MRI hypoperfusion as a determinant of cognitive impairment in adults with Moyamoya angiopathy.

INTRODUCTION: In Moyamoya angiopathy (MMA), mechanisms underlying cognitive impairment remain debated. We aimed to assess the association of cognitive impairment with the degree and the topography of cerebral hypoperfusion in MMA. METHODS: A retrospective analysis of neuropsychological and perfusion MRI data from adults with MMA was performed. Ischemic and haemorrhagic lesion masks were created to account for cerebral lesions in the analysis of cerebral perfusion. Whole brain volume of hypoperfused parenchyma was outlined on perfusion maps using different Tmax thresholds from 4 to 12 s. Regional analysis produced mean Tmax values at different regions of interest. Analyses compared perfusion ratios in patients with and without cognitive impairment, with multivariable logistic regression analysis to identify predictive factors. RESULTS: Cognitive impairment was found in 20/48 (41.7%) patients. Attention/processing speed and memory were equally impaired (24%) followed by executive domain (23%). After adjustment, especially for lesion volume, hypoperfused parenchyma volume outlined by Tmax > 4 s or Tmax > 5 s thresholds was an independent factor of cognitive impairment (OR for Tmax > 4 s = 1.06 [CI 95% 1.008-1.123]) as well as attention/processing speed (OR for Tmax > 4 s = 1.07 [CI 95% 1.003-1.133]) and executive domains (OR for Tmax > 5 s = 1.08 [CI 95% 1.004-1.158]). Regarding cognitive functions, patients with processing speed and flexibility impairment had higher frontal Tmax compared to other ROIs and to patients with normal test scores. DISCUSSION: Cerebral hypoperfusion emerged as an independent factor of cognitive impairment in MMA particularly in attention/processing speed and executive domains, with a strong contribution of frontal areas. CONCLUSION: Considering this association, revascularization surgery could improve cognitive impairment.

Neuroimmune activation is associated with neurological outcome in anoxic and traumatic coma.

The pathophysiological underpinnings of critically disrupted brain connectomes resulting in coma are poorly understood. Inflammation is potentially an important but still undervalued factor. Here, we present a first-in-human prospective study using the 18-kDa translocator protein (TSPO) radioligand 18F-DPA714 for PET imaging to allow in vivo neuroimmune activation quantification in patients with coma (n = 17) following either anoxia or traumatic brain injuries in comparison with age- and sex-matched controls. Our findings yielded novel evidence of an early inflammatory component predominantly located within key cortical and subcortical brain structures that are putatively implicated in consciousness emergence and maintenance after severe brain injury (i.e. mesocircuit and frontoparietal networks). We observed that traumatic and anoxic patients with coma have distinct neuroimmune activation profiles, both in terms of intensity and spatial distribution. Finally, we demonstrated that both the total amount and specific distribution of PET-measurable neuroinflammation within the brain mesocircuit were associated with the patient's recovery potential. We suggest that our results can be developed for use both as a new neuroprognostication tool and as a promising biometric to guide future clinical trials targeting glial activity very early after severe brain injury.

MRI vs CT for Baseline Imaging Evaluation in Acute Large Artery Ischemic Stroke: A Subanalysis of the SWIFT-DIRECT Trial

BACKGROUND AND OBJECTIVES: Whether MRI or CT is preferable for the evaluation of patients with suspected stroke remains a matter of debate, given that the imaging modality acquired at baseline may be a relevant determinant of workflow delays and outcomes with it, in patients with stroke undergoing acute reperfusion therapies. METHODS: In this post hoc analysis of the SWIFT-DIRECT trial that investigated noninferiority of thrombectomy alone vs IV thrombolysis (IVT) + thrombectomy in patients with an acute ischemic anterior circulation large vessel occlusive stroke eligible to receive IVT within 4.5 hours after last seen well, we tested for a potential interaction between baseline imaging modality (MRI/MR-angiography [MRA] vs CT/CT-angiography [CTA]) and the effect of acute treatment (thrombectomy vs IVT + thrombectomy) on clinical and safety outcomes and procedural metrics (primary analysis). Moreover, we examined the association between baseline imaging modality and these outcomes using regression models adjusted for age, sex, baseline NIH Stroke Scale (NIHSS), occlusion location, and Alberta Stroke Program Early CT Score (ASPECTS) (secondary analysis). Endpoints included workflow times, the modified Rankin scale (mRS) score at 90 days, the rate of successful reperfusion, the odds for early neurologic deterioration within 24 hours, and the risk of symptomatic intracranial hemorrhage. The imaging modality acquired was chosen at the discretion of the treating physicians and commonly reflects center-specific standard procedures. RESULTS: Four hundred five of 408 patients enrolled in the SWIFT-DIRECT trial were included in this substudy. Two hundred (49.4%) patients underwent MRI/MRA, and 205 (50.6%) underwent CT/CTA. Patients with MRI/MRA had lower NIHSS scores (16 [interquartile range (IQR) 12-20] vs 18 [IQR 14-20], p = 0.012) and lower ASPECTS (8 [IQR 6-9] vs 8 [IQR 7-9], p = 0.021) compared with those with CT/CTA. In terms of the primary analysis, we found no evidence for an interaction between baseline imaging modality and the effect of IVT + thrombectomy vs thrombectomy alone. Regarding the secondary analysis, MRI/MRA acquisition was associated with workflow delays of approximately 20 minutes, higher odds of functional independence at 90 days (adjusted odds ratio [aOR] 1.65, 95% CI 1.07-2.56), and similar mortality rates (aOR 0.73, 95% CI 0.36-1.47) compared with CT/CTA. DISCUSSION: This post hoc analysis does not suggest treatment effect heterogeneity of IVT + thrombectomy vs thrombectomy alone in large artery stroke patients with different imaging modalities. There was no evidence that functional outcome at 90 days was less favorable following MRI/MRA at baseline compared with CT/CTA, despite significant workflow delays. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03192332.

Evaluation of mechanical thrombectomy in acute ischemic stroke related to a distal arterial occlusion: A randomized controlled trial.

RATIONALE: Mechanical thrombectomy (MT) associated with the best medical treatment (BMT) has recently shown efficacy for the management of acute ischemic stroke (AIS) secondary to a large vessel occlusion. However, evidence is lacking regarding the benefit of MT for more distal occlusions. AIM: To evaluate the efficacy in terms of good clinical outcome at 3 months of MT associated with the BMT over the BMT alone in AIS related to a distal occlusion. METHODS: The DISCOUNT trial is a multicenter open-label randomized controlled trial involving French University hospitals. Adult patients (⩾18 years) with an AIS involving the anterior or posterior circulation secondary to a distal vessel occlusion within 6 h of symptom onset or within 24 h if no hyperintense signal on fluid attenuation inversion recovery acquisition will be randomized 1:1 to receive either MT associated with the BMT (experimental group) or BMT alone (control group). The number of patients to be included is 488. STUDY OUTCOMES: The primary outcome is the rate of good clinical outcome at 3 months defined as a modified Rankin scale (mRS) ⩽2 and evaluated by an independent assessor blinded to the intervention arm. Secondary outcomes include recanalization of the occluded vessel within 48 h, angiographic reperfusion in the experimental group, 3-month excellent clinical outcome (mRS ⩽ 1), all adverse events, and death. A cost utility analysis will estimate the incremental cost per quality-adjusted life year (QALY) gained. DISCUSSION: If positive, this study will open new insights in the management of AISs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05030142 registered on 1 September 2021.

Effect of Bridging Thrombolysis on the Efficacy of Stent Retriever Thrombectomy Techniques : Insights from the SWIFT-DIRECT trial.

BACKGROUND: There are little available data regarding the influence of intravenous thrombolysis (IVT) on the efficacy of different first line endovascular treatment (EVT) techniques. METHODS: We used the dataset of the SWIFT-DIRECT trial which randomized 408 patients to IVT + EVT or EVT alone at 48 international sites. The protocol required the use of a stent retriever (SR), but concomitant use of a balloon guide catheter (BGC) and/or distal aspiration (DA) catheter was left to the discretion of the operators. Four first line techniques were applied in the study population: SR, SR + BGC, SR + DA, SR + DA + BGC. To assess whether the effect of allocation to IVT + EVT versus EVT alone was modified by the first line technique, interaction models were fitted for predefined outcomes. The primary outcome was first pass mTICI 2c­3 reperfusion (FPR). RESULTS: This study included 385 patients of whom 172 were treated with SR + DA, 121 with SR + DA + BGC, 57 with SR + BGC and 35 with SR. There was no evidence that the effect of IVT + EVT versus EVT alone would be modified by the choice of first line technique; however, allocation to IVT + EVT increased the odds of FPR by a factor of 1.68 (95% confidence interval, CI 1.11-2.54). CONCLUSION: This post hoc analysis does not suggest treatment effect heterogeneity of IVT + EVT vs EVT alone in different stent retriever techniques but provides evidence for increased FPR if bridging IVT is administered before stent retriever thrombectomy.

Factors Associated With Fast Early Infarct Growth in Patients With Acute Ischemic Stroke With a Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: The optimal methods for predicting early infarct growth rate (EIGR) in acute ischemic stroke with a large vessel occlusion (LVO) have not been established. We aimed to study the factors associated with EIGR, with a focus on the collateral circulation as assessed by the hypoperfusion intensity ratio (HIR) on perfusion imaging, and determine whether the associations found are consistent across imaging modalities. METHODS: Retrospective multicenter international study including patients with anterior circulation LVO-related acute stroke with witnessed stroke onset and baseline perfusion imaging (MRI or CT) performed within 24 hours from symptom onset. To avoid selection bias, patients were selected from (1) the prospective registries of 4 comprehensive stroke centers with systematic use of perfusion imaging and including both thrombectomy-treated and untreated patients and (2) 1 prospective thrombectomy study where perfusion imaging was acquired per protocol, but treatment decisions were made blinded to the results. EIGR was defined as infarct volume on baseline imaging divided by onset-to-imaging time and fast progressors as EIGR ≥10 mL/h. The HIR, defined as the proportion of time-to-maximum (Tmax) >6 second with Tmax >10 second volume, was measured on perfusion imaging using RAPID software. The factors independently associated with fast progression were studied using multivariable logistic regression models, with separate analyses for CT- and MRI-assessed patients. RESULTS: Overall, 1,127 patients were included (CT, n = 471; MRI, n = 656). Median age was 74 years (interquartile range [IQR] 62-83), 52% were male, median NIH Stroke Scale was 16 (IQR 9-21), median HIR was 0.42 (IQR 0.26-0.58), and 415 (37%) were fast progressors. The HIR was the primary factor associated with fast progression, with very similar results across imaging modalities: The proportion of fast progressors was 4% in the first HIR quartile (i.e., excellent collaterals), ∼15% in the second, ∼50% in the third, and ∼77% in the fourth (p < 0.001 for each imaging modality). Fast progression was independently associated with poor 3-month functional outcome in both the CT and MRI cohorts (p < 0.001 and p = 0.030, respectively). DISCUSSION: The HIR is the primary factor associated with fast infarct progression, regardless of imaging modality. These results have implication for neuroprotection trial design, as well as informing triage decisions at primary stroke centers.

Evaluation of acute mechanical revascularization in minor stroke (NIHSS score ⩽ 5) and large vessel occlusion: The MOSTE multicenter, randomized, clinical trial protocol.

RATIONALE: Mechanical thrombectomy (MT) has become the standard of care for patients with acute ischemic stroke secondary to large vessel occlusion (LVO) of the anterior circulation. Conversely, its benefit in patients with National Institutes of Health Stroke Scale (NIHSS) score ⩽ 5 is unproven. AIM: To demonstrate the superiority of immediate MT plus best medical treatment (BMT) compared to BMT (with secondary MT in case of deterioration) for increasing the rate of modified Rankin Scale (mRS) score ⩽ 1 at 90 days after minor stroke (NIHSS score ⩽ 5) and anterior circulation LVO. SAMPLE SIZE ESTIMATES: To detect an absolute increase of 10% (80% power) in the 90-day mRS score = 0-1 rate in the MT + BMT group, by assuming an mRS score = 0-1 rate of 60% in the BMT group and by considering two interim efficacy/futility analyses (after study completion by 274 and 548 patients), 824 patients must be included by 36 centers in France, Spain, and the USA. METHODS AND DESIGN: MOSTE is an international, multicenter, prospectively randomized into two parallel (1:1) arms, open-label, with blinded endpoint trial. Eligibility criteria are diagnosis of acute ischemic stroke within 23 h of last-seen-well, NIHSS score ⩽ 5, and LVO in the anterior circulation (intracranial internal carotid artery, M1 or M1-M2 segment of the middle cerebral artery). STUDY OUTCOMES: The primary endpoint is the rate of excellent outcome at day 90 (mRS score = 0-1). Secondary endpoints include the rates of 90-day mRS score = 0-2 and score = 0, NIHSS score change, secondary MT, revascularization and infarct volume growth at 24 h, and quality of life and cognitive function at day 90. Safety outcomes (90-day all-cause mortality, procedural complications, symptomatic intracerebral hemorrhage, and rapid NIHSS score worsening) are recorded. DISCUSSION: The MOSTE trial will determine MT efficacy and safety in patients with minor stroke and LVO in the anterior circulation. TRIAL REGISTRATION: MOSTE Trial. NCT03796468.

Immunohistologic Features of Cerebral Venous Thrombosis Due to Vaccine-Induced Immune Thrombotic Thrombocytopenia.

OBJECTIVES: Vaccine-induced immune thrombotic thrombocytopenia (VITT), a recently described entity characterized by thrombosis at unusual locations such as cerebral venous sinus and splanchnic vein, has been rarely described after adenoviral-encoded COVID-19 vaccines. In this study, we report the immunohistological correlates in 3 fatal cases of cerebral venous thrombosis related to VITT analyzed at an academic medical center. METHODS: Detailed neuropathologic studies were performed in 3 cases of cerebral venous thrombosis related to VITT after adenoviral COVID-19 vaccination. RESULTS: Autopsy revealed extensive cerebral vein thrombosis in all 3 cases. Polarized thrombi were observed with a high density of neutrophils in the core and a low density in the tail. Endothelial cells adjacent to the thrombus were largely destroyed. Markers of neutrophil extracellular trap and complement activation were present at the border and within the cerebral vein thrombi. SARS-CoV-2 spike protein was detected within the thrombus and in the adjacent vessel wall. DISCUSSION: Data indicate that neutrophils and complement activation associated with antispike immunity triggered by the vaccine is probably involved in the disease process.

Outcomes After Endovascular Therapy With Procedural Sedation vs General Anesthesia in Patients With Acute Ischemic Stroke: The AMETIS Randomized Clinical Trial.

Importance: General anesthesia and procedural sedation are common practice for mechanical thrombectomy in acute ischemic stroke. However, risks and benefits of each strategy are unclear. Objective: To determine whether general anesthesia or procedural sedation for anterior circulation large-vessel occlusion acute ischemic stroke thrombectomy are associated with a difference in periprocedural complications and 3-month functional outcome. Design, Setting, and Participants: This open-label, blinded end point randomized clinical trial was conducted between August 2017 and February 2020, with final follow-up in May 2020, at 10 centers in France. Adults with occlusion of the intracranial internal carotid artery and/or the proximal middle cerebral artery treated with thrombectomy were enrolled. Interventions: Patients were assigned to receive general anesthesia with tracheal intubation (n = 135) or procedural sedation (n = 138). Main Outcomes and Measures: The prespecified primary composite outcome was functional independence (a score of 0 to 2 on the modified Rankin Scale, which ranges from 0 [no neurologic disability] to 6 [death]) at 90 days and absence of major periprocedural complications (procedure-related serious adverse events, pneumonia, myocardial infarction, cardiogenic acute pulmonary edema, or malignant stroke) at 7 days. Results: Among 273 patients evaluable for the primary outcome in the modified intention-to-treat population, 142 (52.0%) were women, and the mean (SD) age was 71.6 (13.8) years. The primary outcome occurred in 38 of 135 patients (28.2%) assigned to general anesthesia and in 50 of 138 patients (36.2%) assigned to procedural sedation (absolute difference, 8.1 percentage points; 95% CI, -2.3 to 19.1; P = .15). At 90 days, the rate of patients achieving functional independence was 33.3% (45 of 135) with general anesthesia and 39.1% (54 of 138) with procedural sedation (relative risk, 1.18; 95% CI, 0.86-1.61; P = .32). The rate of patients without major periprocedural complications at 7 days was 65.9% (89 of 135) with general anesthesia and 67.4% (93 of 138) with procedural sedation (relative risk, 1.02; 95% CI, 0.86-1.21; P = .80). Conclusions and Relevance: In patients treated with mechanical thrombectomy for anterior circulation acute ischemic stroke, general anesthesia and procedural sedation were associated with similar rates of functional independence and major periprocedural complications. Trial Registration: ClinicalTrials.gov Identifier: NCT03229148.

Quantification of Penumbral Volume in Association With Time From Stroke Onset in Acute Ischemic Stroke With Large Vessel Occlusion.

Importance: The benefit of reperfusion therapies for acute ischemic stroke decreases over time. This decreasing benefit is presumably due to the disappearance of salvageable ischemic brain tissue (ie, the penumbra). Objective: To study the association between stroke onset-to-imaging time and penumbral volume in patients with acute ischemic stroke with a large vessel occlusion. Design, Setting, and Participants: A retrospective, multicenter, cross-sectional study was conducted from January 1, 2015, to June 30, 2022. To limit selection bias, patients were selected from (1) the prospective registries of 2 comprehensive centers with systematic use of magnetic resonance imaging (MRI) with perfusion, including both thrombectomy-treated and untreated patients, and (2) 1 prospective thrombectomy study in which MRI with perfusion was acquired per protocol but treatment decisions were made with clinicians blinded to the results. Consecutive patients with acute stroke with intracranial internal carotid artery or first segment of middle cerebral artery occlusion and adequate quality MRI, including perfusion, performed within 24 hours from known symptoms onset were included in the analysis. Exposures: Time from stroke symptom onset to baseline MRI. Main Outcomes and Measures: Penumbral volume, measured using automated software, was defined as the volume of tissue with critical hypoperfusion (time to maximum >6 seconds) minus the volume of the ischemic core. Substantial penumbra was defined as greater than or equal to 15 mL and a mismatch ratio (time to maximum >6-second volume/core volume) greater than or equal to 1.8. Results: Of 940 patients screened, 516 were excluded (no MRI, n = 19; no perfusion imaging, n = 59; technically inadequate perfusion imaging, n = 75; second segment of the middle cerebral artery occlusion, n = 156; unwitnessed stroke onset, n = 207). Of 424 included patients, 226 (53.3%) were men, and mean (SD) age was 68.9 (15.1) years. Median onset-to-imaging time was 3.8 (IQR, 2.4-5.5) hours. Only 16 patients were admitted beyond 10 hours from symptom onset. Median core volume was 24 (IQR, 8-76) mL and median penumbral volume was 58 (IQR, 29-91) mL. An increment in onset-to-imaging time by 1 hour resulted in a decrease of 3.1 mL of penumbral volume (ß coefficient = -3.1; 95% CI, -4.6 to -1.5; P < .001) and an increase of 3.0 mL of core volume (ß coefficient = 3.0; 95% CI, 1.3-4.7; P < .001) after adjustment for confounders. The presence of a substantial penumbra ranged from approximately 80% in patients imaged at 1 hour to 70% at 5 hours, 60% at 10 hours, and 40% at 15 hours. Conclusions and Relevance: Time is associated with increasing core and decreasing penumbral volumes. Despite this, a substantial percentage of patients have notable penumbra in extended time windows; the findings of this study suggest that a large proportion of patients with large vessel occlusion may benefit from therapeutic interventions.

Association of intravenous thrombolysis and pre-interventional reperfusion: a post hoc analysis of the SWIFT DIRECT trial.

BACKGROUND: A potential benefit of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) is pre-interventional reperfusion. Currently, there are few data on the occurrence of pre-interventional reperfusion in patients randomized to IVT or no IVT before MT. METHODS: SWIFT DIRECT (Solitaire With the Intention For Thrombectomy Plus Intravenous t-PA vs DIRECT Solitaire Stent-retriever Thrombectomy in Acute Anterior Circulation Stroke) was a randomized controlled trial including acute ischemic stroke IVT eligible patients being directly admitted to a comprehensive stroke center, with allocation to IVT with MT versus MT alone. The primary endpoint of this analysis was the occurrence of pre-interventional reperfusion, defined as a pre-interventional expanded Thrombolysis in Cerebral Infarction score of ≥2a. The effect of IVT and potential treatment effect heterogeneity were analyzed using logistic regression analyses. RESULTS: Of 396 patients, pre-interventional reperfusion occurred in 20 (10.0%) patients randomized to IVT with MT, and in 7 (3.6%) patients randomized to MT alone. Receiving IVT favored the occurrence of pre-interventional reperfusion (adjusted OR 2.91, 95% CI 1.23 to 6.87). There was no IVT treatment effect heterogeneity on the occurrence of pre-interventional reperfusion with different strata of Randomization-to-Groin-Puncture time (p for interaction=0.33), although the effect tended to be stronger in patients with a Randomization-to-Groin-Puncture time >28 min (adjusted OR 4.65, 95% CI 1.16 to 18.68). There were no significant differences in rates of functional outcomes between patients with and without pre-interventional reperfusion. CONCLUSION: Even for patients with proximal large vessel occlusions and direct access to MT, IVT resulted in an absolute increase of 6% in rates of pre-interventional reperfusion. The influence of time strata on the occurrence of pre-interventional reperfusion should be studied further in an individual patient data meta-analysis of comparable trials. TRIAL REGISTRATION NUMBER: clinicaltrials.gov NCT03192332.

Influence of prior intravenous thrombolysis in patients treated with mechanical thrombectomy for M2 occlusions: insight from the Endovascular Treatment in Ischemic Stroke (ETIS) registry.

BACKGROUND: Intravenous thrombolysis (IVT) for patients treated with mechanical thrombectomy (MT) for proximal occlusions has recently been questioned through randomized trials. However, few patients with M2 occlusions were included. We investigated the influence of prior IVT for patients presenting M2 occlusions treated with MT in comparison with MT alone. METHODS: We conducted a retrospective analysis of the Endovascular Treatment in Ischemic Stroke (ETIS) registry, a multicenter observational study. Data from consecutive patients treated with MT for M2 occlusions between January 2015 and January 2022 at 26 comprehensive stroke centers were analyzed. The primary endpoint was 90-day modified Rankin Scale score of 0-2. Outcomes were compared using propensity score approaches. We also performed sensitivity analysis in relevant subgroups of patients. RESULTS: Among 1132 patients with M2 occlusions treated with MT, 570 received prior IVT. The two groups were comparable after propensity analysis. The rate of favorable functional outcome was significantly higher in the IVT+MT group compared with the MT alone group (59.8% vs 44.7%; adjusted OR 1.38, 95% CI 1.10 to 1.75, P=0.008). Hemorrhagic and procedural complications were similar in both groups. In sensitivity analysis excluding patients with anticoagulation treatment, favorable recanalization was more frequent in the IVT+MT group (OR 1.37, 95% CI 1.11 to 1.70, P=0.004). CONCLUSIONS: In cases of M2 occlusions, prior IVT combined with MT resulted in better functional outcome than MT alone, without increasing the rate of hemorrhagic or procedural complications. These results suggest the benefit of IVT in patients undergoing MT for M2 occlusions.

Location-weighted versus Volume-weighted Mismatch at MRI for Response to Mechanical Thrombectomy in Acute Stroke.

Background A target mismatch profile can identify good clinical response to recanalization after acute ischemic stroke, but does not consider region specificities. Purpose To test whether location-weighted infarction core and mismatch, determined from diffusion and perfusion MRI performed in patients with acute stroke, could improve prediction of good clinical response to mechanical thrombectomy compared with a target mismatch profile. Materials and Methods In this secondary analysis, two prospectively collected independent stroke data sets (2012-2015 and 2017-2019) were analyzed. From the brain before stroke (BBS) study data (data set 1), an eloquent map was computed through voxel-wise associations between the infarction core (based on diffusion MRI on days 1-3 following stroke) and National Institutes of Health Stroke Scale (NIHSS) score. The French acute multimodal imaging to select patients for mechanical thrombectomy (FRAME) data (data set 2) consisted of large vessel occlusion-related acute ischemic stroke successfully recanalized. From acute MRI studies (performed on arrival, prior to thrombectomy) in data set 2, target mismatch and eloquent (vs noneloquent) infarction core and mismatch were computed from the intersection of diffusion- and perfusion-detected lesions with the coregistered eloquent map. Associations of these imaging metrics with early neurologic improvement were tested in multivariable regression models, and areas under the receiver operating characteristic curve (AUCs) were compared. Results Data sets 1 and 2 included 321 (median age, 69 years [IQR, 58-80 years]; 207 men) and 173 (median age, 74 years [IQR, 65-82 years]; 90 women) patients, respectively. Eloquent mismatch was positively and independently associated with good clinical response (odds ratio [OR], 1.14; 95% CI: 1.02, 1.27; P = .02) and eloquent infarction core was negatively associated with good response (OR, 0.85; 95% CI: 0.77, 0.95; P = .004), while noneloquent mismatch was not associated with good response (OR, 1.03; 95% CI: 0.98, 1.07; P = .20). Moreover, adding eloquent metrics improved the prediction accuracy (AUC, 0.73; 95% CI: 0.65, 0.81) compared with clinical variables alone (AUC, 0.65; 95% CI: 0.56, 0.73; P = .01) or a target mismatch profile (AUC, 0.67; 95% CI: 0.59, 0.76; P = .03). Conclusion Location-weighted infarction core and mismatch on diffusion and perfusion MRI scans improved the identification of patients with acute stroke who would benefit from mechanical thrombectomy compared with the volume-based target mismatch profile. Clinical trial registration no. NCT03045146 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Nael in this issue.

Time to treatment with bridging intravenous alteplase before endovascular treatment:subanalysis of the randomized controlled SWIFT-DIRECT trial.

BACKGROUND: We hypothesized that treatment delays might be an effect modifier regarding risks and benefits of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT). METHODS: We used the dataset of the SWIFT-DIRECT trial, which randomized 408 patients to IVT+MT or MT alone. Potential interactions between assignment to IVT+MT and expected time from onset-to-needle (OTN) as well as expected time from door-to-needle (DTN) were included in regression models. The primary outcome was functional independence (modified Rankin Scale (mRS) 0-2) at 3 months. Secondary outcomes included mRS shift, mortality, recanalization rates, and (symptomatic) intracranial hemorrhage at 24 hours. RESULTS: We included 408 patients (IVT+MT 207, MT 201, median age 72 years (IQR 64-81), 209 (51.2%) female). The expected median OTN and DTN were 142 min and 54 min in the IVT+MT group and 129 min and 51 min in the MT alone group. Overall, there was no significant interaction between OTN and bridging IVT assignment regarding either the functional (adjusted OR (aOR) 0.76, 95% CI 0.45 to 1.30) and safety outcomes or the recanalization rates. Analysis of in-hospital delays showed no significant interaction between DTN and bridging IVT assignment regarding the dichotomized functional outcome (aOR 0.48, 95% CI 0.14 to 1.62), but the shift and mortality analyses suggested a greater benefit of IVT when in-hospital delays were short. CONCLUSIONS: We found no evidence that the effect of bridging IVT on functional independence is modified by overall or in-hospital treatment delays. Considering its low power, this subgroup analysis could have missed a clinically important effect, and exploratory analysis of secondary clinical outcomes indicated a potentially favorable effect of IVT with shorter in-hospital delays. Heterogeneity of the IVT effect size before MT should be further analyzed in individual patient meta-analysis of comparable trials. TRIAL REGISTRATION NUMBER: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03192332.

Effect of intravenous thrombolysis before endovascular therapy on outcome according to collateral status: insight from the ETIS Registry.

BACKGROUND: It is unknown whether collateral status modifies the effect of pretreatment intravenous thrombolysis (IVT) on the outcomes of patients with large vessel occlusions treated with endovascular therapy (EVT). We aimed to assess whether collateral status modifies the effect of IVT on the outcomes of EVT in clinical practice. METHODS: We used data from the ongoing prospective multicentric Endovascular Treatment in Ischemic Stroke (ETIS) Registry in France. Patients with anterior circulation proximal large vessel occlusions treated with EVT within 6 hours of symptom onset were enrolled. Patients were divided into two groups based on pretreatment with IVT. The two groups were matched based on baseline characteristics. We tested the interaction between collateral status and IVT in unadjusted and adjusted models. RESULTS: A total of 1589 patients were enrolled in the study, of whom 55% received IVT. Using a propensity score matching method, 724 no IVT patients were matched to 549 IVT patients. In propensity score weighted analysis, IVT was associated with higher odds of early neurological improvement (OR 1.74; 95% CI 1.33 to 2.26), favorable functional outcome (OR 1.66; 95% CI 1.23 to 2.24), excellent functional outcome (OR 2.04; 95% CI 1.47 to 2.83), and successful reperfusion (OR 2.18; 95% CI 1.51 to 3.16). IVT was not associated with mortality or hemorrhagic complications. There was no interaction between collateral status and IVT association with any of the outcomes. CONCLUSIONS: Collateral status does not modify the effect of pretreatment IVT on the efficacy and safety outcomes of EVT.

Poor clinical outcome despite successful basilar occlusion recanalization in the early time window: incidence and predictors.

BACKGROUND: Endovascular treatment (EVT) for basilar artery occlusions (BAO) is associated with a higher rate of futile recanalization compared with anterior circulation procedures. We aimed to identify the incidence and predictors of poor clinical outcome despite successful reperfusion in current clinical practice. METHODS: We used data from the ETIS (Endovascular Treatment in Ischemic Stroke) registry, a prospective multicenter observational registry of stroke treated with EVT in France. Patients undergoing EVT for acute BAO from January 2014 to May 2019 successfully treated within 8 hours from onset were included. Predictors of 90-day poor outcome (modified Rankin Scale (mRS) 4-6) were researched within patients with successful (modified Thrombolysis In Cerebral Infarction (mTICI 2b-3)) and excellent (mTICI 2c-3) reperfusion. RESULTS: Among 242 patients treated within 8 hours, successful reperfusion was achieved in 195 (80.5%) and excellent reperfusion in 120 (49.5%). Poor outcome was observed in 107 (54.8%) and 60 (50%) patients, respectively. In patients with successful early reperfusion, age, higher initial National Institutes of Health Stroke Scale (NIHSS) score, lower posterior circulation Alberta Stroke Programme Early CT Score (pc-ASPECTS), and absence of prior intravenous thrombolysis were independent predictors of poor outcome. The only treatment factor with an independent predictive value was first-pass mTICI 2b-3 reperfusion (adjusted OR 0.13, 95% CI 0.05 to 0.37, p<0.001). In patients with excellent early reperfusion, independent predictors were age, initial NIHSS score, first-pass mTICI 2c-3 reperfusion, and hemorrhagic transformation on post-interventional imaging. CONCLUSIONS: Early successful reperfusion with EVT occurred in 80.5% of patients, and the only treatment-related factor predictive of clinical outcome was first pass mTICI 2b-3 reperfusion. Further research is warranted to identify the optimal techniques and devices associated with first pass reperfusion in the posterior circulation.

Thrombectomy in basilar artery occlusions: impact of number of passes and futile reperfusion.

BACKGROUND: The number of mechanical thrombectomy (MT) passes is strongly associated with angiographic reperfusion as well as clinical outcomes in patients with anterior circulation ischemic stroke. However, these associations have not been analyzed in patients with basilar artery occlusion (BAO). We investigated the influence of the number of MT passes on the degree of reperfusion and clinical outcomes, and compared outcome after ≤3 passes versus >3 passes. METHODS: We used data from the prospective multicentric Endovascular Treatment in Ischemic Stroke (ETIS) Registry at 18 sites in France. Patients with BAO treated with MT were included. The primary outcome was a favorable outcome, defined as a modified Rankin Scale score of 0-3 at 90 days. We fit mixed multiple regression models, with center as a random effect. RESULTS: We included 275 patients. Successful recanalization (modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3) was achieved in 88.4%, and 41.8% had a favorable outcome. The odds ratio for favorable outcome with each pass above 1 was 0.41 (95% CI 0.23 to 0.73) and for recanalization (mTICI 2b-3) it was 0.70 (95% CI 0.57 to 0.87). In patients with ≤3 passes, the rate of favorable outcome in recanalized versus non-recanalized patients was 50.5% versus 10.0% (p=0.001), while in those with >3 passes it was 16.7% versus 15.2% (p=0.901). CONCLUSIONS: We found that BAO patients had a significant relationship between the number of MT passes and both recanalization and favorable functional outcome. We further found that the benefit of recanalization in BAO patients was significant only when recanalization was achieved within three passes, encouraging at least three passes before stopping the procedure.

Prevalence and characterization of cerebral small vessel disease in young adults with intracerebral hemorrhage.

BACKGROUND AND AIMS: Cerebral small vessel disease (CSVD) is the main cause of intracerebral hemorrhage (ICH) in older individuals but has not been systematically studied in younger people. We aimed to evaluate the prevalence and characteristics of CSVD in young adults with symptomatic ICH. METHODS: We conducted a cohort study of consecutive adults aged 18-50 years with non-traumatic ICH. All patients were evaluated with brain and vascular imaging. Using validated imaging markers (cerebral microbleeds (CMBs), white matter hyperintensities and/or lacunes), patients were categorized as having CSVD-related ICH or non-CSVD-related ICH. Factors associated with CSVD were evaluated using multivariable analyses. CSVD subtypes were characterized using pre-specified criteria. RESULTS: Of 146 young adults with ICH (mean age = 37.7), CSVD was present in 41 patients (28.1%; 95% confidence interval (CI) = 21.0-36.1). In multivariable analysis, older age, male sex, and hypertension were independently associated with the presence of CSVD. Deep perforator arteriopathy (48.8%) and mixed CSVD (31.7%) were the most common CSVD subtypes. CONCLUSION: Our results suggest that CSVD is a frequent cause of ICH in young adults and provide new insights into the characterization of the disease. These findings may have important implications since the treatment and management differ from other causes of ICH.

Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial.

BACKGROUND: Whether thrombectomy alone is equally as effective as intravenous alteplase plus thrombectomy remains controversial. We aimed to determine whether thrombectomy alone would be non-inferior to intravenous alteplase plus thrombectomy in patients presenting with acute ischaemic stroke. METHODS: In this multicentre, randomised, open-label, blinded-outcome trial in Europe and Canada, we recruited patients with stroke due to large vessel occlusion confirmed with CT or magnetic resonance angiography admitted to endovascular centres. Patients were randomly assigned (1:1) via a centralised web server using a deterministic minimisation method to receive stent-retriever thrombectomy alone or intravenous alteplase plus stent-retriever thrombectomy. In both groups, thrombectomy was initiated as fast as possible with any commercially available Solitaire stent-retriever revascularisation device (Medtronic, Irvine, CA, USA). In the combined treatment group, intravenous alteplase (0·9 mg/kg bodyweight, maximum dose 90 mg per patient) was administered as early as possible after randomisation for 60 min with 10% of the calculated dose given as an initial bolus. Personnel assessing the primary outcome were masked to group allocation; patients and treating physicians were not. The primary binary outcome was a score of 2 or less on the modified Rankin scale at 90 days. We assessed the non-inferiority of thrombectomy alone versus intravenous alteplase plus thrombectomy in all randomly assigned and consenting patients using the one-sided lower 95% confidence limit of the Mantel-Haenszel risk difference, with a prespecified non-inferiority margin of 12%. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. This trial is registered with ClinicalTrials.gov, NCT03192332, and is closed to new participants. FINDINGS: Between Nov 29, 2017, and May 7, 2021, 5215 patients were screened and 423 were randomly assigned, of whom 408 (201 thrombectomy alone, 207 intravenous alteplase plus thrombectomy) were included in the primary efficacy analysis. A modified Rankin scale score of 0-2 at 90 days was reached by 114 (57%) of 201 patients assigned to thrombectomy alone and 135 (65%) of 207 patients assigned to intravenous alteplase plus thrombectomy (adjusted risk difference -7·3%, 95% CI -16·6 to 2·1, lower limit of one-sided 95% CI -15·1%, crossing the non-inferiority margin of -12%). Symptomatic intracranial haemorrhage occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy (risk difference -1·0%, 95% CI -4·8 to 2·7). Successful reperfusion was less common in patients assigned to thrombectomy alone (182 [91%] of 201 vs 199 [96%] of 207, risk difference -5·1%, 95% CI -10·2 to 0·0, p=0·047). INTERPRETATION: Thrombectomy alone was not shown to be non-inferior to intravenous alteplase plus thrombectomy and resulted in decreased reperfusion rates. These results do not support omitting intravenous alteplase before thrombectomy in eligible patients. FUNDING: Medtronic and University Hospital Bern.

The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI-neuropathology diagnostic accuracy study.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid ß in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations. METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy. FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard. INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations. FUNDING: US National Institutes of Health (R01 AG26484).