Unruptured Brain Arteriovenous Malformations Research Articles

The use and abuse of survival analysis and Kaplan-Meier curves in surgical trials

BackgroundSurvival analysis based on Cox regression and Kaplan-Meier curves, initially devised for oncology trials, have frequently been used in other contexts where fundamental statistical assumptions (such as a constant hazard ratio) are not satisfied. This is almost always the case in trials that compare surgery with medical management. MethodsWe review a trial that compared extracranial-intracranial bypass surgery (EC-IC bypass) with medical management (MM) of patients with symptomatic occlusion of the carotid or middle cerebral artery, where it was claimed that surgery was of no benefit. We discuss a hypothetical study and review other neurovascular trials which have also used survival analysis to compare results. ResultsThe trial comparing EC-IC bypass and MM did not satisfy the fundamental proportional hazard assumption necessary for valid analyses. This was also the case for two prior EC-IC bypass trials, as well as for other landmark neurovascular studies, such as the trials comparing endarterectomy with MM for carotid stenoses, or for the trial that compared intervention and MM for unruptured brain arteriovenous malformations. While minor deviations may have little effect on large trials, it may be impossible to show the benefits of surgery when trial size is small and deviations large. ConclusionSurvival analyses are inappropriate in RCTs comparing surgery with conservative management, unless survival is calculated after the postoperative period. Alternative ways to compare final clinical outcomes, using for example a fixed follow-up period, should be planned for preventive surgical trials that compare intervention with conservative management.

Changes in inpatient brain arteriovenous malformation management in the United States following the ARUBA trial: analysis of an interrupted time series design

The November 2013 online publication of ARUBA, the first multi-institutional randomized controlled trial for unruptured brain arteriovenous malformations (AVMs), has sparked over 100 publications in protracted debates MethodsThis study sought to examine inpatient management patterns of brain AVMs from 2009 to 2016 and observe if changes in U.S. inpatient management were attributable to the ARUBA publication using interrupted time series of brain AVM studies from the National Inpatient Sample data 2009–2016. Outcomes of interest were use of embolization, surgery, combined embolization and microsurgery, radiotherapy, and observation during that admission. An interrupted time series design compared management trends before and after ARUBA. Segmented linear regression analysis tested for immediate and long-term impacts of ARUBA on management. ResultsElective and asymptomatic patient admissions declined 2009–2016. In keeping with the ARUBA findings, observation for unruptured brain AVMs increased and microsurgery decreased. However, embolization, radiosurgery, and combined embolization and microsurgery also increased. For ruptured brain AVMs, treatment modality trends remained positive with even greater rates of observation, embolization, and combined embolization and microsurgery occurring after ARUBA (data on radiosurgery were scarce). None of the estimates for the change in trends were statistically significant. ConclusionsThe publication of ARUBA was associated with a decrease in microsurgery and increase in observation for unruptured brain AVMs in the US. However, inpatient radiotherapy, embolization, and combined embolization and surgery also increased, suggesting trends moved counter to ARUBA’s conclusions. This analysis suggested that ARUBA had a small impact as clinicians rejected ARUBA’s findings in managing unruptured brain AVMs.

CNS resident macrophages enhance dysfunctional angiogenesis and circulating monocytes infiltration in brain arteriovenous malformation

Myeloid immune cells are abundant in both ruptured and unruptured brain arteriovenous malformations (bAVMs). The role of central nervous system (CNS) resident and circulating monocyte-derived macrophages in bAVM pathogenesis has not been fully understood. We hypothesize that CNS resident macrophages enhance bAVM development and hemorrhage. RNA sequencing using cultured endothelial cells (ECs) and mouse bAVM samples revealed that downregulation of two bAVM causative genes, activin-like kinase 1 (ALK1) or endoglin, increased inflammation and innate immune signaling. To understand the role of CNS resident macrophages in bAVM development and hemorrhage, we administrated a colony-stimulating factor 1 receptor inhibitor to bAVM mice with brain focal Alk1 deletion. Transient depletion of CNS resident macrophages at an early stage of bAVM development mitigated the phenotype severity of bAVM, including a prolonged inhibition of angiogenesis, dysplastic vasculature formation, and infiltration of CNS resident and circulating monocyte-derived macrophages during bAVM development. Transient depletion of CNS resident macrophages increased EC tight junction protein expression, reduced the number of dysplasia vessels and severe hemorrhage in established bAVMs. Thus, EC AVM causative gene mutation can activate CNS resident macrophages promoting bAVM progression. CNS resident macrophage could be a therapeutic target to mitigate the development and severity of bAVMs.

Vascular compactness of unruptured brain arteriovenous malformation predicts risk of hemorrhage after stereotactic radiosurgery

The aim of the study was to investigate whether morphology (i.e. compact/diffuse) of brain arteriovenous malformations (bAVMs) correlates with the incidence of hemorrhagic events in patients receiving Stereotactic Radiosurgery (SRS) for unruptured bAVMs. This retrospective study included 262 adult patients with unruptured bAVMs who underwent upfront SRS. Hemorrhagic events were defined as evidence of blood on CT or MRI. The morphology of bAVMs was evaluated using automated segmentation which calculated the proportion of vessel, brain tissue, and cerebrospinal fluid in bAVMs on T2-weighted MRI. Compactness index, defined as the ratio of vessel to brain tissue, categorized bAVMs into compact and diffuse types based on the optimal cutoff. Cox proportional hazard model was used to identify the independent factors for post-SRS hemorrhage. The median clinical follow-ups was 62.1 months. Post-SRS hemorrhage occurred in 13 (5.0%) patients and one of them had two bleeds, resulting in an annual bleeding rate of 0.8%. Multivariable analysis revealed bAVM morphology (compact versus diffuse), bAVM volume, and prescribed margin dose were significant predictors. The post-SRS hemorrhage rate increased with larger bAVM volume only among the diffuse nidi (1.7 versus 14.9 versus 30.6 hemorrhage per 1000 person-years in bAVM volume < 20 cm3 versus 20–40 cm3 versus > 40 cm3; p = 0.022). The significantly higher post-SRS hemorrhage rate of Spetzler-Martin grade IV–V compared with grade I–III bAVMs (20.0 versus 3.3 hemorrhages per 1000 person-years; p = 0.001) mainly originated from the diffuse bAVMs rather than the compact subgroup (30.9 versus 4.8 hemorrhages per 1000 person-years; p = 0.035). Compact and smaller bAVMs, with higher prescribed margin dose harbor lower risks of post-SRS hemorrhage. The post-SRS hemorrhage rate exceeded 2.2% annually within the diffuse and large (> 40 cm3) bAVMs and the diffuse Spetzler-Martin IV–V bAVMs. These findings may help guide patient selection of SRS for the unruptured bAVMs.

Association of socioeconomic status with the management outcome of unruptured intracranial arteriovenous malformation.

The longitudinal management of unruptured brain arteriovenous malformation (bAVM) is crucial. To date, no study in the United States has evaluated the impact of socioeconomic status (SES) on bAVM outcome. Herein, the authors aimed to clarify the impact of SES, as indicated by the area deprivation index (ADI), on bAVM outcome. A retrospective analysis of an institutional bAVM database was conducted. Non-hereditary hemorrhagic telangiectasia patients with a single unruptured bAVM in the period from 1990 to 2021 were included in the analysis. The ADI was categorized as low (ADI ≤ 15th percentile), mid (15th percentile < ADI < 85th percentile), and high (ADI ≥ 85th percentile), with a low ADI indicating the most advantaged group. Patient baseline and follow-up data were analyzed. The primary outcome of interest was nonindependence (modified Rankin Scale [mRS] score > 2) at the last follow-up. A multivariable logistic regression model was performed. A total of 589 patients with unruptured bAVMs were included in the study. The mean patient age at diagnosis was 37.2 years, and 283 patients (48.0%) were male. Of the bAVMs, 238 (40.4%) had a low Spetzler-Martin grade (SMG < III), 194 (32.9%) had a moderate grade (SMG III), and 157 (26.7%) had a high grade (SMG > III). Sixty-nine patients (11.7%) were in the low-ADI group, 476 (80.8%) in the mid-ADI group, and 44 (7.5%) in high-ADI group. Increasing age (OR 1.02, 95% CI 1.01-1.04, p < 0.001), poor baseline mRS score (OR 3.27, 95% CI 1.32-7.88, p = 0.008), treatment with surgery plus radiosurgery with or without embolization (OR 3.21, 95% CI 1.03-9.81, p = 0.041), mid SMG (OR 1.94, 95% CI 1.11-3.44, p = 0.021), high SMG (OR 2.08, 95% CI 1.13-3.88, p = 0.020), longer follow-up (OR 1.05, 95% CI 1.03-1.08, p < 0.001), and mid ADI (OR 3.08, 95% CI 1.34-8.39, p = 0.015) were significantly associated with a poor outcome. A high ADI tended toward a poor outcome (OR 2.93, 95% CI 0.92-9.88, p = 0.071). Eventual obliteration of a bAVM was the only protective predictor of poor outcome (OR 0.55, 95% CI 0.30-0.98, p = 0.046). This study revealed that relatively disadvantaged patients with unruptured bAVMs are more likely to experience nonindependent outcomes at the last follow-up, after adjusting for confounding variables. An emphasis on social support may be beneficial for patients with a lower SES.

Treatment outcomes for ARUBA-eligible brain arteriovenous malformations: a comparison of real-world data from the NVQI-QOD AVM registry with the ARUBA trial

BackgroundSignificant controversy exists about the management of unruptured cerebral arteriovenous malformations (AVMs). Results from A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) suggested that intervention increases the risk of...

Outcome of 107 conservatively managed unruptured brain arteriovenous malformations: a single center's 30-year experience.

Since the publication of A Randomized Trial of Unruptured Brain AVMs (ARUBA), the management of unruptured brain arteriovenous malformations (bAVMs) has been controversially discussed. Long-term follow-up data on the exclusively conservative management of unruptured bAVMs are scarce. The authors evaluated the long-term outcomes of patients with unruptured untreated bAVMs in a real-life cohort. A retrospective observational cohort of 107 patients (of 897 bAVM patients referred to the authors' institution) with a diagnosis of unruptured and conservatively managed bAVMs is presented. AVMs of all Spetzler-Martin grades were observed. The mean follow-up period was 84 months. In 44% of patients, a follow-up period of 5 years or longer was observed. A national death register comparison completed the outcome analysis. The median age at diagnosis, sex distribution, neurological presentation, and modified Rankin Scale score were comparable to the patients in the medical management arm of the ARUBA study. Patients were mainly young, predominantly male, and in good clinical condition. Similar to the ARUBA cohort, 77% of this study's cohort presented in an excellent clinical status at the time of last follow-up. However, 17% of patients had at least one hemorrhage, resulting in an overall annual hemorrhage risk of 2.7% in the observation period. Moreover, the cumulative 1-, 5-, and 10-year overall hemorrhage rates were 3.0%, 11.3%, and 15.3%, respectively. Consequently, the long-term follow-up AVM-related mortality rate amounted to 8%. The estimated median overall survival after AVM diagnosis was 19.3 years (95% CI 14.0-24.6 years). A multivariate Cox regression model revealed temporal and deep-seated localization as an independent risk factor for AVM hemorrhage, while the presence of seizures reached borderline significance as a risk factor. The authors' results represent the long-term course of unruptured untreated bAVMs. Their data support the conclusion that even in the post-ARUBA era, tailored active treatment options may be offered to patients with unruptured bAVMs. For patient counseling, individual risk factors should be weighed against the center's treatment-specific risks.

Microsurgical Treatment of Arteriovenous Malformations: A Single-Center Study Experience.

The purpose of the study was to assess the functional outcomes after microsurgical resection of arteriovenous malformations (AVMs) and to compare the results between patients eligible for A Randomized Trial of Unruptured Brain Arteriovenous Malformations in this surgical series to the results reported and the ARUBA study. We reviewed the records of 169 patients who underwent microsurgical treatment of arteriovenous malformation (AVMs) in our institution between January 2016 and December 2021. These patients' functional status was assessed using modified Rankin Scale (mRS) scores at the last follow-up and before treatment. The mRS scores at the latest follow-up were classified into good outcomes (mRS < 3) and poor outcomes (mRS ≥ 3). Clinical presentation, patients' demographics, AVM characteristics, follow-up time, and obliteration rate were analyzed. Subgroup analyses were performed on the whole cohort, comparing Spetzler-Martin Grade I and Grade II, and ARUBA-eligible AVMs. The initial hemorrhagic presentation occurred in 71 (42%) out of 169 patients. The majority of the patients presented with headaches (73%). The AVMs were completely obliterated in 166 (98.2%) patients. The series included 65 Spetzler-Martin Grade I (38.5%), 46 Grade II (27.2%), 32 Grade III (18.9%), 22 Grade IV (13%), and 4 Grade V (2.4%) AVMs. There were 98 unruptured and 79 ARUBA-eligible cases. Also, optimal functional outcome was achieved in 145 (85.8%) patients. The overall mortality rate was 5.3% (9/169). The multivariate analysis illustrated that a poor outcome was significantly associated with presurgical mRS ≥3 (p < 0.013; OR, 0.206; 95% CI 0.059-0.713), increasing age (p < 0.045; odds ratio [OR], 1.022; 95% CI 1.000-0.045), and female gender (p < 0.009; OR, 2.991; 95% CI 1.309-6.832). Our study suggests that better outcomes can be obtained using microsurgical resection in the majority of patients with AVMs. Independent predictors of poor outcomes after surgical resection of AVMs include increasing age at the time of surgery, poor presurgical functional status, and female gender. Supposing that patients are more suitable for microsurgery after presurgical examination, outcomes are normally better in that case than those achieved by multimodal interventions (such as conservative treatment or ARUBA treatment arm). Therefore, we recommend early surgical removal on all surgically accessible AVMs to prevent successive hemorrhages and the consequences of poor neurological outcomes.

Management of Adult Unruptured Brain Arteriovenous Malformations: An Updated Network Meta-Analysis.

The management of unruptured brain arteriovenous malformations (ubAVMs) is a complex challenge to neurovascular practitioners. This meta-analysis aimed to identify the optimal management of ubAVMs comparing conservative management, embolization, radiosurgery, microsurgical resection, and multimodality. The search strategy was developed a priori according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the Ovid Medline, Embase, Web of Science, and Cochrane Library databases to identify relevant papers. Using R version 4.1.1., a frequentist network meta-analysis was conducted to compare different management modalities for the ubAVMs. Overall, the conservative group had the lowest risk of rupture (P-score=0.77), and the lowest rate of complications was found in the conservative group (P-score=1). Among different interventions, the multimodality group had the highest rupture risk (P-score=0.34), the lowest overall complications (P-score=0.75), the best functional improvement (P-score=0.65), and the lowest overall mortality (P-score=0.8). However, multimodality treatment showed a significantly higher risk of rupture (odds ratio [OR]=2.13; 95% confidence interval [95% CI]=1.18-3.86) and overall complication rate (OR=5.56; 95% CI=3.37-9.15) compared to conservative management; nevertheless, there were no significant differences in overall mortality or functional independence when considered independently. Conservative management is associated with the lowest rupture risk and complication rate overall. A multimodal approach is the best option when considering mortality rates and functional improvement in the context of existing morbidity/symptoms. Microsurgery, embolization, and radiosurgery alone are similar to the natural history in terms of functional improvement and mortality, but have higher complication rates.

Management of Unruptured Intracranial Aneurysms and Brain Arteriovenous Malformations.

Managing a patient with an unruptured brain aneurysm or brain arteriovenous malformation (AVM) can lead to uncertainty about preventive treatment. While the bleeding risks are low, the morbidity or mortality associated with a hemorrhagic event is not insignificant. The objective of this article is to review the natural history of these vascular entities, the risk factors for hemorrhage, preventive treatment options, and the risks of treatment. Randomized trials to inform preventive treatment strategies for unruptured intracranial aneurysms and brain AVMs are ongoing. Higher angiographic obliteration rates of unruptured intracranial aneurysms have been reported with the flow-diversion technique compared with alternative standard techniques. One randomized trial for unruptured brain AVMs showed a higher rate of morbidity and mortality in patients who underwent interventional treatment compared with observation. The decision to treat a patient with a brain aneurysm should consider patient factors, the patient's life expectancy, aneurysm anatomical factors, and treatment risks. Patients with unruptured brain AVMs should be observed in light of recent clinical trial data or enrolled in an ongoing clinical trial.

350 A Comparison of Incidental and Symptomatic Unruptured Brain Arteriovenous Malformations in Children

INTRODUCTION: Unruptured brain arteriovenous malformations (AVMs) may present with headaches, seizures, and/or neurologic deficits. A smaller number of cases may be discovered incidentally. These lesions remain incompletely understood due to their sparse reporting. METHODS: We performed a retrospective analysis of patients presenting with brain AVMs from 1998 to 2021 at the University of California, San Francisco. Inclusion criteria included age ≤18 at time of presentation with angiographically-proven unruptured AVM diagnosed postnatally. RESULTS: Of 76 children with unruptured AVMs, 66 (86.8%) presented with headaches, seizures, and/or neurologic deficit. Ten (13.1%) were incidentally discovered through unrelated disease workup (50%), cranial trauma (40%), or research study participation (10%). Compared to symptomatic unruptured AVMs, incidental unruptured AVMs possessed smaller mean nidus maximum diameter (2.82 ± 1.1 vs. 3.98 ± 1.52 cm, p = 0.025) and deep venous drainage proportion (20% vs. 61%, p = 0.036). They also presented at earlier ages (10 ± 5.2 vs. 13.5 ± 4 years, p = 0.043) with longer durations to first treatment (541 ± 922 vs. 196 ± 448 days, p = 0.005). During the period of observation, one patient developed recurring headaches and demonstrated AVM nidus growth. Four AVMs greater than 3 centimeters or in deep location were treated with radiosurgery. Six other AVMs were treated with surgical resection with 2 receiving preoperative embolization. Seven AVMs (70%) were obliterated on last follow-up. Postprocedural complications included 2 transient neurologic deficits following resection and 1 delayed seizure development following radiosurgery. The mean follow-up period was 5.1 ± 5.8 years without any hemorrhage episodes. CONCLUSIONS: A substantial proportion of pediatric patients with unruptured AVMs are discovered incidentally. With earlier presentation and more elementary angioarchitecture than symptomatic unruptured AVMs, these incidental lesions provide a snapshot into AVM natural history before symptom development or rupture.

Letter: Risk for Hemorrhage the First 2 Years After Gamma Knife Surgery for Arteriovenous Malformations: An Update.

To the Editor: We have read with great interest the article by Karlsson et al1 titled “Risk for Hemorrhage the First 2 Years After Gamma Knife Surgery for Arteriovenous Malformations: An Update.” The premise of this study was based on the findings of a 2001 study that demonstrated the risk of hemorrhage after gamma knife surgery (GKS) for arteriovenous malformations (AVMs) to be strongly correlated with large AVM size, older age, and lower therapeutic dose.2 However, contradictory data collected 17 years later revealed the risk of hemorrhage was not related to AVM size or patient age.3 To clearly define predictors of hemorrhage, the authors retrospectively reviewed the outcome of 5037 patients treated with GKS for AVM.1 The average rate of hemorrhage was determined to be 2.4%, where larger AVM size, older age, and lower therapeutic dose served as significant (P < .01) risk factors, consistent with findings from the original study.1,2 AVM location (P = .16), embolization (P = .27), and history of pre-GKS hemorrhage (P = .20) were found to be nonsignificant predictors for post-GKS hemorrhage.1 The identification of clear hemorrhage risk factors after GKS for AVM in this large, heterogeneous cohort provides clinicians with more concrete guidelines for AVM management.1 The clinical management of cerebral AVMs remains challenging due to AVM heterogeneity in size, biological composition, anatomic location, and associated symptoms.4 Thus, the treatment of AVMs to reduce hemorrhage risk must be conducted in an individualized manner specific to patient presentation and AVM profile. Although no formal guidelines exist regarding treatment of unruptured AVMs, a landmark randomized trial of unruptured brain arteriovenous malformations (trial) revealed the superiority of medical management compared with interventional therapy.5 Interventional therapy was associated with an increased risk of stroke or death as compared with medical management alone (P < .0001; hazard ratio 3.70; 95% CI 1.85–7.14).5 Five-year follow-up data confirmed these findings.6 With this understanding, along with identifying general risk factors and prevalence rates of AVM hemorrhage after GKS, it would be valuable to investigate the impact of hemorrhage on mortality and morbidity in this cohort of patients undergoing interventional therapy. Doing so, while controlling for confounding variables, such as the Spetzler-Martin grade, AVM nidus morphology or location, would be clinically significant and aid in deciding which patients would truly benefit from GKS. Hemorrhage is the leading cause of morbidity and mortality associated with AVMs.7 Consequently, common symptoms of AVM-related hemorrhage such as seizures and headaches severely impair quality of life (QOL).8,9 While it can be hypothesized that post-GKS AVM hemorrhage would have profound implications for QOL outcomes, there are no reports in the literature detailing this relationship. Future studies should investigate the impact of post-GKS hemorrhage on QOL metrics, especially as GKS continues to improve and be used for more complex disease. This study by Karlsson et al1 provides a strong foundation for the future investigation of invaluable QOL metrics to guide medical decision-making in a manner that targets patient-specific QOL discrepancies while bridging this apparent gap in the literature.

A comparison of incidental and symptomatic unruptured brain arteriovenous malformations in children.

Patients with unruptured brain arteriovenous malformations (AVMs) may present with headaches, seizures, and/or neurological deficits. A smaller number of cases may be discovered incidentally. These lesions remain incompletely understood due to their sparse reporting. Herein, the authors describe the largest series to date comparing the presentation, angioarchitecture, and management of incidental versus symptomatic unruptured AVMs in children. The authors performed a retrospective analysis of patients who presented with brain AVMs from 1998 to 2022 at the University of California, San Francisco. Inclusion criteria were age ≤ 18 years at the time of presentation and an angiographically proven unruptured AVM that had been diagnosed postnatally. Of 76 children with unruptured AVMs, 66 (86.8%) presented with headaches, seizures, and/or neurological deficit. Ten AVMs (13.1%) were incidentally discovered through unrelated disease workup (50%), cranial trauma (40%), or research study participation (10%). Compared with patients with symptomatic unruptured AVMs, patients with incidental unruptured AVMs had a smaller mean ± SD maximum nidus diameter (2.82 ± 1.1 vs 3.98 ± 1.52 cm, p = 0.025) and fewer had deep venous drainage (20% of patients vs 61%, p = 0.036). They also presented at an earlier age (10 ± 5.2 vs 13.5 ± 4 years, p = 0.043) and with longer duration to first treatment (541 ± 922 vs 196 ± 448 days, p = 0.005). During the observation period, 1 patient developed recurring headaches and demonstrated AVM nidus growth. Four AVMs greater than 3 cm in size or in a deep location were treated with radiosurgery. Six other AVMs were treated with resection, with 2 receiving preoperative embolization. Eight AVMs (80%) were obliterated on last follow-up. Postprocedural complications included 2 transient neurological deficits after resection and 1 case of delayed seizure development after radiosurgery. The mean follow-up period was 5.7 ± 5.7 years without any hemorrhage episodes. A substantial proportion of pediatric patients with unruptured AVMs are discovered incidentally. With earlier presentation and more elementary angioarchitecture than symptomatic unruptured AVMs, these incidental lesions provide a snapshot into the natural history of AVM before symptom development or rupture.

Abstract 53: Long-term Treatment Risk Of Hemorrhage In Unruptured Brain Arteriovenous Malformation Patients

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&lt;0.001): between 0-1 year, treatment was associated with higher risk of ICH (HR=3.48, 95% CI: 2.26-5.37, p&lt;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&lt;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.

In Response to: Dicpinigaitis AJ, Ogulnick JV, Mayer AS, Gandhi CD, Al‐Mufti F. Increase in Ruptured Cerebral Arteriovenous Malformations and in the United States: Unintended Consequences of the ARUBA Trial? Stroke Vasc Interv Neurol . 2022;0:e000442. https://doi.org/10.1161/SVIN.122.000442

In Response to: Dicpinigaitis AJ, Ogulnick JV, Mayer AS, Gandhi CD, Al‐Mufti F. Increase in Ruptured Cerebral Arteriovenous Malformations and in the United States: Unintended Consequences of the ARUBA Trial? <i>Stroke Vasc Interv Neurol</i> . 2022;0:e000442. https://doi.org/10.1161/SVIN.122.000442

Surgery Reduces Blood-Brain Barrier Hyperpermeability in Ruptured and Unruptured Brain Arteriovenous Malformations. A DCE-MRI-Based Pilot Study

Surgery Reduces Blood-Brain Barrier Hyperpermeability in Ruptured and Unruptured Brain Arteriovenous Malformations. A DCE-MRI-Based Pilot Study

In Response to: Dicpinigaitis AJ, Ogulnick JV, Mayer AS, Gandhi CD, Al‐Mufti F. Increase in Ruptured Cerebral Arteriovenous Malformations and Mortality in the United States: Unintended Consequences of the ARUBA Trial

In Response to: Dicpinigaitis AJ, Ogulnick JV, Mayer AS, Gandhi CD, Al‐Mufti F. Increase in Ruptured Cerebral Arteriovenous Malformations and Mortality in the United States: Unintended Consequences of the ARUBA Trial

Unruptured brain arteriovenous malformations causing seizures localize to one common brain network.

Seizures are a frequent symptom of unruptured brain arteriovenous malformations (bAVMs). However, the brain regions responsible for these seizures remain unclear. To identify the brain regions causally involved in bAVM-related seizures, we retrospectively reviewed 220 patients with unruptured bAVMs. Using voxel-based lesion-symptom mapping (VLSM) analyses, we tested whether individual brain regions were associated with unruptured bAVM-related seizures. The result revealed that unruptured bAVMs causing seizures are anatomically heterogeneous at the voxel level. Subsequently, lesion network mapping (LNM) analyses was performed to determine whether bAVMs causing seizures belonged to a distributed brain network. LNM analyses indicated that these lesions were located in a functional network characterized by connectivity to the left caudate and precuneus. Moreover, the discrimination performance of the identified seizure network was evaluated in discovery set by calculating the individualized network damage score and was tested in validation set. Based on the calculated network damage scores, patients were divided into low-, medium-, and high-risk groups. The prevalence of seizures significantly differed among the three risk categories in both discovery (p=.003) and validation set (p=.004). Finally, we calculated the percentage of voxels in the canonical resting-state networks that overlapped with the seizure-susceptible brain regions to investigate the involvement of resting-state networks. With an involvement percentage over 50%, the frontoparietal control (82.9%), limbic function (76.7%), and default mode network (69.3%) were considered to be impacted in bAVM-related seizures. Our study identified the seizure-susceptible brain regions for unruptured bAVMs, which could be a plausible neuroimaging biomarker in predicting possible seizures.

Hemorrhage Risk after Stereotactic Radiosurgery for Patients with Unruptured Brain Arteriovenous Malformation: Significance of Vascular Compactness

<h3>Purpose/Objective(s)</h3> Our purpose was to investigate whether the morphology (i.e., compact/ diffuse) of brain arteriovenous malformations (bAVMs) correlates with the incidence of hemorrhagic events in patients with unruptured bAVMs after receiving non-invasive stereotactic radiosurgery (SRS). <h3>Materials/Methods</h3> This study retrospectively included 264 adult patients with unruptured bAVMs undergoing upfront SRS from multi-institutions. Two senior neurosurgeons confirmed the unruptured presentation. The follow-ups were performed in a 6-month interval. Hemorrhagic events were defined as bleeding signs on computed tomography (CT) or magnetic resonance images (MRI). The morphology of bAVMs was evaluated using fully automated segmentation, which calculated the proportion of vessel, brain tissue, and cerebrospinal fluid in bAVMs on T2-weighted MRI. Compactness index, defined as a ratio of vessel to brain tissue, was proposed and further dichotomized based on Youden indices to classify the bAVMs into compact or diffuse type. Cox proportional hazard model was used to identify the independent factors for the occurrence of post-SRS hemorrhage. <h3>Results</h3> The median follow-up duration was 62.1 months. Post-SRS hemorrhage occurred in 14 (5.3%) patients with 2 bAVMs bleeding twice, incurring an annual bleeding risk of 0.9%. Multivariable analysis with stepwise backward variable selection method revealed that bAVM morphology (compact versus diffuse), bAVM volume and prescribed margin dose were significant predictors for post-GKRS hemorrhage. The incidence density of post-GKRS hemorrhage in the compact and diffuse bAVMs were 4.9 and 11.8 (hemorrhagic events/ 1000 person-years (P-Ys)). Among the diffuse bAVMs (n=153), the post-GKRS hemorrhage rate was lower for smaller bAVM volume, <15ml versus 15-30ml versus >30ml (2.2 versus 13.5 versus 26.3 hemorrhagic events/ 1000 P-Ys; p=0.044) and for bAVMs receiving margin dose >16.6 Gy versus <16.6 Gy (5.2 versus 25.8 hemorrhagic events/ 1000 P-Ys; p=0.004). For the compact bAVMs (n=111), the post-GKRS hemorrhage rate was not significantly different between the dose and volume groups. <h3>Conclusion</h3> Compact and smaller bAVMs, with higher prescribed margin dose harbor lower risks of post-SRS hemorrhage. Among the diffuse bAVMs, post-GKRS hemorrhage risk varied with bAVM volume and margin dose. The finding could help guide GKRS treatment decision-making for the unruptured bAVMs.

Impact of ARUBA trial on trends and outcomes in symptomatic non-ruptured brain AVMs: A national sample analysis

IntroductionThe real-world evolution of management and outcomes of patients with unruptured brain arteriovenous malformations (AVMs) has not been well-delineated following the ARUBA trial findings of no general advantage of initial interventional (surgical/endovascular/radiotherapy) vs. initial conservative medical therapy. MethodsWe analyzed the National Inpatient Sample from 2009-2018, capturing 20% of all admissions in the U.S. Validated ICD-9 and -10 codes defined brain AVMs, comorbidities, and the use of interventional modalities. Analyses were performed by year and for the dichotomized periods of pre-ARUBA (2009-2013) vs. post-ARUBA (2014-2018). ResultsAmong the national projected 88,037 AVM admissions, 72,812 (82.7%) were unruptured AVMs and 15,225 (17.3%) were ruptured AVMs. Among uAVMs, 51.4% admitted pre-ARUBA and 48.6% in post-ARUBA period. The post-ARUBA patients were mildly older (median age 53.3 vs. 51.8 (p = 0.001) and had more comorbidities including hypertension, diabetes, obesity, renal impairment, and smoking. Before the first platform report of ARUBA (2009-2012), rates of use of interventional treatments during uAVM admissions trended up from 31.8% to 35.4%. Thereafter, they declined significantly to 26.4% in 2018 (p = 0.02). The decline was driven by a reduction in the frequency of endovascular treatment from 18.8% to 13.9% and inpatient stereotactic radiosurgery from 0.5% to 0.1%. No change occurred in the frequency of microsurgery or combined endovascular and surgical approaches. Adjusted multivariable model of uAVMs showed increased odds of discharge to a long-term inpatient facility or in-hospital death [OR 1.14 (1.02-1.28), p = 0.020] in post-ARUBA. A significantly increased proportion of ruptured AVMs from 17.0% to 23.3% was observed consistently in post-ARUBA. ConclusionNationwide practice in the management of unruptured AVMs changed substantially with the publication of the ARUBA trial in a durable and increasing manner. Fewer admissions with the interventional treatment of unruptured AVMs occurred, and a corresponding increase in admission for ruptured AVMs transpired, as expected with a strategy of watchful waiting and treatment only after an index bleeding event. Further studies are needed to determine whether these trends can be considered to be ARUBA trial effect or are merely coincidental.