs, to estimate the risk with precision, and to create personalized, risk-prediction models. Methods: MARS is an international, multi-center study of 11 cohorts with target enrollment of 4,500 uBAVM patients ascertained through population-based or referral-based studies. We are harmonizing both retrospective and prospective data, including clinical, lifestyle, imaging, and angiographic factors. Treatments, complications, and functional outcomes (physician and patient-reported) will be updated annually between 2018-2022. We propose to: 1) identify predictors of outcome in uBAVMs using IPDMA; 2) test whether long-term outcomes differ by treatment using statistical approaches for causal inference and unbiased estimates; 3) compare treatment outcomes in randomized and non-randomized data to address generalizability; and 4) validate models and provide a novel tool for calculating individualized risks. Eligible sites have: a) prior BAVM publications; b) data from a minimum of 100 uBAVM patients; c) agree to random outcome adjudication; and d) agree to MARS data sharing policy. Discussion: The NIH-funded MARS consortium will provide important and comprehensive characterization of the untreated and treated course of uBAVMs, using large observational datasets and sophisticated epidemiological approaches. The data and models generated will be a useful resource for decision-making. We welcome participation from eligible sites with longitudinal data on uBAVM patients

Background and Purpose— To address the increasing need to counsel patients about treatment indications for unruptured intracranial aneurysms (UIA), we endeavored to develop a consensus on assessment of UIAs among a group of specialists from diverse fields involved in research and treatment of UIAs. Methods— After composition of the research group, a Delphi consensus was initiated to identify and rate all features, which may be relevant to assess UIAs and their treatment by using ranking scales and analysis of inter-rater agreement (IRA) for each factor. IRA was categorized as very high, high, moderate, or low. Results— Ultimately, 39 specialists from 4 specialties agreed (high or very high IRAs) on the following key factors for or against UIA treatment decisions: (1) patient age, life expectancy, and comorbid diseases; (2) previous subarachnoid hemorrhage from a different aneurysm, family history for UIA or subarachnoid hemorrhage, nicotine use; (3) UIA size, location, and lobulation; (4) UIA growth or de novo formation on serial imaging; (5) clinical symptoms (cranial nerve deficit, mass effect, and thromboembolic events from UIAs); and (6) risk factors for UIA treatment (patient age and life expectancy, UIA size, and estimated risk of treatment). However, IRAs for features rated with low relevance were also generally low, which underlined the existing controversy about the natural history of UIAs. Conclusions— Our results highlight that neurovascular specialists currently consider many features as important when evaluating UIAs but also highlight that the appreciation of natural history of UIAs remains uncertain, even within a group of highly informed individuals.

Abstract Perturbations in cerebral hemodynamics at the time of ablation of an arteriovenous shunt have been regarded as important in the pathogenesis of swelling and hemorrhage complicating resection of arteriovenous malformations (AVMs). A carotid-jugular fistula model in the rat had previously been investigated and found to simulate in part the nonhemorrhagic pathophysiology of a large cerebral arteriovenous fistula. Utilizing this model and measuring cerebral blood flow in 14 regions with a [14C]iodoantipyrine autoradiographic technique, the effects of hypocapnea on the cerebral circulation in opened and closed fistulas were investigated. Regional cerebral blood flow (rCBF) in control animals ranged from a median of 53 to 64 ml/100 g/min at a partial arterial carbon dioxide pressure (PaCO2) of 28 ± 2 mm Hg and 85 to 112 ml/100 g/min at a PaCO2 of 40 ± 5 mm Hg. In animals with an open carotid-jugular fistula created 12 weeks before the study, these median rCBF values at comparable PaCO2 levels ranged, respectively, from 15 to 39 ml/100 g/min and 50 to 68 ml/100 g/min (the 25th percentile for the open fistula in the hypocapneic group was 15 ml/100 g/min in 5 of the 14 regions studied). In contrast, median rCBF in the closed fistula group ranged from 73 to 100 ml/100 g/min in hypocapneic animals and from 118 to 187 ml/100 g/min in normocapneic animals. These results demonstrate the preservation of CO2 reactivity; hypoperfusion in the presence of a carotid-jugular fistula, hyperemia on fistula occlusion, and the potential to induce cerebral ischemia with hyperventilation in this model of a cerebral arteriovenous fistula. These data caution against the use of hyperventilation during surgery in patients with cerebral arteriovenous malformations.

Abstract The management of the case of a 9-year-old boy with progressive cognitive impairment due to arteriovenous fistulae at the apex of the inferior sagittal sinus is reported. This represents a unique location for an extraparenchymal deep central arteriovenous malformation. The patient underwent staged ablation of the lesion by surgery. The postoperative course was complicated by expansion of an aneurysmal vein of Galen undergoing thrombosis and hyperperfusion syndrome, but the patient ultimately made a satisfactory recovery.

Abstract Three cases of large cerebral arteriovenous fistulae are presented in which surgical ablation was complicated by brain swelling from hyperperfusion breakthrough believed to be caused by acute intraoperative hypoperfusion superimposed on chronic preoperative hypoperfusion. On the basis of these cases, experimental data, and theoretical considerations, we seriously question the wisdom of using staged surgical resection of cerebral arteriovenous malformation to prevent complications related to alterations in cerebral hemodynamics. The reasons for this concern are: the repeated occurrence of acute-on-chronic hypoperfusion during staged resection; a lack of understanding of the time course for the correction of a disordered autoregulation; risk of hemorrhage between the initial and final resection; difficulty in assessing and substantiating flow reduction after subtotal resection; the rapidity of collateralization; the divergence of flow from large, readily accessible feeding arteries to deep penetrating vessels; and attenuation of the wall thickness in collateral vessels as a consequence of increased flow.

Abstract Three cases are described of infants who developed malignant brain swelling (and in one case hemorrhage) after surgery for vein of Galen malformations. The cause for the brain swelling was felt to be due to hyperperfusion, or the “normal perfusion pressure breakthrough” syndrome. Although well-described for cerebral parenchymal arteriovenous malformations, cases of this complication occurring in vein of Galen malformations have not previously been reported. It is concluded from these cases that infants with large arteriovenous shunts, as attested by cardiac failure and cerebral atrophy, have an increased risk of developing this complication.