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Background: Noncontrast computed tomography hypodensities are a validated predictor of hematoma expansion (HE) in intracerebral hemorrhage and a possible alternative to the computed tomography angiography (CTA) spot sign but their added value to available prediction models remains unclear. We investigated whether the inclusion of hypodensities improves prediction of HE and compared their added value over the spot sign. Methods: Retrospective analysis of patients admitted for primary spontaneous intracerebral hemorrhage at the following 8 university hospitals in Boston, US (1994–2015, prospective), Hamilton, Canada (2010–2016, retrospective), Berlin, Germany (2014–2019, retrospective), Chongqing, China (2011–2015, retrospective), Pavia, Italy (2017–2019, prospective), Ferrara, Italy (2010–2019, retrospective), Brescia, Italy (2020–2021, retrospective), and Bologna, Italy (2015–2019, retrospective). Predictors of HE (hematoma growth >6 mL and/or >33% from baseline to follow-up imaging) were explored with logistic regression. We compared the discrimination of a simple prediction model for HE based on 4 predictors (antitplatelet and anticoagulant treatment, baseline intracerebral hemorrhage volume, and onset-to-imaging time) before and after the inclusion of noncontrast computed tomography hypodensities, using receiver operating characteristic curve and De Long test for area under the curve comparison. Results: A total of 2465 subjects were included, of whom 664 (26.9%) had HE and 1085 (44.0%) had hypodensities. Hypodensities were independently associated with HE after adjustment for confounders in logistic regression (odds ratio, 3.11 [95% CI, 2.55–3.80]; P P =0.025). In the subgroup of patients with a CTA available (n=895, 36.3%), the added value of hypodensities remained statistically significant (area under the curve, 0.68 [95% CI, 0.64–0.73] versus 0.74 [95% CI, 0.70–0.78]; P =0.041) whereas the addition of the CTA spot sign did not provide significant discrimination improvement (area under the curve, 0.74 [95% CI, 0.70–0.78]). Conclusions: Noncontrast computed tomography hypodensities provided a significant added value in the prediction of HE and appear a valuable alternative to the CTA spot sign. Our findings might inform future studies and suggest the possibility to stratify the risk of HE with good discrimination without CTA.

Background and Purpose: Sex-related differences exist in many aspects of acute stroke and were mainly investigated in the early time window with conflicting results. However, data regarding sex disparities in late presenters are scarce. Therefore, we sought to investigate differences in outcomes between women and men treated with endovascular treatment in the late time window. Methods: Analyses were based on the SOLSTICE Consortium (Selection of Late-Window Stroke for Thrombectomy by Imaging Collateral Extent), which was an individual-patient level analysis of seven trials and registries. Baseline characteristics, 90-day functional independence (modified Rankin Scale score ≤2), mortality, and symptomatic intracranial hemorrhage were compared between women and men. Effect of sex on the association of age and successful reperfusion (final Thrombolysis in Cerebral Infarction 2b–3) with outcomes was assessed using multivariable logistic regression adjusted for age, National Institutes of Health Stroke Scale score, Alberta Stroke Program Early CT Score, time from onset to puncture, occlusion location, intravenous thrombolysis, and successful reperfusion, with interaction terms. Results: Among 608 patients treated with endovascular treatment, 50.5% were women. Women were older than men (median age of 72 versus 68 years, P =0.02) and had a lower prevalence of tandem occlusions (14.0% versus 22.9%, P =0.005). Workflow times were similar between sexes. Adjusted outcomes did not differ between women and men. Functional independence at 90 days was achieved by 127 out of 292 women (43.5%) and 135 out of 291 men (46.4%). Mortality at 90 days (54 [18.5%] versus 48 [16.5%]) and symptomatic intracranial hemorrhage (37 [13.3%] versus 33 [11.6%]) were similar between women and men. There was no sex-by-age interaction on functional outcomes. However, men had higher likelihood of mortality ( P interaction =0.003) and symptomatic intracranial hemorrhage ( P interaction =0.017) with advancing age. Sex did not influence the relation between successful reperfusion and outcomes. Conclusions: In this multicenter analysis of late patients treated with endovascular treatment, sex was not associated with functional outcome. However, sex influenced the association between age and safety outcomes, with men experiencing worse outcomes with advancing age.

Perihaematomal oedema is a potential therapeutic target to improve outcome of patients with intracerebral haemorrhage, but its pathophysiology remains poorly elucidated. We investigated the longitudinal changes of cerebral perfusion and their influence on perihaematomal oedema development in 150 patients with intracerebral haemorrhage who underwent computed tomography perfusion within 6 h from onset, at 24 h and at 7 days. Perfusion parameters were measured in haemorrhagic core, perihaematomal rim, surrounding normal appearing and contralateral brain tissue. Computed tomography perfusion parameters gradually improved from the core to the periphery in each time interval with an early increase at 24 h followed by a delayed decline at 7 days compared with admission values (P < 0.001). Multivariable linear regression analysis showed that haematoma volume and cerebral blood flow gradient between normal appearing and perihaematomal rim were independently associated with absolute perihaematomal oedema volume in the different time points (within 6 h, B = 0.128, P = 0.032; at 24 h, B = 0.133, P = 0.016; at 7 days, B = 0.218, P < 0.001). In a secondary analysis with relative perihaematomal oedema as the outcome of interest, cerebral blood flow gradient between normal appearing and perihaematomal rim was an independent predictor of perihaematomal oedema only at 7 days (B = 0.239, P = 0.002). Our findings raise the intriguing hypothesis that perfusion gradients promote perihaematomal oedema development in the subacute phase after intracerebral haemorrhage.

Background: Alzheimer’s disease (AD) is a neurodegenerative pathology covering about 70%of all cases of dementia. Adenosine, a ubiquitous nucleoside, plays a key role in neurodegeneration, through interaction with four receptor subtypes. The A2A receptor is upregulated in peripheral blood cells of patients affected by Parkinson’s and Huntington’s diseases, reflecting the same alteration found in brain tissues. However, whether these changes are also present in AD pathology has not been determined. Objective: In this study we verified any significant difference between AD cases and controls in both brain and platelets and we evaluated whether peripheral A2A receptors may reflect the status of neuronal A2A receptors. Methods: We evaluated the expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, in postmortem AD patients and control subjects, through [3H]ZM 241385 binding experiments. The same analysis was performed in peripheral platelets from AD patients versus controls. Results: The expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, revealed a density (Bmax) of 174±29, 219±33, and 358±84 fmol/mg of proteins, respectively, in postmortem AD patients in comparison to 104±16, 103±19, and 121±20 fmol/mg of proteins in controls (p

Purpose Rapid identification of hematoma expansion (HE) risk at baseline is a priority in intracerebral hemorrhage (ICH) patients and may impact clinical decision making. Predictive scores using clinical features and Non-Contract Computed Tomography (NCCT)-based features exist, however, the extent to which each feature set contributes to identification is limited. This paper aims to investigate the relative value of clinical, radiological, and radiomics features in HE prediction. Methods Original data was retrospectively obtained from three major prospective clinical trials [“Spot Sign” Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy (SPOTLIGHT)NCT01359202; The Spot Sign for Predicting and Treating ICH Growth Study (STOP-IT)NCT00810888] Patients baseline and follow-up scans following ICH were included. Clinical, NCCT radiological, and radiomics features were extracted, and multivariate modeling was conducted on each feature set. Results 317 patients from 38 sites met inclusion criteria. Warfarin use (p=0.001) and GCS score (p=0.046) were significant clinical predictors of HE. The best performing model for HE prediction included clinical, radiological, and radiomic features with an area under the curve (AUC) of 87.7%. NCCT radiological features improved upon clinical benchmark model AUC by 6.5% and a clinical & radiomic combination model by 6.4%. Addition of radiomics features improved goodness of fit of both clinical (p=0.012) and clinical & NCCT radiological (p=0.007) models, with marginal improvements on AUC. Inclusion of NCCT radiological signs was best for ruling out HE whereas the radiomic features were best for ruling in HE. Conclusion NCCT-based radiological and radiomics features can improve HE prediction when added to clinical features.

BackgroundThe benefit, safety, and time intervals of mechanical thrombectomy (MT) in patients with in-hospital stroke (IHS) are unclear. We sought to evaluate the outcomes and treatment times for IHS patients compared with out-of-hospital stroke (OHS) patients receiving MT.MethodsWe analyzed data from the Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS) between 2015 and 2019. We compared the functional outcomes (modified Rankin Scale (mRS) scores) at 3 months, recanalization rates, and symptomatic intracranial hemorrhage (sICH) after MT. Time intervals from stroke onset-to-imaging, onset-to-groin, and onset-to-end MT were recorded for both groups, as were door-to-imaging and door-to-groin for OHS. A multivariate analysis was performed.ResultsOf 5619 patients, 406 (7.2%) had IHS. At 3 months, IHS patients had a lower rate of mRS 0–2 (39% vs 48%, PConclusionDespite favorable time intervals for MT, IHS patients had worse functional outcomes than OHS patients. Delays in IHS management were detected.

BackgroundClinical trials and observational studies have demonstrated the benefit of thrombectomy up to 16 or 24 hours after the patient was last known to be well. This study aimed to evaluate the outcome of stroke patients treated beyond 24 hours from onset.MethodsWe analyzed the outcome of 34 stroke patients (mean age 70.7±12.3 years; median National Institutes of Health Stroke Scale (NIHSS) score 13) treated with endovascular thrombectomy beyond 24 hours from onset who were recruited in the Italian Registry of Endovascular Thrombectomy in Acute Stroke. Selection criteria for patients were: pre-stroke modified Rankin scale (mRS) score of ≤2, non-contrast CT Alberta Stroke Program Early CT score of ≥6, good collaterals on single phase CT angiography (CTA) or multiphase CTA, and CT perfusion mismatch with an infarct core size ≤50% of the total hypoperfusion extent or involving less than one-third of the extent of the middle cerebral artery territory evaluated by visual inspection. The primary outcome measure was functional independence assessed by the mRS at 90 days after onset. Safety outcomes were 90 day mortality and the occurrence of symptomatic intracranial hemorrhage (sICH).ResultsSuccessful recanalization (Thrombolysis in Cerebral Infarction score of 2b or 3) was present in 76.5% of patients. Three month functional independence (mRS score 0–2) was observed in 41.1% of patients. The case fatality rate was 26.5%. and the incidence of sICH was 8.8%.ConclusionsThese findings suggest that, in a real world setting, very late endovascular therapy is feasible in appropriately selected patients.

The SARS-CoV-2 pandemic affected the organization of the healthcare system, and several studies analyzed the impact on hospitalization for non-COVID diseases, in particular during the first wave period. We sought to analyze the impact of the pandemic on stroke care in the province of Ferrara during a longer pandemic period and its different phases.We retrospectively analyzed data of all patients with acute ischemic stroke admitted to the University Hospital of Ferrara from March 2020 to April 2021. Data were compared with nonpandemic reference periods (RP, March-April 2018 and 2019).We observed a 31% reduction in monthly admission rate for ischemic stroke (IRR 0.69; 95% CI 0.51-0.94) and monthly thrombolysis rate (IRR 0.3; 95% CI 0.15-0.66) during the first-COVID-wave (March-April 2020), as compared to RP. A nonsignificant difference was recorded for admission rate when comparing RP with subsequent pandemic phases, but the thrombolysis rate was confirmed reduced. A significant increase in onset to door time (OTD) was observed in the CP-I period (median 230 vs 120 in the RP; p 0.05) with improvement in the subsequent phases but without returning to baseline. Nonsignificant differences in the thrombectomy rates were found over the study period.These findings reflect changing patient attitudes during the COVID-19 pandemic or the success of health system and public health campaigns to reassure patients about the safety of seeking emergency care when needed, not only for more severe stroke symptoms.

We aimed to examine the association between Careggi Collateral Score (CCS) and radiological outcomes in a large multicenter cohort of patients receiving thrombectomy for stroke with occlusion of middle cerebral artery (MCA). We conducted a study on prospectively collected data from 1785 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke. According to the extension of the retrograde reperfusion in the cortical anterior cerebral artery-MCA territories, CCS ranges from 0 (absence of retrograde filling) to 4 (visualization of collaterals until the alar segment of the MCA). Radiological outcomes at 24 h were the presence and severity of infarct growth defined by the absolute change in ASPECTS from baseline to 24 h; presence and severity of cerebral bleeding defined as no ICH, HI-1, HI-2, PH-1, or PH-2; presence and severity of cerebral edema (CED) defined as no CED, CED-1, CED-2, or CED-3. Using CCS = 0 as reference, ORs of CCS grades were significantly associated in the direction of better radiological outcome on infarct growth (0.517 for CCS = 1, 0.413 for CCS = 2, 0.358 for CCS = 3, 0.236 for CCS = 4), cerebral bleeding grading (0.485 for CCS = 1, 0.445 for CCS = 2, 0.400 for CCS = 3, 0.379 for CCS = 4), and CED grading (0.734 for CCS = 1, 0.301 for CCS = 2, 0.295 for CCS = 3, 0.255 for CSS = 4) shift in ordinal regression analysis after adjustment for pre-defined variables (age, NIHSS score, ASPECTS, occlusion site, onset-to-groin puncture time, procedure time, and TICI score). Using CCS = 4 as reference, ORs of CCS grades were significantly associated in the direction of worse radiological outcome on infarct growth (1.521 for CCS = 3, 1.754 for CCS = 2, 2.193 for CCS = 1, 4.244 for CCS = 0), cerebral bleeding grading (2.498 for CCS = 0), and CED grading (1.365 for CCS = 2, 2.876 for CCS = 1, 3.916 for CCS = 0) shift. The CCS could improve the prognostic estimate of radiological outcomes in patients receiving thrombectomy for stroke with MCA occlusion.

The objective of this paper was to explore the utility of time to maximum concentration (TPatients with AIS underwent CTP within 24 hours from onset followed by EVT. Critically hypoperfused tissue and ischemic core volumes were automatically calculated using TA total of 393 patients were included, of whom 298 (75.8%) achieved successful recanalization and 258 (65.5%) achieved good outcome. In multivariable analyses, all TT

Intravenous thrombolysis (IVT)-ineligible patients undergoing direct thrombectomy tended to have poorer functional outcome as compared with IVT-eligible patients undergoing bridging therapy. We aimed to assess radiological and functional outcomes in large vessel occlusion-related stroke patients receiving direct thrombectomy in the presence of absolute exclusion criteria for IVT vs relative exclusion criteria for IVT and vs non-exclusion criteria for IVT. A cohort study on prospectively collected data from 2282 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke cohort for treatment with direct thrombectomy (n = 486, absolute exclusion criteria for IVT alone; n = 384, absolute in combination with relative exclusion criteria for IVT; n = 777, relative exclusion criteria for IVT alone; n = 635, non-exclusion criteria for IVT). After adjustment for unbalanced variables (model 1), ORs for 3-month death was higher in the presence of absolute exclusion criteria for IVT alone (vs relative exclusion criteria for IVT alone) (1.595, 95% CI 1.042–2.440) and in the presence of absolute exclusion criteria for IVT alone (vs non-exclusion criteria for IVT) (1.235, 95% CI 1.014–1.504). After adjustment for predefined variables (model 2: age, sex, pre-stroke mRS ≤ 1, NIHSS, occlusion in the anterior circulation, onset-to-groin time, and procedure time), ORs for 3-month death was higher in the presence of absolute exclusion criteria for IVT alone (vs relative exclusion criteria for IVT alone) (1.235, 95% CI 1.014–1.504) and in the presence of absolute exclusion criteria for IVT alone (vs non-exclusion criteria for IVT) (1.246, 95% CI 1.039–1.495). No significant difference was found between the groups as regards any type of intracerebral hemorrhage and parenchymal hematoma within 24 h, successful and complete recanalization after procedure, and modified Rankin Scale score 0–2 at 3 months. After adjustment for predefined variables of model 2, ORs for death were higher in the presence of recent administration of IV heparin (OR: 2.077), platelet count

Background and Purpose— We investigated whether subarachnoid extension (SAHE) of intracerebral hemorrhage (ICH) is associated with hematoma expansion (HE). Methods— Retrospective analysis of patients with primary spontaneous ICH admitted at 3 academic hospitals in Italy. The study population was divided into a development and a replication cohort. SAHE was rated on baseline noncontrast computed tomography by investigators blinded to clinical data. The main outcome of interest was HE, defined as ICH growth >33% mL and/or >6 mL. Predictors of HE were explored with multivariable logistic regression stratified by ICH location (lobar versus nonlobar). Results— A total of 360 and 192 patients were included in the development and replication cohort, respectively. SAHE was identified with good interrater reliability ( K =0.82), and its frequency was 27.8% in the development and 24.5% in the replication cohort. In univariate analysis, HE was more common in patients with SAHE (52.0% versus 27.3%; P P =0.001) whereas there was no association with HE in nonlobar ICH (odds ratio, 0.55 [95% CI, 0.17–1.84]; P =0.334). The increased risk of HE in lobar ICH with SAHE was confirmed in the replication cohort (odds ratio, 3.46 [95% CI, 1.07–11.20]; P =0.038). Conclusions— SAHE predicts HE in lobar ICH. This may improve the stratification of HE risk in clinical practice or future trials targeting HE. Further research is needed to confirm our findings and characterize the underlying biological mechanisms.

The aim of this study was to investigate the potential role of soluble Human Leukocyte Antigen-G (sHLA-G) molecules as biomarkers predicting outcome in acute ischemic stroke (AIS). Serum levels of total sHLA-G (sHLA-G1/HLA-G5) and its soluble isoforms sHLA-G1 and HLA-G5/G6 were measured by enzyme-linked immunosorbent assay (ELISA) in 92 AIS patients and healthy donors (HD). Incidence of hemorrhagic transformation (HT), size of final infarct volume (FIV) and clinical outcome at 3 months were recorded in AIS patients. Detectable serum levels of sHLA-G1/HLA-G5, HLA-G5/G6 and sHLA-G1 were present in a small proportion of AIS patients (26.1%, 17.4% and 16.3%, respectively) and HD (12.5%, 10.7% and 10.7%, respectively) and were more elevated in AIS patients without HT than in those with HT (p 0.01; p 0.05; p 0.01, respectively). HT was less frequent (p 0.01) in AIS patients with measurable serum concentrations of sHLA-G1/HLA-G5 and HLA-G5/G6. Serum levels of sHLA-G1/HLA-G5 and sHLA-G1 were inversely correlated to FIV (p 0.02), whereas good outcome was more common (p 0.01) in AIS patients with detectable serum concentrations of sHLA-G1/HLA-G5. Taken together, these findings suggest that total sHLA-G could exert a protective effect in a subset of AIS patients, irrespective of its soluble isoforms sHLA-G1 and HLA-G5/G6, and indicate that the prognostic value of serum levels of sHLA-G remains to be established.

The prognostic impact of perihematomal hypoperfusion in patients with acute intracerebral hemorrhage (ICH) remains unclear. We tested the hypothesis that perihematomal hypoperfusion predicts poor ICH outcome and explored whether hematoma growth (HG) is the pathophysiological mechanism behind this association.A prospectively collected single-center cohort of consecutive ICH patients undergoing computed tomography perfusion on admission was analyzed. Cerebral blood flow (pCBF) was measured in the manually outlined perihematomal low-density area. pCBF was categorized into normal (40-55 mL/100 g/min), low ( 40 mL/100 g/min), and high ( 55 mL/100 g/min). HG was calculated as total volume increase from baseline to follow-up CT. A modified Rankin scale 2 at three months was the outcome of interest. The association between cerebral perfusion and outcome was investigated with logistic regression, and potential mediators of this relationship were explored with mediation analysis.A total of 155 subjects were included, of whom 55 (35.5%) had poor outcome. The rates of normal pCBF, low pCBF, and high pCBF were 17.4%, 68.4%, and 14.2%, respectively. After adjustment for confounders and keeping subjects with normal pCBF as reference, the risk of poor outcome was increased in patients with pCBF 40 mL/100 g/min (odds ratio 6.11, 95% confidence interval 1.09-34.35, p = 0.040). HG was inversely correlated with pCBF (R = -0.292, p 0.001) and mediated part of the association between pCBF and outcome (proportion mediated: 82%, p = 0.014).Reduced pCBF is associated with poor ICH outcome in patients with mild-moderate severity. HG appears a plausible biological mediator but does not fully account for this association, and other mechanisms might be involved.

Published data support the hypothesis that viruses could be trigger agents of multiple sclerosis onset. This link is based on evidence of early exposure to viral agents in patients affected by this neurologic disease. JC (JC polyomavirus [JCPyV]), BK (BKPyV), and simian virus 40 (SV40) neurotropic polyomavirus footprints have been detected in brain tissue specimens and samples from patients affected by different neurological diseases. In this investigation, serum samples from patients affected by multiple sclerosis and other inflammatory and noninflammatory neurologic diseases, as well as healthy subjects representing the control, were investigated for immunoglobulin G (IgG) antibodies against JCPyV. To this end, an immunologic approach was employed, which consists of employing indirect enzyme-linked immunosorbent assay testing with synthetic peptides mimicking viral capsid protein 1 antigens. A significantly lower prevalence of IgG antibodies against JCPyV VP1 epitopes, with a low titer, was detected in serum samples from patients with multiple sclerosis (MS) and other neurologic diseases than in healthy subjects. Our study indicates that the prevalence of JCPyV antibodies from patients with multiple sclerosis is 50% lower than in healthy subjects, suggesting specific immune impairments. These results indicate that patients affected by neurological diseases, including MS, respond poorly to JCPyV VP1 antigens, suggesting specific immunologic dysfunctions.

Background: Efficient healthcare workflow leads to faster reperfusion and better functional outcomes of stroke in the early-time window. We investigated the impact of care delays on the outcomes of stroke patients treated with endovascular thrombectomy (EVT) in the late window. Methods: Pooled data from seven randomized clinical trials and registries that only included patients who underwent EVT in the late time window (onset/last known well (LKW) time to imaging time of 6 hours or more) were combined for this analysis. The time intervals from stroke onset to successful reperfusion were analyzed. Logistic regression was used to estimate the likelihood of a functionally independent outcome at 90 days (modified Rankin scale 0-2) for each time interval while adjusting for relevant patients’ characteristics. Negative binomial regression was used to evaluate the relationship between each time interval and the predictors. Results: 584 patients were included in this analysis. The median age was 70 years (IQR: 21), 293 [50.17%] were females, 298 (53.31%) had wake-up strokes, and the median ASPECTS was 8 (IQR: 2). All patients had CT, and CTA imaging, and 360 (61.64%) underwent perfusion imaging. Successful reperfusion was achieved in 469 (80.45%) patients, and 249 (44.54%) had independent outcomes at 90 days. For every 30 minutes delay, the estimated probability of functional independence decreased by 19% for the emergency department (ED) arrival to imaging time interval, by 25% from groin puncture to end of EVT, and by 12% from ED arrival to end of EVT. Older age and higher NIHSS were associated with longer time from imaging to groin puncture. However, only age was associated with a longer estimated times from stroke onset/LKW to arrival in ED and from stroke onset/LKW to the end of EVT. Conclusion: Faster in-hospital care is associated with improved functional independence among late-window patients. Page 1

Background and Purpose: Sex-related differences exist in many aspects of stroke and were mainly investigated in the early time window with conflicting results. However, data regarding sex disparities in late presenters are scarce. Therefore, we sought to investigate differences in outcomes between women and men treated with endovascular treatment (EVT) in the late time window. Methods: Analyses were based on the Selection Of Late-window Stroke for Thrombectomy by Imaging Collateral Extent Consortium, which was an individual-patient level analysis of seven trials and registries. Baseline characteristics, functional independence (modified Rankin Scale ≤ 2), mortality, and symptomatic intracranial hemorrhage (sICH) were compared between women and men. Effect of sex on the association between age, successful reperfusion (Thrombolysis in cerebral infarction 2b-3) and outcomes was assessed using multivariable logistic regression with interaction terms. Results: Among 608 patients treated with EVT, 50.5% were women. Women were older than men by median 4 years and had a lower prevalence of tandem occlusions (14.0% vs. 22.9%). In the subset of patients with available perfusion volumes (n= 195), women had smaller penumbra (median IQR:97 mL [60- 130] vs. 109 mL [73-189]; p= 0.008), and mismatch volumes, (79 mL [49-101] vs. 91 mL [57-158] ; p= 0.02). Pre and intrahospital times were similar between sexes. Outcomes did not differ between women and men, and there was no sex-by-age interaction on functional independence. However, men had higher likelihood of mortality (p interaction = 0.004) and sICH (p interaction = 0.016) with advancing age. Sex did not influence the relation between successful reperfusion and outcomes. Conclusions: In this multicenter analysis of late presenters treated with EVT, sex was not associated with clinical outcomes. However, sex influenced the association between age and safety outcomes with men experiencing worse outcomes with advancing age.

Background and purpose We sought to investigate whether there are gender differences in clinical outcome after stroke due to large vessel occlusion (LVO) after mechanical thrombectomy (EVT) in a large population of real-world patients. Methods From the Italian Registry of Endovascular Thrombectomy, we extracted clinical and outcome data of patients treated for stroke due to large vessel occlusion. We compared clinical and safety outcomes in men and women who underwent EVT alone or in combination with intravenous thrombolysis (IVT) in the total population and in a Propensity Score matched set. Results Among 3422 patients included in the study, 1801 (52.6%) were women. Despite older age at onset (mean 72.4 vs 68.7; p Conclusions Subject to the limitations of a non-randomized comparison, women with stroke due to LVO treated with mechanical thrombectomy had a better chance to achieve complete recanalization, and 3-month functional independence than men. The results could be driven by women who underwent combined treatment.

Background: Hematoma expansion (HE) is common and associated with poor outcome in intracerebral hemorrhage (ICH) with unclear symptom onset (USO). Aims: We tested the association between non-contrast computed tomography (NCCT) markers and HE in this population. Methods: Retrospective analysis of patients with primary spontaneous ICH admitted at five centers in the United States and Italy. Baseline NCCT was analyzed for presence of the following markers: intrahematoma hypodensities, heterogeneous density, blend sign, and irregular shape. Variables associated with HE (hematoma growth > 6 mL and/or > 33% from baseline to follow-up imaging) were explored with multivariable logistic regression. Results: Of 2074 patients screened, we included 646 subjects (median age = 75, 53.9% males), of whom 178 (27.6%) had HE. Hypodensities (odds ratio (OR) = 2.67, 95% confidence interval (CI) = 1.79–3.98), heterogeneous density (OR = 2.16, 95% CI = 1.46–3.21), blend sign (OR = 2.28, 95% CI = 1.38–3.75) and irregular shape (OR = 1.82, 95% CI = 1.21–2.75) were independently associated with a higher risk of HE, after adjustment for confounders (ICH volume, anticoagulation, and time from last seen well (LSW) to NCCT). Hypodensities had the highest sensitivity for HE (0.69), whereas blend sign was the most specific marker (0.90). All NCCT markers were more frequent in early presenters (time from LSW to NCCT ⩽ 6 h, n = 189, 29.3%), and more sensitive in this population as well (hypodensities had 0.77 sensitivity). Conclusion: NCCT markers are associated with HE in ICH with USO. These findings require prospective replication and suggest that NCCT features may help the stratification of HE in future studies on USO patients.

Purpose Intracerebral hemorrhage (ICH) is an uncommon but deadly event in patients with COVID-19 and its imaging features remain poorly characterized. We aimed to describe the clinical and imaging features of COVID-19-associated ICH. Methods Multicenter, retrospective, case–control analysis comparing ICH in COVID-19 patients (COV19 +) versus controls without COVID-19 (COV19 −). Clinical presentation, laboratory markers, and severity of COVID-19 disease were recorded. Non-contrast computed tomography (NCCT) markers (intrahematoma hypodensity, heterogeneous density, blend sign, irregular shape fluid level), ICH location, and hematoma volume (ABC/2 method) were analyzed. The outcome of interest was ultraearly hematoma growth (uHG) (defined as NCCT baseline ICH volume/onset-to-imaging time), whose predictors were explored with multivariable linear regression. Results A total of 33 COV19 + patients and 321 COV19 − controls with ICH were included. Demographic characteristics and vascular risk factors were similar in the two groups. Multifocal ICH and NCCT markers were significantly more common in the COV19 + population. uHG was significantly higher among COV19 + patients (median 6.2 mL/h vs 3.1 mL/h, p = 0.027), and this finding remained significant after adjustment for confounding factors (systolic blood pressure, antiplatelet and anticoagulant therapy), in linear regression (B(SE) = 0.31 (0.11), p = 0.005). This association remained consistent also after the exclusion of patients under anticoagulant treatment (B(SE) = 0.29 (0.13), p = 0.026). Conclusions ICH in COV19 + patients has distinct NCCT imaging features and a higher speed of bleeding. This association is not mediated by antithrombotic therapy and deserves further research to characterize the underlying biological mechanisms.

To test the hypothesis that the combined analysis of non-contrast CT (NCCT) and CT perfusion (CTP) imaging markers improves prediction of hematoma expansion (HE) and outcome in intracerebral hemorrhage (ICH).Retrospective, single-center analysis of patients with primary ICH undergoing NCCT and CTP within 6 h from onset. NCCT images were assessed for the presence of intrahematomal hypodensity and shape irregularity. Perihematomal cerebral blood volume and spot sign were assessed on CTP. The main outcomes of the analysis were HE (growth6 mL and/or33%) and poor functional prognosis (90 days modified Rankin Scale 3-6). Predictors of HE and outcome were explored with logistic regression.A total of 150 subjects were included (median age 68, 47.1% males) of whom 54 (36%) had HE and 52 (34.7%) had poor outcome. The number of imaging markers on baseline imaging was independently associated with HE (odds ratio 2.66, 95% confidence interval 1.70-4.17, p0.001) and outcome (odds ratio 1.64, 95% CI 1.06-2.56, p = 0.027). Patients with the simultaneous presence of all the four markers had the highest risk of HE and unfavorable prognosis (mean predicted probability of 91% and 79% respectively). The combined-markers analysis outperformed the sensitivity of the single markers analyzed separately. In particular, the presence of at least one marker identified patients with HE and poor outcome with 91% and 87% sensitivity respectively.NCCT and CTP markers provide additional yield in the prediction of HE and ICH outcome.• Perihematomal hypoperfusion is associated with hematoma expansion and poor outcome in acute intracerebral hemorrhage. • Non-contrast CT and CT perfusion markers improve prediction of hematoma expansion and unfavorable prognosis. • A multimodal CT protocol including CT perfusion will help the identification of patients at high risk of clinical deterioration and poor outcome.

Background: Hematoma expansion (HE) is an appealing therapeutic target in intracerebral hemorrhage (ICH) and non-contrast computed tomography (NCCT) features are promising predictors of HE. Aims: We investigated whether onset-to-CT time influences the diagnostic performance of NCCT markers for HE. Methods: Retrospective multicentre analysis of patients with primary ICH. The following NCCT markers were analyzed: hypodensities, heterogeneous density, blend sign, and irregular shape. HE was defined as growth ⩾6 mL and/or ⩾33%. We calculated the sensitivity, specificity, positive, and negative predictive values (PPVs and NPVs) of NCCT markers for HE, stratified by onset-to-CT time (6 h). Results: We included 1135 patients (median age 69, 53% males), of whom 307 (27%) experienced HE. Overall hypodensities had the highest sensitivity (0.68) and blend sign the highest specificity (0.87) for HE. Hypodensities were more common and had higher sensitivity (0.80) in patients with imaging within 2 h. The same result was observed for heterogeneous density, whereas irregular shape had a similar prevalence across time strata and higher sensitivity (0.79) beyond 6 h from onset. The frequency of blend sign increased with longer onset-to-CT time, whereas its specificity declined after 6 h from onset. Conclusion: The diagnostic performance of NCCT markers is influenced by imaging time. Hypodensities identified four out of five patients with HE within 2 h from onset, whereas irregular shape performed better in late presenters. Our findings may improve the use of NCCT markers in future studies and trials targeting HE.

BACKGROUND The aim of this study was to characterize the temporal evolution and prognostic significance of perihematomal perfusion in acute intracerebral haemorrhage (ICH). METHODS A single-centre prospective cohort of patients with primary spontaneous ICH receives computed tomography perfusion (CTP) within 6 h from onset (T0) and at 7 days (T7). Cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were measured in the manually outlined perihematomal low-density area. Poor functional prognosis (modified Rankin Scale 3-6) at 90 days was the outcome of interest, and predictors were explored with multivariable logistic regression. RESULTS A total of 150 patients were studied, of whom 52 (34.7%) had a mRS 3-6 at 90 days. Perihematomal perfusion decreased from T0 to T7 in all patients, but the magnitude of CBF and CBV reduction was larger in patients with unfavourable outcome (median CBF change -7.8 vs. -6.0 ml/100 g/min, p

Background and purposeCollateral assessment using CT angiography is a promising modality for selecting patients for endovascular thrombectomy (EVT) in the late window (6–24 hours). The outcome of these patients compared with those selected using perfusion imaging is not clear.MethodsWe pooled data from seven trials and registries of EVT-treated patients in the late-time window. Patients were classified according to the baseline imaging into collateral imaging alone (collateral cohort) and perfusion plus collateral imaging (perfusion cohort). The primary outcome was the proportion of patients achieving independent 90-day functional outcome (modified Rankin Scale ‘mRS’ 0–2). We used the propensity score–weighting method to balance important predictors between the cohorts.ResultsIn 608 patients, the median onset/last-known-well to emergency arrival time was 8.8 hours and 53.2% had wake-up strokes. Both cohorts had collateral imaging and 379 (62.3%) had perfusion imaging. Independent functional outcome was achieved in 43.1% overall: 168/379 patients (45.5%) in the perfusion cohort versus 94/214 (43.9%) in the collateral cohort (p=0.71). A logistic regression model adjusting for inverse-probability-weighting showed no difference in 90-day mRS score of 0–2 among the perfusion versus collateral cohorts (adjusted OR 1.05, 95% CI 0.69 to 1.59, p=0.83) or in a favourable shift in 90-day mRS (common adjusted OR 1.01, 95% CI 0.69 to 1.47, p=0.97).ConclusionThis pooled analysis of late window EVT showed comparable functional outcomes in patients selected for EVT using collateral imaging alone compared with patients selected using perfusion and collateral imaging.PROSPERO registration numberCRD42020222003.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: The objectives of the review are to estimate the benefits and harms of: azathioprine (AZA) compared with placebo or other disease ‐modifying treatments (DMTs) as first‐choice treatment for relapsing forms of multiple sclerosis (MS); AZA compared with placebo or other DMTs for relapsing forms of MS when switching from another DMT; AZA compared with placebo or other DMTs as first‐choice treatment for progressive forms of MS; and AZA compared with placebo or other DMTs for progressive forms of MS when switching from another DMT.

Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis.

The pathophysiological determinants of irregular intracerebral hemorrhage (ICH) shape are unclear. We aimed at characterizing the relationship between perihematomal perfusion and ICH shape. A single-center cohort of patients with primary ICH was analyzed. Patients underwent computed tomography perfusion within 6 h from onset. Cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were calculated in the manually outlined perihematomal low-density region. ICH shape was rated on baseline non-contrast CT following international consensus criteria, and predictors of irregular shape were explored with logistic regression. A total of 150 patients were included, of whom 66 (44%) had irregular shape. Perihematomal CBF was lower in irregular ICH (median 23 vs 35 mL/100 g/min, p

ObjectiveTo investigate the prevalence, predictors, and prognostic effect of hematoma expansion (HE) in patients with intracerebral hemorrhage (ICH) with unclear symptom onset (USO).MethodsWe performed a retrospective analysis of patients with primary spontaneous ICH admitted at 5 academic medical centers in the United States and Italy. HE (volume increase >6 mL or >33% from baseline to follow-up noncontrast CT [NCCT]) and mortality at 30 days were the outcomes of interest. Baseline NCCT was also analyzed for presence of hypodensities (any hypodense region within the hematoma margins). Predictors of HE and mortality were explored with multivariable logistic regression.ResultsWe enrolled 2,165 participants, 1,022 in the development cohort and 1,143 in the replication cohort, of whom 352 (34.4%) and 407 (35.6%) had ICH with USO, respectively. When compared with participants having a clear symptom onset, patients with USO had a similar frequency of HE (25.0% vs 21.9%, p = 0.269 and 29.9% vs 31.5%, p = 0.423). Among patients with USO, HE was independently associated with mortality after adjustment for confounders (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.43–4.89, p = 0.002). This finding was similar in the replication cohort (OR 3.46, 95% CI 1.86–6.44, p < 0.001). The presence of NCCT hypodensities in patients with USO was an independent predictor of HE in the development (OR 2.59, 95% CI 1.27–5.28, p = 0.009) and replication (OR 2.43, 95% CI 1.42–4.17, p = 0.001) population.ConclusionHE is common in patients with USO and independently associated with worse outcome. These findings suggest that patients with USO may be enrolled in clinical trials of medical treatments targeting HE.

Background and Purpose: Observational studies have suggested a link between fibromuscular dysplasia and spontaneous cervical artery dissection (sCeAD). However, whether patients with coexistence of the two conditions have distinctive clinical characteristics has not been extensively investigated. Methods: In a cohort of consecutive patients with first-ever sCeAD, enrolled in the setting of the multicenter IPSYS CeAD study (Italian Project on Stroke in Young Adults Cervical Artery Dissection) between January 2000 and June 2019, we compared demographic and clinical characteristics, risk factor profile, vascular pathology, and midterm outcome of patients with coexistent cerebrovascular fibromuscular dysplasia (cFMD; cFMD+) with those of patients without cFMD (cFMD–). Results: A total of 1283 sCeAD patients (mean age, 47.8±11.4 years; women, 545 [42.5%]) qualified for the analysis, of whom 103 (8.0%) were diagnosed with cFMD+. In multivariable analysis, history of migraine (odds ratio, 1.78 [95% CI, 1.13–2.79]), the presence of intracranial aneurysms (odds ratio, 8.71 [95% CI, 4.06–18.68]), and the occurrence of minor traumas before the event (odds ratio, 0.48 [95% CI, 0.26–0.89]) were associated with cFMD. After a median follow-up of 34.0 months (25th to 75th percentile, 60.0), 39 (3.3%) patients had recurrent sCeAD events. cFMD+ and history of migraine predicted independently the risk of recurrent sCeAD (hazard ratio, 3.40 [95% CI, 1.58–7.31] and 2.07 [95% CI, 1.06–4.03], respectively) in multivariable Cox proportional hazards analysis. Conclusions: Risk factor profile of sCeAD patients with cFMD differs from that of patients without cFMD. cFMD and migraine are independent predictors of midterm risk of sCeAD recurrence.

Background The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood–cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction. Methods The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40–60 and 9.0 over 60 years. Results 1209 subjects were included in the study. 718 females and 491 males (age: 15–88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p Conclusions Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach.

Background and Purpose: As numerous questions remain about the best anesthetic strategy during thrombectomy, we assessed functional and radiological outcomes in stroke patients treated with thrombectomy in presence of general anesthesia (GA) versus conscious sedation (CS) and local anesthesia (LA). Methods: We conducted a cohort study on prospectively collected data from 4429 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke. Results: GA was used in 2013 patients, CS in 1285 patients, and LA in 1131 patients. The rates of 3-month modified Rankin Scale score of 0–1 were 32.7%, 33.7%, and 38.1% in the GA, CS, and LA groups: GA versus CS: odds ratios after adjustment for unbalanced variables (adjusted odds ratio [aOR]), 0.811 (95% CI, 0.602–1.091); and GA versus LA: aOR, 0.714 (95% CI, 0.515–0.990). The rates of modified Rankin Scale score of 0–2 were 42.5%, 46.6%, and 52.4% in the GA, CS, and LA groups: GA versus CS: aOR, 0.902 (95% CI, 0.689–1.180); and GA versus LA: aOR, 0.769 (95% CI, 0.566–0.998). The rates of 3-month death were 21.5%, 19.7%, and 14.8% in the GA, CS, and LA groups: GA versus CS: aOR, 0.872 (95% CI, 0.644–1.181); and GA versus LA: aOR, 1.235 (95% CI, 0.844–1.807). The rates of parenchymal hematoma were 9%, 12.6%, and 11.3% in the GA, CS, and LA groups: GA versus CS: aOR, 0.380 (95% CI, 0.262–0.551); and GA versus LA: aOR, 0.532 (95% CI, 0.337–0.838). After model of adjustment for predefined variables (age, sex, thrombolysis, National Institutes of Health Stroke Scale, onset-to-groin time, anterior large vessel occlusion, procedure time, prestroke modified Rankin Scale score of Conclusions: GA during thrombectomy was associated with worse 3-month functional outcomes, especially when compared with LA. The inclusion of an LA arm in future randomized clinical trials of anesthesia strategy is recommended.

Hypoperfusion in the perihematomal rim is common in acute intracerebral hemorrhage (ICH) but its determinants remain incompletely characterized. Despite known biological differences between deep and lobar ICH, the association between ICH location and cerebral perfusion has not been investigated. We tested the hypothesis that perihematomal perfusion differs between deep and lobar ICH. Prospectively collected cohort of subjects with primary spontaneous ICH undergoing CT perfusion on admission. Cerebral blood flow (CBF), blood volume (CBV), and mean transit time (MTT) were measured in the manually outlined perihematomal low-density area. The association between perihematomal perfusion and ICH location was explored with multivariable linear regression. A total of 155 patients were enrolled (59 with a lobar bleeding). In univariate analysis, median perihematomal CBF and CBV were lower in lobar ICH compared with deep ICH (23.8 vs 33.4 mL/100 g/min, p = 0.001 and 1.7 vs 2.3 mL/100 g, p = 0.001, respectively). Lobar ICH location remained inversely associated with CBF (β = − 0.17, p = 0.038) and CBV (β = − 0.19, p = 0.023) after adjustment for confounders in linear regression. Lobar ICH location is inversely related with perihematomal CBF and CBV. Further studies are needed to confirm this association and define the underlying biological mechanisms.

Objective: Whether migraine modifies after spontaneous cervical artery dissection (sCeAD) more than after other stroke etiologic subtypes has never been adequately investigated. Methods: In the setting of the Italian Project on Stroke in Young Adults (IPSYS), we compared the course of migraine before and after acute brain infarct in a group of migraine patients with sCeAD and a group of migraine patients whose ischemia was due to a cause other than CeAD (non-CeAD IS), matched by sex, age (± 3 years), and migraine subtype.We applied linear mixed models to evaluate pre-event vs post-event changes and differences between sCeAD and non-CeAD IS patients. Results: Eighty-seven patients per group (migraine without aura/migraine with aura, 67/20) qualified for the analysis. After the acute event, migraine headaches disappeared in 14.0% of CeAD patients vs 0.0% of non-CeAD IS patients (p ≤ 0.001). Migraine frequency (patients suffering at least 1 attack, from 93.1 to 80.5%, p = 0.001), pain intensity (from 6.7 ± 1.7 to 4.6 ± 2.6 in a 0 to 10 pain scale, p ≤ 0.001), and use of acute anti-migraine medications (patients taking at least 1 preparation, from 81.6 to 64.4%, p = 0.007) also improved significantly after CeAD as opposed to that observed after non-CeAD IS. Conclusion: The spontaneous improvement of migraine after sCeAD reinforces the hypothesis of a pathogenic link between the two conditions

Background An alteration of autophagy and mitophagy, two highly conserved lysosome-dependent degradation pathways involved in the maintenance of cellular homeostasis, has been associated with multiple sclerosis (MS). Objective To search the level of autophagy-related 5 (ATG5) and Parkin proteins, as markers of autophagy and mitophagy respectively, and lactate in a cohort of MS patients. Methods Cerebrospinal fluid (CSF) and serum samples from 60 MS patients were analyzed: 30 with magnetic resonance imaging (MRI) evidence of disease activity, gadolinium (Gd)-based contrast agent positive (Gd+), and 30 without MRI evidence of disease activity (Gd−). ATG5, Parkin, and lactate were measured using commercially available products. Results and conclusions Serum levels of ATG5, Parkin, and lactate were more elevated in Gd+ than in Gd− MS patients (p