Derdeyn, Colin P.

OBJECTIVE Cranial dural arteriovenous fistulas (dAVFs) are rare lesions, hampering efforts to understand them and improve their care. To address this challenge, investigators with an established record of dAVF investigation formed an international, multicenter consortium aimed at better elucidating dAVF pathophysiology, imaging characteristics, natural history, and patient outcomes. This report describes the design of the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) and includes characterization of the 1077-patient cohort. METHODS Potential collaborators with established interest in the field were identified via systematic review of the literature. To ensure uniformity of data collection, a quality control process was instituted. Data were retrospectively obtained. RESULTS CONDOR comprises 14 centers in the United States, the United Kingdom, the Netherlands, and Japan that have pooled their data from 1077 dAVF patients seen between 1990 and 2017. The cohort includes 359 patients (33%) with Borden type I dAVFs, 175 (16%) with Borden type II fistulas, and 529 (49%) with Borden type III fistulas. Overall, 852 patients (79%) presented with fistula-related symptoms: 427 (40%) presented with nonaggressive symptoms such as tinnitus or orbital phenomena, 258 (24%) presented with intracranial hemorrhage, and 167 (16%) presented with nonhemorrhagic neurological deficits. A smaller proportion (224 patients, 21%), whose dAVFs were discovered incidentally, were asymptomatic. Many patients (85%, 911/1077) underwent treatment via endovascular embolization (55%, 587/1077), surgery (10%, 103/1077), radiosurgery (3%, 36/1077), or multimodal therapy (17%, 184/1077). The overall angiographic cure rate was 83% (758/911 treated), and treatment-related permanent neurological morbidity was 2% (27/1467 total procedures). The median time from diagnosis to follow-up was 380 days (IQR 120–1038.5 days). CONCLUSIONS With more than 1000 patients, the CONDOR registry represents the largest registry of cranial dAVF patient data in the world. These unique, well-annotated data will enable multiple future analyses to be performed to better understand dAVFs and their management.

OBJECTIVE Cranial dural arteriovenous fistulas (dAVFs) are often treated with endovascular therapy, but occasionally a multimodality approach including surgery and/or radiosurgery is utilized. Recurrence after an initial angiographic cure has been reported, with estimated rates ranging from 2% to 14.3%, but few risk factors have been identified. The objective of this study was to identify risk factors associated with recurrence of dAVF after putative cure. METHODS The Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) data were retrospectively reviewed. All patients with angiographic cure after treatment and subsequent angiographic follow-up were included. The primary outcome was recurrence, with risk factor analysis. Secondary outcomes included clinical outcomes, morbidity, and mortality associated with recurrence. Risk factor analysis was performed comparing the group of patients who experienced recurrence with those with durable cure (regardless of multiple recurrences). Time-to-event analysis was performed using all collective recurrence events (multiple per patients in some cases). RESULTS Of the 1077 patients included in the primary CONDOR data set, 457 met inclusion criteria. A total of 32 patients (7%) experienced 34 events of recurrence at a mean of 368.7 days (median 192 days). The recurrence rate was 4.5% overall. Kaplan-Meier analysis predicted long-term recurrence rates approaching 11% at 3 years. Grade III dAVFs treated with endovascular therapy were statistically significantly more likely to experience recurrence than those treated surgically (13.3% vs 0%, p = 0.0001). Tentorial location, cortical venous drainage, and deep cerebral venous drainage were all risk factors for recurrence. Endovascular intervention and radiosurgery were associated with recurrence. Six recurrences were symptomatic, including 2 with hemorrhage, 3 with nonhemorrhagic neurological deficit, and 1 with progressive flow-related symptoms (decreased vision). CONCLUSIONS Recurrence of dAVFs after putative cure can occur after endovascular treatment. Risk factors include tentorial location, cortical venous drainage, and deep cerebral drainage. Multimodality therapy can be used to achieve cure after recurrence. A delayed long-term angiographic evaluation (at least 1 year from cure) may be warranted, especially in cases with risk factors for recurrence.

Background and Purpose: Dural arteriovenous fistulae can present with hemorrhage, but there remains a paucity of data regarding subsequent outcomes. We sought to use the CONDOR (Consortium for Dural Arteriovenous Fistula Outcomes Research), a multi-institutional registry, to characterize the morbidity and mortality of dural arteriovenous fistula–related hemorrhage. Methods: A retrospective review of patients in CONDOR who presented with dural arteriovenous fistula–related hemorrhage was performed. Patient characteristics, clinical follow-up, and radiographic details were analyzed for associations with poor outcome (defined as modified Rankin Scale score ≥3). Results: The CONDOR dataset yielded 262 patients with incident hemorrhage, with median follow-up of 1.4 years. Poor outcome was observed in 17.0% (95% CI, 12.3%–21.7%) at follow-up, including a 3.6% (95% CI, 1.3%–6.0%) mortality. Age and anticoagulant use were associated with poor outcome on multivariable analysis (odds ratio, 1.04, odds ratio, 5.1 respectively). Subtype of hemorrhage and venous shunting pattern of the lesion did not affect outcome significantly. Conclusions: Within the CONDOR registry, dural arteriovenous fistula–related hemorrhage was associated with a relatively lower morbidity and mortality than published outcomes from other arterialized cerebrovascular lesions but still at clinically consequential rates.

Background: Noninvasive fractional flow measures with CT angiography (CTA) have revolutionized cardiology, yet the complex anatomy of the cerebral circulation and boundary conditions challenge the study of intracranial atherosclerosis. We developed a framework for systematic computational fluid dynamics (CFD) of middle cerebral artery (MCA) stenosis with CTA in SAMMPRIS. Methods: A 3D geometric mesh was generated from CTA source images, followed by CFD processing in Ansys (ICEM, CFX) on a Cray supercomputer. Reference boundary conditions were applied with an ICA inlet and outlets at the ACA and distal MCA to yield quantitative maps of intraluminal pressure drops (ΔP or fractional flow), blood flow velocity (V) and turbulent kinetic energy (TKE) with wall shear stress (WSS) mapped along the arteries. CFD parameters were then compared with SAMMPRIS angiography variables. Results: Of 451 SAMMPRIS (70-99% symptomatic stenosis) subjects, CTA was acquired at enrollment in 41 MCA cases. CFD results were successfully attained in 30, limited by anatomy (e.g. across branch points) in 7/11 and poor CTA resolution in 4/11. Fractional flow (ΔP) across stenosis was mean 0.64 ± SD 0.33, with maximal stenosis velocity of mean 192 ± SD 101 cm/s and maximal WSS 0.36 ± SD 0.25 mm Hg. SAMMPRIS angiography percent stenosis was unrelated to ΔP -0.163 (p=0.399), velocity 0.126 (p=0.514) or WSS 0.078 (p=0.689). Worse collateral blood flow grades were associated with larger ΔP (p=0.137), higher velocity (p=0.059), higher WSS (p=0.112). Asymmetric WSS with high and low regions on opposing arterial walls was measured in the post-stenotic segment in 25/30 (83%). TKE maps revealed focal increases in the post-stenotic region, yet not above abnormal thresholds based on arterial diameter. Conclusions: CTA CFD of intracranial atherosclerosis provides detailed noninvasive measures of hemodynamics.

Background: Collateral blood flow, modulated by inflammation and arteriogenesis, alters ischemic injury in intracranial atherosclerosis. We investigated the potential link between several inflammatory and arteriogenic biomarkers with angiographic findings at enrollment in BIOSIS/SAMMPRIS. Methods: Baseline angiography and blood biomarkers of BIOSIS/SAMMPRIS, which included subjects with stroke or TIA due to 70-99% intracranial stenosis were analyzed. Collateral blood flow status at angiography was categorized by the combination of antegrade flow (TICI) and corresponding extent of collaterals (ASITN/SIR). Collateral status was analyzed with respect to blood progenitor cell markers (CD34) at baseline and inflammatory biomarkers (Plasminogen Activator Inhibitor-1 (PAI-1), E-selectin, high sensitivity C-reactive protein (hsCRP) and Lipoprotein-associated phospholipase A2 (Lp-PLA 2 ) activity and concentrations) at baseline, 30 days and 4 months. Results: 376 subjects (mean age 60.44 years SD 11; 149/376 (39.6%) women) enrolled in BIOSIS/SAMMPRIS had angiography of collaterals and biomarker data. Collateral perfusion was impaired in 71 (19%) and intermediate in 188 (50%), with robust collaterals in 117 (30%) subjects. Better collateral status was associated with younger age (p=0.001), male sex (p=0.029) and greater baseline physical activity (p=0.007). Baseline blood progenitor cell (CD34+) counts were unrelated to angiographic features at enrollment, whereas inflammatory Lp-PLA 2 activity was linked (p=0.059) with blood flow categories, and lower hsCRP (p=0.025) with better collaterals. Lp-PLA 2 activity was lowest in those with robust collaterals at 30 days (p=0.070) and 4 months (p=0.120). Those with robust collaterals had the greatest decrease in Lp-PLA 2 activity (p=0.021) and concentration (p=0.027) by 30 days, with a continued decline of Lp-PLA 2 activity (p=0.037) to 4 months. Disparate trends in inflammatory markers were seen in the medical and stenting arms. Conclusions: Inflammatory biomarkers are linked with collateral blood flow status in intracranial atherosclerosis. The impact of physical activity, medications and other therapeutic investigations may disclose important mechanisms to avert ischemia.

Background: Poor collateral circulation and hypoperfusion may lead to recurrent stroke in intracranial atherosclerotic disease (ICAD). The role of perfusion in silent strokes and potentially insidious cognitive impairment in ICAD is unknown. We used evidence of impaired perfusion at angiography in SAMMPRIS to predict subsequent cognitive changes. Methods: Angiography at enrollment in the SAMMPRIS trial was independently evaluated, blind to clinical data and cognitive testing. Antegrade flow in the symptomatic arterial territory and corresponding collateral flow were scored. Impaired perfusion was defined by poor antegrade and poor collateral flow. Serial testing with the Montreal Cognitive Assessment (MoCA) was done in subjects without aphasia or neglect at baseline, 4 mo, 12 mo and closeout, or until subjects had a clinical stroke endpoint. Results: 207 subjects (median age 61, range 33-81 years; 37% women) had baseline MoCA scores with angiography data on territorial perfusion. Baseline MoCA scores (mean 24.2±4.1) were similar between categories of antegrade flow and collateral circulation. Impaired perfusion was noted in 33/207 (16%). Serial MoCA revealed that changes in cognition over time were different at 4 mo, 12 mo and closeout based on the presence of impaired perfusion at baseline (p<0.001). After more modest (mean MoCA change = 0.5 increase from baseline, p=0.80) early improved cognitive function at 4 mo, those with impaired perfusion had cognitive decline at 12 mo (mean MoCA change, p<0.01) unlike the continued improvement in other subjects. Cognitive changes in those with impaired perfusion were associated with a higher frequency of subsequent stroke in the territory. Conclusions: Impaired perfusion in the symptomatic arterial territory of ICAD predicts cognitive outcomes that may precede recurrent ischemia. Future studies may define the role of noninvasive perfusion imaging in ICAD to predict cognitive trajectories and recurrent stroke.

Background and Purpose: Given the benign natural history of intracranial low-grade dural arteriovenous fistulas (dAVFs), their routine treatment remains controversial. The aim of this study is to compare the outcomes of low-grade dAVF treatment to conservative management. Methods: We performed a retrospective review of dAVF patients derived from 12 institutions participating in the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR). Patients with low-grade (Borden I) dAVFs were included and categorized into treatment and observation cohorts. Primary outcome was defined as modified Rankin Scale (mRS) score at final follow-up. Secondary outcomes were rates of excellent (mRS 0-1) and good (mRS 0-2) functional outcomes, symptomatic improvement, mortality, and obliteration at final follow-up. Results: The treatment and observation cohorts comprised 230 and 112 patients, respectively. At last follow up, no difference in primary or secondary outcomes was observed between the two cohorts, with the exception of obliteration, which was higher in the treatment cohort (79.3% vs. 28.2%, p<0.001; Table 1). The two cohorts were then matched in a 1:1 ratio, resulting in 64 patients in each matched cohort. No difference in primary or secondary outcomes was observed between the matched cohorts, with the exception of obliteration, which was higher in the matched treatment cohort (75.4% vs. 28.6%, p<0.001; Table 2). Subgroup analysis of symptomatic patients demonstrated higher obliteration rate in the treatment cohort, but no difference in primary or other secondary outcomes were found. Conclusions: Low-grade dAVF treatment was not associated with increased functional disability compared to conservative management. Although higher obliteration rates were achieved in the treatment cohort, rates of symptomatic improvement were similar between the two cohorts. This study did not provide evidence to support the routine treatment of low-grade dAVFs.

Abstract BACKGROUND Low-grade intracranial dural arteriovenous fistulas (dAVF) have a benign natural history in the majority of cases. The benefit from treatment of these lesions is controversial. OBJECTIVE To compare the outcomes of observation versus intervention for low-grade dAVFs. METHODS We retrospectively reviewed dAVF patients from institutions participating in the CONsortium for Dural arteriovenous fistula Outcomes Research (CONDOR). Patients with low-grade (Borden type I) dAVFs were included and categorized into intervention or observation cohorts. The intervention and observation cohorts were matched in a 1:1 ratio using propensity scores. Primary outcome was modified Rankin Scale (mRS) at final follow-up. Secondary outcomes were excellent (mRS 0-1) and good (mRS 0-2) outcomes, symptomatic improvement, mortality, and obliteration at final follow-up. RESULTS The intervention and observation cohorts comprised 230 and 125 patients, respectively. We found no differences in primary or secondary outcomes between the 2 unmatched cohorts at last follow-up (mean duration 36 mo), except obliteration rate was higher in the intervention cohort (78.5% vs 24.1%, P < .001). The matched intervention and observation cohorts each comprised 78 patients. We also found no differences in primary or secondary outcomes between the matched cohorts except obliteration was also more likely in the matched intervention cohort ( P < .001). Procedural complication rates in the unmatched and matched intervention cohorts were 15.4% and 19.2%, respectively. CONCLUSION Intervention for low-grade intracranial dAVFs achieves superior obliteration rates compared to conservative management, but it fails to improve neurological or functional outcomes. Our findings do not support the routine treatment of low-grade dAVFs.

Background and Purpose— Several angiographic factors of dural arteriovenous fistulas (dAVFs) are associated with aggressive presentation and poor natural history. We examined the association of magnetic resonance imaging T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) hyperintensity with aggressive presentation. Methods— A cohort of dAVF patients from 2 centers was retrospectively examined. T2/FLAIR hyperintensity was determined by blinded, de-identified review and compared with angiographic grade and presenting symptoms. Results— T2/FLAIR hyperintensity was only identified in dAVF patients with cortical venous drainage (CVD). Among patients with CVD, those with T2/FLAIR hyperintensity were more likely to present with aggressive symptoms (20/23, 87.0%) than those without (6/21, 28.5%), P <0.001. All cured dAVFs with symptom resolution and available post-treatment imaging had resolution of T2/FLAIR hyperintensity. Conclusions— T2/FLAIR hyperintensity strongly correlates with aggressive presentation and CVD in dAVF patients, and may identify a subset that would benefit from early treatment.