Most Promising Approaches to Improve Brain AVM Management: ARISE I Consensus Recommendations.

Brain arteriovenous malformations (bAVMs) are complex, and rare arteriovenous shunts that present with a wide range of signs and symptoms, with intracerebral hemorrhage being the most severe. Despite prior societal position statements, there is no consensus on the management of these lesions. ARISE (Aneurysm/bAVM/cSDH Roundtable Discussion With Industry and Stroke Experts) was convened to discuss evidence-based approaches and enhance our understanding of these complex lesions. ARISE identified the need to develop scales to predict the risk of rupture of bAVMs, and the use of common data elements to perform prospective registries and clinical studies. Additionally, the group underscored the need for comprehensive patient management with specialized centers with expertise in cranial and spinal microsurgery, neurological endovascular surgery, and stereotactic radiosurgery. The collection of prospective multicenter data and gross specimens was deemed essential for improving bAVM characterization, genetic evaluation, and phenotyping. Finally, bAVMs should be managed within a multidisciplinary framework, with clinical studies and research conducted collaboratively across multiple centers, harnessing the collective expertise and centralization of resources.

Percutaneous Disc Biopsy versus Bone Biopsy for the Identification of Infectious Agents in Osteomyelitis/Discitis.

PURPOSE: To determine whether sampling of the disc or bone is more likely to yield positive tissue culture results in patients with vertebral discitis and osteomyelitis (VDO). MATERIALS AND METHODS: Retrospective review was performed of consecutive patients who underwent vertebral disc or vertebral body biopsy at a single institution between February 2019 and May 2023. Inclusion criteria were age ≥18 years, presumed VDO on spinal magnetic resonance (MR) imaging, absence of paraspinal abscess, and technically successful percutaneous biopsy with fluoroscopic guidance. The primary outcome was a positive biopsy culture result, and secondary outcomes included complications such as nerve injury and segmental artery injury. RESULTS: Sixty-six patients met the inclusion criteria; 36 patients (55%) underwent disc biopsy, and 30 patients (45%) underwent bone biopsy. Six patients required a repeat biopsy for an initially negative culture result. No significant demographic, laboratory, antibiotic administration, or pain medication use differences were observed between the 2 groups. Patients who underwent bone biopsy were more likely to have a history of intravenous drug use (26.7%) compared with patients who underwent disc biopsy (5.5%; P = .017). Positive tissue culture results were observed in 41% of patients who underwent disc biopsy and 15% of patients who underwent bone biopsy (P = .016). No vessel or nerve injuries were detected after procedure in either group. CONCLUSIONS: Percutaneous disc biopsy is more likely to yield a positive tissue culture result than vertebral body biopsy in patients with VDO.

Thrombectomy for anterior circulation stroke beyond 6 h from time last known well (AURORA): a systematic review and individual patient data meta-analysis.

BACKGROUND: Trials examining the benefit of thrombectomy in anterior circulation proximal large vessel occlusion stroke have enrolled patients considered to have salvageable brain tissue, who were randomly assigned beyond 6 h and (depending on study protocol) up to 24 h from time last seen well. We aimed to estimate the benefit of thrombectomy overall and in prespecified subgroups through individual patient data meta-analysis. METHODS: We did a systematic review and individual patient data meta-analysis between Jan 1, 2010, and March 1, 2021, of randomised controlled trials of endovascular stroke therapy. In the Analysis Of Pooled Data From Randomized Studies Of Thrombectomy More Than 6 Hours After Last Known Well (AURORA) collaboration, the primary outcome was disability on the modified Rankin Scale (mRS) at 90 days, analysed by ordinal logistic regression. Key safety outcomes were symptomatic intracerebral haemorrhage and mortality within 90 days. FINDINGS: Patient level data from 505 individuals (n=266 intervention, n=239 control; mean age 68·6 years [SD 13·7], 259 [51·3%] women) were included from six trials that met inclusion criteria of 17 screened published randomised trials. Primary outcome analysis showed a benefit of thrombectomy with an unadjusted common odds ratio (OR) of 2·42 (95% CI 1·76-3·33; p<0·0001) and an adjusted common OR (for age, gender, baseline stroke severity, extent of infarction on baseline head CT, and time from onset to random assignment) of 2·54 (1·83-3·54; p<0·0001). Thrombectomy was associated with higher rates of independence in activities of daily living (mRS 0-2) than best medical therapy alone (122 [45·9%] of 266 vs 46 [19·3%] of 238; p<0·0001). No significant difference between intervention and control groups was found when analysing either 90-day mortality (44 [16·5%] of 266 vs 46 [19·3%] of 238) or symptomatic intracerebral haemorrhage (14 [5·3%] of 266 vs eight [3·3%] of 239). No heterogeneity of treatment effect was noted across subgroups defined by age, gender, baseline stroke severity, vessel occlusion site, baseline Alberta Stroke Program Early CT Score, and mode of presentation; treatment effect was stronger in patients randomly assigned within 12-24 h (common OR 5·86 [95% CI 3·14-10·94]) than those randomly assigned within 6-12 h (1·76 [1·18-2·62]; pinteraction=0·0087). INTERPRETATION: These findings strengthen the evidence for benefit of endovascular thrombectomy in patients with evidence of reversible cerebral ischaemia across the 6-24 h time window and are relevant to clinical practice. Our findings suggest that in these patients, thrombectomy should not be withheld on the basis of mode of presentation or of the point in time of presentation within the 6-24 h time window. FUNDING: Stryker Neurovascular.

Intravenous tPA (Tissue-Type Plasminogen Activator) Correlates With Favorable Venous Outflow Profiles in Acute Ischemic Stroke.

BACKGROUND: Intravenous tPA (tissue-type plasminogen activator) is often administered before endovascular thrombectomy (EVT). Recent studies have questioned whether tPA is necessary given the high rates of arterial recanalization achieved by EVT, but whether tPA impacts venous outflow (VO) is unknown. We investigated whether tPA improves VO profiles on baseline computed tomography (CT) angiography (CTA) images before EVT. METHODS: Retrospective multicenter cohort study of patients with acute ischemic stroke due to large vessel occlusion undergoing EVT triage. Included patients underwent CT, CTA, and CT perfusion before EVT. VO profiles were determined by opacification of the vein of Labbé, sphenoparietal sinus, and superficial middle cerebral vein on CTA as 0, not visible; 1, moderate opacification; and 2, full. Pial arterial collaterals were graded on CTA, and tissue-level collaterals were assessed on CT perfusion using the hypoperfusion intensity ratio. Clinical and demographic data were determined from the electronic medical record. Using multivariable regression analysis, we determined the correlation between tPA administration and favorable VO profiles. RESULTS: Seven hundred seventeen patients met inclusion criteria. Three hundred sixty-five patients received tPA (tPA+), while 352 patients were not treated with tPA (tPA-). Fewer tPA+ patients had atrial fibrillation (n=128 [35%] versus n=156 [44%]; P=0.012) and anticoagulants/antiplatelet treatment before acute ischemic stroke due to large vessel occlusion onset (n=130 [36%] versus n=178 [52%]; P<0.001) compared with tPA- patients. One hundred eighty-five patients (51%) in the tPA+ and 100 patients (28%) in the tPA- group exhibited favorable VO (P<0.001). Multivariable regression analysis showed that tPA administration was a strong independent predictor of favorable VO profiles (OR, 2.6 [95% CI, 1.7-4.0]; P<0.001) after control for favorable pial arterial CTA collaterals, favorable tissue-level collaterals on CT perfusion, age, presentation National Institutes of Health Stroke Scale, antiplatelet/anticoagulant treatment, history of atrial fibrillation and time from symptom onset to imaging. CONCLUSIONS: In patients with acute ischemic stroke due to large vessel occlusion undergoing thrombectomy triage, tPA administration was strongly associated with the presence of favorable VO profiles.

Perfusion Imaging Collateral Scores Predict Infarct Growth in Non-Reperfused DEFUSE 3 Patients.

OBJECTIVE: This study evaluated the associations of perfusion imaging collateral profiles with radiographic and clinical outcome in late presenting, non-reperfused patients in the DEFUSE 3 clinical trial. METHODS: Non-reperfused patients in both treatment arms were included. Baseline ischemic core, Tmax >6s, and Tmax >10s perfusion volumes were calculated with RAPID software; infarct volumes obtained 24 hours after randomization were manually determined from DWI or CT. Substantial infarct growth was defined as a >25mL increase between baseline and 24-hour follow-up. Hypoperfusion Intensity Ratio (HIR) was defined as the proportion of the Tmax >6s lesion with Tmax >10s delay; CBV index was calculated by RAPID from mean CBV values within the Tmax >6s lesion compared to regions of normal CBV. RESULTS: Eighty-four patients were included. ROC analysis showed HIR ≥0.34 (AUC=0.68) and CBV index ≤0.74 (AUC=0.72) optimally predicted substantial infarct growth in follow-up. Median growth was 23.4 versus 73.2mL with HIR threshold of 0.34 (p=0.005), and 24.3 versus 58.7mL with CBV index threshold of 0.74 (p=0.004). If baseline HIR and CBV index were both favorable, median growth was 21.7mL, 40.9mL if one was favorable, and 108.2mL if both were unfavorable (p<0.001). Baseline perfusion profile was not associated with 90-day functional outcome. CONCLUSIONS: Perfusion collateral scores forecast infarct growth in late presenting, non-reperfused ischemic stroke patients. These parameters may be useful for guiding transfer decisions, such as need for repeat imaging upon thrombectomy center arrival, and may help identify slow progressing patients more likely to have persistent salvageable ischemic tissue beyond 24 hours.

Renal Safety of Multimodal Brain Imaging Followed by Endovascular Therapy.

BACKGROUND AND PURPOSE: Contrast-enhanced noninvasive angiography and perfusion imaging are recommended to identify eligible patients for endovascular therapy (EVT) in extended time windows (>6 hours or wake-up). If eligible, additional intraarterial contrast exposure will occur during EVT. We aimed to study the renal safety in the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) population, selected with contrast-enhanced multimodal Imaging and randomized to EVT versus medical management. METHODS: In the randomized DEFUSE 3 trial population, we compared changes in serum creatinine between baseline (before randomization) and 24 hours later. The primary outcome was the relative change in creatinine level between baseline and 24 hours in the EVT versus medical arm. The secondary outcome was a comparison between computed tomography (CT) versus magnetic resonance imaging selection in the EVT arm. The safety outcome was a comparison of the proportion of patients with criteria for contrast-associated kidney injury in the EVT versus medical arm and a comparison between CT versus magnetic resonance imaging selection in the EVT arm. RESULTS: In the DEFUSE 3 population (n=182, age 69±13, 51% female), mean creatinine decreased from a baseline of 0.98±0.33 mg/dL to 0.88±0.28 mg/dL at 24 hours (P<0.001). There was no difference in change between treatment groups: relative to baseline, there was a 6.3% reduction in the EVT group versus 9.2% in the medical group, P=0.294. Absolute decrease -0.08±0.18 in EVT versus -0.12±0.18 in medical, P=0.135; Among patients treated with EVT, there was no difference in 24-hour creatinine level changes between patients who were selected with CT angiography/CT perfusion (-0.08±0.18) versus magnetic resonance imaging (-0.07±0.19), P=0.808 or 6.8% reduction versus 4.8%, P=0.696. In the EVT arm, contrast-associated kidney injury was encountered in 4 out of 91 (4.4%) versus 2/90 (2.2%) in the medical arm P=0.682. In the EVT arm, contrast-associated kidney injury was evenly distributed between magnetic resonance imaging (1/22, 4.6%) versus CT 3 out of 69 (4.4%), P=1.0. CONCLUSIONS: Perfusion imaging before EVT was not associated with evidence of decline in renal function. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02586415.

Favorable Venous Outflow Profiles Correlate With Favorable Tissue-Level Collaterals and Clinical Outcome.

BACKGROUND AND PURPOSE: Patients with acute ischemic stroke due to large vessel occlusion and favorable tissue-level collaterals (TLCs) likely have robust cortical venous outflow (VO). We hypothesized that favorable VO predicts robust TLC and good clinical outcomes. METHODS: Multicenter retrospective cohort study of consecutive acute ischemic stroke due to large vessel occlusion patients who underwent thrombectomy triage. Included patients had interpretable prethrombectomy computed tomography, computed tomography angiography, and cerebral perfusion imaging. TLCs were measured on cerebral perfusion studies using the hypoperfusion intensity ratio (volume ratio of brain tissue with [Tmax >10 s/Tmax >6 s]). VO was determined by opacification of the vein of Labbé, sphenoparietal sinus, and superficial middle cerebral vein on computed tomography angiography as 0, not visible; 1, moderate opacification; and 2, full. Clinical and demographic data were determined from the electronic medical record. Using multivariable regression analyses, we determined the association between VO and (1) favorable TLC status (defined as hypoperfusion intensity ratio ≤0.4) and (2) good functional outcome (modified Rankin Scale score, 0-2). RESULTS: Six hundred forty-nine patients met inclusion criteria. Patients with favorable VO were younger (median age, 72 [interquartile range (IQR), 62-80] versus 77 [IQR, 66-84] years), had a lower baseline National Institutes of Health Stroke Scale (median, 12 [IQR, 7-17] versus 19 [IQR, 13-20]), and had a higher Alberta Stroke Program Early Computed Tomography Score (median, 9 [IQR, 7-10] versus 7 [IQR, 6-9]). Favorable VO strongly predicted favorable TLC (odds ratio, 4.5 [95% CI, 3.1-6.5]; P<0.001) in an adjusted regression analysis. Favorable VO also predicted good clinical outcome (odds ratio, 10 [95% CI, 6.2-16.0]; P<0.001), while controlling for favorable TLC, age, glucose, baseline National Institutes of Health Stroke Scale, and good vessel reperfusion status. CONCLUSIONS: In this selective retrospective cohort study of acute ischemic stroke due to large vessel occlusion patients undergoing thrombectomy triage, favorable VO profiles correlated with favorable TLC and were associated with good functional outcomes after treatment. Future prospective studies should independently validate our findings.

Quality of Life in Physical, Social, and Cognitive Domains Improves With Endovascular Therapy in the DEFUSE 3 Trial.

BACKGROUND AND PURPOSE: The DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) randomized clinical trial demonstrated the efficacy of endovascular therapy in treating ischemic stroke 6 to 16 hours after onset, resulting in better functional outcomes than standard medical therapy alone. The objective of this secondary analysis is to analyze the effect of late-window endovascular treatment of ischemic stroke on quality of life (QoL) outcomes. METHODS: Patients (n=182) who presented between 6 and 16 hours after they were last known to be well with acute anterior circulation ischemic stroke were randomized to endovascular thrombectomy plus standard medical therapy or standard medical therapy alone and followed-up through 90 days poststroke. QoL at day 90 was assessed with the QoL in Neurological Disorders measurement tool. RESULTS: Of the 146 subjects alive at day 90, 136 (95%) filled out QoL in Neurological Disorders short forms. Patients treated with endovascular therapy had better QoL scores in each domain: mobility, social participation, cognitive function, and depression (P<0.01 for all). Variables other than endovascular therapy that were independently associated with better QoL included lower baseline National Institutes of Health Stroke Scale, younger age, and male sex. The degree to which the modified Rankin Scale captures differences in QoL between patients varied by domain; the modified Rankin Scale score accounted for a high proportion of the variability in mobility (Rs2=0.82), a moderate proportion in social participation (Rs2=0.62), and a low proportion in cognition (Rs2=0.31) and depression (Rs2=0.19). CONCLUSIONS: Patients treated with endovascular therapy 6 to 16 hours after stroke have better QoL than patients treated with medical therapy alone, including better mobility, more social participation, superior cognition, and less depression. The modified Rankin Scale fails to capture patients' outcomes in cognition and depression, which should therefore be assessed with dedicated QoL tools. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02586415.

Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging.

BACKGROUND: Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms. METHODS: We conducted a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard medical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90. RESULTS: The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical-therapy group (P=0.05), and there was no significant between-group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18). CONCLUSIONS: Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415 .).

Venous Outflow Profiles Are Linked to Cerebral Edema Formation at Noncontrast Head CT after Treatment in Acute Ischemic Stroke Regardless of Collateral Vessel Status at CT Angiography.

Background Ischemic lesion net water uptake (NWU) at noncontrast head CT enables quantification of cerebral edema in patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Purpose To assess whether favorable venous outflow (VO) profiles at CT angiography are associated with reduced NWU and good functional outcomes in patients with AIS due to LVO. Materials and Methods This multicenter retrospective cohort study evaluated consecutive patients with AIS due to LVO who underwent thrombectomy triage between January 2013 and December 2019. Arterial collateral vessel status (Tan scale) and venous output were measured at CT angiography. Venous outflow was graded with use of the cortical vein opacification score, which quantifies opacification of the vein of Labbé, sphenoparietal sinus, and superficial middle cerebral vein. Favorable VO was regarded as a score of 3-6 and unfavorable VO as a score of 0-2. NWU was determined at follow-up noncontrast CT. Multivariable regression analyses were performed to determine the association between favorable VO profiles and NWU after treatment and good functional outcome (modified Rankin Scale, ≤2). Results A total of 580 patients were included. Of the 580 patients, 231 had favorable VO (104 women; median age, 73 years [interquartile range {IQR}, 62-81 years]) and 349 had unfavorable VO (190 women; median age, 77 years [IQR, 66-84 years]). Compared with patients with unfavorable VO, those with favorable VO exhibited lower baseline National Institutes of Health Stroke Scale score (median, 12.5 [IQR, 7-17] vs 17 [IQR, 13-21]), higher Alberta Stroke Program Early CT Score (median, 9 [IQR, 7-10] vs 7 [IQR, 6-8]), and less NWU after treatment (median, 7% [IQR, 4.6%-11.5%] vs 17.9% [IQR, 12.3%-22.2%]). In a multivariable regression analysis, NWU mean difference between patients with unfavorable VO and those with favorable VO was 6.1% (95% CI: 4.9, 7.3; P < .001) regardless of arterial CT angiography collateral vessel status (b coefficient, 0.72 [95% CI: -0.59, 2.03; P = .28]). Favorable VO (odds ratio [OR]: 4.1 [95% CI: 2.2, 7.7]; P < .001) and reduced NWU after treatment (OR: 0.77 [95% CI: 0.73, 0.83]; P < .001) were independently associated with good functional outcomes. Conclusion Favorable venous outflow (VO) correlated with reduced ischemic net water uptake (NWU) after treatment. Reduced NWU and favorable VO were associated with good functional outcomes regardless of CT angiography arterial collateral vessel status. © RSNA, 2021 Online supplemental material is available for this article.

Distinct intra-arterial clot localization affects tissue-level collaterals and venous outflow profiles.

BACKGROUND AND PURPOSE: Arterial clot localization affects collateral flow to ischemic brain in patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). We determined the association between vessel occlusion locations, tissue-level collaterals (TLC), and venous outflow (VO) profiles and their impact on good functional outcomes. METHODS: We conducted a multicenter retrospective cohort study of consecutive AIS-LVO patients who underwent thrombectomy triage. Baseline computed tomographic angiography (CTA) was used to localize vessel occlusion, which was dichotomized into proximal vessel occlusion (PVO; internal carotid artery and proximal first segment of the middle cerebral artery [M1]) and distal vessel occlusion (DVO; distal M1 and M2), and to assess collateral scores. TLC were assessed on computed tomographic perfusion data using the hypoperfusion intensity ratio. VO was determined on baseline CTA by the cortical vein opacification score. Primary outcomes were favorable VO and TLC; secondary outcome was the modified Rankin Scale after 90 days. RESULTS: A total of 649 patients met inclusion criteria. Of these, 376 patients (58%) had a PVO and 273 patients (42%) had a DVO. Multivariate ordinal logistic regression showed that DVO predicted favorable TLC (odds ratio [OR] = 1.77, 95% confidence interval [CI] = 1.24-2.52, p = 0.002) and favorable VO (OR = 7.2, 95% CI = 5.2-11.9, p < 0.001). DVO (OR = 3.4, 95% CI = 2.1-5.6, p < 0.001), favorable VO (OR = 6.4, 95% CI = 3.8-10.6, p < 0.001), and favorable TLC (OR = 3.2, 95% CI = 2-5.3, p < 0.001), but not CTA collaterals (OR = 1.07, 95% CI = 0.60-1.91, p = 0.813), were predictors of good functional outcome. CONCLUSIONS: DVO in AIS-LVO patients correlates with favorable TLC and VO profiles, which are associated with good functional outcome.

Persistent Target Mismatch Profile >24 Hours After Stroke Onset in DEFUSE 3.

Background and Purpose- Efficacy of endovascular thrombectomy has been demonstrated up to 24 hours after stroke onset in patients selected with perfusion imaging. We hypothesized that a persistent favorable perfusion profile exists in some patients beyond 24 hours from the onset and can be predicted by a lower baseline hypoperfusion intensity ratio, which indicates favorable collaterals. Methods- We identified control arm patients from the DEFUSE 3 trial (The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) with a diffusion weighted imaging and perfusion magnetic resonance imaging performed 24 hours following randomization and compared imaging and clinical variables between patients with persistent mismatch versus patients who no longer had a mismatch 24 hours after randomization. Results- Eighteen percent of the control arm patients had a persistent favorable profile >38 hours after last known well time. These patients had similar baseline diffusion weighted imaging and Tmax >6 seconds volumes as patients whose initially favorable perfusion profile became unfavorable (diffusion weighted imaging lesion 7 versus 17 mL; P=0.17, Tmax >6 seconds 98 versus 100 mL; P=0.48) yet experienced less infarct growth (15 versus 59 mL; P<0.001) and had 3-fold smaller infarct volumes (15 versus 59 mL; P<0.001) 24 hours after randomization. Patients with a persistent favorable perfusion profile had a significantly lower hypoperfusion intensity ratio on baseline imaging (0.2 versus 0.4; P<0.01). Favorable clinical outcome at 90 days occurred in only 10% of the persistent mismatch patients. Conclusions- About 20% of patients with a middle cerebral artery or internal carotid artery occlusion who present in an extended time window and are not treated with thrombectomy have a persistent mismatch for at least an additional 24 hours. These patients have a favorable hypoperfusion intensity ratio at presentation, may experience delayed infarct expansion, and have poor clinical outcomes. Clinical trials are needed to determine if patients with a favorable perfusion profile benefit from reperfusion beyond 24 hours. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02586415.

Ischemic Core and Hypoperfusion Volumes Correlate With Infarct Size 24 Hours After Randomization in DEFUSE 3.

Background and Purpose- Accurate prediction of the subsequent infarct volume early after stroke onset helps determine appropriate interventions and prognosis. In the DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke), we evaluated the accuracy of baseline ischemic core and hypoperfusion volumes for predicting infarct volume 24 hours after randomization to endovascular thrombectomy versus medical management. We also assessed if the union of baseline ischemic core and the volume of persistent hypoperfusion at 24 hours after randomization predicts infarct volume. Methods- Patients in DEFUSE 3 with computed tomography perfusion imaging or magnetic resonance diffusion weighted imaging/perfusion imaging acquired at baseline and at 24 hours after randomization were included. Ischemic core and Tmax >6s hypoperfusion volumes at baseline and follow-up were calculated using RAPID software and compared with the infarct volumes obtained 24 hours after randomization. Patients were stratified by reperfusion status for analyses. Results- Of 125 eligible patients, 59 patients with >90% reperfusion had a strong correlation between baseline ischemic core volume and infarct volume 24 hours postrandomization ( r=0.83; P<0.0001), and 14 patients with <10% reperfusion had a strong correlation between baseline Tmax >6s volume and infarct volume 24 hours postrandomization ( r=0.77; P<0.001). In the 52 patients with 10% to 90% reperfusion, as well as in all 125 patients, the union of the baseline ischemic core and the follow-up Tmax >6s perfusion volume was highly correlated with infarct volume 24 hours postrandomization (for N=125; r=0.83; P<0.0001), with a median absolute difference of 21.3 mL between observed and predicted infarct volumes. Conclusions- The union of the irreversibly injured ischemic core and persistently hypoperfused tissue volumes, as identified by computed tomography perfusion or magnetic resonance diffusion weighted imaging/perfusion, predicted infarct volume at 24 hours after randomization in DEFUSE 3 patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02586415.

Hypoperfusion Intensity Ratio Is Correlated With Patient Eligibility for Thrombectomy.

Background and Purpose- Hypoperfusion intensity ratio (HIR) is associated with collateral status in acute ischemic stroke patients with anterior circulation large vessel occlusion. We assessed whether HIR was correlated to patient eligibility for mechanical thrombectomy (MT). Methods- We performed a retrospective cohort study of consecutive acute ischemic stroke patients with a proximal middle cerebral artery or internal carotid artery occlusion who underwent MT triage with computed tomography or magnetic resonance perfusion imaging. Clinical data, ischemic core (mL), HIR (defined as time-to-maximum [TMax] >10 seconds/TMax >6 seconds), mismatch volume between core and penumbra, and MT details were assessed. Primary outcome was favorable HIR collateral score (HIR <0.4) between patients who underwent MT (MT+) and those who did not (MT-) according to American Heart Association guidelines both in the <6 hours and 6 to 24 hours windows. Secondary outcomes were favorable HIR score in MT- subgroups (National Institutes of Health Stroke Scale <6 versus core >70 mL) and core-penumbra mismatch volumes. Patients who did not meet guidelines were not included. Results- We included 197 patients (145 MT+ and 52 MT-). MT+ patients had a significantly lower median HIR compared with MT- patients (0.4 [interquartile range, 0.2-0.5] versus 0.6 [interquartile range, 0.5-0.8]; P<0.001) and a higher mismatch volume (96 versus 27 mL, P<0.001). Among MT- patients, 43 had a core >70 mL, and 9 had a National Institutes of Health Stroke Scale <6. MT- patients with National Institutes of Health Stroke Scale <6 had a lower HIR than MT- patients with core >70 mL (0.2 [interquartile range, 0.2-0.3] versus 0.7 [interquartile range, 0.6-0.8], P<0.001) but their HIR was not significantly different that MT+ patients. Conclusions- Patients who meet American Heart Association guidelines for thrombectomy are more likely to have favorable collaterals (low HIR). HIR may be used as a marker of eligibility for MT triage.

Rapid Neurologic Improvement Predicts Favorable Outcome 90 Days After Thrombectomy in the DEFUSE 3 Study.

Background and Purpose- Thrombectomy in late time windows leads to improved outcomes in patients with ischemic stroke due to large vessel occlusion. We determined whether patients with rapid neurological improvement (RNI) 24 hours after thrombectomy were more likely to have a favorable clinical outcome in the DEFUSE 3 study (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3). Methods- All patients who underwent thrombectomy in DEFUSE 3 were included. RNI was defined as a reduction of ≥8 on the National Institutes of Health Stroke Scale or National Institutes of Health Stroke Scale zero to one 24 hours after thrombectomy. Clinical outcomes were assessed by an ordinal analysis modified Rankin Scale score and a dichotomous analysis for 90-day independence (modified Rankin Scale score, 0-2). Results- Ninety-one patients in DEFUSE 3 underwent thrombectomy with follow-up data; 31 patients (34%) experienced RNI (RNI+) after thrombectomy and 60 patients (66%) did not (RNI-). Patient demographics and stroke presentation and imaging details were similar between RNI+ and RNI- patients. Reperfusion (Thrombolysis in Cerebral Infarction 2b-3) after thrombectomy was achieved in 26 (84%) RNI+ and 43 (72%) RNI- ( P=0.2). Symptomatic intracranial hemorrhage occurred in no RNI+ and 8% of RNI- patients ( P=0.2). RNI was associated with a favorable modified Rankin Scale shift at day 90 (odds ratio, 3.8; CI, 1.7-8.6; P=0.001) and higher rates of modified Rankin Scale zero to 2 (61% versus 37%; odds ratio, 2.7; CI, 1.1-6.7; P=0.03). Mortality was 3% in RNI+ versus 18% in RNI- ( P=0.05). RNI+ patients had lower median 24-hour National Institutes of Health Stroke Scale (5 [interquartile range (IQR), 1-7] versus 13 [IQR, 7.5-21]; P<0.001), smaller 24-hour infarction volume (21 [IQR, 5-32] versus 65 [IQR, 27-145] mL; P<0.001), and less 24-hour infarct growth (8 [IQR, 1-18] versus 37 [IQR, 16-105] mL; P<0.001) compared with RNI- patients. Hospital stay was shorter in RNI+ (3.7 [IQR, 2.9-7.1] versus 7.4 [IQR, 5.2-12.1] days in RNI-; P<0.001). Conclusions- RNI following thrombectomy correlates with favorable clinical and radiographic outcomes and reduced hospital length of stay. RNI was a favorable prognostic sign following late-window thrombectomy in DEFUSE 3. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02586415.

Thrombectomy Results in Reduced Hospital Stay, More Home-Time, and More Favorable Living Situations in DEFUSE 3.

Background and Purpose- The DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) demonstrated that endovascular thrombectomy in the 6- to 16-hour time window improves functional outcomes of patients with evidence of salvageable tissue on baseline computed tomography or magnetic resonance imaging. The purpose of this study is to assess the effect of endovascular therapy on length of hospital stay, home-time during the first 3 months poststroke, and living situation poststroke in DEFUSE 3. Methods- Duration of hospital stay and home-time (number of days during the 90-day poststroke period that the patient resides in their own home or in that of a relative) were compared between treatment groups using the Wilcoxon rank-sum test. Patient living situation was assessed at discharge, 30 days, and 90 days on an ordinal 4-point scale (home, acute rehabilitation unit, institutionalized care, or hospice/death) and differences between groups were analyzed using the Cochran-Armitage trend test. Results- Median length of hospital stay was 9.1 (interquartile range, 6.2-15.0) days in the medical group versus 6.5 (interquartile range, 3.7-9.3) days in the endovascular group (P<0.001). Median home-time during the first 90 days after stroke was 0 (interquartile range, 0-53) days in the medical group versus 55 (interquartile range, 0-83) days in the endovascular group (P<0.001). The endovascular group had more favorable living situations at time of discharge (P<0.001), 30 days (P<0.001), and 90 days (P<0.001) poststroke. Conclusions- Endovascular thrombectomy resulted in reduced hospital stay, more home-time, and more desirable living situations in the 90 days after stroke. These results provide evidence that endovascular therapy in the delayed time window can improve quality of life for stroke patients and reduce healthcare costs. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02586415.

Results From DEFUSE 3: Good Collaterals Are Associated With Reduced Ischemic Core Growth but Not Neurologic Outcome

Background and Purpose- The effect of leptomeningeal collaterals for acute ischemic stroke patients with large vessel occlusion in the late window (>6 hours from last known normal) remains unknown. We sought to determine if collateral status on baseline computed tomography angiography impacted neurological outcome, ischemic core growth, and moderated the effect of endovascular thrombectomy in the late window. Methods- This is a prespecified analysis of DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke). We included patients with computed tomography angiography as their baseline imaging and rated collateral status using the validated scales described by Tan and Maas. The primary outcome is functional independence (modified Rankin Scale score of ≤2). Additional outcomes include the full range of the modified Rankin Scale, baseline ischemic core volume, change from baseline in the ischemic core volume at 24 hours, and death at 90 days. Results- Of the 130 patients in our cohort, 33 (25%) had poor collaterals and 97 (75%) had good collaterals. There was no difference in the rate of functional independence with good versus poor collaterals in unadjusted analysis (30% versus 39%; P=0.3) or after adjustment for treatment arm (odds ratio [95% CI], 0.61 [0.26-1.45]). Good collaterals were associated with significantly smaller ischemic core volume and less ischemic core growth. The difference in the treatment effect of endovascular thrombectomy was not significant ( P=0.8). Collateral status also did not affect the rate of stroke-related death (n [%], good versus poor collaterals, 18/97 [19%] versus 8/33 [24%], P=0.5]. Conclusions- In DEFUSE 3 patients, good leptomeningeal collaterals on single phase computed tomography angiography were not predictive of functional independence or death and did not impact the treatment effect of endovascular thrombectomy. These unexpected findings require further study to confirm their validity and to better understand the role of collaterals for stroke patients with anterior circulation large vessel occlusion in the late therapeutic window. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02586415.

Contralateral Hemispheric Cerebral Blood Flow Measured With Arterial Spin Labeling Can Predict Outcome in Acute Stroke.

Background and Purpose- Imaging is frequently used to select acute stroke patients for intra-arterial therapy. Quantitative cerebral blood flow can be measured noninvasively with arterial spin labeling magnetic resonance imaging. Cerebral blood flow levels in the contralateral (unaffected) hemisphere may affect capacity for collateral flow and patient outcome. The goal of this study was to determine whether higher contralateral cerebral blood flow (cCBF) in acute stroke identifies patients with better 90-day functional outcome. Methods- Patients were part of the prospective, multicenter iCAS study (Imaging Collaterals in Acute Stroke) between 2013 and 2017. Consecutive patients were enrolled after being diagnosed with anterior circulation acute ischemic stroke. Inclusion criteria were ischemic anterior circulation stroke, baseline National Institutes of Health Stroke Scale score ≥1, prestroke modified Rankin Scale score ≤2, onset-to-imaging time <24 hours, with imaging including diffusion-weighted imaging and arterial spin labeling. Patients were dichotomized into high and low cCBF groups based on median cCBF. Outcomes were assessed by day-1 and day-5 National Institutes of Health Stroke Scale; and day-30 and day-90 modified Rankin Scale. Multivariable logistic regression was used to test whether cCBF predicted good neurological outcome (modified Rankin Scale score, 0-2) at 90 days. Results- Seventy-seven patients (41 women) met the inclusion criteria with median (interquartile range) age of 66 (55-76) yrs, onset-to-imaging time of 4.8 (3.6-7.7) hours, and baseline National Institutes of Health Stroke Scale score of 13 (9-20). Median cCBF was 38.9 (31.2-44.5) mL per 100 g/min. Higher cCBF predicted good outcome at day 90 (odds ratio, 4.6 [95% CI, 1.4-14.7]; P=0.01), after controlling for baseline National Institutes of Health Stroke Scale, diffusion-weighted imaging lesion volume, and intra-arterial therapy. Conclusions- Higher quantitative cCBF at baseline is a significant predictor of good neurological outcome at day 90. cCBF levels may inform decisions regarding stroke triage, treatment of acute stroke, and general outcome prognosis. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02225730.

Early Cerebral Vein After Endovascular Ischemic Stroke Treatment Predicts Symptomatic Reperfusion Hemorrhage.

BACKGROUND AND PURPOSE: Parenchymal hemorrhage (PH) after endovascular mechanical thrombectomy in acute ischemic stroke leads to worse outcomes. Better clinical and imaging biomarkers of symptomatic reperfusion PH are needed to identify patients at risk. We identified clinical and imaging predictors of reperfusion PH after endovascular mechanical thrombectomy with attention to early cerebral veins (ECVs) on postreperfusion digital subtraction angiography. METHODS: We performed a retrospective cohort study of consecutive acute ischemic stroke patients undergoing endovascular mechanical thrombectomy at our neurovascular referral center. Clinical and imaging characteristics were collected from patient health records, and random forest variable importance measures were used to identify predictors of symptomatic PH. Predictors of secondary outcomes, including 90-day mortality, functional dependence (modified Rankin Scale score, >2), and National Institutes of Health Stroke Scale shift, were also determined. Diagnostic test characteristics of ECV for symptomatic PH were determined using a receiver operating characteristic analysis. Differences between patients with and without symptomatic PH were assessed with Fisher exact test and the Wilcoxon rank sum (Mann-Whitney U test) test at the 0.05 significance level. RESULTS: Of 64 patients with anterior circulation large-vessel occlusion identified, 6 (9.4%) developed symptomatic PH. ECV was the strongest predictor of symptomatic PH with more than twice the importance of the next best predictor, male sex. Although ECV was also predictive of 90-day mortality and functional dependence, other characteristics were more important than ECV for these outcomes. The sensitivity and specificity of ECV alone for subsequent hemorrhage were both 0.83, with an area under the curve of 0.83 and 95% confidence interval of 0.66 to 1.00. CONCLUSIONS: ECV on postendovascular mechanical thrombectomy digital subtraction angiography is highly diagnostic of subsequent symptomatic reperfusion hemorrhage in this data set. This finding has important implications for post-treatment management of blood pressure and anticoagulation.

Time From Imaging to Endovascular Reperfusion Predicts Outcome in Acute Stroke.

BACKGROUND AND PURPOSE: This study aims to describe the relationship between computed tomographic (CT) perfusion (CTP)-to-reperfusion time and clinical and radiological outcomes, in a cohort of patients who achieve successful reperfusion for acute ischemic stroke. METHODS: We included data from the CRISP (Computed Tomographic Perfusion to Predict Response in Ischemic Stroke Project) in which all patients underwent a baseline CTP scan before endovascular therapy. Patients were included if they had a mismatch on their baseline CTP scan and achieved successful endovascular reperfusion. Patients with mismatch were categorized into target mismatch and malignant mismatch profiles, according to the volume of their Tmax >10s lesion volume (target mismatch, <100 mL; malignant mismatch, >100 mL). We investigated the impact of CTP-to-reperfusion times on probability of achieving functional independence (modified Rankin Scale, 0-2) at day 90 and radiographic outcomes at day 5. RESULTS: Of 156 included patients, 108 (59%) had the target mismatch profile, and 48 (26%) had the malignant mismatch profile. In patients with the target mismatch profile, CTP-to-reperfusion time showed no association with functional independence (P=0.84), whereas in patients with malignant mismatch profile, CTP-to-reperfusion time was strongly associated with lower probability of functional independence (odds ratio, 0.08; P=0.003). Compared with patients with target mismatch, those with the malignant mismatch profile had significantly more infarct growth (90 [49-166] versus 43 [18-81] mL; P=0.006) and larger final infarct volumes (110 [61-155] versus 48 [21-99] mL; P=0.001). CONCLUSIONS: Compared with target mismatch patients, those with the malignant profile experience faster infarct growth and a steeper decline in the odds of functional independence, with longer delays between baseline imaging and reperfusion. However, this does not exclude the possibility of treatment benefit in patients with a malignant profile.