A bibliometric analysis of tenecteplase research utilizing a commonly used citation index.

BACKGROUND AND PURPOSE: Tenecteplase is increasingly being used as a first-line treatment for acute ischemic stroke after several randomized studies demonstrated its safety and efficacy, resulting in a massive increase in the number of published studies on this topic. Our aim was to investigate the most impactful authors and relevant journals that have been instrumental in validating this treatment, in hopes of identifying objective research trends that may assist scientists, health organizations, and funding agencies to collaborate and plan future avenues of research. METHODS: Using the search terms "Tenecteplase" and "Tenecteplase" AND "Stroke," 2683 and 1150 references were queried, respectively, using the abstract and citation database, Scopus. Scopus Citation Analysis was used to categorize the countries and authors who produced the most research. Metadata was retrieved and transferred to bibliographic visualization software, VOSviewer, for co-authorship and co-occurrence analyses to identify trends in tenecteplase research. RESULTS: Data visualization software identified three tenecteplase research clusters - myocardial infarction, pulmonary embolism, and acute ischemic stroke. Our bibliographic analysis graphically identified that ischemic stroke currently leads both myocardial infarction and pulmonary embolism in annual publications pertaining to tenecteplase therapy, and further pinpointed perfusion imaging and wake-up strokes as the most relevant areas of study. The United States led all countries in tenecteplase publications, including exclusively stroke studies. The European Heart Journal led all journals in overall publications, while Stroke led all journals in stroke-related studies. CONCLUSIONS: Through the use of bibliographic analysis and data visualization, we identified major articles and journals that reflected and shaped the current landscape of tenecteplase; recognized authors who engaged in tenecteplase research as it progressed from cardiopulmonary disease to stroke; and postulated future avenues of research.

Association between the degree of vertebrobasilar stenosis, location, infarction pattern, and QMRA flow state.

BACKGROUND AND PURPOSE: We aimed to investigate the relationship between the degree and location of vertebrobasilar stenosis and quantitative magnetic resonance angiography (QMRA) distal flow. METHODS: We retrospectively reviewed patients who presented with acute ischemic stroke with ≥50% stenosis of the extracranial or intracranial vertebral or basilar arteries, and QMRA performed within 1 year of stroke. Standardized techniques were used to measure stenosis and to dichotomize vertebrobasilar distal flow status. Patients were grouped based on the involved artery and the severity of disease. All p-values were calculated using chi-squared analysis and Fisher exact test with statistical significance defined as p < .05. RESULTS: Sixty-nine patients met study inclusion, consisting of 31 with low distal flow and 38 with normal distal flow. The presence of severe stenosis or occlusion was 100% sensitive, but only 47% predictive and 26% specific of a low distal flow state. Bilateral vertebral disease was only 55% sensitive but was 71% predictive and 82% specific of a low-flow state and was five times and nearly three times more likely to result in a low-flow state compared to unilateral vertebral disease (14%) and isolated basilar disease (28%), respectively. CONCLUSIONS: Severe stenosis of ≥70% may mark the minimal threshold required to cause hemodynamic insufficiency in the posterior circulation, but nearly half of these patients may remain hemodynamically sufficient. Bilateral vertebral stenosis resulted in a fivefold increase in QMRA low distal flow status compared to unilateral vertebral disease. These results may have implications in the design of future treatment trials of intracranial atherosclerotic disease.

Ghost infarct core: A systematic review of the frequency, magnitude, and variables of CT perfusion overestimation.

BACKGROUND AND PURPOSE: CT perfusion (CTP) imaging is now widely used to select patients with large vessel occlusions for mechanical thrombectomy. Ghost infarct core (GIC) phenomenon has been coined to describe CTP core overestimation and has been investigated in several retrospective studies. Our aim is to review the frequency, magnitude, and variables associated with this phenomenon. METHODS: A primary literature search resulted in eight studies documenting median time from symptom onset to CTP, median estimated core size, median final infarct volume, median core overestimation of the GIC population, recanalization rates, good outcomes, and collateral status for this systematic review. RESULTS: All the studies investigated patients who underwent CTP within 6 hours of symptom onset, ranging from median times of 105 to 309 minutes. The frequency of core overestimation varied from 6% to 58.4%, while the median estimated ischemic core and final infarction volume ranged from 7 to 27 mL and 12 to 31 mL, respectively. The median core overestimation ranged from 3.6 to 30 mL with upper quartile ranges up to 58 mL. GIC was found to be a highly time-and-collateral-dependent process that increases in frequency and magnitude as the time from symptom onset to imaging decreases and in the presence of poor collaterals. CONCLUSIONS: CTP ischemic core overestimation appears to be a relatively common phenomenon that is most frequent in patients with poor collaterals imaged within the acute time window. Early perfusion imaging should be interpreted with caution to prevent the inadvertent exclusion of patients from highly effective reperfusion therapies.

An Unusual Presentation of Stroke and Reperfusion: A Case Report.

Intravenous tissue plasminogen activator (tPA) is a mainstay of therapy in acute ischemic stroke but transient neurologic changes related to reperfusion have not been well described. One of the authors (ISN) experienced a cardioembolic stroke due to apical hypertrophic cardiomyopathy with a left ventricular apical aneurysm. He received tPA and we describe his unusual cognitive symptoms during the infusion. The patient's presenting neurologic deficit improved with tPA, suggesting reperfusion. His subsequent restlessness, disorientation, and déjà vu lasted about 10 minutes and resolved spontaneously. Imaging studies confirmed an ischemic infarction in the left posterior cerebral artery (PCA) distribution. Cardiac events, including arrhythmias related to coronary reperfusion after myocardial infarction, are well described. Neurologic events due to reperfusion have not been previously described in patients with stroke. We describe a case of transient neurologic symptoms during revascularization of an embolic stroke.

Retrospective review COVID-19 vaccine induced thrombotic thrombocytopenia and cerebral venous thrombosis-what can we learn from the immune response.

INTRODUCTION: Cerebral Venous Thrombosis (CVT), prior to the COVID pandemic, was rare representing 0.5 of all strokes, with the diagnosis made by MRI or CT venography.1-,3 COVID-19 patients compared to general populations have a 30-60 times greater risk of CVT compared to non-affected populations, and up to a third of severe COVID patients may have thrombotic complications.4-8 Currently, vaccines are the best way to prevent severe COVID-19. In February 2021, reports of CVT and Vaccine-induced immune thrombotic thrombocytopenia (VITT) related to adenovirus viral vector vaccines including the Oxford-AstraZeneca vaccine (AZD1222 (ChAdOx1)) and Johnson & Johnson COVID-19 vaccine (JNJ-78436735 (Ad26.COV2·S)), were noted, with a 1/583,000 incidence from Johnson and Johnson vaccine in the United States.11, 12 This study retrospectively analyzed CVT and cross-sectional venography at an Eastern Medical Center from 2018 to 2021, and presents radiographic examples of CVT and what is learned from the immune response. METHODS: After IRB approval, a retrospective review of cross-sectional CTV and MRVs from January 1st 2018 to April 30th 2021, at a single health system was performed. Indications, vaccine status, patient age, sex, and positive finding incidence were specifically assessed during March and April for each year. A multivariable-adjusted trends analysis using Poisson regression estimated venogram frequencies and multivariable logistic regression compared sex, age, indications and vaccination status. RESULTS AND DISCUSSION: From January 1, 2018 to April 30, 2021, (Fig. 1), a total of n = 2206 in patient and emergency room cross-sectional venograms were obtained, with 322 CTVs and 1884 MRVs. In 2018, 2019, 2020, respective totals of cross-sectional venograms were 568, 657, 660, compared to 321 cross-sectional venograms in the first four months of 2021. CTV in 2018, 2019, 2020, respective totals were 51, 86, 97, MRV totals were 517, 571, 563, compared to the 2021 first four month totals of 88 CTVs and 233 MRVs. March, April 2018, 2019, 2020, CTVs respectively were 6, 17, 11, compared to the 2021 first four months of 59 CTVs, comprising 63% of the total 93 CTVs, respective MRVs were 79, 97, 52, compared to 143 MRVs in the first four months of 2021 for 39% of the total 371 MRVs. In March, April 2020 during the pandemic onset, cross-sectional imaging at the East Coast Medical Center decreased, as priorities were on maintaining patient ventilation, high level of care and limiting spread of disease. In March/April 2021, reports of VITT and CVT likely contributed to increased CTVs and MRVs, of 39.65% [1.20-1.63] increase (P < 0.001) from prior. In March, April 2021 of 202 venograms obtained, 158 (78.2.%) were unvaccinated patients, 16 positive for CVT (10.1%), 44 were on vaccinated patients (21.7%), 8 specifically ordered with vaccination as a clinical indication, 2 positive for CVT (4.5%), (odds ratio = 0.52 [0.12-2.38], p = 0.200). CONCLUSION: CTV prior to the COVID pandemic, was rare, responsible for 0.5 of all strokes, at the onset of the pandemic in the East Coast, overall cross-sectional imaging volumes declined due to maintaining ventilation, high levels of care and limiting disease spread, although COVID-19 patients have a 30-60 times greater risk of CVT compared to the general population, and vaccination is currently the best option to mitigate severe disease. In early 2021, reports of adenoviral vector COVID vaccines causing CTV and VITT, led to at 39.65% increase in cross-sectional venography, however, in this study unvaccinated patients in 2021 had higher incidence of CVT (10.1%), compared to the vaccinated patients (4.5%). Clinicians should be aware that VITT CVT may present with a headache 5-30 days post-vaccination with thrombosis best diagnosed on CTV or MRV. If thrombosis is present with thrombocytopenia, platelets <150 × 109, elevated D-Dimer >4000 FEU, and positive anti-PF4 ELISA assay, the diagnosis is definitive.13 VITT CVT resembles spontaneous autoimmune heparin induced thrombocytopenia (HIT), and is postulated to occur from platelet factor 4 (PF4) binding to vaccine adenoviral vectors forming a novel antigen, anti-PF4 memory B-cells and anti-PF4 (VITT) antibodies.14-17.

Hypoperfusion Intensity Ratio is Associated with Stroke Mechanism in Patients Undergoing Mechanical Thrombectomy.

BACKGROUND: Hypoperfusion Intensity Ratio (HIR), defined as Tmax >10s/Tmax >6s on computed tomography perfusion (CTP), and stroke mechanisms have been independently correlated with angiographic collaterals and patient outcomes. Slowly developing atherosclerotic stenosis may foster collateral development, whereas cardioembolic occlusion may occur before collaterals mature. We hypothesized that favorable HIR is associated with large artery atherosclerosis (LAA) stroke mechanism and good clinical outcome. METHODS: Retrospective study of consecutive endovascularly-treated stroke patients with intracranial ICA or MCA M1/M2 occlusions, who underwent CTP before intervention, between January 2018 and August 2021. Patients were dichotomized into LAA+ or LAA- based on presence of LAA on angiography. HIR was dichotomized into favorable (HIR+) or unfavorable (HIR-) groups based on published thresholds. Good early outcome was defined as discharge mRS of 0-2. Bivariate and multivariable logistic regression were performed. RESULTS: 143 patients met inclusion. 21/143 were LAA+ (15%) and 65/143 (45%) were HIR+. HIR+ was significantly more frequent in LAA+ patients (67% vs. 42%, p= 0.035). Controlling for demographics, stroke severity, imaging findings, and medical comorbidities, LAA+ remained independently associated with HIR+ (OR 5.37 [95% CI 1.43 - 20.14]; p=0.013) as did smaller infarction core volume (<30 mL of CBF <30%: OR 7.92 [95% CI 2.27 - 27.64]; p = 0.001). HIR+ was not associated with good clinical outcome. CONCLUSIONS: Large artery atherosclerosis was independently associated with favorable HIR in patients undergoing mechanical thrombectomy. While favorable HIR was associated with smaller pre-treatment core infarcts, reflecting more robust collaterals, it was not associated with good clinical outcome.

Vertebrobasilar Stroke: Association Between Infarction Patterns and Quantitative Magnetic Resonance Angiography Flow State.

Background Treatment and prognosis of vertebrobasilar atherosclerotic disease differs depending on stroke mechanism, such as artery-to-artery embolism, branch atheromatous disease, and hemodynamic ischemia. Our aim was to investigate the relationship between infarction pattern and flow status using quantitative magnetic resonance angiography (QMRA), to determine the validity of using infarction patterns to infer stroke mechanism. Methods and Results This is a retrospective study of patients with ischemic stroke with intra- or extracranial vertebrobasilar atherosclerotic stenosis, who underwent magnetic resonance imaging of the brain, neurovascular imaging, and QMRA, between 2009 and 2021. Patients with cerebral infarction predating or following QMRA by ≥1 year, or QMRA studies performed for basilar thrombosis, vertebral dissection, or only postangioplasty/stenting, were excluded. Poststenotic flow (basilar and posterior cerebral arteries) was dichotomized as low-flow or normal-flow based on published criteria. Of 1211 consecutive patients who underwent QMRA noninvasive optimal analysis, 69 met inclusion. Mixed patterns were most common (46.4%), followed by perforator (23.2%), borderzone (14.5%), and territorial (15.9%). Patients with low-flow had a significantly higher rate of borderzone+ patterns (borderzone alone or in mixed pattern) compared with patients with normal-flow (77.4% low-flow versus 39.5% normal-flow, P=0.002). Borderzone+ patterns were associated with 61.5% probability of low-flow state, while no borderzone (perforator/territorial) patterns were associated with 76.7% probability of normal-flow state. Conclusions Borderzone infarction pattern (alone or mixed) was associated with low poststenotic posterior circulation flow by QMRA. However, borderzone pattern only moderately predicted low-flow state, and may be an unreliable flow marker. Therefore, infarct topography may complement, but should not replace hemodynamic studies to establish flow status.

Cerebrovascular Complications of COVID-19.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) evolved quickly into a global pandemic with myriad systemic complications, including stroke. We report the largest case series to date of cerebrovascular complications of COVID-19 and compare with stroke patients without infection. METHODS: Retrospective case series of COVID-19 patients with imaging-confirmed stroke, treated at 11 hospitals in New York, between March 14 and April 26, 2020. Demographic, clinical, laboratory, imaging, and outcome data were collected, and cases were compared with date-matched controls without COVID-19 from 1 year prior. RESULTS: Eighty-six COVID-19-positive stroke cases were identified (mean age, 67.4 years; 44.2% women). Ischemic stroke (83.7%) and nonfocal neurological presentations (67.4%) predominated, commonly involving multivascular distributions (45.8%) with associated hemorrhage (20.8%). Compared with controls (n=499), COVID-19 was associated with in-hospital stroke onset (47.7% versus 5.0%; P<0.001), mortality (29.1% versus 9.0%; P<0.001), and Black/multiracial race (58.1% versus 36.9%; P=0.001). COVID-19 was the strongest independent risk factor for in-hospital stroke (odds ratio, 20.9 [95% CI, 10.4-42.2]; P<0.001), whereas COVID-19, older age, and intracranial hemorrhage independently predicted mortality. CONCLUSIONS: COVID-19 is an independent risk factor for stroke in hospitalized patients and mortality, and stroke presentations are frequently atypical.

Cerebral venous thrombosis: A typical presentation of COVID-19 in the young.

OBJECTIVE: Identify clinical and radiographic features of venous infarct as a presenting feature of COVID-19 in the young. BACKGROUND: SARS-CoV-2 infection causes hypercoagulability and inflammation leading to venous thrombotic events (VTE). Although elderly patients with comorbidities are at higher risk, COVID-19 may also cause VTE in a broader patient population without these risks. Neurologic complications and manifestations of COVID-19, including neuropathies, seizures, strokes and encephalopathy usually occur in severe established cases of COVID-19 infection who primarily present with respiratory distress. CASE DESCRIPTION: Case report of a 29-year-old woman, with no significant past medical history or comorbidities, presenting with new onset seizures. Further questioning revealed a one-week history of headaches, low-grade fever, mild cough and shortness of breath, diagnosed as COVID-19. Imaging revealed a left temporoparietal hemorrhagic venous infarction with left transverse and sigmoid sinus thrombosis treated with full dose anticoagulation and antiepileptics. CONCLUSION: Although elderly patients with comorbidities are considered highest risk for COVID-19 neurologic complications, usually when systemic symptoms are severe, this case report emphasizes that young individuals are at risk for VTE with neurologic complications even when systemic symptoms are mild, likely induced by COVID-19 associated hypercoagulable state.

Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial.

BACKGROUND: In A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), randomisation was halted at a mean follow-up of 33·3 months after a prespecified interim analysis showed that medical management alone was superior to the combination of medical management and interventional therapy in preventing symptomatic stroke or death. We aimed to study whether these differences persisted through 5-years' follow-up. METHODS: ARUBA was a non-blinded, randomised trial done at 39 clinical centres in nine countries. Adults (age ≥18 years) diagnosed with an unruptured brain arteriovenous malformation, who had never undergone interventional therapy, and were considered by participating clinical centres to be suitable for intervention to eradicate the lesion, were eligible for inclusion. Patients were randomly assigned (1:1) by a web-based data collection system, stratified by clinical centre in a random permuted block design with block sizes of two, four, and six, to medical management alone or with interventional therapy (neurosurgery, embolisation, or stereotactic radiotherapy, alone or in any combination, sequence, or number). Although patients and investigators at a given centre were not masked to treatment assignment, investigators at other centres and those in the clinical coordinating centre were not informed of assignment or outcomes at any of the centres. The primary outcome was time to death or symptomatic stroke confirmed by imaging, assessed by a neurologist at each centre not involved in the management of participants' care, and monitored by an independent committee using an adaptive approach with interim analyses. Enrolment began on April 4, 2007, and was halted on April 15, 2013, after which follow-up continued until July 15, 2015. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00389181. FINDINGS: Of 1740 patients screened, 226 were randomly assigned to medical management alone (n=110) or medical management plus interventional therapy (n=116). During a mean follow-up of 50·4 months (SD 22·9), the incidence of death or symptomatic stroke was lower with medical management alone (15 of 110, 3·39 per 100 patient-years) than with medical management with interventional therapy (41 of 116, 12·32 per 100 patient-years; hazard ratio 0·31, 95% CI 0·17 to 0·56). Two patients in the medical management group and four in the interventional therapy group (two attributed to intervention) died during follow-up. Adverse events were observed less often in patients allocated to medical management compared with interventional therapy (283 vs 369; 58·97 vs 78·73 per 100 patient-years; risk difference -19·76, 95% CI -30·33 to -9·19). INTERPRETATION: After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured brain arteriovenous malformation. The data concerning the disparity in outcomes should affect standard specialist practice and the information presented to patients. The even longer-term risks and differences between the two therapeutic approaches remains uncertain. FUNDING: National Institute of Neurological Disorders and Stroke for the randomisation phase and Vital Projects Fund for the follow-up phase.

Occult paroxysmal atrial fibrillation in non-cryptogenic ischemic stroke.

OBJECTIVE: To determine the prevalence and risk factors for paroxysmal atrial fibrillation (PAF) diagnosis in non- cryptogenic ischemic stroke (CIS) patients. METHODS: In this pilot-prospective cohort study of non-CIS patients from September 2014 to September 2017, 53 patients were enrolled. 51/53 patients were implanted within 10 days of stroke onset with the Reveal LINQ insertable cardiac monitor and monitored until PAF detection or a minimum of 12 months. Inclusion required diagnosis of a non-AF stroke etiology, age ≥ 40, and either a virtual CHADS2 score ≥ 3 or ≥ 2 PAF-related comorbidities. RESULTS: Over a median monitoring period of 398 days, PAF was detected in 6/51 (11.8%) patients and anticoagulation was initiated in 5/6 (83.3%). Median time to PAF detection was 87 days (range 0-356 days). Median longest PAF episode was 96 min (range 1 to 1122 min), and 4/6 had multiple PAF recordings. Mean left atrial volume index was significantly higher in PAF patients (31.0 vs. 23.2 cc/m2; p = 0.04). CONCLUSION: Long-term monitoring of non-CIS patients detected PAF in a clinically relevant proportion of patients, resulting in stroke prevention therapy optimization. Further study to confirm these findings and refine the subset that would benefit from long-term cardiac monitoring is warranted.

Prevalence and Risk Factors for Paroxysmal Atrial Fibrillation and Flutter Detection after Cryptogenic Ischemic Stroke.

INTRODUCTION: Long-term cardiac monitoring with implantable loop recorders (ILRs) has revealed occult paroxysmal atrial fibrillation and flutter (PAF) in a substantial minority of cryptogenic ischemic stroke (CIS) patients. Herein, we aim to define the prevalence, clinical relevance, and risk factors for PAF detection following early poststroke ILR implantation. MATERIALS AND METHODS: A retrospective study of CIS patients (n = 100, mean age 65.8 years; 52.5% female) who underwent ILR insertion during, or soon after, index stroke admission. Patients were prospectively followed by the study cardiac electrophysiologist who confirmed the PAF diagnosis. Univariate and multivariate analyses compared clinical, laboratory, cardiac, and imaging variables between PAF patients and non-PAF patients. RESULTS: PAF was detected in 31 of 100 (31%) CIS patients, and anticoagulation was initiated in almost all (30 of 31, 96.8%). Factors associated with PAF detection include older age (mean [year] 72.9 versus 62.9; P = .003), white race (odds ratio [OR], 4.5; confidence interval [CI], 1.8-10.8; P = .001), prolonged PR interval (PR > 175 ms; OR, 3.3; CI, 1.2-9.4; P = .022), larger left atrial (LA) diameter (mean [cm] 3.7 versus 3.5; P = .044) and LA volume index (mean [cc/m2]; 30.6 versus 24.2; P = .014), and lower hemoglobin (Hb)A1c (mean [%] 6.0 versus 6.4; P = .036). Controlling for age, obesity (body mass index > 30 kg/m2; OR, 1.2; CI, 1.1-1.4; P = .033) was independently associated with PAF detection. DISCUSSION: PAF was detected with high prevalence following early postcryptogenic stroke ILR implantation and resulted in significant management changes. Older age, increased PR interval, LA enlargement, and lower HbA1c are significantly associated with PAF detection. Controlling for age, obesity is an independent risk factor. A larger prospective study is warranted to confirm these findings.

Improving Regional Stroke Systems of Care.

PURPOSE OF REVIEW: Acute ischemic stroke (AIS) care is rapidly evolving. This review discusses current diagnostic, therapeutic, and process models that can expedite stroke treatment to achieve best outcomes. RECENT FINDINGS: Use of stent retrievers after selection via advanced imaging is safe and effective, and is an important option for AIS patients with large vessel occlusion (LVO). Significant time delays occur before and during patient transfers, and upon comprehensive stroke center (CSC) arrival, and have deleterious effects on functional outcome. Removing obstacles, enhancing inter-facility communication, and creating acute stroke management processes and protocols are paramount strategies to enhance network efficiency. Inter-departmental CSC collaboration can significantly reduce door-to-treatment times. Streamlined stroke systems of care may result in higher treatment rates and better functional outcomes for AIS patients, simultaneously conserving healthcare dollars. Stroke systems of care should be structured regionally to minimize time to treatment. A proactive approach must be employed; a management plan incorporating stroke team prenotification and parallel processes between departments can save valuable time, maximize brain salvage, and reduce disability from stroke.

Functional impairments for outcomes in a randomized trial of unruptured brain AVMs.

OBJECTIVE: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA). METHODS: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013. RESULTS: After a median of 33.3 months of follow-up (interquartile range 16.3-49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score ≥2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11-0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04-0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001). CONCLUSION: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades. CLINICALTRIALSGOV IDENTIFIER: NCT00389181. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over ≈3 years.