Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial.

RATIONALE: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. AIMS: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. METHODS AND DESIGN: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. STUDY OUTCOMES: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. SAMPLE SIZE: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. DISCUSSION: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31.

Microglial TNFR2 signaling regulates the inflammatory response after CNS injury in a sex-specific fashion.

Microglia, the resident immune cells of the central nervous system (CNS), play a major role in damage progression and tissue remodeling after acute CNS injury, including ischemic stroke (IS) and spinal cord injury (SCI). Understanding the molecular mechanisms regulating microglial responses to injury may thus reveal novel therapeutic targets to promote CNS repair. Here, we investigated the role of microglial tumor necrosis factor receptor 2 (TNFR2), a transmembrane receptor previously associated with pro-survival and neuroprotective responses, in shaping the neuroinflammatory environment after CNS injury. By inducing experimental IS and SCI in Cx3cr1CreER:Tnfrsf1bfl/fl mice, selectively lacking TNFR2 in microglia, and corresponding Tnfrsf1bfl/fl littermate controls, we found that ablation of microglial TNFR2 significantly reduces lesion size and pro-inflammatory cytokine levels, and favors infiltration of leukocytes after injury. Interestingly, these effects were paralleled by opposite sex-specific modifications of microglial reactivity, which was found to be limited in female TNFR2-ablated mice compared to controls, whereas it was enhanced in males. In addition, we show that TNFR2 protein levels in the cerebrospinal fluid (CSF) of human subjects affected by IS and SCI, as well as healthy donors, significantly correlate with disease stage and severity, representing a valuable tool to monitor the inflammatory response after acute CNS injury. Hence, these results advance our understanding of the mechanisms regulating microglia reactivity after acute CNS injury, aiding the development of sex- and microglia-specific, personalized neuroregenerative strategies.

Predictors of functional outcome after thrombectomy for M2 occlusions: a large scale experience from clinical practice.

Mechanical thrombectomy (MT) for acute ischemic stroke with medium vessel occlusions is still a matter of debate. We sought to identify factors associated with clinical outcome after MT for M2-occlusions based on data from the German Stroke Registry-Endovascular Treatment (GSR-ET). All patients prospectively enrolled in the GSR-ET from 05/2015 to 12/2021 were analyzed (NCT03356392). Inclusion criteria were primary M2-occlusions and availability of relevant clinical data. Factors associated with excellent/good outcome (modified Rankin scale mRS 0-1/0-2), poor outcome/death (mRS 5-6) and mRS-increase pre-stroke to day 90 were determined in multivariable logistic regression. 1348 patients were included. 1128(84%) had successful recanalization, 595(44%) achieved good outcome, 402 (30%) had poor outcome. Successful recanalization (odds ratio [OR] 4.27 [95% confidence interval 3.12-5.91], p < 0.001), higher Alberta stroke program early CT score (OR 1.25 [1.18-1.32], p < 0.001) and i.v. thrombolysis (OR 1.28 [1.07-1.54], p < 0.01) increased probability of good outcome, while age (OR 0.95 [0.94-0.95], p < 0.001), higher pre-stroke-mRS (OR 0.36 [0.31-0.40], p < 0.001), higher baseline NIHSS (OR 0.89 [0.88-0.91], p < 0.001), diabetes (OR 0.52 [0.42-0.64], p < 0.001), higher number of passes (OR 0.75 [0.70-0.80], p < 0.001) and intracranial hemorrhage (OR 0.26 [0.14-0.46], p < 0.001) decreased the probability of good outcome. Additional predictors of mRS-increase pre-stroke to 90d were dissections, perforations (OR 1.59 [1.11-2.29], p < 0.05) and clot migration, embolization (OR 1.67 [1.21-2.30], p < 0.01). Corresponding to large-vessel-occlusions, younger age, low pre-stroke-mRS, low severity of acute clinical disability, i.v. thrombolysis and successful recanalization were associated with good outcome while diabetes and higher number of passes decreased probability of good outcome after MT in M2 occlusions. Treatment related complications increased probability of mRS increase pre-stroke to 90d.

Thrombectomy for M2 Occlusions: Predictors of Successful and Futile Recanalization.

BACKGROUND: Patient-specific factors associated with successful recanalization in mechanical thrombectomy (MT) have been evaluated for acute ischemic stroke with large vessel occlusion. However, MT for M2 occlusions is still a matter of debate, and predictors of successful and futile recanalization have not been assessed in detail. We sought to identify predictors of recanalization success in patients with M2 occlusions undergoing MT based on large-scale clinical data. METHODS: All patients prospectively enrolled in the German Stroke Registry (May, 2015 to December, 2021) were screened (N=13 082). Inclusion criteria for the complete case analysis were isolated M2 occlusions. Standard descriptive statistics and multivariable logistic regression analysis were used to identify factors associated with successful recanalization (Thrombolysis in Cerebral Infarction [TICI]≥2b), complete recanalization (TICI=3) and futile recanalization (TICI≥2b with 90-day modified Rankin Scale [mRS] score >2). RESULTS: One thousand two hundred ninety-four patients were included, thereof 439 (33.9%) with TICI=2b and 643 (49.7%) with TICI=3. Five hundred sixty-nine (44%) patients had good functional outcome (90-day mRS score ≤2). In multivariable logistic regression, general anesthesia (adjusted odds ratio [aOR], 1.47 [95% CI, 1.05-2.09]; P<0.05) was associated with higher probability of TICI≥2b while intraprocedural change from local to general anesthesia (aOR, 0.49 [0.26-0.95]; P<0.05) and higher pre-mRS (aOR, 0.75 [0.67-0.85]; P<0.001) lowered probability of successful recanalization. Futile recanalization was associated with higher age (aOR, 1.05 [1.04-1.07]; P<0.001), higher prestroke mRS (aOR, 3.12 [2.49-3.91]; P<0.001), higher NIHSS at admission (aOR, 1.11 [1.08-1.14]; P<0.001), diabetes (aOR, 1.96 [1.38-2.8]; P<0.001), higher number of passes (aOR, 1.29 [1.14-1.46]; P<0.001), and adverse events (aOR, 1.82 [1.2-2.74]; P<0.01). Higher Alberta Stroke Program Early CT Score (aOR, 0.85 [0.76-0.94]; P<0.01) and IV thrombolysis (aOR, 0.71 [0.52-0.97]; P<0.05) reduced risk of futile recanalization. CONCLUSIONS: In patients with M2 occlusions, successful recanalization was significantly associated with general anesthesia and low prestroke mRS, while intraprocedural change from conscious sedation to general anesthesia increased risk of unsuccessful recanalization, presumably caused by difficult anatomy and movement of patients in these cases. Futile recanalization was associated with severe prestroke mRS, comorbidity diabetes, number of passes and adverse events during treatment. IV thrombolysis reduced the risk of futile recanalization.

Association Between Recanalization Attempts and Functional Outcome After Thrombectomy for Large Ischemic Stroke.

BACKGROUND: Recently, 3 randomized controlled trials provided high-level evidence that patients with large ischemic stroke achieved better functional outcomes after endovascular therapy than with medical care alone. We aimed to investigate whether the clinical benefit of endovascular therapy is associated with the number of recanalization attempts in extensive baseline infarction. METHODS: This retrospective multicenter study enrolled patients from the German Stroke Registry who underwent endovascular therapy for anterior circulation large vessel occlusion between 2015 and 2021. Large ischemic stroke was defined as an Alberta Stroke Program Early Computed Tomography Score of 3 to 5. The study cohort was divided into patients with unsuccessful reperfusion (Thrombolysis in Cerebral Infarction score, 0-2a) and successful reperfusion (Thrombolysis in Cerebral Infarction score, 2b/3) at attempts 1, 2, 3, or ≥4. The primary outcome was favorable functional outcome defined as modified Rankin Scale score of 0 to 3 at 90 days. Safety outcomes were symptomatic intracranial hemorrhage after 24 hours and death within 90 days. Multivariable logistic regression was used to identify independent determinants of primary and secondary outcomes. RESULTS: A total of 348 patients met the inclusion criteria. Successful reperfusion was observed in 83.3% and favorable functional outcomes in 36.2%. Successful reperfusion at attempts 1 (adjusted odds ratio, 5.97 [95% CI, 1.71-24.43]; P=0.008) and 2 (adjusted odds ratio, 6.32 [95% CI, 1.73-26.92]; P=0.008) increased the odds of favorable functional outcome, whereas success at attempts 3 or ≥4 did not. Patients with >2 attempts showed higher rates of symptomatic intracranial hemorrhage (12.8% versus 6.5%; P=0.046). Successful reperfusion at any attempt lowered the odds of death compared with unsuccessful reperfusion. CONCLUSIONS: In patients with large vessel occlusion and Alberta Stroke Program Early Computed Tomography Score of 3 to 5, the clinical benefit of endovascular therapy was linked to the number of recanalization attempts required for successful reperfusion. Our findings encourage to perform at least 2 recanalization attempts to seek for successful reperfusion in large ischemic strokes, while >2 attempts should follow a careful risk-benefit assessment in these highly affected patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03356392.

Association Between Intravenous Thrombolysis and Clinical Outcomes Among Patients With Ischemic Stroke and Unsuccessful Mechanical Reperfusion.

Importance: Clinical evidence of the potential treatment benefit of intravenous thrombolysis preceding unsuccessful mechanical thrombectomy (MT) is scarce. Objective: To determine whether intravenous thrombolysis (IVT) prior to unsuccessful MT improves functional outcomes in patients with acute ischemic stroke. Design, Setting, and Participants: Patients were enrolled in this retrospective cohort study from the prospective, observational, multicenter German Stroke Registry-Endovascular Treatment between May 1, 2015, and December 31, 2021. This study compared IVT plus MT vs MT alone in patients with acute ischemic stroke due to anterior circulation large-vessel occlusion in whom mechanical reperfusion was unsuccessful. Unsuccessful mechanical reperfusion was defined as failed (final modified Thrombolysis in Cerebral Infarction grade of 0 or 1) or partial (grade 2a). Patients meeting the inclusion criteria were matched by treatment group using 1:1 propensity score matching. Interventions: Mechanical thrombectomy with or without IVT. Main Outcomes and Measures: Primary outcome was functional independence at 90 days, defined as a modified Rankin Scale score of 0 to 2. Safety outcomes were the occurrence of symptomatic intracranial hemorrhage and death. Results: After matching, 746 patients were compared by treatment arms (median age, 78 [IQR, 68-84] years; 438 women [58.7%]). The proportion of patients who were functionally independent at 90 days was 68 of 373 (18.2%) in the IVT plus MT and 42 of 373 (11.3%) in the MT alone group (adjusted odds ratio [AOR], 2.63 [95% CI, 1.41-5.11]; P = .003). There was a shift toward better functional outcomes on the modified Rankin Scale favoring IVT plus MT (adjusted common OR, 1.98 [95% CI, 1.35-2.92]; P < .001). The treatment benefit of IVT was greater in patients with partial reperfusion compared with failed reperfusion. There was no difference in symptomatic intracranial hemorrhages between treatment groups (AOR, 0.71 [95% CI, 0.29-1.81]; P = .45), while the death rate was lower after IVT plus MT (AOR, 0.54 [95% CI, 0.34-0.86]; P = .01). Conclusions and Relevance: These findings suggest that prior IVT was safe and improved functional outcomes at 90 days. Partial reperfusion was associated with a greater treatment benefit of IVT, indicating a positive interaction between IVT and MT. These results support current guidelines that all eligible patients with stroke should receive IVT before MT and add a new perspective to the debate on noninferiority of combined stroke treatment.

How much of the outcome improvement after successful recanalization is explained by follow-up infarct volume reduction?

BACKGROUND: Follow-up infarct volume (FIV) is used as surrogate for treatment efficiency in mechanical thrombectomy (MT). However, previous works suggest that MT-related FIV reduction has only limited association with outcome comparing MT independently of recanalization success versus medical care. It remains unclear to what extent the relationship between successful recanalization versus persistent occlusion and functional outcome is explained by FIV reduction. OBJECTIVE: To determine whether FIV mediates the relationship between successful recanalization and functional outcome. METHODS: All patients from our institution enrolled in the German Stroke Registry (May 2015-December 2019) with anterior circulation stroke; availability of the relevant clinical data, and follow-up-CT were analyzed. The effect of FIV reduction on functional outcome (90-day modified Rankin Scale (mRS) score ≤2) after successful recanalization (Thrombolysis in Cerebral Infarction ≥2b) was quantified using mediation analysis. RESULTS: 429 patients were included, of whom, 309 (72 %) had successful recanalization and 127 (39%) had good functional outcome. Good outcome was associated with age (OR=0.89, P<0.001), pre-stroke mRS score (OR=0.38, P<0.001), FIV (OR=0.98, P<0.001), hypertension (OR=2.08, P<0.05), and successful recanalization (OR=3.57, P<0.01). Using linear regression in the mediator pathway, FIV was associated with Alberta Stroke program Early CT Score (coefficient (Co)=-26.13, P<0.001), admission National Institutes of Health Stroke Scale score (Co=3.69, P<0.001), age (Co=-1.18, P<0.05), and successful recanalization (Co=-85.22, P<0.001). Successful recanalization increased the probability of good outcome by 23 percentage points (pp) (95% CI 16pp to 29pp). 56% (95% CI 38% to 78%) of the improvement in good outcome was explained by FIV reduction. CONCLUSION: 56% (95% CI 38% to 78%) of outcome improvement after successful recanalization was explained by FIV reduction. Results corroborate pathophysiological assumptions and confirm the value of FIV as an imaging endpoint in clinical trials. 44% (95% CI 22% to 62%) of the improvement in outcome was not explained by FIV reduction and reflects the remaining mismatch between radiological and clinical outcome measures.

RCT versus real-world cohorts: Differences in patient characteristics drive associations with outcome after EVT.

Background: The selection of patients with large-vessel occlusion (LVO) stroke for endovascular treatment (EVT) depends on patient characteristics and procedural metrics. The relation of these variables to functional outcome after EVT has been assessed in numerous datasets from both randomized controlled trials (RCT) and real-world registries, but whether differences in their case mix modulate outcome prediction is unknown. Methods: We leveraged data from individual patients with anterior LVO stroke treated with EVT from completed RCTs from the Virtual International Stroke Trials Archive (N = 479) and from the German Stroke Registry (N = 4079). Cohorts were compared regarding (i) patient characteristics and procedural pre-EVT metrics, (ii) these variables' relation to functional outcome, and (iii) the performance of derived outcome prediction models. Relation to outcome (functional dependence defined by a modified Rankin Scale score of 3-6 at 90 days) was analyzed by logistic regression models and a machine learning algorithm. Results: Ten out of 11 analyzed baseline variables differed between the RCT and real-world cohort: RCT patients were younger, had higher admission NIHSS scores, and received thrombolysis more often (all p < 0.0001). Largest differences at the level of individual outcome predictors were observed for age (RCT: adjusted odds ratio (aOR), 1.29 (95% CI, 1.10-1.53) vs real-world aOR, 1.65 (95% CI, 1.54-1.78) per 10-year increments, p < 0.001). Treatment with intravenous thrombolysis was not significantly associated with functional outcome in the RCT cohort (aOR, 1.64 (95 % CI, 0.91-3.00)), but in the real-world cohort (aOR, 0.81 (95% CI, 0.69-0.96); p for cohort heterogeneity = 0.056). Outcome prediction was more accurate when constructing and testing the model using real-world data compared to construction with RCT data and testing on real-world data (area under the curve, 0.82 (95% CI, 0.79-0.85) vs 0.79 (95% CI, 0.77-0.80), p = 0.004). Conclusions: RCT and real-world cohorts considerably differ in patient characteristics, individual outcome predictor strength, and overall outcome prediction model performance.

Thrombectomy in M2 occlusion compared to M1 occlusion: treatment effects of Thrombolysis In Cerebral Infarction (TICI) 2b and TICI 3 recanalization on functional outcome.

BACKGROUND: Emerging data suggest that mechanical thrombectomy (MT) might also be safe and efficient for medium and distal occlusions. This study aims to compare average treatment effects on functional outcome of different degrees of recanalization after MT in patients with M2 occlusion and M1 occlusion. METHODS: All patients enrolled in the German Stroke Registry (GSR) between June 2015 and December 2021 were analyzed. Inclusion criteria were stroke with primary M1 occlusion or M2 occlusion, and availability of relevant clinical data. 4259 patients were included, thereof 1353 with M2 occlusion and 2906 with M1 occlusion. Treatment effects were analyzed using double-robust inverse-probability-weighted regression-adjustment (IPWRA) estimators to control for confounding covariates. Binarized endpoint metrics were defined as good outcome with modified Rankin Scale (mRS) ≤2 at 90 days, and linearized endpoint metrics were defined as mRS shift pre-stroke to 90 days. Effects were evaluated for near complete recanalization (Thrombolysis In Cerebral Infarction scale (TICI) 2b) and complete recanalization (TICI 3). RESULTS: Treatment effect estimation for TICI ≥2b versus TICI <2b in M2 occlusions showed an increase in the probability of a good outcome from 27% to 47% with a number-needed-to-treat (NNT) of 5. For M1 occlusions the probability of a good outcome increased from 16% to 38% with NNT 4.5. TICI 3 versus TICI 2b increased the probability of a good outcome by 7 percentage points in M1 occlusions; for M2 occlusions the beneficial effect was not significant. CONCLUSIONS: Results suggest that successful recanalization with TICI ≥2b versus TICI <2b after MT in M2 occlusions provides significant patient benefit with treatment effects comparable to M1 occlusions. The probability of functional independence increased by 20 percentage points (NNT 5) and stroke-related mRS increase was reduced by 0.9 mRS points. In contrast to M1 occlusions, complete recanalization TICI 3 versus TICI 2b had lower additional beneficial effect.

Benefit and risk of intravenous alteplase in patients with acute large vessel occlusion stroke and low ASPECTS.

BACKGROUND: The benefit of best medical treatment including intravenous alteplase (IVT) before mechanical thrombectomy (MT) in patients with acute ischemic stroke and extensive early ischemic changes on baseline CT remains uncertain. The purpose of this study was to evaluate the benefit of IVT for patients with low ASPECTS (Alberta Stroke Programme Early CT Score) compared with patients with or without MT. METHODS: This multicenter study pooled consecutive patients with anterior circulation acute stroke and ASPECTS≤5 to analyze the impact of IVT on functional outcome, and to compare bridging IVT with direct MT. Functional endpoints were the rates of good (modified Rankin Scale (mRS) score ≤2) and very poor (mRS ≥5) outcome at day 90. Safety endpoint was the occurrence of symptomatic intracranial hemorrhage (sICH). RESULTS: 429 patients were included. 290 (68%) received IVT and 168 (39%) underwent MT. The rate of good functional outcome was 14.4% (95% CI 7.1% to 21.8%) for patients who received bridging IVT and 24.4% (95% CI 16.5% to 32.2%) for those who underwent direct MT. The rate of sICH was significantly higher in patients with bridging IVT compared with direct MT (17.8% vs 6.4%, p=0.004). In multivariable logistic regression analysis, IVT was significantly associated with very poor outcome (OR 2.22, 95% CI 1.05 to 4.73, p=0.04) and sICH (OR 3.44, 95% CI 1.18 to 10.07, p=0.02). Successful recanalization, age, and ASPECTS were associated with good functional outcome. CONCLUSIONS: Bridging IVT in patients with low ASPECTS was associated with very poor functional outcome and an increased risk of sICH. The benefit of this treatment should therefore be carefully weighed in such scenarios. Further randomized controlled trials are required to validate our findings.

Endovascular treatment of acute tandem lesions in patients with mild anterior circulation stroke.

BACKGROUND: In patients with mild strokes the risk-benefit ratio of endovascular treatment (EVT) for tandem lesions has yet to be evaluated outside of current guideline recommendations. This study investigates the frequency as well as procedural and safety outcomes in daily clinical practice. METHODS: Using data from the German Stroke Registry-Endovascular Treatment (GSR-ET) we analyzed patients with anterior circulation stroke due to tandem-lesions and mild deficits. These patients were defined as ≤5 on the National Institutes of Health Stroke Scale (NIHSS). Recanalization was assessed with the modified Thrombolysis in Cerebral Infarction Scale (mTICI). Early neurological and long-term functional outcomes were assessed with the NIHSS change and modified Rankin scale (mRS), respectively. Safety assessment included periprocedural complications and the rate of symptomatic intracerebral hemorrhage (sICH). RESULTS: A total of 61 patients met the inclusion criteria and were treated endovascularly for tandem lesions. The median age was 68 (IQR:59-76) and 32.9% (20) were female. Patients were admitted to the hospital with a median NIHSS score of 4 (IQR:2-5) and a median Alberta Stroke Programme Early CT Score (ASPECTS) of 9 (IQR:8-10). Successful recanalization (mTICI 2b-3) was observed in 86.9% (53). NIHSS decreased non-significantly (p=0.382) from baseline to two points (IQR:1-9) at discharge. Excellent (mRS≤1) and favorable (mRS≤2) long-term functional outcome at 90-days was 55.8% (29) and 69.2% (36), respectively. Mortality rates at 90-days were 9.6% (5) and sICH occurred in 8.2% (5). CONCLUSIONS: EVT for tandem lesions in patients with mild anterior circulation stroke appears to be feasible but may lead to increased rates of sICH. Further studies comparing endovascular with best medical treatment (BMT) especially investigating the risk of periprocedural hemorrhagic complications, are needed.

Endovascular thrombectomy in young patients with stroke.

BACKGROUND: Endovascular treatment (ET) is standard of care in patients with acute ischemic stroke due to large vessel occlusion, but data on ET in young patients remain limited. AIM: We aim to compare outcomes for young stroke patients undergoing ET in a matched cohort. METHODS: We analyzed patients from an observational multicenter cohort with acute ischemic stroke and ET, the German Stroke Registry-Endovascular Treatment trial. Baseline characteristics, procedural parameters, and functional outcome at 90 days were compared between young (<50 years) and older (⩾50 years) patients with and without nearest-neighbor 1:1 propensity score matching. RESULTS: Out of 6628 acute ischemic stroke patients treated with ET, 363 (5.5%) were young. Young patients differed with regard to prognostic outcome characteristics. Specifically, National Institutes of Health Stroke Scale (NIHSS) at admission was lower (median 13, interquartile range (IQR) 8-17 vs. 15, IQR 9-19, p < 0.001), and prestroke dependence was less frequent (2.9% vs. 12.2%, p < 0.001) than in older patients. Compared to a matched cohort of older patients, ET was faster (time from groin puncture to flow restoration, 35 vs. 45 min, p < 0.001) and intracranial hemorrhage was less frequent in young patients (10.0% vs. 25.9%, p < 0.001). Good functional outcome (modified Rankin Scale (mRS) 0-2) at 3 months was achieved more frequently in young patients (71.6% vs. 44.1%, p < 0.001), and overall mortality was lower (6.7% vs. 25.4%, p < 0.001). Among previously employed young patients (n = 177), 37.9% returned to work at 3-month follow-up, while 74.1% of the remaining patients were still undergoing rehabilitation. CONCLUSION: Young stroke patients undergoing ET have better outcomes compared to older patients, even when matched for prestroke condition, comorbidities, and stroke severity. Hence, more liberal guidelines to perform ET for younger patients may have to be established by future studies.

Side matters: differences in functional outcome and quality of life after thrombectomy in left and right hemispheric stroke.

BACKGROUND: Patients with a left (LHS) or right hemispheric stroke (RHS) differ in terms of clinical symptoms due to lateralization of specific cortical functions. Studies on functional outcome after stroke and endovascular thrombectomy (EVT) comparing both hemispheres showed conflicting results so far. The impact of stroke laterality on patient-reported health-related quality of life (HRQoL) after EVT has not yet been adequately addressed and still remains unclear. METHODS: Consecutive stroke thrombectomy patients, derived from a multi-center, prospective registry (German Stroke Registry) between June 2015 and December 2019, were included in this study. At 90 days, outcome after EVT was assessed by the modified Rankin scale (mRS) and HRQoL using the European QoL-five dimensions questionnaire utility-index (EQ-5D-I; higher values indicate better HRQoL) in patients with LHS and RHS. Adjusted regression analysis was applied to evaluate the influence of stroke laterality on outcome after EVT. RESULTS: In total, 5683 patients were analyzed. Of these, 2953 patients (52.8%) had LHS and 2637 (47.2%) RHS. LHS patients had a higher baseline NIHSS (16 vs. 13, p < 0.001) and a higher ASPECTS (9 vs. 8, p < 0.001) compared to RHS patients. Among survivors, patients with LHS less frequently had a self-reported affected mobility (p = 0.037), suffered less often from pain (p = 0.04) and anxiety/depression (p = 0.032) three months after EVT. After adjusting for confounders (age, sex, baseline NIHSS), LHS was associated with a better HRQoL (ß coefficient 0.04, CI 95% 0.017-0.063; p = 0.001), and better functional outcome assessed by lower values on the mRS (ß coefficient - 0.109, CI 95% - 0.217-0.000; p = 0.049). CONCLUSIONS: Ninety days after EVT, LHS patients have a better functional outcome and HRQoL. Patients with RHS should be actively assessed and treated for pain, anxiety and depression to improve their HRQoL after EVT.

Association of Thrombectomy With Functional Outcome for Patients With Ischemic Stroke Who Presented in the Extended Time Window With Extensive Signs of Infarction.

Importance: Only limited data are available about a potential benefit associated with endovascular treatment (EVT) for patients with ischemic stroke presenting in the extended time window who also show signs of extensive infarction. Objective: To assess the association of recanalization after EVT with functional outcomes for patients with ischemic stroke presenting in the extended time window who also show signs of extensive infarction. Design, Setting, and Participants: This retrospective, multicenter cohort study included patients enrolled in the German Stroke Registry-Endovascular Treatment with an Alberta Stroke Program Early CT Score (ASPECTS) of 5 or less who presented between 6 and 24 hours after stroke onset and underwent computed tomography and subsequent EVT between July 1, 2015, and December 31, 2019. Main Outcomes and Measures: The primary end point was a modified Rankin Scale (mRS) score of 3 or less at day 90. The association between recanalization (defined as the occurrence of a modified Thrombolysis in Cerebral Infarction Scale score of 2b or 3) and outcome was assessed using logistic regression and inverse probability weighting analysis. Intervention: Endovascular treatment. Results: Of 5853 patients, 285 (5%; 146 men [51%]; median age, 73 years [IQR, 62-81 years]) met the inclusion criteria and were analyzed. Of these 285 patients, 79 (27.7%) had an mRS score of 3 or less at day 90. The rate of successful recanalization was 75% (215 of 285) and was independently associated with a higher probability of reaching an mRS score of 3 or less (adjusted odds ratio, 4.39; 95% CI, 1.79-10.72; P < .001). In inverse probability weighting analysis, a modified Thrombolysis in Cerebral Infarction Scale score of 2b or 3 was associated with a 19% increase (95% CI, 9%-29%; P < .001) in the probability for an mRS score of 3 or more. Multivariable logistic regression analysis suggested a significant treatment benefit associated with vessel recanalization in a time window of up to 17.6 hours and ASPECTS of 3 to 5. The rate of secondary symptomatic intracerebral hemorrhage was 6.3% (18 of 285). Conclusions and Relevance: In this cohort study reflecting daily clinical practice, vessel recanalization for patients with a low ASPECTS and extended time window was associated with better functional outcomes in a time window up to 17.6 hours and ASPECTS of 3 to 5. The results of this study encourage current randomized clinical trials to enroll patients with a low ASPECTS, even within the extended time window.

Continuing early mTICI 2b recanalization may improve functional outcome but is associated with a higher risk of intracranial hemorrhage.

Background: Successful reperfusion (mTICI 2c/3) and low number of passes are key determinants for good clinical outcome in acute large vessel occlusion. While final mTICI 2c/3 reperfusion is superior to partial reperfusion (mTICI 2b) it remains unclear if this is also true for the subgroup of patients with early mTICI 2b (achieved in ≤2 retrieval attempts) reperfusion who are secondarily improved to mTICI 2c/3. This study was designed to examine if early mTICI2b should be continued or stopped during mechanical thrombectomy (MT). Methods: Nine hundred and thirteen ischemic stroke patients who received MT were retrospectively analyzed. Angiography runs following each recanalization attempt were scored for mTICI. The patients with early mTICI 2b reperfusions were dichotomized in "TICI2b-stopped" (MT withdrawal after mTICI 2b was achieved with first or second retrieval) and "TICI2b-continued" (MT was continued after mTICI 2b was achieved with first or second retrieval). Functional outcome was obtained after 90 days using the modified Rankin scale (mRS90). Results: Of 362 Patients with a M1-occlusion, 100 patients fulfilled the inclusion criteria with an early mTICI 2b. 78/100 patients were included in the "TICI2b-stopped" group and 22/100 patients were in the "TICI2b-continued" group. Of these 22 patients, none had a final mTICI score lower than 2b and 11 patients had a final mTICI score of 2c/3. Regarding good functional outcome at mRS90, "TICI2b-continued" showed by trend a slight advantage of 40.1 vs. 35.6% in "TICI2b-stopped" but in multivariate logistic regression analysis adjusted for confounders, no significant difference was found between the two groups (OR 0.75, 95% CI 0.19-2.87, p = 0.67). Symptomatic intracranial hemorrhage was significantly higher in "TICI2b-continued" compared to "TICI2b-stopped" (31.8 vs. 10.3%, p = 0.031). Conclusion: Successfully improving an early mTICI 2b to mTICI 2c/3 reperfusion is possible in a substantial number of patients and might improve functional outcome. However, an increase in symptomatic intracranial hemorrhage (SICH) due to further retrieval attempts may diminish the potential functional benefit to continue early mTICI 2b. To support this finding, further investigation with more power is needed to account for the low number of events regarding SICH.

Early surrogates of outcome after thrombectomy in posterior circulation stroke.

BACKGROUND: Early surrogates for functional outcome in anterior circulation stroke have been described with the National Institute of Health Stroke Scale (NIHSS) at 24 h being reported as the most accurate metric. We compare discriminatory power of established definitions of early neurological improvement (ENI) and NIHSS scores at admission and 24 h to predict functional outcome at 90 days after thrombectomy in posterior circulation stroke (PCS). METHODS: All patients enrolled in the German Stroke Registry (June 2015-December 2019) with PCS and at least vertebral or basilar artery occlusions were included. NIHSS admission, 24 h and ENI definitions (improvement of 8/10 NIHSS points or 0/1 NIHSS points at 24 h) were compared for predicting functional outcome at 90 days. Favourable and good outcome were defined as modified Rankin Scale (mRS) 0-2 and 0-3. Multivariable logistic regression analysis was conducted to identify factors impairing predictive power. RESULTS: Three hundred and eighty-seven patients were included. NIHSS 24 h had the highest discriminative power with receiver operator characteristics area under the curve of 0.87 (95% confidence interval: 0.83; 0.90) for good and 0.89 (0.85; 0.92) for favourable outcome; optimal cut-off values were ≤9 and ≤5. Higher age (odds ratio = 1.10 [1.05; 1.16]), adverse events during treatment (9.46 [1.52; 72.5]) and until discharge (18.34 [2.33; 172]) and high NIHSS scores at 24 h (1.29 [1.10; 1.53]) were independent predictors for turning the outcome prognosis from good (mRS ≤3) to poor (mRS ≥4). CONCLUSIONS: NIHSS 24 h ≤9 points serves best as surrogate for good functional outcome after thrombectomy in PCS. Advanced age, severe neurological symptoms at admission and adverse events decrease its predictive value.

How Much of the Thrombectomy Related Improvement in Functional Outcome Is Already Apparent at 24 Hours and at Hospital Discharge?

BACKGROUND: Early neurological status has been described as predictor of functional outcome in patients with anterior circulation stroke after mechanical thrombectomy. It remains unclear to what proportion the improvement of functional outcome at day 90 is already apparent at 24 hours and at hospital discharge and how later factors impact outcome. METHODS: All patients enrolled in the German Stroke Registry (June 2015-December 2019) with anterior circulation stroke and availability of baseline data and neurological status were included. A mediation analysis was conducted to investigate the effect of successful recanalization (Thrombolysis in Cerebral Infarction scale score ≥2b) on good functional outcome (modified Rankin Scale score ≤2 at day 90) with mediation through neurological status (National Institutes of Health Stroke Scale [NIHSS] at 24 hours and at hospital discharge). RESULTS: Three thousand fifty-seven patients fulfilled the inclusion criteria, thereof 2589 (85%) with successful recanalization and 1180 (39%) with good functional outcome. In a multivariate logistic regression analysis, probability of good outcome was significantly associated with age (odds ratio [95% CI], 0.95 [0.94-0.96]), prestroke modified Rankin Scale (0.48 [0.42-0.55]), admission-NIHSS (0.96 [0.94-0.98]), 24-hour NIHSS (0.83 [0.81-0.84]), diabetes (0.56 [0.43-0.72]), proximal middle cerebral artery occlusions (0.78 [0.62-0.97]), passes (0.88 [0.82-0.95]), Alberta Stroke Program Early CT Score (1.07 [1.00-1.14]), successful recanalization (2.39 [1.68-3.43]), intracerebral hemorrhage (0.51 [0.35-0.73]), and recurrent strokes (0.54 [0.32-0.92]). Mediation analysis showed a 20 percentage points (95% CI' 17-24 percentage points) increase of probability of good functional outcome after successful recanalization. Fifty-four percent (95% CI' 44%-66%) of the improvement in functional outcome was explained by 24-hour NIHSS and 75% (95% CI' 62%-90%) by NIHSS at hospital discharge. CONCLUSIONS: Fifty-four percent of the improvement in functional outcome after successful recanalization is apparent in NIHSS at 24 hours, 75% in NIHSS at hospital discharge. Other unknown factors not apparent in NIHSS at the 2 time points investigated account for the remaining effect on long term outcome, suggesting, among others, clinical relevance of delayed neurological improvement and deterioration. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03356392.

Health-related quality of life after thrombectomy in young-onset versus older stroke patients: a multicenter analysis.

BACKGROUND: Information is lacking on self-reported health-related quality of life (HRQoL) as a complementary outcome measure in addition to the modified Rankin scale (mRS) in young patients with ischemic stroke after endovascular thrombectomy (EVT) compared with older patients. METHODS: Data on consecutive patients with stroke who underwent thrombectomy (June 2015-2019) from a multicenter prospective registry (German Stroke Registry) were analyzed. HRQoL was measured by the European QoL-5 dimension questionnaire utility index (EQ-5D-I; higher values indicate better HRQoL) 3 months after stroke in patients aged ≤55 and >55 years. Multivariate regression analyses identified predictors of better HRQoL. RESULTS: Of 4561 included patients, 526 (11.5%) were ≤55 years old. Young-onset patients had a better outcome assessed by mRS (mRS 0-2: 64.3% vs 31.8%, p<0.001) and EQ-5D-I (mean 0.639 vs 0.342, p<0.001). Young survivors after EVT had fewer complaints in the EQ-5D domains mobility (p<0.001), self-care (p<0.001), usual activities (p<0.001) and pain/discomfort (p=0.008), whereas no difference was observed in anxiety/depression (p=0.819). Adjusted regression analysis for 90-day mRS showed no difference in HRQoL between the two subgroups of patients. Lower age, National Institutes of Health Stroke Scale score and pre-stroke mRS, a higher Alberta Stroke Program Early CT Score, concomitant intravenous thrombolysis therapy and successful recanalization were associated with better HRQoL in both patient subgroups. CONCLUSIONS: Young-onset stroke patients have a better HRQoL after EVT than older patients. Their higher HRQoL is mainly explained by less physical disability assessed by mRS. Depressive symptoms should be actively assessed and targeted in rehabilitation therapies of young-onset stroke patients to improve quality of life after stroke.

Study Criteria Applied to Real Life-A Multicenter Analysis of Stroke Patients Undergoing Endovascular Treatment in Clinical Practice.

Background Randomized controlled clinical trials (RCT) have demonstrated the efficacy of endovascular treatment in anterior circulation large vessel occlusions. However, outcome of patients treated in daily practice differs from the results of the clinical trials. We hypothesize that this is attributable to the study criteria and that application of the criteria on patients undergoing endovascular therapy in daily routine would improve their outcome. Methods and Results Data from a multicenter prospective registry of GSR-ET (German Stroke Registry - Endovascular Treatment) was used. Inclusion criteria and selectivity of SWIFT-PRIME (Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment trial), MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands trial), ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times trial), DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo trial) and DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke trial) trials were analyzed. Baseline characteristics, procedural and outcome data of patients from GSR-ET before and after selection were compared with the results of the RCTs. Furthermore, outcome of patients who underwent endovascular treatment despite not fulfilling the RCT criteria was analyzed. A total of 2611 patients were included (median age, 75 years; 49.6% women; median National Institute of Health Stroke Scale, 16). A minority of patients met all inclusion criteria, ranging from 3% (DEFUSE-3 criteria) to 35% (MR CLEAN criteria). Of the patients fulfilling the MR CLEAN criteria, 41% of patients had a good clinical outcome, compared with 34% of patients that did not fulfill MR CLEAN criteria. Conclusions The RCTs represent a selected population with higher rates of good clinical outcome compared with daily practice. The good outcomes of RCTs can be reproduced in clinical routine in patients who fulfill the RCT inclusion criteria. Furthermore, patients who did not meet the criteria of the RCT still had substantial rates of good clinical outcome.