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.

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.

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.

Characterization of Extracranial Giant Cell Arteritis with Intracranial Involvement and its Rapidly Progressive Subtype.

OBJECTIVE: The objective of this study was to characterize patients with extracranial giant cell arteritis with intracranial involvement. METHODS: In a multicenter retrospective study, we included 31 patients with systemic giant cell arteritis (GCA) with intracranial involvement. Clinical characteristics, pattern of arterial involvement, and cytokine profiles were assessed. Patients with GCA without intracranial involvement (n = 17), and with intracranial atherosclerosis (n = 25) served as controls. RESULTS: Erythrocyte sedimentation rate (ESR) was elevated in 18 patients (69.2%) with and in 16 patients (100%) without intracranial involvement (p = 0.02). Headache was complained by 15 patients (50.0%) with and 13 patients (76.5%) without intracranial involvement (p = 0.03). Posterior circulation arteries were affected in 26 patients (83.9%), anterior circulation arteries in 17 patients (54.8%), and both territories in 12 patients (38.7%). Patients with GCA had vertebral artery stenosis proximal and, in contrast, patients with atherosclerosis distal to the origin of posterior inferior cerebellar artery (PICA). Among patients with GCA with intracranial involvement, 11 patients (37.9%) had a rapid progressive disease course characterized by short-term recurrent ischemic events. The median modified Rankin Scale (mRS) at follow-up in these patients was 4 (interquartile range [IQR] = 2.0-6.0) and 4 patients (36.4%) died. Vessel wall expression of IL-6 and IL-17 was significantly increased in patients with rapid progressive course. INTERPRETATION: Typical characteristics of GCA, headache, and an elevated ESR, are frequently absent in patients with intracranial involvement. However, differentiation of intracranial GCA from atherosclerosis can be facilitated by the typical pattern of vertebral artery stenosis. About one-third of patients with intracranial GCA had a rapid progressive course with poor outcome. IL-17 and IL-6 may represent potential future treatment targets. ANN NEUROL 2021;90:118-129.

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.

Number of Retrieval Attempts Rather Than Procedure Time Is Associated With Risk of Symptomatic Intracranial Hemorrhage.

Endovascular therapy is the standard of care in the treatment of acute ischemic stroke due to large-vessel occlusion. A direct association between the number of device passes and the occurrence of symptomatic intracranial hemorrhage (SICH) has been suggested. This study represents an in-depth investigation of the hypothesis that >3 retrieval attempts is associated with an increased rate of SICH in a large multicenter patient cohort. Two thousand six hundred eleven patients from the prospective German Stroke Registry were analyzed. Patients who received Endovascular therapy for acute large-vessel occlusion of the anterior circulation with known admission National Institutes of Health Stroke Scale and Alberta Stroke Program Early CT Score, final Thrombolysis in Cerebral Infarction, and number of retrieval passes were included. The primary outcome was defined as SICH. The secondary outcome was any type of radiologically confirmed intracranial hemorrhage within the first 24 hours. Multivariate mixed-effects models were used to adjust for cluster effects of the participating centers, as well as for confounders. Five hundred ninety-three patients fulfilled the inclusion criteria. The median number of retrieval passes was 2 [interquartile range, 1­3]. SICH occurred in 26 cases (4.4%), whereas intracranial hemorrhage was identified by neuroimaging in 85 (14.3%) cases. More than 3 retrieval passes was the strongest predictor for SICH (odds ratio, 3.61 [95% CI, 1.38­9.42], P=0.0089) following adjustment for age, admission National Institutes of Health Stroke Scale, admission Alberta Stroke Program Early CT Score, and Thrombolysis in Cerebral Infarction, as well as time from symptom onset to flow restoration. Baseline Alberta Stroke Program Early CT Score of 8 to 9 (odds ratio, 0.26 [95% CI, 0.07­0.89], P=0.032) or 10 (odds ratio, 0.21 [95% CI, 0.06­0.78], P=0.020) were significant protective factors against the occurrence of SICH. More than 3 retrieval attempts is associated with a significant increase in SICH risk, regardless of patient age, baseline National Institutes of Health Stroke Scale, or procedure time. This should be considered when deciding whether to continue a procedure, especially in patients with large baseline infarctions. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356392.

Good Clinical Outcome Decreases With Number of Retrieval Attempts in Stroke Thrombectomy: Beyond the First-Pass Effect.

BACKGROUND AND PURPOSE: Endovascular therapy is the standard of care in the treatment of acute ischemic stroke due to large-vessel occlusion. Often, more than one retrieval attempt is needed to achieve reperfusion. We aimed to quantify the influence of endovascular therapy on clinical outcome depending on the number of retrievals needed for successful reperfusion in a large multi-center cohort. METHODS: For this observational cohort study, 2611 patients from the prospective German Stroke Registry included between June 2015 and April 2018 were analyzed. Patients who received endovascular therapy for acute anterior circulation stroke with known admission National Institutes of Health Stroke Scale score and Alberta Stroke Program Early CT Score, final Thrombolysis in Cerebral Infarction score, and number of retrievals were included. Successful reperfusion was defined as a Thrombolysis in Cerebral Infarction score of 2b or 3. The primary outcome was defined as functional independence (modified Rankin Scale score of 0-2) at day 90. Multivariate mixed-effects models were used to adjust for cluster effects of the participating centers and confounders. RESULTS: The inclusion criteria were met by 1225 patients. The odds of good clinical outcome decreased with every retrieval attempt required for successful reperfusion: the first retrieval had the highest odds of good clinical outcome (adjusted odds ratio, 6.45 [95% CI, 4.0-10.4]), followed by the second attempt (adjusted odds ratio, 4.56 [95% CI, 2.7-7.7]), and finally the third (adjusted odds ratio, 3.16 [95% CI, 1.8-5.6]). CONCLUSIONS: Successful reperfusion within the first 3 retrieval attempts is associated with improved clinical outcome compared with patients without reperfusion. We conclude that at least 3 retrieval attempts should be performed in endovascular therapy of anterior circulation strokes. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03356392.

Endovascular Treatment for Acute Stroke in Cerebral Amyloid Angiopathy.

Background and Purpose: We aimed to compare outcome of endovascular thrombectomy in acute ischemic stroke in patients with and without cerebral amyloid angiopathy (CAA). Methods: We included patients with and without possible or probable CAA based on the modified Boston criteria from an observational multicenter cohort of patients with acute ischemic stroke and endovascular thrombectomy, the German Stroke Registry Endovascular Treatment trial. We analyzed baseline characteristics, procedural parameters, and functional outcome after 90 days. Results: Twenty-eight (17.3%) of 162 acute ischemic stroke patients were diagnosed with CAA based on iron-sensitive magnetic resonance imaging performed before endovascular thrombectomy. CAA patients were less likely to have a good 90-day outcome (14.3 versus 37.8%). National Institutes of Health Stroke Scale score (adjusted odds ratio, 0.88; P<0.001), successful recanalization (adjusted odds ratio 6.82; P=0.005), and CAA (adjusted odds ratio 0.28; P=0.049) were independent outcome predictors. Intravenous thrombolysis was associated with an increased rate of good outcome (36.3% versus 0%, P=0.031) in CAA. Conclusions: Endovascular thrombectomy with or without thrombolysis appears beneficial in acute ischemic stroke patients with possible or probable CAA, but is associated with a worse functional outcome. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356392.

Thrombectomy in Extensive Stroke May Not Be Beneficial and Is Associated With Increased Risk for Hemorrhage.

Background and Purpose: This study evaluates the benefit of endovascular treatment (EVT) for patients with extensive baseline stroke compared with best medical treatment. Methods: This retrospective, multicenter study compares EVT and best medical treatment for computed tomography (CT)­based selection of patients with extensive baseline infarcts (Alberta Stroke Program Early CT Score ≤5) attributed to anterior circulation stroke. Patients were selected from the German Stroke Registry and 3 tertiary stroke centers. Primary functional end points were rates of good (modified Rankin Scale score of ≤3) and very poor outcome (modified Rankin Scale score of ≥5) at 90 days. Secondary safety end point was the occurrence of symptomatic intracerebral hemorrhage. Angiographic outcome was evaluated with the modified Thrombolysis in Cerebral Infarction Scale. Results: After 1:1 pair matching, a total of 248 patients were compared by treatment arm. Good functional outcome was observed in 27.4% in the EVT group, and in 25% in the best medical treatment group (P=0.665). Advanced age (adjusted odds ratio, 1.08 [95% CI, 1.05­1.10], P<0.001) and symptomatic intracerebral hemorrhage (adjusted odds ratio, 6.35 [95% CI, 2.08­19.35], P<0.001) were independently associated with very poor outcome. Mortality (43.5% versus 28.9%, P=0.025) and symptomatic intracerebral hemorrhage (16.1% versus 5.6%, P=0.008) were significantly higher in the EVT group. The lowest rates of good functional outcome (≈15%) were observed in groups of failed and partial recanalization (modified Thrombolysis in Cerebral Infarction Scale score of 0/1­2a), whereas patients with complete recanalization (modified Thrombolysis in Cerebral Infarction Scale score of 3) with recanalization attempts ≤2 benefitted the most (modified Rankin Scale score of ≤3:42.3%, P=0.074) compared with best medical treatment. Conclusions: In daily clinical practice, EVT for CT­based selected patients with low Alberta Stroke Program Early CT Score anterior circulation stroke may not be beneficial and is associated with increased risk for hemorrhage and mortality, especially in the elderly. However, first- or second-pass complete recanalization seems to reveal a clinical benefit of EVT highlighting the vulnerability of the low Alberta Stroke Program Early CT Score subgroup. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356392.

Early clinical surrogates for outcome prediction after stroke thrombectomy in daily clinical practice.

BACKGROUND AND PURPOSE: To investigate early clinical surrogates for long-term independency of patients treated with thrombectomy for large vessel occlusion stroke in daily clinical routine. METHODS: All patients with anterior circulation stroke enrolled in the German Stroke Registry-Endovascular Treatment from 07/2015 to 04/2018 were analysed. National Institute of Health Stroke Scale (NIHSS) on admission, NIHSS percentage change, NIHSS delta and NIHSS at 24 hours as well as existing binary definitions of early neurological improvement (ENI; improvement of 8 (major ENI)/10 (dramatic ENI) NIHSS points or reaching 0/1 were compared for predicting functional outcome at 90 days using the modified Rankin Scale (mRS). Excellent and favourable outcome were defined as 0-1 and 0-2, respectively. RESULTS: Among 2262 endovasculary treated patients with acute ischaemic anterior circulation stroke, NIHSS at 24 hours had the highest discriminative ability to predict excellent (receiver operator characteristics (ROC)NIHSS 24 hours area under the curve (AUC) 0.86 (0.84-0.88)) and favourable long-term functional outcome (ROCNIHSS 24 hours AUC 0.86 (0.85-0.88)) in comparison to NIHSS percentage change (ROC% change AUC mRS ≤1: 0.81 (0.78-0.83) mRS ≤2: 0.81 (0.79-0.83)), NIHSS delta change (ROCΔ change AUC mRS ≤1: 0.74 (0.72-0.77), mRS ≤2: 0.77 (0.74-0.79)) and NIHSS admission (ROCAdm AUC mRS ≤1: 0.70 (0.68-0.73), mRS ≤2: 0.67 (0.68-0.71)). Advanced age was the only independent predictor (adjusted OR 1.05, 95% CI 1.03 to 1.07, p<0.001) for turning the outcome prognosis from favourable (mRS ≤2) to poor (mRS ≥4) at 90 days. CONCLUSION: The NIHSS at 24 hours postintervention with a threshold of ≤8 points serves best as a surrogate for long-term functional outcome after thrombectomy for anterior circulation stroke in daily clinical practice. Only advanced age significantly decreases its predictive value.

Stroke patients treated by thrombectomy in real life differ from cohorts of the clinical trials: a prospective observational study.

BACKGROUND: Randomized controlled trials (RCTs) demonstrated efficacy and safety of endovascular treatment (ET) in anterior circulation large vessel occlusions (LVO). We aimed at investigating how stroke patients treated by thrombectomy in clinical practice and their outcome compare to cohorts and results of thrombectomy trials. METHODS: In a prospective study, we consecutively included stroke patients treated by thrombectomy (2015-2017). Baseline characteristics, procedural and outcome data were analyzed. Outcome was assessed by modified Rankin Scale (mRS) at 90 days. Ordinal regression analysis was performed to identify predictors of outcome. RESULTS: Thrombectomy was applied in 264 patients (median 75 years, 49.6% female). Median baseline National Institutes of Health Stroke Scale (NIHSS) was 16, 58.0% received concomitant intravenous thrombolysis, 62.1% were referred from external hospitals. Median Alberta Stroke Program Early CT Score (ASPECTS) was 7. Successful recanalization (modified Thrombolysis in Cerebral Infarction Score, mTICI 2b/3) was achieved in 72.0%. Symptomatic intracranial hemorrhage (sICH) occurred in 4.5%. Independent outcome (mRS 0-2) was achieved in 26.2%, poor outcome (mRS 5-6) in 49.2%. Only 33.5% met the stringent enrolment criteria of previous RCTs. Lower age, baseline NIHSS, pre-stroke mRS, higher ASPECTS, and successful recanalization were independent predictors of favourable outcome. CONCLUSIONS: The majority of stroke patients treated by ET in clinical practice would not have qualified for randomization in prior RCTs. Outcome in real-life patient cohorts is worse than in the highly selected cohorts from randomized trials, while rates of successful recanalization, sICH and outcome predictors are the same. Our findings support ET in broader patient populations than in the RCTs and may improve treatment decision in individual stroke patients with LVO in clinical practice.

Highest Lesion Growth Rates in Patients With Hyperacute Stroke: When Time Is Brain Particularly Matters.

Background and Purpose- The early growth of ischemic lesions has been described as being nonlinear, with lesion growth rates at their highest during the earliest period after stroke onset. We hypothesized that the time gap from imaging to revascularization results in higher lesion growth in patients with hyperacute presentation. Methods- Fifty-one patients with ischemic stroke with initial multimodal computed tomography (CT), follow-up CT after 24 hours, and successful endovascular recanalization were included and separated into 2 groups according to their median time from symptom onset to imaging (eg, hyperacute versus acute). The difference in Alberta Stroke Program Early CT Score (ASPECTS) between initial CT and follow-up CT was assessed, as well as volumetric lesion growth from early ischemic core in admission perfusion CT and total lesion volume in follow-up CT. Results- The median time from onset to imaging was 1.85 hours. There was no significant difference in admission ASPECTS (mean, 8.5 versus 8.2) or time from imaging to recanalization in both groups (median, 2.7 versus 2.4 hours; P=0.4). The mean (SD) lesion growth assessed by ASPECTS difference was 2.7 (2.3) in the hyperacute group and 1.6 (1.3) in the acute group (P=0.03). The mean (SD) volumetric difference in the hyperacute group was 26.6 mL (43.2 mL) and 17.2 mL (26.3 mL; P=0.36) in the acute group, respectively. For every passing hour after onset, ASPECTS lesion growth was reduced by 0.4. Conclusions- Patients in the hyperacute phase showed increased ASPECTS lesion growth from imaging to recanalization suggesting a particular benefit of faster recanalization times in this group of patients with stroke.

Recanalization Rate per Retrieval Attempt in Mechanical Thrombectomy for Acute Ischemic Stroke.

Background and Purpose- In acute ischemic stroke, mechanical thrombectomy allows flow restoration in the majority of cases. In case of an unsuccessful retrieval, little is known about how many retrieval attempts should be performed before stopping the procedure. This study assessed the recanalization rate and clinical outcome per retrieval maneuver. Methods- In this analysis, 330 patients with acute large vessel occlusion treated exclusively with stentrieval devices were included. Successful recanalization was defined as Thrombolysis in Cerebral Infarction 2b-3, a good clinical outcome was defined as modified Rankin Scale at 90 days of ≤2. Results- The median number of retrieval attempts was 1 (interquartile range, 1-2, maximum 8). Recanalization rates per retrieval attempt were highest for the first retrieval (46.8%) and lowest for the fifth retrieval (22.7%). After 3 retrieval attempts, 67.9% of patients were successfully recanalized. Patients with 1 to 3 retrieval attempts had higher rates of good clinical outcome (28.9% versus 7.4%; P=0.018). The number of passes was an independent negative predictor of good clinical outcome (adjusted odds ratio, 0.65; 95% CI, 0.435-0.970; P=0.035). Conclusions- Two-thirds of occlusions were successfully recanalized with up to 3 retrieval attempts. Further attempts had good recanalization rates, but the rate of favorable clinical outcome did not improve.

Apolipoprotein E-ε4 deficiency and cognitive function in hepatitis C virus-infected patients.

Hepatitis C virus (HCV) causes not only liver damage in certain patients but can also lead to neuropsychiatric symptoms. Previous studies have shown that the type 4 allele of the gene for apolipoprotein E (APOE) is strongly protective against HCV-induced damage in liver. In this study, we have investigated the possibility that APOE genotype is involved in the action of HCV in brain. One hundred HCV-infected patients with mild liver disease underwent a neurological examination and a comprehensive psychometric testing of attention and memory function. In addition, patients completed questionnaires for the assessment of fatigue, health-related quality of life and mood disturbances. Apolipoprotein E gene genotyping was carried out on saliva using buccal swabs. The APOE-ε4 allele frequency was significantly lower in patients with an impairment of working memory, compared to those with a normal working memory test result (P = 0.003). A lower APOE-ε4 allele frequency was also observed in patients with definitely altered attention ability (P = 0.008), but here, the P-value missed the level of significance after application of the Bonferroni correction. Our data suggest that the APOE-ε4 allele is protective against attention deficit and especially against poor working memory in HCV-infected subjects with mild liver disease. Considering the role of apolipoprotein E in the life cycle of the virus, the findings shed interesting new light upon possible pathomechanisms behind the development of neuropsychiatric symptoms in hepatitis C infection.

Endovascular treatment of primary M3 occlusion stroke in clinical practice: analysis of the German Stroke Registry.

BACKGROUND: Endovascular treatment (ET) options for acute stroke due to distal middle cerebral artery occlusions are rapidly evolving, but data on outcome and safety are sparse. We therefore performed an analysis of patients undergoing ET for primary M3 occlusions in routine clinical practice in a nationwide registry. METHODS: Patients enrolled between 01/20 and 12/21 in the prospective, multicenter German Stroke Registry-Endovascular Treatment (GSR-ET) were screened for mechanical thrombectomy performed for primary M3 occlusion. We analyzed neurological deficit as measured by the National Institute of Health Stroke Scale (NIHSS), symptomatic intracranial hemorrhage (sICH), thrombectomy technique, successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] score of 2b-3) and functional outcome as measured by the modified Rankin Scale (mRS) at discharge and 90 days. RESULTS: Out of 5574 patients, 11 patients (0.2%, median age 80 years, 54.5% female) underwent ET for primary M3 occlusion. All patients had pre-admission mRS ≤ 1, median NIHSS on admission was 8, and successful reperfusion was achieved in 6/11 patients (54.5%). While no vasospasm, dissection or perforation was reported, symptomatic intracranial hemorrhage occurred in 2 patients (18.2%). Favorable outcome (mRS ≤ 2) was achieved in 6/11 patients (54.5%) at 90-day follow-up. CONCLUSIONS: ET for primary M3 occlusions is rarely performed. While technically feasible, the procedure's potential benefits must be carefully weighed against its associated risks, including clinically relevant complications. Caution and further research is needed to optimize patient selection for this intervention. TRIAL REGISTRATION: GSR-ET; ClinicalTrials.gov Identifier: NCT03356392; Trial Registration Date: 11/29/2017.

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.

Circulating endothelial cells as potential diagnostic biomarkers in primary central nervous system vasculitis.

OBJECTIVE: Histological evidence is considered the only proof of primary central nervous system vasculitis (PCNSV). However, brain biopsy is often omitted or delayed because of the invasiveness and possible complications of the procedure. Circulating endothelial cells (CEC) were shown to be elevated in patients with active antineutrophil cytoplasmic antibody-associated vasculitis. We hypothesise that CEC are also elevated in patients with active PCNSV and may contribute to the diagnosis. METHODS: CEC were assessed in 18 patients, 3 of whom had biopsy-proven PCNSV and 15 clinical, cerebrospinal fluid and imaging data, highly suggestive of PCNSV. In 3 of these 15 patients CEC assessment was performed after initiation of successful immunosuppressive therapy. CEC numbers of all patients were compared to those of 16 healthy volunteers and 123 subjects with cerebrovascular risk factors and/or ischaemic stroke, who had been studied in our group before. CEC were assessed by immunomagnetic isolation from peripheral blood. RESULTS: In patients with proven and suspected active PCNSV, CEC were extremely elevated (>400 cells/ml in most of the patients) and significantly higher than in healthy and disease controls (p≤0.01 for each group). CEC significantly decreased with immunosuppressive treatment. CONCLUSIONS: For the first time it is shown that CEC are significantly elevated in patients with active PCNSV in contrast to other pathologies associated with brain infarction and correlate with disease activity. Sensitivity and specificity of the method for diagnosing PCNSV and the use of the method for treatment monitoring should be addressed in future prospective studies with a larger patient group.